FN Thomson Reuters Web of Science™ VR 1.0 PT J AU O'Connor, MY Thoreson, CK Ricks, M Courville, AB Thomas, F Yao, JH Katzmarzyk, PT Sumner, AE AF O'Connor, Michelle Y. Thoreson, Caroline K. Ricks, Madia Courville, Amber B. Thomas, Francine Yao, Jianhua Katzmarzyk, Peter T. Sumner, Anne E. TI Worse Cardiometabolic Health in African Immigrant Men than African American Men: Reconsideration of the Healthy Immigrant Effect SO METABOLIC SYNDROME AND RELATED DISORDERS LA English DT Article ID BODY-MASS INDEX; VISCERAL ADIPOSITY; JAPANESE-AMERICANS; INSULIN-RESISTANCE; UNITED-STATES; METABOLIC SYNDROME; HEART-DISEASE; PREVALENCE; OBESITY; ADULTS AB Background: The healthy immigrant effect is a phrase that has been used for decades to describe better cardiometabolic health in African immigrants than African Americans. The recent global increase in cardiometabolic diseases raises the possibility that immigrant health may be changing. Therefore, a new assessment of cardiometabolic health in African immigrants is warranted. Methods: Glucose tolerance status, blood pressure, and visceral adipose tissue (VAT) volume were compared in 214 self-identified healthy men comprised of 138 African immigrants, 76 African Americans, mean age 36 +/- 9 years [mean +/- standard deviation (SD); range 20-64 years]. Insulin resistance was defined by the lowest quartile of the insulin sensitivity index (S-I <= 2.28 mU/L-1.min(-1)). The waist circumference (WC) which predicts insulin resistance was determined using receiver operating characteristic curves and the Youden index. Results: Body mass index (BMI) and WC were lower in African immigrants than African Americans (BMI, 27.4 +/- 3.8 vs. 29.3 +/- 5.5 kg/m(2), P < 0.01; WC, 91 +/- 11 vs. 97 +/- 16 cm, P < 0.01). However, blood pressure, fasting glucose, and 2-hr glucose were higher in the African immigrants (all P < 0.01). In addition, African immigrants had a higher prevalence of previously undiagnosed diabetes (8% vs. 0%, P < 0.01) and prediabetes (35% vs. 22%, P < 0.01). After adjusting for WC, African immigrants had more visceral adipose tissue (VAT) than African Americans (P < 0.01). Consequently, the WC that predicted insulin resistance was 92 cm in African immigrants but 102 cm in African Americans. Conclusion: African immigrants were less obese than African Americans but had worse cardiometabolic health, specifically higher glucose levels, more hypertension, and greater visceral adiposity. Overall, the healthy immigrant effect may no longer be valid. C1 [O'Connor, Michelle Y.; Thoreson, Caroline K.; Ricks, Madia; Sumner, Anne E.] NIDDK, DEOB, NIH, Bethesda, MD 20892 USA. [Courville, Amber B.] NIH, Dept Nutr, Ctr Clin, Bethesda, MD 20892 USA. [Thomas, Francine; Yao, Jianhua] NIH, Dept Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Katzmarzyk, Peter T.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Baton Rouge, LA USA. RP Sumner, AE (reprint author), NIDDK, DEOB, NIH, Bldg 10-CRC,Room 6-5940,MSC 1612, Bethesda, MD 20892 USA. EM annes@intra.niddk.nih.gov OI Katzmarzyk, Peter/0000-0002-9280-6022 FU NIDDK, National Institutes of Health (NIH); NIH Clinical Center FX Michelle Y. O'Connor, Caroline K. Thoreson, Madia Ricks, and Anne E. Sumner were supported by the intramural program of NIDDK, National Institutes of Health (NIH). Amber B. Courville, Francine Thomas, and Jack Yao were supported by the NIH Clinical Center. NR 36 TC 12 Z9 12 U1 0 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-4196 EI 1557-8518 J9 METAB SYNDR RELAT D JI Metab. Syndr. Relat. Disord. PD AUG PY 2014 VL 12 IS 6 BP 347 EP 353 DI 10.1089/met.2014.0026 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AM9JB UT WOS:000340196500007 PM 24814168 ER PT J AU Fung, KL Tepede, AK Pluchino, KM Pouliot, LM Pixley, JN Hall, MD Gottesman, MM AF Fung, King Leung Tepede, Abisola K. Pluchino, Kristen M. Pouliot, Lynn M. Pixley, Jessica N. Hall, Matthew D. Gottesman, Michael M. TI Uptake of Compounds That Selectively Kill Multidrug-Resistant Cells: The Copper Transporter SLC31A1 (CTR1) Increases Cellular Accumulation of the Thiosemicarbazone NSC73306 SO MOLECULAR PHARMACEUTICS LA English DT Article DE multidrug resistance; collateral sensitivity; MDRI sensitivity; CTRI; thiosernicarbazone ID OVARIAN-CARCINOMA CELLS; ISATIN-BETA-THIOSEMICARBAZONES; P-GLYCOPROTEIN; SACCHAROMYCES-CEREVISIAE; COLLATERAL SENSITIVITY; MEMBRANE TRANSPORTERS; CISPLATIN TRANSPORT; ANTICANCER DRUGS; CROSS-RESISTANCE; CANCER AB Acquired drug resistance in cancer continues to be a challenge in cancer therapy, in part due to overexpression of the drug efflux transporter P-glycoprotein (P-gp, MDRI, ABCB1). NSC73306 is a thiosemicarbazone compound that displays greater toxicity against cells expressing functional P-gp than against other cells. Here, we investigate the cellular uptake of NSC73306, and examine its interaction with P-gp and copper transporter 1 (CTRL SLC31A1). Overexpression of P-gp sensitizes LLC-PKI cells to NSC73306. Cisplatin (IC50 = 77 mu M), cyclosporin A (IC50 = 500 mu M), and verapamil (IC50 = 700 mu M) inhibited cellular accumulation of [H-3]NSC73306. Cellular hypertmdcity of NSC73306 to P-gp-expressing cells was inhibited by cisplatin in a dose-dependent manner. Cells transiently expressing the cisplatin uptake transporter CTRI (SLC3IA1) showed increased[H-3]NSC73306 accumulation. In contrast, CTR1 knockdown decreased [H-3]NSC73306 accumulation. The presence of NSC73306 reduced CTR1 levels, similar to the negative feedback of CTRI levels by copper or cisplatin. Surprisingly, although cisplatin is a substrate of CTR1, we found that CTR1 protein was overexpressed in high-level cisplatin-resistant KB-CP20 and BEL7404-CP20 cell lines. We confirmed that the CTR1 protein was functional, as uptake of NSC73306 was increased in KB-CP20 cells compared to their drug-sensitive parental cells, and downregulation of CTR1 in KB-CP20 cells reduced [3H]NSC73306 accumulation. These results suggest that NSC73306 is a transport substrate of CTR1. C1 [Fung, King Leung; Tepede, Abisola K.; Pluchino, Kristen M.; Pouliot, Lynn M.; Pixley, Jessica N.; Hall, Matthew D.; Gottesman, Michael M.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM mgottesman@nih.gov FU National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. We thank the Developmental Therapeutics Program, Division of Cancer Treatment and Development, National Cancer Institute, for providing NSC73306. We thank George Leiman for editorial assistance. NR 56 TC 6 Z9 7 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD AUG PY 2014 VL 11 IS 8 BP 2692 EP 2702 DI 10.1021/mp500114e PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA AM6NW UT WOS:000339982900019 PM 24800945 ER PT J AU Manji, HK Insel, TW Narayan, VA AF Manji, Husseini K. Insel, Thomas W. Narayan, Vaibhav A. TI Harnessing the informatics revolution for neuroscience drug R&D SO NATURE REVIEWS DRUG DISCOVERY LA English DT Editorial Material C1 [Manji, Husseini K.; Narayan, Vaibhav A.] Johnson & Johnson, Neurosci Janssen Pharmaceut, Titusville, NJ 08560 USA. [Insel, Thomas W.] NIMH, NIH, Bethesda, MD 20892 USA. RP Manji, HK (reprint author), Johnson & Johnson, Neurosci Janssen Pharmaceut, 1125 Trenton Harbourton Rd, Titusville, NJ 08560 USA. EM hmanji@its.jnj.com NR 5 TC 3 Z9 3 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD AUG PY 2014 VL 13 IS 8 BP 561 EP 562 DI 10.1038/nrd4395 PG 2 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA AM7UZ UT WOS:000340075500001 PM 25082275 ER PT J AU Kunkel, TA Burgers, PM AF Kunkel, Thomas A. Burgers, Peter M. TI Delivering nonidentical twins SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Editorial Material ID DNA-POLYMERASE EPSILON; REPLICATION; REPAIR; PCNA; CHROMATIN; MECHANISM; DOMAINS; ALPHA C1 [Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Kunkel, Thomas A.] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. [Burgers, Peter M.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU Intramural NIH HHS; NIEHS NIH HHS [Z01 ES065070]; NIGMS NIH HHS [GM032431, R01 GM032431] NR 23 TC 12 Z9 12 U1 2 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD AUG PY 2014 VL 21 IS 8 BP 649 EP 651 DI 10.1038/nsmb.2852 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AM7UN UT WOS:000340074300001 PM 24997601 ER PT J AU Hall, TMT AF Hall, Traci M. Tanaka TI Expanding the RNA-recognition code of PUF proteins SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Editorial Material ID BINDING SPECIFICITY; POCKET C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Hall, TMT (reprint author), NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM hall4@niehs.nih.gov NR 20 TC 5 Z9 5 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD AUG PY 2014 VL 21 IS 8 BP 653 EP 655 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AM7UN UT WOS:000340074300003 PM 25093524 ER PT J AU Warner, KD Chen, MC Song, WJ Strack, RL Thorn, A Jaffrey, SR Ferre-D'Amare, AR AF Warner, Katherine Deigan Chen, Michael C. Song, Wenjiao Strack, Rita L. Thorn, Andrea Jaffrey, Samie R. Ferre-D'Amare, Adrian R. TI Structural basis for activity of highly efficient RNA mimics of green fluorescent protein SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID DI-GMP; QUADRUPLEX; RIBOSWITCH; RECOGNITION; PERSPECTIVE; METABOLITES; CHROMOPHORE; SPINACH; COMPLEX; ACID AB GFP and its derivatives revolutionized the study of proteins. Spinach is a recently reported in vitro-evolved RNA mimic of GFP, which as genetically encoded fusions makes possible live-cell, real-time imaging of biological RNAs without resorting to large RNA-binding protein-GFP fusions. To elucidate the molecular basis of Spinach fluorescence, we solved the cocrystal structure of Spinach bound to its cognate exogenous chromophore, showing that Spinach activates the small molecule by immobilizing it between a base triple, a G-quadruplex and an unpaired G. Mutational and NMR analyses indicate that the G-quadruplex is essential for Spinach fluorescence, is also present in other fluorogenic RNAs and may represent a general strategy for RNAs to induce fluorescence of chromophores. The structure guided the design of a miniaturized 'Baby Spinach', and it provides a foundation for structure-driven design and tuning of fluorescent RNAs. C1 [Warner, Katherine Deigan; Chen, Michael C.; Ferre-D'Amare, Adrian R.] NHLBI, Biochem & Biophys Ctr, Bethesda, MD 20892 USA. [Song, Wenjiao; Strack, Rita L.; Jaffrey, Samie R.] Cornell Univ, Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10021 USA. [Thorn, Andrea] MRC, Mol Biol Lab, Cambridge CB2 2QH, England. RP Ferre-D'Amare, AR (reprint author), NHLBI, Biochem & Biophys Ctr, Bldg 10, Bethesda, MD 20892 USA. EM adrian.ferre@nih.gov OI Strack, Rita/0000-0003-1845-7116 FU US National Institutes of Health (NIH) [GM103403, GM103393]; US Department of Energy; NIH [R01 NS010249, F32 GM106683]; European Union; NIH-Oxford-Cambridge Research Scholars Program; intramural program of the NHLBI, NIH FX We thank the staff at beamlines 5.0.2 of the Advanced Light Source (ALS), 24-ID-C of the Advanced Photon Source (APS) and 11-1 of the Stanford Synchrotron Radiation Lightsource (SSRL) for crystallographic data collection; G. Piszczek (US National Heart, Lung and Blood Institute, NHLBI) for fluorescence spectroscopy; X. Fang (US National Cancer Institute) and the staff of APS 12-ID-C for SAXS; D.-Y. Lee (NHLBI) for MS; X. Wu (NHLBI) for fluorescence microscopy; N. Tjandra for NMR; J. Grimmett and T. Darling for MRC Laboratory of Molecular Biology computer-cluster support; and N. Baird, P. Emsley, C. Jones, F. Long, G. Murshudov, R. Nicholls, K. Perry, M. Lau, A. Roll-Mecak, M. Warner, K. Weeks and J. Zhang for discussions. This work was partly conducted at the ALS on the Berkeley Center for Structural Biology beamlines, at the APS on the 24-ID-C (NE-CAT) and 12-ID-C beamlines and at SSRL, which are all supported by the US National Institutes of Health (NIH, GM103403 and GM103393 to APS and SSRL, respectively). Use of ALS, APS and SSRL was supported by the US Department of Energy. This work was supported in part by the NIH (R01 NS010249 to S.R.J. and F32 GM106683 to R.L.S.), the European Union FP7 Marie-Curie IEF program (AT.), the NIH-Oxford-Cambridge Research Scholars Program (K.D.W. and M.C.C.) and the intramural program of the NHLBI, NIH. NR 40 TC 62 Z9 62 U1 17 U2 88 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD AUG PY 2014 VL 21 IS 8 BP 658 EP 663 DI 10.1038/nsmb.2865 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AM7UN UT WOS:000340074300005 PM 25026079 ER PT J AU Park, SY Park, JE Kim, TS Kim, JH Kwak, MJ Ku, B Tian, L Murugan, RN Ahn, M Komiya, S Hojo, H Kim, NH Kim, BY Bang, JK Erikson, RL Lee, KW Kim, SJ Oh, BH Yang, W Lee, KS AF Park, Suk-Youl Park, Jung-Eun Kim, Tae-Sung Kim, Ju Hee Kwak, Mi-Jeong Ku, Bonsu Tian, Lan Murugan, Ravichandran N. Ahn, Mija Komiya, Shinobu Hojo, Hironobu Kim, Nam-Hyung Kim, Bo Yeon Bang, Jeong K. Erikson, Raymond L. Lee, Ki Won Kim, Seung Jun Oh, Byung-Ha Yang, Wei Lee, Kyung S. TI Molecular basis for unidirectional scaffold switching of human Plk4 in centriole biogenesis SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID POLO-BOX DOMAIN; DUPLICATION; RECRUITMENT; CEP152; CENTROSOMES; ELEGANS; CELLS; CPAP AB Polo-like kinase 4 (Plk4) is a key regulator of centriole duplication, an event critical for the maintenance of genomic integrity. We show that Plk4 relocalizes from the inner Cep192 ring to the outer Cep152 ring as newly recruited Cep152 assembles around the Cep192-encircled daughter centriole. Crystal-structure analyses revealed that Cep192- and Cep152-derived peptides bind the cryptic polo box (CPB) of Plk4 in opposite orientations and in a mutually exclusive manner. The Cep152 peptide bound to the CPB markedly better than did the Cep192 peptide and effectively 'snatched' the CPB away from a preformed CPB Cep192 peptide complex. A cancer-associated Cep152 mutation impairing the Plk4 interaction induced defects in procentriole assembly and chromosome segregation. Thus, Plk4 is intricately regulated in time and space through ordered interactions with two distinct scaffolds, Cep192 and Cep152, and a failure in this process may lead to human cancer. C1 [Park, Suk-Youl; Park, Jung-Eun; Kim, Tae-Sung; Lee, Kyung S.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Park, Suk-Youl; Lee, Ki Won] Seoul Natl Univ, Adv Inst Convergence Technol, Suwon, South Korea. [Kim, Ju Hee; Ku, Bonsu; Kim, Seung Jun] Korea Res Inst Biosci & Biotechnol, Med Prote Res Ctr, Taejon, South Korea. [Kwak, Mi-Jeong; Oh, Byung-Ha] Korea Adv Inst Sci & Technol, Inst BioCentury, Dept Biol Sci, Taejon 305701, South Korea. [Tian, Lan; Yang, Wei] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Murugan, Ravichandran N.; Ahn, Mija; Bang, Jeong K.] Korea Basic Sci Inst, Div Magnet Resonance, Ochang, South Korea. [Komiya, Shinobu] Tokai Univ, Dept Appl Biochem, Kanagawa 2591100, Japan. [Hojo, Hironobu] Osaka Univ, Inst Prot Res, Osaka, Japan. [Kim, Nam-Hyung] Chungbuk Natl Univ, Dept Anim Sci, Cheongju, South Korea. [Kim, Bo Yeon] Korea Res Inst Biosci & Biotechnol, Chem Biol Res Ctr, Ochang, South Korea. [Erikson, Raymond L.] Harvard Univ, Biol Labs, Cambridge, MA 02138 USA. [Lee, Ki Won] Seoul Natl Univ, Dept Agr Biotechnol, Seoul, South Korea. RP Lee, KS (reprint author), NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. EM kiwon@snu.ac.kr; ksj@kribb.re.kr; bhoh@kaist.ac.kr; weiy@mail.nih.gov; kyunglee@mail.nih.gov RI Oh, Byung-Ha/C-2061-2011; Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 FU intramural research grants of the US National Cancer Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Research Foundation of Korea (NRF) Global Research Laboratory program [K20815000001]; NRF [2011-0030027]; NRF National Leap Research Program [2010-0029233]; Global Frontier Project [NRF-M1AXA002-2012M3A6A4054949]; Korea Basic Science Institute [T33418]; World Class Institute program grant - Ministry of Science, ICT and Future Planning of the Republic of Korea [2009-002]; Next-Generation BioGreen 21 Program from the Rural Development Administration, Republic of Korea [PJ009594]; Ministry of Education, Sports, Science and Technology of Japan [23380065] FX We are grateful to V. Barr and S. Garfield for critical reading of the manuscript and B. Chhun and E. Shumsky for technical assistance on 3D-SIM. This work was supported in part by intramural research grants of the US National Cancer Institute (K.S.L.) and National Institute of Diabetes and Digestive and Kidney Diseases (WY.); National Research Foundation of Korea (NRF) Global Research Laboratory program grant K20815000001 (B.H.O.); NRF grant 2011-0030027 (S.J.K.); NRF National Leap Research Program (no. 2010-0029233) and Global Frontier Project (NRF-M1AXA002-2012M3A6A4054949) grants (K.W.L.); Korea Basic Science Institute grant T33418 (J.K.B.); World Class Institute program grant 2009-002 (B.Y.K.) funded by the Ministry of Science, ICT and Future Planning of the Republic of Korea; Next-Generation BioGreen 21 Program grant PJ009594 (N.-H.K.) from the Rural Development Administration, Republic of Korea; and a grant-in-aid for scientific research (23380065) from the Ministry of Education, Sports, Science and Technology of Japan (H.H.). NR 30 TC 20 Z9 21 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD AUG PY 2014 VL 21 IS 8 BP 696 EP 703 DI 10.1038/nsmb.2846 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AM7UN UT WOS:000340074300010 PM 24997597 ER PT J AU Cheng, Y Cawley, NX Loh, YP AF Cheng, Yong Cawley, Niamh X. Loh, Y. Peng TI Carboxypeptidase E (NF-alpha 1): a new trophic factor in neuroprotection SO NEUROSCIENCE BULLETIN LA English DT Review DE carboxypeptidase E; NF-alpha 1; neuroprotection; stress; neurodegenerative disease ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; HIPPOCAMPAL-NEURONS; ALZHEIMERS-DISEASE; PROCESSING ENZYME; GENE-EXPRESSION; NERVOUS-SYSTEM; MICE; PATHWAY; BRAIN; DEGENERATION AB Carboxypeptidase E (CPE) is a prohormone-processing enzyme and sorting receptor that functions intracellularly. However, recent studies have demonstrated that CPE acts as a trophic factor extracellularly to up-regulate the expression of a pro-survival gene. This mini-review summarizes the roles of CPE in neuroprotection and the implications for neurodegenerative diseases. C1 [Cheng, Yong; Cawley, Niamh X.; Loh, Y. Peng] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Loh, YP (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov OI Cheng, Yong/0000-0002-7529-4408 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA FX This review was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. NR 32 TC 7 Z9 8 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1673-7067 EI 1995-8218 J9 NEUROSCI BULL JI Neurosci. Bull. PD AUG PY 2014 VL 30 IS 4 BP 692 EP 696 DI 10.1007/s12264-013-1430-z PG 5 WC Neurosciences SC Neurosciences & Neurology GA AM7TK UT WOS:000340071400015 PM 24691800 ER PT J AU Mitchell, JE King, WC Chen, JY Devlin, MJ Flum, D Garcia, L Inabet, W Pender, JR Kalarchian, MA Khandelwal, S Marcus, MD Schrope, B Strain, G Wolfe, B Yanovski, S AF Mitchell, James E. King, Wendy C. Chen, Jia-Yuh Devlin, Michael J. Flum, David Garcia, Luis Inabet, William Pender, John R. Kalarchian, Melissa A. Khandelwal, Saurabh Marcus, Marsha D. Schrope, Beth Strain, Gladys Wolfe, Bruce Yanovski, Susan TI Course of Depressive Symptoms and Treatment in the Longitudinal Assessment of Bariatric Surgery (LABS-2) Study SO OBESITY LA English DT Article DE Roux-en-Y gastric bypass; laparoscopic adjustable gastric band; severe obesity; weight loss; treatment; depression; antidepressant medication ID GASTRIC BYPASS-SURGERY; QUALITY-OF-LIFE; SEVERE OBESITY; WEIGHT-LOSS; EATING BEHAVIOR; FOLLOW-UP; OUTCOMES; INTERVENTION; INVENTORY; SEQUELAE AB ObjectiveTo examine changes in depressive symptoms and treatment in the first 3 years following bariatric surgery. MethodsThe longitudinal assessment of bariatric surgery-2 (LABS-2) is an observational cohort study of adults (n=2,458) who underwent a bariatric surgical procedure at 1 of 10 US hospitals between 2006 and 2009. This study includes 2,148 participants who completed the Beck depression inventory (BDI) at baseline andone follow-up visit in years 1-3. ResultsAt baseline, 40.4% self-reported treatment for depression. At least mild depressive symptoms (BDI score10) were reported by 28.3%; moderate (BDI score 19-29) and severe (BDI score 30) symptoms were uncommon (4.2 and 0.5%, respectively). Mild-to-severe depressive symptoms independently increased the odds (OR=1.75; P=0.03) of a major adverse event within 30 days of surgery. Compared with baseline, symptom severity was significantly lower at all follow-up time points (e.g., mild-to-severe symptomatology was 8.9%, 6 months; 8.4%, 1year; 12.2%, 2 years; 15.6%, 3 years; ps<0.001), but increased between 1 and 3 years postoperatively (P<0.01). Change in depressive symptoms was significantly related to change in body mass index (r=0.42; P<0001). ConclusionBariatric surgery has a positive impact on depressive features. However, data suggest some deterioration in improvement after the first postoperative year. LABS-2, #NCT00465829, . C1 [Mitchell, James E.; Garcia, Luis] Neuropsychiat Res Inst, Fargo, ND 58103 USA. [Mitchell, James E.; Garcia, Luis] Univ N Dakota, Sch Med, Fargo, ND USA. [King, Wendy C.; Chen, Jia-Yuh] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Devlin, Michael J.; Inabet, William; Schrope, Beth] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Flum, David; Khandelwal, Saurabh] Univ Washington, Sch Med, Seattle, WA USA. [Pender, John R.] E Carolina Univ, Brody Sch Med, Greenville, NC USA. [Kalarchian, Melissa A.; Marcus, Marsha D.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Strain, Gladys] Weill Cornell Med Sch, New York, NY USA. [Wolfe, Bruce] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Yanovski, Susan] NIDDK, NIH, Bethesda, MD USA. RP Mitchell, JE (reprint author), Neuropsychiat Res Inst, Fargo, ND 58103 USA. EM jmitchell@nrifargo.com OI King, Wendy/0000-0002-0740-0029; Kalarchian, Melissa/0000-0003-2099-9299 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DCC-U01 DK066557]; Cornell University Medical Center CTRC, Columbia [U01-DK66667, UL1-RR024996]; University of Washington, CTRC [U01-DK66568, M01RR-00037]; Neuropsychiatric Research Institute [U01-DK66471]; East Carolina University [U01-DK66526]; University of Pittsburgh Medical Center, CTRC [U01-DK66585, UL1-RR024153]; Oregon Health and Science University [U01-DK66555] FX This research was supported by grants DCC-U01 DK066557 from National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Columbia-U01-DK66667, UL1-RR024996 from Cornell University Medical Center CTRC; U01-DK66568, M01RR-00037 from University of Washington, CTRC; U01-DK66471 from Neuropsychiatric Research Institute; U01-DK66526 from East Carolina University; U01-DK66585, UL1-RR024153 from University of Pittsburgh Medical Center, CTRC; U01-DK66555 from Oregon Health and Science University. NR 35 TC 30 Z9 31 U1 7 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD AUG PY 2014 VL 22 IS 8 BP 1799 EP 1806 DI 10.1002/oby.20738 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AN0SY UT WOS:000340295500007 PM 24634371 ER PT J AU Muller, MJ Baracos, V Bosy-Westphal, A Dulloo, AG Eckel, J Fearon, KCH Hall, KD Pietrobelli, A Sorensen, TIA Speakman, J Trayhurn, P Visser, M Heymsfield, SB AF Mueller, M. J. Baracos, V. Bosy-Westphal, A. Dulloo, A. G. Eckel, J. Fearon, K. C. H. Hall, K. D. Pietrobelli, A. Sorensen, T. I. A. Speakman, J. Trayhurn, P. Visser, M. Heymsfield, S. B. TI Functional body composition and related aspects in research on obesity and cachexia: report on the 12th Stock Conference held on 6 and 7 September 2013 in Hamburg, Germany SO OBESITY REVIEWS LA English DT Article DE Adipose tissue; body composition; metabolism; muscle mass ID HUMAN SKELETAL-MUSCLE; BONE-MINERAL DENSITY; ADIPOSE-SPECIFIC PROTEIN; LOW-BIRTH-WEIGHT; CANCER CACHEXIA; MASS INDEX; POSTMENOPAUSAL WOMEN; ENERGY-EXPENDITURE; FRACTURE RISK; HEALTHY-MEN AB The 12th Stock Conference addressed body composition and related functions in two extreme situations, obesity and cancer cachexia. The concept of 'functional body composition' integrates body components into regulatory systems relating the mass of organs and tissues to corresponding in vivo functions and metabolic processes. This concept adds to an understanding of organ/tissue mass and function in the context of metabolic adaptations to weight change and disease. During weight gain and loss, there are associated changes in individual body components while the relationships between organ and tissue mass are fixed. Thus an understanding of body weight regulation involves an examination of the relationships between organs and tissues rather than individual organ and tissue masses only. The between organ/tissue mass relationships are associated with and explained by crosstalks between organs and tissues mediated by cytokines, hormones and metabolites that are coupled with changes in body weight, composition and function as observed in obesity and cancer cachexia. In addition to established roles in intermediary metabolism, cell function and inflammation, organ-tissue crosstalk mediators are determinants of body composition and its change with weight gain and loss. The 12th Stock Conference supported Michael Stocks' concept of gaining new insights by integrating research ideas from obesity and cancer cachexia. The conference presentations provide an in-depth understanding of body composition and metabolism. C1 [Mueller, M. J.] Univ Kiel, Inst Humanernahrung & Lebensmittelkunde, D-24105 Kiel, Germany. [Baracos, V.] Univ Alberta, Dept Oncol, Cross Canc Inst, Edmonton, AB T6G 2M7, Canada. [Bosy-Westphal, A.] Univ Hohenheim, Inst Nutr & Dietet, Hohenheim, Germany. [Dulloo, A. G.] Univ Fribourg, Dept Med Physiol, CH-1700 Fribourg, Switzerland. [Eckel, J.] German Diabet Ctr, Dusseldorf, Germany. [Fearon, K. C. H.] Western Gen Hosp, Colorectal Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Hall, K. D.] NIDDK, Bethesda, MD 20892 USA. [Pietrobelli, A.] Univ Verona, Sch Med, I-37100 Verona, Italy. [Sorensen, T. I. A.] Univ Copenhagen, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Capital Region, Denmark. [Sorensen, T. I. A.] Bispebjerg Hosp, Inst Prevent Med, DK-2400 Copenhagen, Capital Region, Denmark. [Sorensen, T. I. A.] Frederiksberg Univ Hosp, Inst Prevent Med, Copenhagen, Capital Region, Denmark. [Speakman, J.] Chinese Acad Sci, Inst Genet & Dev Biol, Beijing, Peoples R China. [Speakman, J.] Univ Aberdeen, Inst Biol & Environm Sci, Aberdeen AB9 1FX, Scotland. [Trayhurn, P.] Univ Liverpool, Obes Biol Unit, Liverpool, Bucks, England. [Trayhurn, P.] Univ Buckingham, Buckingham, Bucks, England. [Visser, M.] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Visser, M.] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. [Heymsfield, S. B.] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. RP Muller, MJ (reprint author), Univ Kiel, Inst Humanernahrung & Lebensmittelkunde, Dusternbrooker Weg 17, D-24105 Kiel, Germany. EM mmueller@nutrfoodsc.uni-kiel.de RI John, Speakman/A-9494-2008; OI John, Speakman/0000-0002-2457-1823; Baracos, Vickie/0000-0002-9609-1001 FU BMBF Competence Network Obesity (CNO), Germany; Seca, Hamburg; Zensa Analytic, Frankfurt; EchoMRI TM, Houston; Cosmed Companies, Fridolfing FX The authors wish to thank IASO for giving them the opportunity to organize the 2013 Stock Conference. Special thanks to David York and Natasha Joyner from IASO for their help in preparing and conducting the conference. The financial support provided by the following is acknowledged: BMBF Competence Network Obesity (CNO), Germany; Seca, Hamburg; Zensa Analytic, Frankfurt; EchoMRI TM, Houston; and Cosmed Companies, Fridolfing. NR 127 TC 7 Z9 7 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1467-7881 EI 1467-789X J9 OBES REV JI Obes. Rev. PD AUG PY 2014 VL 15 IS 8 BP 640 EP 656 DI 10.1111/obr.12187 PG 17 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AM8BH UT WOS:000340093700003 PM 24835453 ER PT J AU Sinder, BP White, LE Salemi, JD Ominsky, MS Caird, MS Marini, JC Kozloff, KM AF Sinder, B. P. White, L. E. Salemi, J. D. Ominsky, M. S. Caird, M. S. Marini, J. C. Kozloff, K. M. TI Adult Brtl/+ mouse model of osteogenesis imperfecta demonstrates anabolic response to sclerostin antibody treatment with increased bone mass and strength SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Mouse model; Osteogenesis imperfecta; Osteoporosis; Sclerostin antibody ID MINERAL DENSITY; PARATHYROID-HORMONE; TERIPARATIDE TREATMENT; OVARIECTOMIZED RATS; MARROW COMPOSITION; DECREASED BONE; SKELETAL SITES; FRACTURE RATE; ALENDRONATE; REGARDLESS AB Treatments to reduce fracture rates in adults with osteogenesis imperfecta are limited. Sclerostin antibody, developed for treating osteoporosis, has not been explored in adults with OI. This study demonstrates that treatment of adult OI mice respond favorably to sclerostin antibody therapy despite retention of the OI-causing defect. Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk. Although OI fracture risk is greatest before puberty, adults with OI remain at risk of fracture. Antiresorptive bisphosphonates are commonly used to treat adult OI, but have shown mixed efficacy. New treatments which consistently improve bone mass throughout the skeleton may improve patient outcomes. Neutralizing antibodies to sclerostin (Scl-Ab) are a novel anabolic therapy that have shown efficacy in preclinical studies by stimulating bone formation via the canonical wnt signaling pathway. The purpose of this study was to evaluate Scl-Ab in an adult 6 month old Brtl/+ model of OI that harbors a typical heterozygous OI-causing Gly > Cys substitution on Col1a1. Six-month-old WT and Brtl/+ mice were treated with Scl-Ab (25 mg/kg, 2x/week) or Veh for 5 weeks. OCN and TRACP5b serum assays, dynamic histomorphometry, microCT and mechanical testing were performed. Adult Brtl/+ mice demonstrated a strong anabolic response to Scl-Ab with increased serum osteocalcin and bone formation rate. This anabolic response led to improved trabecular and cortical bone mass in the femur. Mechanical testing revealed Scl-Ab increased Brtl/+ femoral stiffness and strength. Scl-Ab was successfully anabolic in an adult Brtl/+ model of OI. C1 [Sinder, B. P.; White, L. E.; Salemi, J. D.; Caird, M. S.; Kozloff, K. M.] Univ Michigan, Dept Orthopaed Surg, Orthopaed Res Labs, Ann Arbor, MI 48109 USA. [Sinder, B. P.; Salemi, J. D.; Kozloff, K. M.] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA. [Ominsky, M. S.] Amgen Inc, Dept Metab Disorders, Thousand Oaks, CA 91320 USA. [Marini, J. C.] NICHHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20892 USA. RP Kozloff, KM (reprint author), Univ Michigan, Dept Orthopaed Surg, Orthopaed Res Labs, 2015 Biomed Sci Res Bldg,109 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. EM kenkoz@umich.edu FU NIH [R01AR062522] FX The authors thank Bonnie Nolan, Kathy Sweet and Marry Eddy for their contributions. Scl-Ab was provided by Amgen and UCB Pharma. Funding support from NIH to KMK (R01AR062522) is gratefully acknowledged. Study designed and conducted by BPS and KMK. Data collected by BPS, LEW, and JDS. Data analyzed and interpreted by BPS, LEW, JDS, MSO, MSC, JCM, and KMK. The manuscript was written by BPS and KMK and revised and approved by all authors. KMK takes responsibility for the integrity of the data analysis. NR 33 TC 15 Z9 15 U1 1 U2 6 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD AUG PY 2014 VL 25 IS 8 BP 2097 EP 2107 DI 10.1007/s00198-014-2737-y PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AM5JV UT WOS:000339895100012 PM 24803333 ER PT J AU Wang, Z Ward, MM Chan, L Bhattacharyya, T AF Wang, Z. Ward, M. M. Chan, L. Bhattacharyya, T. TI Adherence to oral bisphosphonates and the risk of subtrochanteric and femoral shaft fractures among female medicare beneficiaries SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Bisphosphonates; Fracture; Osteoporosis; Atypical femur fracture ID DIAPHYSEAL FEMUR FRACTURES; CLAIMS DATABASES; NATIONAL COHORT; ALENDRONATE; WOMEN; THERAPY; TRENDS; USERS; RATES AB Previous studies have shown an association between duration of bisphosphonate use and atypical femur fractures. This cohort study showed an increasingly higher risk of subtrochanteric and femoral shaft fractures among those who were more adherent to oral bisphosphonates. Long-term use of oral bisphosphonates has been implicated in an increased risk of atypical femur fractures located in subtrochanteric and femoral shaft regions. Another measure of drug exposure, medication adherence, however, has not been investigated. Among all Medicare fee-for-service female beneficiaries from 2006-2010, we followed 522,287 new bisphosphonate users from their index prescription until being censored or having a primary diagnosis of closed subtrochanteric/femoral shaft or intertrochanteric/femoral neck fractures. Data about radiographs of fracture site and features were not available. Adherence was classified according to the medication possession ratio (MPR) as the following: MPR < 1/3 as less compliant, MPR a parts per thousand yenaEuro parts per thousand 1/3-aEuro parts per thousand < 2/3 as compliant, and MPR a parts per thousand yenaEuro parts per thousand 2/3 as highly compliant. Alternative cutoff points at 50 and 80 % were also used. Survival analysis was used to determine the cumulative incidence and hazard of subtrochanteric/femoral shaft or intertrochanteric/femoral neck fractures. There was a graded increase in incidence of subtrochanteric/femoral shaft fractures as the level of adherence increased (Gray's test, P < 0.001). The adjusted hazard ratio (HR) for the highly compliant vs. the less compliant was 1.23 (95 % Confidence Interval [CI] 1.06-1.43) overall, became significant after 2 years of follow-up (HR = 1.51, 95 % CI 1.06-2.15) and reached the highest risk in the fifth year (HR = 4.06, 95 % CI 1.47-11.19). However, age-adjusted incidence rates of intertrochanteric/femoral neck fractures were significantly lower among highly compliant beneficiaries, compared to less compliant users (HR = 0.69, 95 % CI 0.66-0.73). Similar results were obtained when the cutoff points for being compliant and highly compliant were set at 50 and 80 %, respectively. Subtrochanteric/femoral shaft fractures, unlike intertrochanteric/femoral neck fractures, are positively associated with higher adherence to long-term (a parts per thousand yen3 years) oral bisphosphonates in the elderly female Medicare population. C1 [Wang, Z.; Ward, M. M.; Bhattacharyya, T.] NIAMSD, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Chan, L.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Bhattacharyya, T (reprint author), Bldg 10 CRC 4-1350,10 Ctr Dr, Bethesda, MD 20892 USA. EM timothy.bhattacharyya@nih.gov FU Intramural Research Program at NIAMS/NIH FX This study was funded by the Intramural Research Program at NIAMS/NIH. We want to thank Shannon Pietzsch from General Dynamic Information Technology, Inc., Drs. Elizabeth Rasch and Alex Constantin from Department of Rehabilitation Medicine of NIH Clinical Center, and Dr. Seo Young Kim from Brigham and Woman's hospital for their supports. NR 27 TC 9 Z9 11 U1 0 U2 3 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD AUG PY 2014 VL 25 IS 8 BP 2109 EP 2116 DI 10.1007/s00198-014-2738-x PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AM5JV UT WOS:000339895100013 PM 24846316 ER PT J AU Petersen, GL Finnerup, NB Colloca, L Amanzio, M Price, DD Jensen, TS Vase, L AF Petersen, Gitte Laue Finnerup, Nanna Brix Colloca, Luana Amanzio, Martina Price, Donald D. Jensen, Troels Staehelin Vase, Lene TI The magnitude of nocebo effects in pain: A meta-analysis SO PAIN LA English DT Review DE Nocebo; Placebo; Pain; Magnitude; Verbal suggestion; Conditioning ID CLINICAL ANALGESIC TRIALS; PARKINSONS-DISEASE; PLACEBO ANALGESIA; RESPONSES; MECHANISMS; HYPERALGESIA; EXPECTATION; MOTOR AB The investigation- of nocebo effects is evolving, and a few literature reviews have emerged, although so far without quantifying such effects. This meta-analysis investigated nocebo effects in pain. We searched the databases PubMed, EMBASE, Scopus, and the Cochrane Controlled Trial Register with the term "nocebo." Only studies that investigated nocebo effects as the effects that followed the administration of an inert treatment along with verbal suggestions of symptom worsening and that included a no-treatment control condition were eligible. Ten studies fulfilled the selection criteria. The effect sizes were calculated using Cohen!s d and Hedges' g. The overall magnitude of the nocebo effect was moderate to large (lowest g= 0.62 [0.24-1.01] and highest g = 1.03 [0.63-1.43]) and highly variable (range of g= -0.43 to 4.05). The magnitudes and range of effect sizes was similar to those of placebo effects (d = 0.81) in mechanistic studies. In studies in which nocebo effects were induced by a combination of verbal suggestions and conditioning, the effect size was larger (lowest g = 0.76 [0.39-1.14] and highest g = 1.17 [0.52-1.81]) than in studies in which nocebo effects were induced by verbal suggestions alone (lowest g= 0.64 [-0.25 to 1.53] and highest g= 0.87 [0.40-1.34]). These findings are similar to those in the placebo literature. As the magnitude of the nocebo effect is variable and sometimes large, this meta-analysis demonstrates the importance of minimizing nocebo effects in clinical practice. (C) 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. C1 [Petersen, Gitte Laue; Vase, Lene] Aarhus Univ, Sch Business & Social Sci, Dept Psychol & Behav Sci, DK-8000 Aarhus C, Denmark. [Petersen, Gitte Laue; Finnerup, Nanna Brix; Jensen, Troels Staehelin; Vase, Lene] Aarhus Univ Hosp, Danish Pain Res Ctr, DK-8000 Aarhus, Denmark. [Colloca, Luana] NIMH, NCCAM, Bethesda, MD 20892 USA. [Colloca, Luana] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. [Amanzio, Martina] Univ Turin, INN, Dept Psychol, Turin, Italy. [Price, Donald D.] Univ Florida, Dept Oral & Maxillofacial Surg, Div Neurosci, Gainesville, FL USA. RP Petersen, GL (reprint author), Aarhus Univ, Sch Business & Social Sci, Dept Psychol & Behav Sci, Bartholins Alle 9, DK-8000 Aarhus C, Denmark. EM gittel@psy.au.dk RI Price, Donald/A-3094-2008; Amanzio, Martina/A-9085-2010; Jensen, Troels /A-3418-2009; OI Price, Donald/0000-0002-8971-7184; Amanzio, Martina/0000-0002-2504-032X; Jensen, Troels /0000-0002-3487-6380; Colloca, Luana/0000-0002-6503-4709 FU Innovative Medicines Initiative Joint Undertaking (IMI JU) [115007]; European Union; EFPIA; MINDLab UNIK initiative at Aarhus University - Danish Ministry of Science, Technology and Innovation; National Center for Complementary and Alternative Medicine; National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA FX This work is part of the Europain Collaboration and funded by the Innovative Medicines Initiative Joint Undertaking (IMI JU) grant No. 115007, resources which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and EFPIA companies in kind contribution (www.imi.europa.eu). It was also supported by the MINDLab UNIK initiative at Aarhus University, which is funded by the Danish Ministry of Science, Technology and Innovation.; L.C. is supported by the Intramural Program of the National Center for Complementary and Alternative Medicine, the Intramural Program of the National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA. NR 66 TC 32 Z9 32 U1 9 U2 34 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD AUG PY 2014 VL 155 IS 8 BP 1426 EP 1434 DI 10.1016/j.pain.2014.04.016 PG 9 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA AN0YL UT WOS:000340309800005 PM 24780622 ER PT J AU Atlas, LY Lindquist, MA Bolger, N Wager, TD AF Atlas, Lauren Y. Lindquist, Martin A. Bolger, Niall Wager, Tor D. TI Brain mediators of the effects of noxious heat on pain SO PAIN LA English DT Article DE fMRI; Mediation; Neuroimaging; Nociception; Pain; Connectivity; Human ID PREFRONTAL CORTEX; NEURAL MECHANISMS; CARDIOVASCULAR-RESPONSES; FUNCTIONAL CONNECTIVITY; INDIVIDUAL-DIFFERENCES; ORBITOFRONTAL CORTEX; NEUROPATHIC PAIN; COGNITIVE TASK; SOCIAL THREAT; FMRI AB Recent human neuroimaging studies have investigated the neural correlates of either noxious stimulus intensity or reported pain. Although useful, analyzing brain relationships with stimulus intensity and behavior separately does not address how sensation and pain are linked in the central nervous system. In this study, we used multi-level mediation analysis to identify brain mediators of pain regions in which trial-by-trial responses to heat explained variability in the relationship between noxious stimulus intensity (across 4 levels) and pain. This approach has the potential to identify multiple circuits with complementary roles in pain genesis. Brain mediators of noxious heat effects on pain included targets of ascending nociceptive pathways (anterior cingulate, insula, SII, and medial thalamus) and also prefrontal and subcortical regions not associated with nociceptive pathways per se. Cluster analysis revealed that mediators were grouped into several distinct functional networks, including the following: somatosensory, paralimbic, and striatal-cerebellar networks that increased with stimulus intensity; and 2 networks co-localized with "default mode" regions in which stimulus intensity-related decreases mediated increased pain. We also identified "thermosensory" regions that responded to increasing noxious heat but did not predict pain reports. Finally, several regions did not respond to noxious input, but their activity predicted pain; these included ventromedial prefrontal cortex, dorsolateral prefrontal cortex, cerebellar regions, and supplementary motor cortices. These regions likely underlie both nociceptive and non-nociceptive processes that contribute to pain, such as attention and decision-making processes. Overall, these results elucidate how multiple distinct brain systems jointly contribute to the central generation of pain. (C) 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. C1 [Atlas, Lauren Y.] Natl Ctr Complementary & Alternat Med, Sect Affect Neuroscience & Pain, US Natl Inst Hlth, Bethesda, MD USA. [Lindquist, Martin A.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Bolger, Niall] Columbia Univ, Dept Psychol, New York, NY 10027 USA. [Wager, Tor D.] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. RP Atlas, LY (reprint author), NIH, Bldg 10,CRC Rm 4-1741,MSC 1302, Bethesda, MD 20892 USA. EM lauren.atlas@nih.gov FU National Institutes of Health [RO1 MH076136, DA027794] FX The authors acknowledge Katherine Dahl and Natalie Johnston for assistance with data collection. Funding was provided by National Institutes of Health grants RO1 MH076136 and DA027794. NR 85 TC 18 Z9 19 U1 0 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD AUG PY 2014 VL 155 IS 8 BP 1632 EP 1648 DI 10.1016/j.pain.2014.05.015 PG 17 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA AN0YL UT WOS:000340309800027 PM 24845572 ER PT J AU Mooney, J Spalding, N Poland, F Grayson, P Leduc, R McAlear, CA Richesson, RL Shereff, D Merkel, PA Watts, RA AF Mooney, Janice Spalding, Nicola Poland, Fiona Grayson, Peter Leduc, Renee McAlear, Carol A. Richesson, Rachel L. Shereff, Denise Merkel, Peter A. Watts, Richard A. TI The informational needs of patients with ANCA-associated vasculitis-development of an informational needs questionnaire SO RHEUMATOLOGY LA English DT Article DE ANCA-associated vasculitis; granulomatosis with polyangiitis; eosinophilic granulomatosis with polyangiitis; microscopic polyangiitis; vasculitis; informational needs questionnaire ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; QUALITY-OF-LIFE; RHEUMATOID-ARTHRITIS; BREAST-CANCER; KNOWLEDGE QUESTIONNAIRE; VESSEL VASCULITIS; SELF-MANAGEMENT; RARE DISEASES; GRANULOMATOSIS; EDUCATION AB Objective. The aim of the study was to compare the informational needs of patients with ANCA-associated vasculitis (AAV). Methods. We developed a Vasculitis Informational Needs Questionnaire that was distributed to members of Vasculitis UK (VUK) by mail and registrants of the Vasculitis Clinical Research Consortium (VCRC) online registry with self-reported AAV. Patients were asked to use a 5-point scale (1 = not important, 5 = extremely important) to rank aspects of information in the following domains: disease, investigations, medication, disease management and psychosocial care. The source and preferred method of educational delivery were recorded. Results. There were 314 VUK and 273 VCRC respondents. Respondents rated information on diagnosis, prognosis, investigations, treatment and side effects as extremely important. Information on patient support groups and psychosocial care was less important. There was no difference in the ratings of needs based on group, sex, age, disease duration, disease or method of questionnaire delivery. The most-preferred methods of providing information for both groups were by a doctor (with or without written material) or web based; educational courses and compact disc/digital video disc (CD/DVD) were the least-preferred methods. Conclusion. This study demonstrates that people with AAV seek specific information concerning their disease, treatment regimes and side effects and the results of investigations. Individuals preferred to receive this information from a doctor. Patients with AAV should be treated in a similar manner to patients with other chronic illnesses in which patient education is a fundamental part of care. C1 [Mooney, Janice] Univ E Anglia, Sch Nursing Sci, Norwich NR4 7TJ, Norfolk, England. [Spalding, Nicola; Poland, Fiona] Univ E Anglia, Sch Allied Hlth Profess, Norwich NR4 7TJ, Norfolk, England. [Grayson, Peter] NIAMSD, NIH, Bethesda, MD 20892 USA. [Leduc, Renee] Univ S Florida, Pediat Epidemiol Ctr, Tampa, FL USA. [McAlear, Carol A.; Shereff, Denise; Merkel, Peter A.] Univ Penn, Div Rheumatol, Philadelphia, PA 19104 USA. [Richesson, Rachel L.] Duke Univ, Sch Nursing, Durham, NC USA. [Watts, Richard A.] Univ E Anglia, Norwich Med Sch, Norwich NR4 7TJ, Norfolk, England. RP Mooney, J (reprint author), Univ E Anglia, Sch Nursing Sci, Norwich NR4 7TJ, Norfolk, England. EM j.mooney@uea.ac.uk FU Arthritis Research UK [17793]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [U54AR057319]; NIH Office of Rare Diseases Research (ORDR) FX Arthritis Research UK funded the development of the questionnaire through an education grant (17793). The Vasculitis Clinical Research Consortium is part of the NIH Rare Diseases Clinical Research Network (RDCRN). This work was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54AR057319) and the NIH Office of Rare Diseases Research (ORDR). NR 44 TC 4 Z9 4 U1 1 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 EI 1462-0332 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD AUG PY 2014 VL 53 IS 8 BP 1414 EP 1421 DI 10.1093/rheumatology/keu026 PG 8 WC Rheumatology SC Rheumatology GA AM7MS UT WOS:000340052100010 PM 24625507 ER PT J AU Ferrer, M Corneo, B Davis, J Wan, Q Miyagishima, KJ King, R Maminishkis, A Marugan, J Sharma, R Shure, M Temple, S Miller, S Bharti, K AF Ferrer, Marc Corneo, Barbara Davis, Janine Wan, Qin Miyagishima, Kiyoharu Joshua King, Rebecca Maminishkis, Arvydas Marugan, Juan Sharma, Ruchi Shure, Michael Temple, Sally Miller, Sheldon Bharti, Kapil TI A Multiplex High-Throughput Gene Expression Assay to Simultaneously Detect Disease and Functional Markers in Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article DE Gene expression; Reprogramming; Retina; Stem cell; Induced pluripotency; iPS; Retinal pigmented epithelium ID EARLY MOUSE EMBRYO; MOLECULAR SIGNATURE; HUMAN ES; DIFFERENTIATION; CARDIOMYOCYTES; MECHANISMS; PHYSIOLOGY; PROTEINS; MODEL; FATE AB There is continuing interest in the development of lineage-specific cells from induced pluripotent stem (iPS) cells for use in cell therapies and drug discovery. Although in most cases differentiated cells show features of the desired lineage, they retain fetal gene expression and do not fully mature into "adult-like" cells. Such cells may not serve as an effective therapy because, once implanted, immature cells pose the risk of uncontrolled growth. Therefore, there is a need to optimize lineage-specific stem cell differentiation protocols to produce cells that no longer express fetal genes and have attained "adult-like" phenotypes. Toward that goal, it is critical to develop assays that simultaneously measure cell function and disease markers in high-throughput format. Here, we use a multiplex high-throughput gene expression assay that simultaneously detects endogenous expression of multiple developmental, functional, and disease markers in iPS cell-derived retinal pigment epithelium (RPE). We optimized protocols to differentiate iPS cell-derived RPE that was then grown in 96- and 384-well plates. As a proof of principle, we demonstrate differential expression of eight genes in iPS cells, iPS cell-derived RPE at two different differentiation stages, and primary human RPE using this multiplex assay. The data obtained from the multiplex gene expression assay are significantly correlated with standard quantitative reverse transcription-polymerase chain reaction-based measurements, confirming the ability of this high-throughput assay to measure relevant gene expression changes. This assay provides the basis to screen for compounds that improve RPE function and maturation and target disease pathways, thus providing the basis for effective treatments of several retinal degenerative diseases. C1 [Ferrer, Marc; King, Rebecca; Marugan, Juan] NIH, Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Corneo, Barbara; Temple, Sally] Neural Stem Cell Inst, Rensselaer, NY USA. [Davis, Janine; Sharma, Ruchi; Bharti, Kapil] NEI, NIH, Unit Ocular & Stem Cell Translat Res, Bethesda, MD 20892 USA. [Wan, Qin; Miyagishima, Kiyoharu Joshua; Maminishkis, Arvydas; Miller, Sheldon] NEI, NIH, Sect Epithelial & Retinal Physiol & Dis, Bethesda, MD 20892 USA. [Shure, Michael] Affymetrix, Santa Clara, CA USA. RP Bharti, K (reprint author), NEI, NIH, Unit Ocular & Stem Cell Translat Res, 10 Ctr Dr,Bldg 10,Room 10B10, Bethesda, MD 20892 USA. EM kapilbharti@nei.nih.gov FU National Eye Institute intramural funds; NIH CRM awards; NIH Common Fund Molecular Libraries and Imaging Program [U54 MH084681] FX We thank Dr. Rong Li, Fang Hua, and Omar Memon (National Eye Institute) and Patricia Lederman (NSCI) for technical assistance and Dr. Sunita D'Souza (Mt. Sinai School of Medicine) for reagents. This work was supported by National Eye Institute intramural funds and NIH CRM awards to Drs. Kapil Bharti and Sheldon Miller and funding from the NIH Common Fund Molecular Libraries and Imaging Program, Grant U54 MH084681 to NIH Center for Advancing Translational Sciences. NR 32 TC 11 Z9 11 U1 0 U2 18 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 EI 2157-6580 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD AUG PY 2014 VL 3 IS 8 BP 911 EP 922 DI 10.5966/sctm.2013-0192 PG 12 WC Cell & Tissue Engineering SC Cell Biology GA AM7CH UT WOS:000340021800014 PM 24873859 ER PT J AU Rasola, A Neckers, L Picard, D AF Rasola, Andrea Neckers, Len Picard, Didier TI Mitochondrial oxidative phosphorylation TRAP(1)ped in tumor cells SO TRENDS IN CELL BIOLOGY LA English DT Review DE TRAP1; mitochondria; chaperones; cancer metabolism; ROS ID NECROSIS-FACTOR RECEPTOR; CANCER-CELLS; PERMEABILITY TRANSITION; PARKINSONS-DISEASE; CHAPERONE TRAP1; HEXOKINASE-II; CLINICAL OPPORTUNITIES; ENERGY-METABOLISM; PROTEIN-1 TRAP-1; PROTECTS CELLS AB Many tumors undergo a dramatic metabolic shift known as the Warburg effect in which glucose utilization is favored and oxidative phosphorylation is down-regulated, even when oxygen availability is plentiful. However, the mechanistic basis for this switch has remained unclear. Recently several independent groups identified tumor necrosis factor receptor-associated protein 1 (TRAP1), a mitochondrial molecular chaperone of the heat shock protein 90 (Hsp90) family, as a key modulator of mitochondria! respiration. Although all reports agree that this activity of TRAP1 has important implications for neoplastic progression, data from the different groups only partially overlap, suggesting that TRAP1 may have complex and possibly contextual effects on tumorigenesis. In this review we analyze these recent findings and attempt to reconcile these observations. C1 [Rasola, Andrea] Univ Padua, CNR, Inst Neurosci, I-35121 Padua, Italy. [Rasola, Andrea] Univ Padua, Dept Biomed Sci, I-35121 Padua, Italy. [Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Picard, Didier] Univ Geneva, Dept Cell Biol, CH-1211 Geneva 4, Switzerland. RP Rasola, A (reprint author), Univ Padua, CNR, Inst Neurosci, I-35121 Padua, Italy. EM rasola@bio.unipd.it OI Rasola, Andrea/0000-0003-4522-3008 FU Progetti di Ateneo dell'Universita di Padova; US National Cancer Institute; Swiss National Science Foundation; Canton de Geneve FX The authors are grateful to Giulia Guzzo and Paolo Bernardi for critical reading of the manuscript. A.R. is supported by Progetti di Ateneo dell'Universita di Padova. L.N. is supported by the Intramural Research Program of the US National Cancer Institute. D.P. is supported by the Swiss National Science Foundation and the Canton de Geneve. NR 86 TC 23 Z9 23 U1 0 U2 14 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD AUG PY 2014 VL 24 IS 8 BP 455 EP 463 DI 10.1016/j.tcb.2014.03.005 PG 9 WC Cell Biology SC Cell Biology GA AN0YA UT WOS:000340308700003 PM 24731398 ER PT J AU Mills, KL AF Mills, Kathryn L. TI Effects of Internet use on the adolescent brain: despite popular claims, experimental evidence remains scarce SO TRENDS IN COGNITIVE SCIENCES LA English DT Editorial Material ID MEMORY; CONSEQUENCES AB Twenty-five years have passed since the invention of the World Wide Web changed society by allowing unfettered access to the Internet. How this technological revolution has affected brain development continues to be an open question. There is particular concern about how Internet use is affecting the brains of adolescents. This Forum article discusses the possible effects of the Internet, as well as the behaviors and capabilities associated with its use, on the adolescent brain. C1 [Mills, Kathryn L.] UCL, Inst Cognit Neurosci, London, England. [Mills, Kathryn L.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Mills, KL (reprint author), UCL, Inst Cognit Neurosci, London, England. EM kathryn.l.mills@gmail.com NR 14 TC 7 Z9 7 U1 5 U2 49 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD AUG PY 2014 VL 18 IS 8 BP 385 EP 387 DI 10.1016/j.tics.2014.04.011 PG 3 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA AN1EH UT WOS:000340325000001 PM 25064168 ER PT J AU Wong, G Qiu, XG Olinger, GG Kobinger, GP AF Wong, Gary Qiu, Xiangguo Olinger, Gene G. Kobinger, Gary P. TI Post-exposure therapy of filovirus infections SO TRENDS IN MICROBIOLOGY LA English DT Review DE filovirus; Ebola; Marburg; monoclonal antibodies; immunotherapy; post-exposure ID ANTICOAGULANT PROTEIN C2; EBOLA HEMORRHAGIC-FEVER; NONHUMAN-PRIMATES; VESICULAR-STOMATITIS; MONOCLONAL-ANTIBODIES; VIRUS INFECTION; RHESUS-MONKEYS; MEDIATED PROTECTION; ZAIRE-EBOLAVIRUS; MARBURG VIRUSES AB Filovirus infections cause fatal hemorrhagic fever characterized by the initial onset of general symptoms before rapid progression to severe disease; the most virulent species can cause death to susceptible hosts within 10 days after the appearance of symptoms. Before the advent of monoclonal antibody (mAb) therapy, infection of non-human primates (NHPs) with the most virulent filovirus species was fatal if interventions were not administered within minutes. A novel nucleoside analogue, BCX4430, has since been shown to also demonstrate protective efficacy with a delayed treatment start. This review summarizes and evaluates the potential of current experimental candidates for treating filovirus disease with regard to their feasibility and use in the clinic, and assesses the most promising strategies towards the future development of a pan-filovirus medical countermeasure. C1 [Wong, Gary; Qiu, Xiangguo; Kobinger, Gary P.] Publ Hlth Agcy Canada, Natl Microbiol Lab, Special Pathogens Program, Winnipeg, MB, Canada. [Wong, Gary; Kobinger, Gary P.] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [Olinger, Gene G.] NIAID, Integrated Res Facil, NIH, Frederick, MD USA. [Kobinger, Gary P.] Univ Manitoba, Dept Immunol, Winnipeg, MB, Canada. [Kobinger, Gary P.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Kobinger, GP (reprint author), Publ Hlth Agcy Canada, Natl Microbiol Lab, Special Pathogens Program, Winnipeg, MB, Canada. EM gary.kobinger@phac-aspc.gc.ca FU Public Health Agency of Canada (PHAC); Canadian Institute for Health Research (CIHR) - Canadian Safety and Security Program (CSSP); Canadian Institute for Health Research (CIHR) FX This work was supported by the Public Health Agency of Canada (PHAC) and funded by a Canadian Safety and Security Program (CSSP) grant to G.P.K. and X.Q. G.W. is the recipient of a Doctoral Research Award from the Canadian Institute for Health Research (CIHR). NR 65 TC 33 Z9 40 U1 5 U2 72 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0966-842X EI 1878-4380 J9 TRENDS MICROBIOL JI Trends Microbiol. PD AUG PY 2014 VL 22 IS 8 BP 456 EP 463 DI 10.1016/j.tim.2014.04.002 PG 8 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA AN1CK UT WOS:000340320100007 PM 24794572 ER PT J AU Metwalli, AR Rosner, IL Cullen, J Chen, YM Brand, T Brassell, SA Lesperance, J Porter, C Sterbis, J McLeod, DG AF Metwalli, Adam R. Rosner, Inger L. Cullen, Jennifer Chen, Yongmei Brand, Timothy Brassell, Stephen A. Lesperance, James Porter, Christopher Sterbis, Joseph McLeod, David G. TI Elevated alkaline phosphatase velocity strongly predicts overall survival and the risk of bone metastases in castrate-resistant prostate cancer SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Prostate cancer; Bone metastasis; Bone metastasis-free survival; Overall survival; Alkaline phosphatase; Prostate-specific antigen (PSA); PSA doubling time (PSADT); Alkaline phosphatase velocity (APV) ID PLACEBO-CONTROLLED TRIAL; RADICAL PROSTATECTOMY; SERUM CONSTITUENTS; TURNOVER MARKERS; NATURAL-HISTORY; MEN; ANTIGEN; PROGRESSION; DENOSUMAB; ACID AB Objectives: In patients with a rising prostate-specific antigen (PSA) level during treatment with androgen deprivation therapy, identification of men who progress to bone metastasis and death remains problematic. Accurate risk stratification models are needed to better predict risk for bone metastasis and death among patients with castration-resistant prostate cancer (CRPC). This study evaluates whether alkaline phosphatase (AP) kinetics predicts bone metastasis and death in patients with CRPC. Methods and materials: A retrospective cohort study of 9,547 patients who underwent treatment for prostate cancer was conducted using the Center for Prostate Disease Research Multi-center National Database. From the entire cohort, 347 were found to have CRPC and, of those, 165 had 2 or more AP measurements during follow-up. To determine the AP velocity (APV), the slope of the linear regression line of all AP values was plotted over time. Rapid APV was defined as the uppermost quartile of APV values, which was found to be >= 6.3 IU/1/y. CRPC was defined as 2 consecutive rising PSA values after achieving a PSA nadir < 4 ng/ml and documented testosterone values less than 50 ng/dl. The primary study outcomes included bone metastasis free survival (BMFS) and overall survival (OS). Results: Rapid APV and PSA doubling time (PSADT) less than 10 months were strong predictors of both BMFS and OS in a multivariable analysis. Faster PSADT was a stronger predictor for BMFS (odds ratio [OR] = 12.1, P < 0.0001 vs. OR = 2.7, P = 0.011), whereas rapid APV was a stronger predictor of poorer OS (OR = 5.11, P = 0.0001 vs. OR = 3.98, P = 0.0034). In those with both a rapid APV and a faster PSADT, the odds of developing bone metastasis and death exceeded 50%. Conclusion: APV is an independent predictor of OS and BMFS in patients with CRPC. APV, in conjunction with PSA-based clinical parameters, may be used to better identify patients with CRPC who are at the highest risk of metastasis and death. These findings need validation in prospective studies. Published by Elsevier Inc. C1 [Metwalli, Adam R.; Rosner, Inger L.; Cullen, Jennifer; Chen, Yongmei; Brand, Timothy; Brassell, Stephen A.; Lesperance, James; Porter, Christopher; Sterbis, Joseph; McLeod, David G.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Metwalli, AR (reprint author), NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. EM adam.metwalli@nih.gov FU Center for Prostate Disease Research (CPDR); Uniformed Services University of the Health Sciences; Intramural Research Program of the Clinical Research Center; National Cancer Institute, National Institutes of Health, Bethesda, MD, US FX This research was supported and funded through the Center for Prostate Disease Research (CPDR), the Uniformed Services University of the Health Sciences, the Intramural Research Program of the Clinical Research Center, and the National Cancer Institute, National Institutes of Health, Bethesda, MD, US. NR 22 TC 4 Z9 4 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD AUG PY 2014 VL 32 IS 6 BP 761 EP 768 DI 10.1016/j.urolonc.2014.03.024 PG 8 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AN1KX UT WOS:000340343400004 PM 24929891 ER PT J AU McDermott, MM Carr, J Liu, K Kramer, CM Yuan, C Tian, L Criqui, MH Guralnik, JM Ferrucci, L Zhao, LH Xu, DX Kibbe, M Berry, J Carroll, TJ AF McDermott, Mary M. Carr, James Liu, Kiang Kramer, Christopher M. Yuan, Chun Tian, Lu Criqui, Michael H. Guralnik, Jack M. Ferrucci, Luigi Zhao, Lihui Xu, Dongxiang Kibbe, Melina Berry, Jarett Carroll, Timothy J. TI Collateral vessel number, plaque burden, and functional decline in peripheral artery disease SO VASCULAR MEDICINE LA English DT Article DE atherosclerotic plaque; intermittent claudication; peripheral artery disease; physical functioning ID ANKLE-BRACHIAL INDEX; PHASE-II MULTICENTER; INTERMITTENT CLAUDICATION; DOUBLE-BLIND; THERAPEUTIC ANGIOGENESIS; MR-ANGIOGRAPHY; LEG SYMPTOMS; PERFORMANCE; CLASSIFICATION; OSTEOARTHRITIS AB Associations of collateral vessels and lower extremity plaque with functional decline are unknown. Among people with peripheral artery disease (PAD), we determined whether greater superficial femoral artery (SFA) plaque burden combined with fewer lower extremity collateral vessels was associated with faster functional decline, compared to less plaque and/or more numerous collateral vessels. A total of 226 participants with ankle-brachial index (ABI) <1.00 underwent magnetic resonance imaging of lower extremity collateral vessels and cross-sectional imaging of the proximal SFA. Participants were categorized as follows: Group 1 (best), maximum plaque area < median and collateral vessel number >= 6 (median); Group 2, maximum plaque area < median and collateral vessel number <6; Group 3, maximum plaque area > median and collateral vessel number >= 6; Group 4 (worst), maximum plaque area > median and collateral vessel number <6. Functional measures were performed at baseline and annually for 2 years. Analyses adjust for age, sex, race, comorbidities, and other confounders. Annual changes in usual-paced walking velocity were: Group 1, +0.01 m/s; Group 2, -0.02 m/s; Group 3, -0.01 m/s; Group 4, -0.05 m/s (p-trend= 0.008). Group 4 had greater decline than Group 1 (p<0.001), Group 2 (p=0.029), and Group 3 (p=0.010). Similar trends were observed for fastest-paced 4-meter walking velocity (p-trend=0.018). Results were not substantially changed when analyses were repeated with additional adjustment for ABI. However, there were no associations of SFA plaque burden and collateral vessel number with decline in 6-minute walk. In summary, a larger SFA plaque burden combined with fewer collateral vessels is associated with a faster decline in usual and fastest-paced walking velocity in PAD. C1 [McDermott, Mary M.; Carr, James; Liu, Kiang; Zhao, Lihui; Kibbe, Melina; Carroll, Timothy J.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Kramer, Christopher M.] Univ Virginia, Charlottesville, VA USA. [Yuan, Chun] Univ Washington, Seattle, WA 98195 USA. [Yuan, Chun; Xu, Dongxiang] Univ Washington, Sch Med, Seattle, WA USA. [Tian, Lu] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Criqui, Michael H.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Guralnik, Jack M.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Ferrucci, Luigi] NIA, Bethesda, MD 20892 USA. [Kibbe, Melina] Jesse Brown VA Med Ctr, Chicago, IL USA. [Berry, Jarett] Univ Texas Southwestern, Dallas, TX USA. RP McDermott, MM (reprint author), Northwestern Univ, Feinberg Sch Med, 750 North Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu RI Carroll, Timothy/B-6934-2009 FU [R01-HL083064]; [R01-HL109244] FX Supported by R01-HL083064 and R01-HL109244. NR 32 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X EI 1477-0377 J9 VASC MED JI Vasc. Med. PD AUG PY 2014 VL 19 IS 4 BP 281 EP 288 DI 10.1177/1358863X14540362 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AM8WZ UT WOS:000340161000005 PM 25047855 ER PT J AU Nelson, MI Balmaseda, A Kuan, G Saborio, S Lin, XD Halpin, RA Stockwell, TB Wentworth, DE Harris, E Gordon, A AF Nelson, Martha I. Balmaseda, Angel Kuan, Guillermina Saborio, Saira Lin, Xudong Halpin, Rebecca A. Stockwell, Timothy B. Wentworth, David E. Harris, Eva Gordon, Aubree TI The evolutionary dynamics of influenza A and B viruses in the tropical city of Managua, Nicaragua SO VIROLOGY LA English DT Article DE Influenza; Evolution; Central America; Molecular epidemiology ID PERSISTENCE AB Despite mounting evidence of the high disease burden of influenza in tropical regions, relatively little viral sequence data is available from tropical countries in the Western hemisphere. To understand the evolutionary dynamics of influenza A and B viruses in Managua, Nicaragua, we performed a phylogenetic analysis of 1956 influenza viruses, including 335 collected for this study during 2007-2010 from a population-based cohort in Managua. North America was consistently identified as the most significant source of influenza virus diversity in Managua, although South America and Mexico were important viral sources during the 2009 A/H1N1 pandemic. The low number of viral introductions of Central American origin may reflect differences in the seasonality of influenza in Nicaragua versus neighboring countries, and underscores the need for additional data in this understudied region. (C) 2014 Elsevier Inc. All rights reserved. C1 [Nelson, Martha I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Balmaseda, Angel; Saborio, Saira] Minist Hlth, Ctr Nacl Diagnost & Referencia, Lab Nacl Virol, Managua, Nicaragua. [Kuan, Guillermina] Minist Hlth, Ctr Salud Socrates Flores Vivas, Managua, Nicaragua. [Lin, Xudong; Halpin, Rebecca A.; Stockwell, Timothy B.; Wentworth, David E.] J Craig Venter Inst, Rockville, MD USA. [Harris, Eva; Gordon, Aubree] Div Infect Dis & Vaccinol, Berkeley, CA USA. [Gordon, Aubree] Univ Calif Berkeley, Sch Publ Hlth, Div Epidemiol, Berkeley, CA 94720 USA. RP Gordon, A (reprint author), NIH, Fogarty Int Ctr, 16 Ctr Dr,Bldg 16,Room 202, Bethesda, MD 20892 USA. EM nelsonma@mail.nih.gov; aubreegordon@berkeley.edu OI Gordon, Aubree/0000-0002-9352-7877; Wentworth, David/0000-0002-5190-980X FU Multinational Influenza Seasonal Mortality Study (MISMS); Office of Global Affairs at the Department of Health and Human Services (DHHS); National Institute of Allergy and Infectious Diseases, National Institutes of Health [U01 AI088654]; Fogarty International Center, National Institutes of Health [K02 TW009483]; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200900007C] FX We thank the study team of the Nicaraguan Influenza Cohort Study in the Centro de Salud Socrates Flores Vivas, and the Laboratorio Nacional de Virologia at the Centro Nacional de Diagnostic y Referencia of the Nicaraguan Ministry of Health, as well as the Sustainable Sciences Institute (SSI). We are also grateful to the study participants and their families. We thank Cecile Viboud of Fogarty International Center, NIH, for her thoughtful inputs. This work was supported in part by the Multinational Influenza Seasonal Mortality Study (MISMS), an on-going international collaborative effort to understand influenza epidemiology and evolution, led by the Fogarty International Center, NIH, with funding from the Office of Global Affairs at the Department of Health and Human Services (DHHS) [MIN] and by the National Institute of Allergy and Infectious Diseases, National Institutes of Health grant number U01 AI088654 (EH, AG) and the Fogarty International Center, National Institutes of Health [grant number K02 TW009483 (AG). This project has also been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services under the contract number HHSN272200900007C. NR 29 TC 3 Z9 3 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD AUG PY 2014 VL 462 BP 81 EP 90 DI 10.1016/j.virol.2014.05.025 PG 10 WC Virology SC Virology GA AM9TY UT WOS:000340225100009 PM 24959982 ER PT J AU Philbin, MM Tanner, AE DuVal, A Ellen, JM Xu, JH Kapogiannis, B Bethel, J Fortenberry, JD AF Philbin, Morgan M. Tanner, Amanda E. DuVal, Anna Ellen, Jonathan M. Xu, Jiahong Kapogiannis, Bill Bethel, Jim Fortenberry, J. Dennis CA Adolescent Trials Network HIV AIDS TI Factors Affecting Linkage to Care and Engagement in Care for Newly Diagnosed HIV-Positive Adolescents Within Fifteen Adolescent Medicine Clinics in the United States SO AIDS AND BEHAVIOR LA English DT Article DE Adolescents; HIV; Linkage to care; Engagement in care ID ANTIRETROVIRAL TREATMENT ACCESS; RETENTION; HEALTH; INTERVENTION; PREVENTION; INFECTION; COMMUNITY; MULTISITE; SURVIVAL; ADULTS AB Early linkage to care and engagement in care are critical for initiation of medical interventions. However, over 50 % of newly diagnosed persons do not receive HIV-related care within 6 months of diagnosis. We evaluated a linkage to care and engagement in care initiative for HIV-positive adolescents in 15 U.S.-based clinics. Structural and client-level factors (e.g. demographic and behavioral characteristics, clinic staff and location) were evaluated as predictors of successful linkage and engagement. Within 32 months, 1,172/1,679 (69.8 %) of adolescents were linked to care of which 1,043/1,172 (89 %) were engaged in care. Only 62.1 % (1,043/1,679) of adolescents were linked and engaged in care. Linkage to care failure was attributed to adolescent, provider, and clinic-specific factors. Many adolescents provided incomplete data during the linkage process or failed to attend appointments, both associated with failure to linkage to care. Additional improvements in HIV care will require creative approaches to coordinated data sharing, as well as continued outreach services to support newly diagnosed adolescents. C1 [Philbin, Morgan M.] Columbia Univ, New York State Psychiat Inst, HIV Ctr Clin & Behav Studies, New York, NY 10027 USA. [Tanner, Amanda E.] Univ N Carolina, Dept Publ Hlth Educ, Greensboro, NC 27412 USA. [DuVal, Anna] Johns Hopkins Sch Med, Dept Pediat, Baltimore, MD USA. [Ellen, Jonathan M.] Johns Hopkins Univ, Sch Med, Johns Hopkins Med, Dept Pediat,All Childrens Hosp, St Petersburg, FL USA. [Xu, Jiahong; Bethel, Jim] WESTAT Corp, Rockville, MD 20850 USA. [Kapogiannis, Bill] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD USA. [Fortenberry, J. Dennis] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. RP Philbin, MM (reprint author), Columbia Univ, New York State Psychiat Inst, HIV Ctr Clin & Behav Studies, New York, NY 10027 USA. EM mp3243@columbia.edu FU NICHD NIH HHS [5 U01 HD 40474, 5 U01 HD 40533, U01 HD040474, U01 HD040533]; NIMH NIH HHS [P30 MH043520, T32 MH019139]; NIMHD NIH HHS [L60 MD009069] NR 37 TC 13 Z9 13 U1 2 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD AUG PY 2014 VL 18 IS 8 BP 1501 EP 1510 DI 10.1007/s10461-013-0650-6 PG 10 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA AM5AS UT WOS:000339868100011 PM 24682848 ER PT J AU Glasgow, RE Kessler, RS Ory, MG Roby, D Gorin, SS Krist, A AF Glasgow, Russell E. Kessler, Rodger S. Ory, Marcia G. Roby, Dylan Gorin, Sherri Sheinfeld Krist, Alex TI Conducting Rapid, Relevant Research Lessons Learned from the My Own Health Report Project SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID PRIMARY-CARE; OUTCOMES; TRIAL; TRANSLATION; EDUCATION; BEHAVIOR; DESIGN; POLICY AB The lengthy and uncertain translation of research into clinical practice is well documented. Much of the current "gold standard" clinical research is slow, expensive, and lacks perceived relevance for practitioners and decision makers. In contrast, we summarize experiences conducting the My Own Health Report (MOHR) project to collect and address patient reported measures using principles of rapid, relevant pragmatic research. The methods used for rapid design and fielding of the MOHR project to improve attention to health behaviors and mental health are detailed. Within the multisite, pragmatic, implementation-focused MOHR study, we describe the four phases of the research and the key decisions made and actions taken within each. We provide concrete examples of how relevant research can be conducted transparently to rapidly provide information to practitioners. Data were collected and analyzed in 2013. The multisite (seven research centers partnered with 18 clinics) cluster randomized pragmatic delayed intervention trial was conducted in less than 18 months from receipt of funding applications to completion of data collection. Phases that were especially accelerated included funding and review, and recruitment and implementation. Conducting complex studies rapidly and efficiently is a realistic goal. Key lessons learned for prevention research include use of existing research networks; use of web-based assessment/feedback tools that are tailored to fit local needs; engaging relevant stakeholders early on and throughout the process to minimize need for redesign; and making pragmatic decisions that balance internal and external validity concerns rather than waiting for perfect solutions. C1 [Glasgow, Russell E.] Univ Colorado, Sch Med, Colorado Hlth Outcomes Program, Denver, CO USA. [Kessler, Rodger S.] Univ Vermont, Dept Family Med, Burlington, VT USA. [Ory, Marcia G.] Texas A&M Hlth Sci Sch Publ Hlth, Dept Hlth Promot & Community Hlth Sci, College Stn, TX USA. [Roby, Dylan] Univ Calif Los Angeles, Dept Hlth Policy & Management, Los Angeles, CA USA. [Gorin, Sherri Sheinfeld] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Gorin, Sherri Sheinfeld] Columbia Univ, Herbert Irving Comprehens Canc Ctr, New York, NY USA. [Krist, Alex] Virginia Commonwealth Univ, Dept Family Med & Populat Hlth, Richmond, VA USA. RP Glasgow, RE (reprint author), Univ Colorado Denver, Colorado Hlth Outcomes Program, 13199 E Montview Blvd,Suite 300,Mail Stop F443, Aurora, CO 80045 USA. EM russell.glasgow@ucdenver.edu FU National Cancer Institute; Agency for Healthcare Research and Quality; NIH Office of Behavioral and Social Science Research FX Financial support provided by National Cancer Institute, Agency for Healthcare Research and Quality, and NIH Office of Behavioral and Social Science Research. NR 34 TC 11 Z9 11 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 2014 VL 47 IS 2 BP 212 EP 219 DI 10.1016/j.amepre.2014.03.007 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AM2NE UT WOS:000339687300014 PM 24953520 ER PT J AU Ambrose, BK Rostron, BL Johnson, SE Portnoy, DB Apelberg, BJ Kaufman, AR Choiniere, CJ AF Ambrose, Bridget K. Rostron, Brian L. Johnson, Sarah E. Portnoy, David B. Apelberg, Benjamin J. Kaufman, Annette R. Choiniere, Conrad J. TI Perceptions of the Relative Harm of Cigarettes and E-cigarettes Among U.S. Youth SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID NICOTINE DEPENDENCE SYMPTOMS; ADOLESCENT SMOKERS; UNREALISTIC OPTIMISM; SMOKING; RISKS AB Background: Despite progress in reducing youth smoking, adolescents remain highly susceptible to tobacco use. Of concern is whether youth perceive electronic cigarettes (e-cigarettes) as a preferable alternative to conventional cigarettes. Purpose: To describe cigarette harm perception patterns among youth based on the frequency and intensity of cigarette smoking, and examine the relative harm perceptions of conventional versus e-cigarettes, using data from a large, nationally representative sample of U.S. youth. Methods: Data from the 2012 National Youth Tobacco Survey (N=24,658) were analyzed in 2013 to identify patterns of cigarette harm perceptions. Multinomial logistic regression was conducted to identify associations between demographic and tobacco use characteristics and cigarette harm perception patterns. Logistic regression was conducted to examine the relationship between cigarette harm perceptions and the perception of e-cigarettes as less harmful than cigarettes for current, ever, and never cigarette smokers. Results: The majority of youth (64.2%) perceived the harmfulness of cigarettes as dose-dependent. Approximately one in three students perceived e-cigarettes as less harmful than conventional cigarettes. Regardless of cigarette smoking status, ever users of e-cigarettes and those with "dose-dependent" cigarette harm perceptions consistently were more likely to perceive e-cigarettes as less harmful than conventional cigarettes. Conclusions: Many youth perceive tobacco use on a continuum of harm. Youth who perceive gradations in harm-both by frequency and intensity of cigarette use and by type of product-may be particularly susceptible to e-cigarette use. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Ambrose, Bridget K.; Rostron, Brian L.; Johnson, Sarah E.; Portnoy, David B.; Apelberg, Benjamin J.; Choiniere, Conrad J.] US FDA, Ctr Tobacco Prod, Off Sci, Rockville, MD 20850 USA. [Kaufman, Annette R.] NCI, Tobacco Control Res Branch, NIH, Rockville, MD USA. RP Ambrose, BK (reprint author), US FDA, Ctr Tobacco Prod, Off Sci, 9200 Corp Blvd, Rockville, MD 20850 USA. EM bridget.ambrose@fda.hhs.gov OI Portnoy, David/0000-0003-2175-9457 FU U.S. Food and Drug Administration, Center for Tobacco Products FX Publication of this article was supported by the U.S. Food and Drug Administration, Center for Tobacco Products. NR 21 TC 35 Z9 35 U1 3 U2 36 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 2014 VL 47 IS 2 SU 1 BP S53 EP S60 DI 10.1016/j.amepre.2014.04.016 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AM2NF UT WOS:000339687400006 PM 25044196 ER PT J AU Johnson, SE Wu, CC Coleman, BN Choiniere, CJ AF Johnson, Sarah E. Wu, Charles C. Coleman, Blair N. Choiniere, Conrad J. TI Self-Reported Exposure to Tobacco Warning Labels Among U.S. Middle and High School Students SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID HEALTH WARNINGS; CANADIAN SMOKERS; SMOKING; MESSAGES; ADOLESCENTS; PRODUCTS; BEHAVIOR; WEAROUT; IMPACT AB Background: Warning labels on tobacco products are a means to communicate information about the negative health effects of tobacco use to current and potential users. Most tobacco use begins in early adolescence, making it particularly important to understand the degree to which warning labels reach adolescents. Purpose: To examine the extent to which youth report (1) seeing the current warnings on cigarettes and smokeless tobacco (SLT) products in the U.S. and (2) that seeing warnings makes them think about the health risks associated with tobacco use. Methods: Exposure to warning labels on cigarettes and SLT, as well as the degree to which adolescents report thinking about health risks in response to warnings, was examined among U.S. middle and high school students using data from the 2012 National Youth Tobacco Survey (NYTS) and analyzed in 2013. Results: Current data suggest that less than half of adolescents who saw a cigarette pack (46.9%) or SLT product (40.3%) reported seeing the warning label "most of the time" or "always." Among adolescents who reported seeing a warning, less than one third reported that cigarette (30.4%) or SLT (25.2%) warning labels made them think about health risks "a lot." These rates were even lower among current tobacco users (<14%). Conclusions: Current warning labels for cigarettes and SLT could be improved by implementing warnings that incorporate features that make them salient and more likely to evoke thoughts about health risks. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Johnson, Sarah E.; Coleman, Blair N.; Choiniere, Conrad J.] US FDA, Ctr Tobacco Prod, Off Sci, Rockville, MD 20850 USA. [Wu, Charles C.] NIH, Off Extramural Res, Bethesda, MD 20892 USA. RP Johnson, SE (reprint author), US FDA, Ctr Tobacco Prod, Off Sci, 9200 Corp Blvd, Rockville, MD 20850 USA. EM sarah.johnson@fda.hhs.gov FU U.S. Food and Drug Administration, Center for Tobacco Products FX Publication of this article was supported by the U.S. Food and Drug Administration, Center for Tobacco Products. NR 29 TC 7 Z9 7 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 2014 VL 47 IS 2 SU 1 BP S69 EP S75 DI 10.1016/j.amepre.2014.05.005 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AM2NF UT WOS:000339687400008 PM 25044198 ER PT J AU Portnoy, DB Wu, CC Tworek, C Chen, JP Borek, N AF Portnoy, David B. Wu, Charles C. Tworek, Cindy Chen, Jiping Borek, Nicolette TI Youth Curiosity About Cigarettes, Smokeless Tobacco, and Cigars SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID HIGH-SCHOOL-STUDENTS; UNITED-STATES; ESTABLISHED SMOKING; ADOLESCENTS; INITIATION; SUSCEPTIBILITY; PREDICTOR; MIDDLE AB Background: Curiosity about cigarettes is a reliable predictor of susceptibility to smoking and established use among youth. Related research has been limited to cigarettes, and lacks national-level estimates. Factors associated with curiosity about tobacco products, such as advertising, have been postulated but rarely tested. Purpose: To describe the prevalence of curiosity about cigarettes, smokeless tobacco, and cigars among youth and explore the association between curiosity and self-reported tobacco advertising exposure. Methods: Data from the 2012 National Youth Tobacco Survey, a nationally representative survey of 24,658 students, were used. In 2013, estimates weighted to the national youth school population were calculated for curiosity about cigarettes, smokeless tobacco, and cigars among never users of any tobacco product. Associations between tobacco advertising and curiosity were explored using multivariable regressions. Results: Curiosity about cigarettes (28.8%); cigars (19.5%); and smokeless tobacco (9.7%) was found, and many youth were curious about more than one product. Exposure to point-of-sale advertising (e.g., OR=1.35, 95% CI=1.19, 1.54 for cigarette curiosity); tobacco company communications (e.g., OR=1.70, 95% CI=1.38, 2.09 for cigarette curiosity); and tobacco products, as well as viewing tobacco use in TV/movies (e.g., OR=1.37, 95% CI=1.20, 1.58 for cigarette curiosity) were associated with curiosity about each examined tobacco product. Conclusions: Despite decreasing use of tobacco products, youth remain curious about them. Curiosity is associated with various forms of tobacco advertising. These findings suggest the importance of measuring curiosity as an early warning signal for potential future tobacco use and evaluating continued efforts to limit exposure to tobacco marketing among youth. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Portnoy, David B.; Tworek, Cindy; Chen, Jiping; Borek, Nicolette] US FDA, Off Sci, Ctr Tobacco Prod, Rockville, MD 20850 USA. [Wu, Charles C.] NIH, Off Extramural Res, Bethesda, MD 20892 USA. RP Portnoy, DB (reprint author), US FDA, Off Sci, Ctr Tobacco Prod, 9200 Corp Blvd,CORP 300H, Rockville, MD 20850 USA. EM david.portnoy@fda.hhs.gov OI Portnoy, David/0000-0003-2175-9457 FU U.S. Food and Drug Administration, Center for Tobacco Products FX Publication of this article was supported by the U.S. Food and Drug Administration, Center for Tobacco Products. NR 29 TC 12 Z9 12 U1 1 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 2014 VL 47 IS 2 SU 1 BP S76 EP S86 DI 10.1016/j.amepre.2014.04.012 PG 11 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AM2NF UT WOS:000339687400009 PM 25044199 ER PT J AU Tworek, C Schauer, GL Wu, CC Malarcher, AM Jackson, KJ Hoffman, AC AF Tworek, Cindy Schauer, Gillian L. Wu, Charles C. Malarcher, Ann M. Jackson, Kia J. Hoffman, Allison C. TI Youth Tobacco Cessation Quitting Intentions and Past-Year Quit Attempts SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID HIGH-SCHOOL-STUDENTS; UNITED-STATES; SMOKING-CESSATION; COLLEGE-STUDENTS; USE PREVENTION; PRODUCT USE; ADOLESCENTS; SMOKERS; ADULTS; MIDDLE AB Background: Despite declining use of conventional tobacco products, youth use of non-cigarette tobacco has become prevalent; however, quitting behaviors remain largely unexplored. Purpose: To examine nationally representative data on quit intentions and past-year attempts to quit all tobacco use among current youth tobacco users. Methods: In 2013, data were analyzed from the 2012 National Youth Tobacco Survey (NYTS). Weighted prevalence estimates of quit intentions and past-year quit attempts for current youth tobacco users are presented. Results: Prevalence of quit intentions and past-year attempts to quit all tobacco use were 52.8% and 51.5%, respectively, among current youth tobacco users. Among non mutually exclusive, groups, current cigarette smokers had the highest prevalence of quit intentions (56.8%) and past-year quit attempts (52.5%), whereas current hookah users had the lowest prevalence of quit intentions (41.5%) and past-year quit attempts (43.7%). Quit intentions among black, non-Hispanics (65.0%) and Hispanics (60.4%) were significantly higher versus white, non-Hispanics (47.5%). Youth reporting parental advice against tobacco had significantly higher prevalence of quit intentions (56.7%) and past-year quit attempts (55.0%) than those not reporting parental advice. Youth who agreed all tobacco products are dangerous (58.5%) had significantly higher prevalence of quit intentions than those who disagreed (37.0%). Conclusions: Continued efforts are needed to better understand youth motivation for quitting all tobacco products. Public health messaging about the dangers of all tobacco and cessation efforts should be aimed at the full range of tobacco products, not just cigarettes, and tailored to meet the needs of youth polytobacco users. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Tworek, Cindy; Jackson, Kia J.; Hoffman, Allison C.] US FDA, Ctr Tobacco Prod, Off Sci, Rockville, MD 20850 USA. [Wu, Charles C.] NIH, Off Extramural Res, Bethesda, MD 20892 USA. [Schauer, Gillian L.; Malarcher, Ann M.] CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. RP Tworek, C (reprint author), US FDA, Ctr Tobacco Prod, Off Sci, 9200 Corp Blvd, Rockville, MD 20850 USA. EM cindy.tworek@fda.hhs.gov FU U.S. Food and Drug Administration, Center for Tobacco Products FX Publication of this article was supported by the U.S. Food and Drug Administration, Center for Tobacco Products. NR 38 TC 7 Z9 7 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 2014 VL 47 IS 2 SU 1 BP S15 EP S27 DI 10.1016/j.amepre.2014.05.009 PG 13 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AM2NF UT WOS:000339687400003 PM 25044192 ER PT J AU Heimburger, DC Warner, TL Carothers, CL Blevins, M Thomas, Y Gardner, P Primack, A Vermund, SH AF Heimburger, Douglas C. Warner, Tokesha L. Carothers, Catherine Lem Blevins, Meridith Thomas, Yolanda Gardner, Pierce Primack, Aron Vermund, Sten H. TI Recruiting Post-Doctoral Fellows into Global Health Research: Selecting NIH Fogarty International Clinical Research Fellows SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID TRAINING-PROGRAMS; RESEARCH SCHOLARS; NEXT-GENERATION; WORKFORCE; DISEASES AB From 2008 to 2012, the National Institutes of Health (NIH) Fogarty International Clinical Research Fellows Program (FICRF) provided 1-year mentored research training at low- and middle-income country sites for American and international post-doctoral health professionals. We examined the FICRF applicant pool, proposed research topics, selection process, and characteristics of enrollees to assess trends in global health research interest and factors associated with applicant competitiveness. The majority (58%) of 67 US and 57 international Fellows were women, and 83% of Fellows had medical degrees. Most applicants were in clinical fellowships (41%) or residencies (24%). More applicants proposing infectious disease projects were supported (59%) than applicants proposing non-communicable disease (NCD) projects (41%), although projects that combined both topic areas were most successful (69%). The numbers of applicants proposing research on NCDs and the numbers of these applicants awarded fellowships rose dramatically over time. Funding provided to the FICRF varied significantly among NIH Institutes and Centers and was strongly associated with the research topics awarded. C1 [Heimburger, Douglas C.; Carothers, Catherine Lem; Blevins, Meridith; Vermund, Sten H.] Vanderbilt Univ, Vanderbilt Inst Global Hlth, Nashville, TN 37203 USA. Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37203 USA. Vanderbilt Univ, Sch Med, Dept Biostat, Nashville, TN 37203 USA. Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37203 USA. Univ Georgia, Off Vice President Res, Athens, GA 30602 USA. Vanderbilt Univ, Fogarty Int Clin Res Scholars & Fellows Support C, Nashville, TN 37203 USA. [Gardner, Pierce] SUNY Stony Brook, Sch Med, Stony Brook, NY 11794 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Warner, Tokesha L.] Univ Georgia, Off Vice President Res, GrantSMART Off, Athens, GA 30602 USA. RP Heimburger, DC (reprint author), Vanderbilt Univ, Inst Global Hlth, 2525 West End Ave,Suite 750, Nashville, TN 37203 USA. EM douglas.heimburger@vanderbilt.edu; tlwarner@uga.edu; catherine.lem@vanderbilt.edu; meridith.blevins@vanderbilt.edu; ythomas@ficrsconsultant.com; pgardner@stonybrookmedicine.edu; aprimack@rcn.co; sten.vermund@vanderbilt.edu RI Warner, Tokesha/M-4735-2014; OI Warner, Tokesha/0000-0003-1809-102X; Blevins, Meridith/0000-0002-3861-9859 FU NIH Office of the Director; FIC; OAR; NCI; National Eye Institute; National Heart, Blood, and Lung Institute; National Institute of Dental and Craniofacial Research; National Institute on Drug Abuse; National Institute of Mental Health; NIAID; NIH Office of Research on Women's Health through the FICRF Program at Vanderbilt-Association of American Medical Schools [R24 TW007988]; American Recovery and Reinvestment Act; Vanderbilt Institute for Clinical and Translational Research (VICTR from National Center for Advancing Translational Sciences/NIH) [UL1TR000445] FX This work was supported by the NIH Office of the Director, FIC, OAR, NCI, National Eye Institute, National Heart, Blood, and Lung Institute, National Institute of Dental and Craniofacial Research, National Institute on Drug Abuse, National Institute of Mental Health, NIAID, and NIH Office of Research on Women's Health through the FICRF Program at Vanderbilt-Association of American Medical Schools (Grant R24 TW007988). Additional support was received from the American Recovery and Reinvestment Act (http://recovery.nih.gov/) in 2010 and 2011 and the Vanderbilt Institute for Clinical and Translational Research (VICTR; Grant UL1TR000445 from National Center for Advancing Translational Sciences/NIH). NR 13 TC 5 Z9 5 U1 0 U2 5 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD AUG PY 2014 VL 91 IS 2 BP 219 EP 224 DI 10.4269/ajtmh.13-0741 PG 6 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA AM4ZD UT WOS:000339863800005 PM 24865678 ER PT J AU Vassilopoulos, A Pennington, JD Andresson, T Rees, DM Bosley, AD Fearnley, IM Ham, A Flynn, CR Hill, S Rose, KL Kim, HS Deng, CX Walker, JE Gius, D AF Vassilopoulos, Athanassios Pennington, J. Daniel Andresson, Thorkell Rees, David M. Bosley, Allen D. Fearnley, Ian M. Ham, Amy Flynn, Charles Robb Hill, Salisha Rose, Kristie Lindsey Kim, Hyun-Seok Deng, Chu-Xia Walker, John E. Gius, David TI SIRT3 Deacetylates ATP Synthase F-1 Complex Proteins in Response to Nutrient- and Exercise-Induced Stress SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID LYSINE ACETYLATION; GENE-EXPRESSION; MITOCHONDRIA; DEFICIENCY; METABOLISM; HYPERACETYLATION; HOMEOSTASIS; ACTIVATION; OXIDATION; CHROMATIN AB Aims: Adenosine triphosphate (ATP) synthase uses chemiosmotic energy across the inner mitochondrial membrane to convert adenosine diphosphate and orthophosphate into ATP, whereas genetic deletion of Sirt3 decreases mitochondrial ATP levels. Here, we investigate the mechanistic connection between SIRT3 and energy homeostasis. Results: By using both in vitro and in vivo experiments, we demonstrate that ATP synthase F-1 proteins alpha, beta, gamma, and Oligomycin sensitivity-conferring protein (OSCP) contain SIRT3-specific reversible acetyl-lysines that are evolutionarily conserved and bind to SIRT3. OSCP was further investigated and lysine 139 is a nutrient-sensitive SIRT3-dependent deacetylation target. Site directed mutants demonstrate that OSCPK139 directs, at least in part, mitochondrial ATP production and mice lacking Sirt3 exhibit decreased ATP muscle levels, increased ATP synthase protein acetylation, and an exercise-induced stress-deficient phenotype. Innovation: This work connects the aging and nutrient response, via SIRT3 direction of the mitochondrial acetylome, to the regulation of mitochondrial energy homeostasis under nutrient-stress conditions by deacetylating ATP synthase proteins. Conclusion: Our data suggest that acetylome signaling contributes to mitochondrial energy homeostasis by SIRT3-mediated deacetylation of ATP synthase proteins. C1 [Vassilopoulos, Athanassios; Gius, David] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Dept Radiat Oncol, Chicago, IL 60614 USA. [Vassilopoulos, Athanassios; Deng, Chu-Xia] Natl Inst Diabet Digest & Kidney Dis, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. [Pennington, J. Daniel; Rees, David M.; Fearnley, Ian M.; Walker, John E.] Med Res Council Mitochondrial Biol Unit, Cambridge, England. [Andresson, Thorkell; Bosley, Allen D.] SAIC Frederick Inc, Lab Prote & Analyt Technol, Adv Technol Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Ham, Amy] Belmont Univ, Coll Pharm, Dept Pharmaceut Social & Adm Sci, Nashville, TN USA. [Flynn, Charles Robb] Vanderbilt Univ, Sch Med, Dept Surg, Nashville, TN 37212 USA. [Hill, Salisha; Rose, Kristie Lindsey] Vanderbilt Univ, Sch Med, Mass Spectrometry Res Ctr, Nashville, TN 37212 USA. [Kim, Hyun-Seok] Ewha Womans Univ, Coll Nat Sci, Dept Life Sci, Seoul, South Korea. RP Gius, D (reprint author), Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Dept Radiat Oncol, Rm 3-119,Lurie Res Bldg, Chicago, IL 60614 USA. EM chuxiad@bldg10.niddk.nih.gov; david.gius@northwestern.edu RI Flynn, Charles/M-3895-2015; deng, chuxia/N-6713-2016 OI Flynn, Charles/0000-0002-3749-0598; FU Department of Defense [NCI-1R01CA152601-01, 1R01CA152799-01A1, 1R01CA168292-01A1, BC093803]; Hirshberg Foundation for Pancreatic Cancer; NIDDK/NIH; NCI; CCR/NIH; NIA [F30AG030839] FX DG is supported by NCI-1R01CA152601-01, 1R01CA152799-01A1, 1R01CA168292-01A1, and BC093803 from the Department of Defense and a Hirshberg Foundation for Pancreatic Cancer Research Seed Grant Award. C-XD was supported (in part) by the Intramural Research Program of the NIDDK/NIH. TA is supported (in part) by the Intramural Research Program of the NCI and CCR/NIH. JDP is supported by NIA F30AG030839. The authors thank Mike Runswick, MBE, for providing bovine heart ATP synthase. They also thank Kamburapola Jayawardena and Mike Harbour for technical assistance with mass spectrometry. They are grateful to Melissa Stauffer, PhD, of Scientific Editing Solutions, for editorial assistance. NR 30 TC 40 Z9 42 U1 0 U2 12 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD AUG 1 PY 2014 VL 21 IS 4 BP 551 EP 564 DI 10.1089/ars.2013.5420 PG 14 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA AM2DP UT WOS:000339659600002 PM 24252090 ER PT J AU Sukal-Moulton, T Clancy, T Zhang, LQ Gaebler-Spira, D AF Sukal-Moulton, Theresa Clancy, Theresa Zhang, Li-Qun Gaebler-Spira, Deborah TI Clinical Application of a Robotic Ankle Training Program for Cerebral Palsy Compared to the Research Laboratory Application: Does It Translate to Practice? SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Ankle; Cerebral palsy; Exercise; Rehabilitation; Resistance training; Robotics ID PHYSICAL-THERAPY; CHILDREN; RELIABILITY; REHABILITATION; CLASSIFICATION; INTERVENTIONS; VALIDATION; DISORDERS; SCALE AB Objective: To determine the clinical efficacy of an ankle robotic rehabilitation protocol for patients with cerebral palsy. Design: The clinic cohort was identified from a retrospective chart review in a before-after intervention trial design and compared with a previously published prospective research cohort. Setting: Rehabilitation hospital. Participants: Children (N=28; mean age, 8.2 +/- 3.62y) with Gross Motor Function Classification System levels I, II, or ifi who were referred for ankle stretching and strengthening used a robotic ankle device in a clinic setting. Clinic results were compared with a previously published cohort of participants (N=12; mean age, 7.8 +/- 2.91y) seen in a research laboratory-based intervention protocol. Interventions: Patients in the clinic cohort were seen 2 times per week for 75-minute sessions for a total of 6 weeks. The first 30 minutes of the session were spent using the robotic ankle device for ankle stretching and strengthening, and the remaining 45 minutes were spent on functional movement activities. There was no control group. Main Outcome Measures: We compared pre- and postintervention measures of plantarflexor and dorsiflexor range of motion, strength, spasticity, mobility (Timed Up and Go test, 6-minute walk test, 10-m walk test), balance (Pediatric Balance Scale), Selective Control Assessment of the Lower Extremity (SCALE), and gross motor function measure (GMFM). Results: Significant improvements were found for the clinic cohort in all main outcome measures except for the GMFM. These improvements were equivalent to those reported in the research cohort, except for larger SCALE test changes in the research cohort. Conclusions: These findings suggest that translation of repetitive, goal-directed biofeedback training into the clinic setting is both feasible and beneficial for patients with cerebral palsy. (C) 2014 by the American Congress of Rehabilitation Medicine C1 [Sukal-Moulton, Theresa; Clancy, Theresa; Zhang, Li-Qun; Gaebler-Spira, Deborah] Rehabil Inst Chicago, Chicago, IL 60611 USA. [Sukal-Moulton, Theresa] NIH, Ctr Clin, Rehabil Med Funct & Appl Biomech Sect, Bethesda, MD 20892 USA. [Zhang, Li-Qun] Northwestern Univ, Evanston, IL USA. [Zhang, Li-Qun; Gaebler-Spira, Deborah] Northwestern Univ, Chicago, IL USA. RP Gaebler-Spira, D (reprint author), Rehabil Inst Chicago, 321 E Super St, Chicago, IL 60611 USA. EM dgaebler@ric.org FU Intramural NIH HHS; NICHD NIH HHS [R42 HD043664, R42-HD043664] NR 30 TC 5 Z9 7 U1 2 U2 15 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 EI 1532-821X J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD AUG PY 2014 VL 95 IS 8 BP 1433 EP 1440 DI 10.1016/j.apmr.2014.04.010 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA AM2ND UT WOS:000339687200003 PM 24792141 ER PT J AU Fang, ZZ Gonzalez, FJ AF Fang, Zhong-Ze Gonzalez, Frank J. TI LC-MS-based metabolomics: an update SO ARCHIVES OF TOXICOLOGY LA English DT Review DE Metabolomics; Xenobiotic metabolism; Toxicology; Pathogenesis ID INFLAMMATORY-BOWEL-DISEASE; CHROMATOGRAPHY-MASS SPECTROMETRY; BILE-ACID HOMEOSTASIS; STABLE-ISOTOPE; INDUCED HEPATOTOXICITY; ANALYSIS REVEALS; DRUG-METABOLISM; LIVER-DISEASE; IN-VIVO; RECEPTOR AB Liquid chromatography-mass spectrometry (LC-MS)-based metabolomics can have a major impact in multiple research fields, especially when combined with other technologies, such as stable isotope tracers and genetically modified mice. This review highlights recent applications of metabolomic technology in the study of xenobiotic metabolism and toxicity, and the understanding of disease pathogenesis and therapeutics. Metabolomics has been employed to study metabolism of noscapine, an aryl hydrocarbon receptor antagonist, and to determine the mechanisms of liver toxicities of rifampicin and isoniazid, trichloroethylene, and gemfibrozil. Metabolomics-based insights into the pathogenesis of inflammatory bowel disease, alcohol-induced liver diseases, non-alcoholic steatohepatitis, and farnesoid X receptor signaling pathway-based therapeutic target discovery will also be discussed. Limitations in metabolomics technology such as sample preparation and lack of LC-MS databases and metabolite standards, need to be resolved in order to improve and broaden the application of metabolomic studies. C1 [Fang, Zhong-Ze; Gonzalez, Frank J.] NIH, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NIH, Lab Metab, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute; National Institutes of Health [1R01ES022186-01] FX This work was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, and 1R01ES022186-01, National Institutes of Health. NR 76 TC 24 Z9 25 U1 8 U2 122 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 EI 1432-0738 J9 ARCH TOXICOL JI Arch. Toxicol. PD AUG PY 2014 VL 88 IS 8 BP 1491 EP 1502 DI 10.1007/s00204-014-1234-6 PG 12 WC Toxicology SC Toxicology GA AM5LB UT WOS:000339898700003 PM 24710571 ER PT J AU Waalkes, MP Qu, W Tokar, EJ Kissling, GE Dixon, D AF Waalkes, Michael P. Qu, Wei Tokar, Erik J. Kissling, Grace E. Dixon, Darlene TI Lung tumors in mice induced by "whole-life" inorganic arsenic exposure at human-relevant doses SO ARCHIVES OF TOXICOLOGY LA English DT Article DE Arsenic; Carcinogenesis; Mice; Whole-life exposure; Lung cancer ID DRINKING-WATER; IN-UTERO; CD1 MICE; POSTNATAL DIETHYLSTILBESTROL; CANCER-MORTALITY; GENE ACTIVATION; ADRENAL-TUMORS; YOUNG-ADULTS; PULMONARY; ALTERS AB In mice, inorganic arsenic in the drinking water in the parts per million range via the dam during in utero life or with whole-life exposure is a multi-site carcinogen in the offspring. However, human arsenic exposure is typically in the parts per billion (ppb) range. Thus, we studied "whole-life" inorganic arsenic carcinogenesis in mice at levels more relevant to humans. Breeder male and female CD1 mice were exposed to 0, 50, 500 or 5,000 ppb arsenic (as sodium arsenite) in the drinking water for 3 weeks prior to breeding, during pregnancy and lactation, and after weaning (at week 3) groups of male and female offspring (initial n = 40) were exposed for up to 2 years. Tumors were assessed in these offspring. Arsenic exposure had no effect on pregnant dam weights or water consumption, litter size, offspring birthweight or weight at weaning compared to control. In male offspring mice, arsenic exposure increased (p < 0.05) bronchiolo-alveolar tumor (adenoma or carcinoma) incidence at 50-ppb group (51 %) and 500-ppb group (54 %), but not at 5,000-ppb group (28 %) compared to control (22 %). These arsenic-induced bronchiolo-alveolar tumors included increased (p < 0.05) carcinoma at 50-ppb group (27 %) compared to controls (8 %). An increase (p < 0.05) in lung adenoma (25 %) in the 50-ppb group compared to control (11 %) occurred in female offspring. Thus, in CD1 mice whole-life arsenic exposure induced lung tumors at human-relevant doses (i.e., 50 and 500 ppb). C1 [Waalkes, Michael P.; Qu, Wei; Tokar, Erik J.] NIEHS, Inorgan Toxicol Grp, Natl Toxicol Program Lab, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] NIEHS, Biostat Branch, Div Intramural Res, Res Triangle Pk, NC 27709 USA. [Dixon, Darlene] NIEHS, Mol Pathogenesis Grp, Natl Toxicol Program Lab, DNTP, Res Triangle Pk, NC 27709 USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Toxicol Grp, Natl Toxicol Program Lab, Div Natl Toxicol Program, 111 Alexander Dr,MD E1-07,POB 12233, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU DNTP, NIEHS; National Cancer Institute, Center for Cancer Research FX The authors wish to thank Dr. Bhalchandra Diwan, NCI-Frederick for aid with experimental design, Drs. Thayer, Sills and Bucher, DNTP, for critical evaluation of this manuscript, Dan Logsdon and Mark Schrader NCI-Frederick for expert technical assistance in animal husbandry, for provision of critical information on diet and water, and provision of diet samples, and Matthew Bell, DNTP, for assistance with graphics. This research was supported in part by the DNTP, NIEHS and in part by the National Cancer Institute, Center for Cancer Research. NR 34 TC 22 Z9 22 U1 4 U2 15 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 EI 1432-0738 J9 ARCH TOXICOL JI Arch. Toxicol. PD AUG PY 2014 VL 88 IS 8 BP 1619 EP 1629 DI 10.1007/s00204-014-1305-8 PG 11 WC Toxicology SC Toxicology GA AM5LB UT WOS:000339898700013 PM 25005685 ER PT J AU Toti, KS Moss, SM Paoletta, S Gao, ZG Jacobson, KA Van Calenbergh, S AF Toti, Kiran S. Moss, Steven M. Paoletta, Silvia Gao, Zhan-Guo Jacobson, Kenneth A. Van Calenbergh, Serge TI Synthesis and evaluation of N-6-substituted apioadenosines as potential adenosine A(3) receptor modulators SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE G protein-coupled receptor; Apionucleosides; Adenosine A(3) receptor ID A(3)-ADENOSINE RECEPTOR; NUCLEOSIDES; 2-ARYLETHYNYL; SUBSTITUTIONS; PHARMACOLOGY; EFFICACY; AGONISTS; ANALOGS; DESIGN AB Adenosine receptors (ARs) trigger signal transduction pathways inside the cell when activated by extracellular adenosine. Selective modulation of the A(3)AR subtype may be beneficial in controlling diseases such as colorectal cancer and rheumatoid arthritis. Here, we report the synthesis and evaluation of beta-D-apio-D-furano- and alpha-D-apio-L-furanoadenosines and derivatives thereof. Introduction of a 2-methoxy-5-chlorobenzyl group at N-6 of beta-D-apio-D-furanoadenosine afforded an A(3)AR antagonist (10c, K = 0.98 mu M), while a similar modification of an alpha-D-apio-L-furanoadenosine gave rise to a partial agonist (11c, K-i = 3.07 mu M). The structural basis for this difference was examined by docking to an A(3)AR model; the antagonist lacked a crucial interaction with Thr94. Published by Elsevier Ltd. C1 [Toti, Kiran S.; Van Calenbergh, Serge] Univ Ghent, Fac Pharmaceut Sci, Med Chem Lab, B-9000 Ghent, Belgium. [Moss, Steven M.; Paoletta, Silvia; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Van Calenbergh, S (reprint author), Univ Ghent, Fac Pharmaceut Sci, Med Chem Lab, Harelbekestr 72, B-9000 Ghent, Belgium. EM serge.vancalenbergh@ugent.be RI Jacobson, Kenneth/A-1530-2009; Van Calenbergh, Serge/A-3167-2008 OI Jacobson, Kenneth/0000-0001-8104-1493; Van Calenbergh, Serge/0000-0002-4201-1264 FU Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. NR 34 TC 3 Z9 3 U1 0 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD AUG 1 PY 2014 VL 22 IS 15 BP 4257 EP 4268 DI 10.1016/j.bmc.2014.05.036 PG 12 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA AM4XO UT WOS:000339859700049 PM 24931275 ER PT J AU Landis, JR Williams, DA Lucia, MS Clauw, DJ Naliboff, BD Robinson, NA van Bokhoven, A Sutcliffe, S Schaeffer, AJ Rodriguez, LV Mayer, EA Lai, HH Krieger, JN Kreder, KJ Afari, N Andriole, GL Bradley, CS Griffith, JW Klumpp, DJ Hong, BA Lutgendorf, SK Buchwald, D Yang, CC Mackey, S Pontari, MA Hanno, P Kusek, JW Mullins, C Clemens, JQ AF Landis, J. Richard Williams, David A. Lucia, M. Scott Clauw, Daniel J. Naliboff, Bruce D. Robinson, Nancy A. van Bokhoven, Adrie Sutcliffe, Siobhan Schaeffer, Anthony J. Rodriguez, Larissa V. Mayer, Emeran A. Lai, H. Henry Krieger, John N. Kreder, Karl J. Afari, Niloofar Andriole, Gerald L. Bradley, Catherine S. Griffith, James W. Klumpp, David J. Hong, Barry A. Lutgendorf, Susan K. Buchwald, Dedra Yang, Claire C. Mackey, Sean Pontari, Michel A. Hanno, Philip Kusek, John W. Mullins, Chris Clemens, J. Quentin CA MAPP Res Network Study Grp TI The MAPP research network: design, patient characterization and operations SO BMC UROLOGY LA English DT Article DE Urologic chronic pelvic pain syndromes; Interstitial cystitis; Chronic prostatitis; Urine biomarkers; Plasma biomarkers; Non-urologic associated syndromes; Quantitative sensory testing (QST); Neuroimaging ID PELVIC PAIN SYNDROME; CYSTITIS/PAINFUL BLADDER SYNDROME; CHRONIC PROSTATITIS COHORT; LONGITUDINAL DATA-ANALYSIS; LOW-BACK-PAIN; INTERSTITIAL CYSTITIS; SYMPTOM INDEX; SYNDROME/INTERSTITIAL CYSTITIS; CENTRAL SENSITIZATION; ERECTILE DYSFUNCTION AB Background: The "Multidisciplinary Approach to the Study of Chronic Pelvic Pain" (MAPP) Research Network was established by the NIDDK to better understand the pathophysiology of urologic chronic pelvic pain syndromes (UCPPS), to inform future clinical trials and improve clinical care. The evolution, organization, and scientific scope of the MAPP Research Network, and the unique approach of the network's central study and common data elements are described. Methods: The primary scientific protocol for the Trans-MAPP Epidemiology/Phenotyping (EP) Study comprises a multi-site, longitudinal observational study, including bi-weekly internet-based symptom assessments, following a comprehensive in-clinic deep-phenotyping array of urological symptoms, non-urological symptoms and psychosocial factors to evaluate men and women with UCPPS. Healthy controls, matched on sex and age, as well as "positive" controls meeting the non-urologic associated syndromes (NUAS) criteria for one or more of the target conditions of Fibromyalgia (FM), Chronic Fatigue Syndrome (CFS) or Irritable Bowel Syndrome (IBS), were also evaluated. Additional, complementary studies addressing diverse hypotheses are integrated into the Trans-MAPP EP Study to provide a systemic characterization of study participants, including biomarker discovery studies of infectious agents, quantitative sensory testing, and structural and resting state neuroimaging and functional neurobiology studies. A highly novel effort to develop and assess clinically relevant animal models of UCPPS was also undertaken to allow improved translation between clinical and mechanistic studies. Recruitment into the central study occurred at six Discovery Sites in the United States, resulting in a total of 1,039 enrolled participants, exceeding the original targets. The biospecimen collection rate at baseline visits reached nearly 100%, and 279 participants underwent common neuroimaging through a standardized protocol. An extended follow-up study for 161 of the UCPPS participants is ongoing. Discussion: The MAPP Research Network represents a novel, comprehensive approach to the study of UCPPS, as well as other concomitant NUAS. Findings are expected to provide significant advances in understanding UCPPS pathophysiology that will ultimately inform future clinical trials and lead to improvements in patient care. Furthermore, the structure and methodologies developed by the MAPP Network provide the foundation upon which future studies of other urologic or non-urologic disorders can be based. C1 [Landis, J. Richard; Robinson, Nancy A.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Williams, David A.; Clauw, Daniel J.] Univ Michigan, Dept Anesthesiol Med & Psychiat, Ann Arbor, MI 48109 USA. [Lucia, M. Scott; van Bokhoven, Adrie] Univ Colorado, Dept Pathol, Anschutz Med Campus, Aurora, CO USA. [Naliboff, Bruce D.] Univ Calif Los Angeles, Dept Med Psychiat & Gastroenterol, Los Angeles, CA USA. [Sutcliffe, Siobhan] Washington Univ, Dept Surg, Div Publ Hlth Sci, St Louis, MO 63110 USA. [Schaeffer, Anthony J.; Klumpp, David J.] Northwestern Univ, Dept Urol, Chicago, IL 60611 USA. [Rodriguez, Larissa V.] Univ So Calif, Dept Urol, Beverly Hills, CA USA. [Mayer, Emeran A.] Univ Calif Los Angeles, Div Digest Dis, Los Angeles, CA USA. [Lai, H. Henry; Andriole, Gerald L.] Washington Univ, Sch Med, Dept Surg, Div Urol Surg, St Louis, MO 63110 USA. [Krieger, John N.; Yang, Claire C.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Kreder, Karl J.] Univ Iowa, Dept Urol, Iowa City, IA 52242 USA. [Afari, Niloofar] Univ Calif San Diego, VA Ctr Excellence Stress & Mental Hlth, San Diego, CA 92103 USA. [Bradley, Catherine S.; Lutgendorf, Susan K.] Univ Iowa, Dept Obstet & Gynecol Urol & Epidemiol, Iowa City, IA USA. [Griffith, James W.] Northwestern Univ, Dept Med Social Sci, Chicago, IL 60611 USA. [Hong, Barry A.] Washington Univ, Sch Med, Dept Psychiat & Med, St Louis, MO USA. [Buchwald, Dedra] Univ Washington, Dept Epidemiol & Med, Seattle, WA 98195 USA. [Mackey, Sean] Stanford Univ, Sch Med, Dept Anesthesiol, Div Pain Med, Palo Alto, CA 94304 USA. [Pontari, Michel A.] Temple Univ, Sch Med, Dept Urol, Philadelphia, PA 19122 USA. [Hanno, Philip] Univ Penn, Perelman Sch Med, Dept Urol, Philadelphia, PA 19104 USA. [Kusek, John W.; Mullins, Chris] NIDDK, NIH, Bethesda, MD USA. [Clemens, J. Quentin] Univ Michigan, Dept Urol, Div Neurourol & Pelv Reconstruct Surg, Ann Arbor, MI 48109 USA. RP Clemens, JQ (reprint author), Univ Michigan, Dept Urol, Div Neurourol & Pelv Reconstruct Surg, Ann Arbor, MI 48109 USA. EM qclemens@med.umich.edu RI Griffith, James/O-2551-2016; OI Griffith, James/0000-0002-4840-8692; Sutcliffe, Siobhan/0000-0002-4613-8107; Ness, Timothy/0000-0002-7908-4459 FU NIH [U01 DK82315, U01 DK82316, U01 DK82325, U01 DK82333, U01 DK82342, U01 DK82344, U01 DK82345, U01 DK82370] FX The MAPP Research Network acknowledges support through NIH grants: U01 DK82315, U01 DK82316, U01 DK82325, U01 DK82333, U01 DK82342, U01 DK82344, U01 DK82345, and U01 DK82370. The NIDDK and MAPP Network investigators wish to thank the Interstitial Cystitis Association (ICA) and the Prostatitis Foundation (PF) for their assistance in study participant recruitment and other network efforts. NR 63 TC 33 Z9 33 U1 3 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2490 J9 BMC UROL JI BMC Urol. PD AUG 1 PY 2014 VL 14 AR 58 DI 10.1186/1471-2490-14-58 PG 17 WC Urology & Nephrology SC Urology & Nephrology GA AM6WD UT WOS:000340005200001 PM 25085119 ER PT J AU Bajo, M Madamba, SG Roberto, M Blednov, YA Sagi, VN Roberts, E Rice, KC Harris, RA Siggins, GR AF Bajo, Michal Madamba, Samuel G. Roberto, Marisa Blednov, Yuri A. Sagi, Vasudeva N. Roberts, Edward Rice, Kenner C. Harris, R. Adron Siggins, George R. TI Innate immune factors modulate ethanol interaction with GABAergic transmission in mouse central amygdala SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Alcohol; LPS; Neuroimmune; Inflammation; Drug abuse; Extended amygdala; Toll-like receptor ID TOLL-LIKE RECEPTORS; ENHANCES INFLAMMATORY MEDIATORS; CONDITIONED TASTE-AVERSION; RAT CENTRAL AMYGDALA; GABA RELEASE; DEPENDENT RATS; LIPID-RAFTS; ALCOHOL DEPENDENCE; SYNAPTIC CURRENTS; EXTENDED AMYGDALA AB Excessive ethanol drinking in rodent models may involve activation of the innate immune system, especially toll-like receptor 4 (TLR4) signaling pathways. We used intracellular recording of evoked GABAergic inhibitory postsynaptic potentials (eIPSPs) in central amygdala (CeA) neurons to examine the role of TLR4 activation by lipopolysaccharide (LPS) and deletion of its adapter protein CD14 in acute ethanol effects on the GABAergic system. Ethanol (44, 66 or 100 mM) and LPS (25 and 50 mu g/ml) both augmented eIPSPs in CeA of wild type (WT) mice. Ethanol (44 mM) decreased paired-pulse facilitation (PPF), suggesting a presynaptic mechanism of action. Acute LPS (25 mu g/ml) had no effect on PPF and significantly increased the mean miniature IPSC amplitude, indicating a postsynaptic mechanism of action. Acute LPS pre-treatment potentiated ethanol (44 mM) effects on eIPSPs in WT mice and restored ethanol's augmenting effects on the eIPSP amplitude in CD14 knockout (CD14 KO) mice. Both the LPS and ethanol (44-66 mM) augmentation of eIPSPs was diminished significantly in most CeA neurons of CD14 KO mice; however, ethanol at the highest concentration tested (100 mM) still increased eIPSP amplitudes. By contrast, ethanol pretreatment occluded LPS augmentation of eIPSPs in WT mice and had no significant effect in CD14 KO mice. Furthermore, (+)-naloxone, a TLR4-MD-2 complex inhibitor, blocked LPS effects on eIPSPs in WT mice and delayed the ethanol-induced potentiation of GABAergic transmission. In CeA neurons of CD14 KO mice, (+)-naloxone alone diminished eIPSPs, and subsequent co-application of 100 mM ethanol restored the eIPSPs to baseline levels. In summary, our results indicate that TLR4 and CD14 signaling play an important role in the acute ethanol effects on GABAergic transmission in the CeA and support the idea that CD14 and TLR4 may be therapeutic targets for treatment of alcohol abuse. (C) 2014 Elsevier Inc. All rights reserved. C1 [Bajo, Michal; Madamba, Samuel G.; Roberto, Marisa] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Sagi, Vasudeva N.; Roberts, Edward] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. [Siggins, George R.] Scripps Res Inst, Dept Mol & Cellular Neurosci, La Jolla, CA 92037 USA. [Blednov, Yuri A.; Harris, R. Adron] Univ Texas Austin, Waggoner Ctr Alcohol & Addict Res, Austin, TX 78712 USA. [Rice, Kenner C.] Natl Inst Drug Abuse, Chem Biol Res Branch, Rockville, MD 20852 USA. [Rice, Kenner C.] NIAAA, Rockville, MD 20852 USA. RP Bajo, M (reprint author), Scripps Res Inst, Comm Neurobiol Addict Disorders, SP30-1150,10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. EM mbajo@scripps.edu; geobob@scripps.edu FU NIH/NIAAA [U01-AA013498, U01-AA013520, U01-AA013517]; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX Support for this study was provided by NIH/NIAAA Grants U01-AA013498, U01-AA013520, and U01-AA013517 (as part of the INIA West consortium). A portion of this work was supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. The authors declare no conflict of interest. (+)-naloxone was provided by Dr. George Koob and synthesized by Drs. Kenner Rice from the NIH/NIAA and Edward Roberts from The Scripps Research Institute. NR 90 TC 16 Z9 16 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 EI 1090-2139 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD AUG PY 2014 VL 40 BP 191 EP 202 DI 10.1016/j.bbi.2014.03.007 PG 12 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA AL9JW UT WOS:000339458400022 PM 24675033 ER PT J AU George, SM Bernstein, L Smith, AW Neuhouser, ML Baumgartner, KB Baumgartner, RN Ballard-Barbash, R AF George, Stephanie M. Bernstein, Leslie Smith, Ashley W. Neuhouser, Marian L. Baumgartner, Kathy B. Baumgartner, Richard N. Ballard-Barbash, Rachel TI Central adiposity after breast cancer diagnosis is related to mortality in the Health, Eating, Activity, and Lifestyle study SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Central obesity; Breast cancer; Mortality; Insulin resistance; Inflammation ID PHYSICAL-ACTIVITY; SURVIVORS; QUESTIONNAIRE; INDEX-2005; OBESITY; WOMEN AB We examined whether waist circumference (WC) and waist-to-hip ratio (WHR) after breast cancer diagnosis are associated with all-cause or breast cancer-specific mortality and explored potential biological pathways mediating these relationships. Our analysis included 621 women diagnosed with local or regional breast cancer who participated in the Health, Eating, Activity, and Lifestyle study. At 30 (+/- 4) months postdiagnosis, trained staff measured participants' waist and hip circumferences and obtained fasting serum samples for biomarker assays for assays of insulin, glucose, C-peptide, insulin growth factor-1 and binding protein-3, C-reactive protein (CRP), and adiponectin. We estimated multivariate hazard ratios (HR) and 95 % confidence intervals (CI) for death over similar to 9.5 years of follow-up. After adjustment for measured body mass index, treatment, comorbidities, race/ethnicity, diet quality, and postdiagnosis physical activity, WC was positively associated with all-cause mortality (HRq4:q1: 2.99, 95 % CI 1.14, 7.86) but its positive association with breast cancer-specific mortality was not statistically significant (HRq4:q1: 2.69, 95 % CI 0.69, 12.01). WHR was positively associated with all-cause mortality (HRq4:q1: 2.10, 95 % CI 1.08, 4.05) and breast cancer-specific mortality (HRq4:q1: 4.02, 95 % CI 1.31, 12.31). After adjustment for homeostatic model assessment (HOMA) score and C-reactive protein, risk estimates were attenuated and not statistically significant. In this diverse breast cancer survivor cohort, postdiagnosis WC and WHR were associated with all-cause mortality. Insulin resistance and inflammation may mediate the effects of central adiposity on mortality among breast cancer patients. C1 [George, Stephanie M.; Smith, Ashley W.; Ballard-Barbash, Rachel] NCI, Appl Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Dept Populat Sci, Duarte, CA 91010 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. [Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Baumgartner, Kathy B.; Baumgartner, Richard N.] Univ Louisville, James Graham Brown Canc Ctr, Dept Epidemiol & Populat Hlth, Louisville, KY 40292 USA. RP George, SM (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. EM Stephanie.george@nih.gov FU National Cancer Institute [N01-CN-75036-20, NO1-CN-05228, NO1-PC-67010]; National Cancer Institute FX We would like to thank Dr. Charles L. Wiggins, Dr. Anne McTiernan, Anita Ambs, HEAL study managers, Todd Gibson of Information Management Systems, and the HEAL study participants. This study was supported by the National Cancer Institute Grants N01-CN-75036-20, NO1-CN-05228, NO1-PC-67010, and, in part, by the Applied Research Program of the National Cancer Institute. NR 36 TC 11 Z9 11 U1 3 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD AUG PY 2014 VL 146 IS 3 BP 647 EP 655 DI 10.1007/s10549-014-3048-x PG 9 WC Oncology SC Oncology GA AM4KV UT WOS:000339824300019 PM 25056184 ER PT J AU Wimberly, H Han, G Pinnaduwage, D Murphy, LC Yang, XR Andrulis, IL Sherman, M Figueroa, J Rimm, DL AF Wimberly, Hallie Han, Gang Pinnaduwage, Dushanthi Murphy, Leigh C. Yang, Xiaohong Rose Andrulis, Irene L. Sherman, Mark Figueroa, Jonine Rimm, David L. TI ER beta splice variant expression in four large cohorts of human breast cancer patient tumors SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Estrogen receptors; Breast cancer prognosis and prediction; Triple-negative breast cancer; Quantitative immunofluorescence; Antibody validation ID ESTROGEN-RECEPTOR-BETA; RANDOMIZED-TRIALS; PROTEIN EXPRESSION; TAMOXIFEN THERAPY; GENE-EXPRESSION; POOR-PROGNOSIS; ALPHA; ISOFORMS; CLONING; CELLS AB Though the role of Estrogen Receptor (ER)alpha in breast cancer has been studied extensively, there is little consensus about the role of alternative ER isoform ER beta in breast cancer biology. ER beta has significant sequence homology to ER alpha but is located on a different chromosome and maintains both overlapping and unique functional attributes. Five variants exist, resulting from alternative splicing of the C-terminal region of ER beta. The relevance of ER beta variants in breast cancer outcomes and response to therapy is difficult to assess because of conflicting reports in the literature, likely due to variable methods used to assess ER beta in patient tumors. Here, we quantitatively assess expression of ER beta splice variants on over 2,000 breast cancer patient samples. Antibodies against ER beta variants were validated for staining specificity in cell lines by siRNA knockdown of ESR2 and staining reproducibility on formalin-fixed paraffin-embedded tissue by quantitative immunofluorescence (QIF) using AQUA technology. We found antibodies against splice variants ER beta 1 and ER beta 5, but not ER beta 2/cx, which were sensitive, specific, and reproducible. QIF staining of validated antibodies showed both ER beta 1 and ER beta 5 QIF scores, which have a normal (bell shaped) distribution on most cohorts assessed, and their expression is significantly associated with each other. Extensive survival analyses show that ER beta 1 is not a prognostic or predictive biomarker for breast cancer. ER beta 5 appears to be a context-dependent marker of worse outcome in HER2-positive and triple-negative patients, suggesting an unknown biological function in the absence of ER alpha. C1 [Wimberly, Hallie; Rimm, David L.] Yale Univ, Dept Pathol, Sch Med, New Haven, CT 06520 USA. [Han, Gang] Yale Univ, Yale Ctr Analyt Sci, Sch Publ Hlth, New Haven, CT 06520 USA. [Pinnaduwage, Dushanthi; Andrulis, Irene L.] Univ Toronto, Dept Mol Genet & Lab Med & Pathobiol, Toronto, ON M5S 1A8, Canada. [Pinnaduwage, Dushanthi] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Murphy, Leigh C.] Univ Manitoba, Dept Biochem & Mol Genet, Winnipeg, MB, Canada. [Yang, Xiaohong Rose] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Sherman, Mark] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Figueroa, Jonine] NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, Bethesda, MD 20892 USA. RP Rimm, DL (reprint author), Yale Univ, Dept Pathol, Sch Med, BML116,310 Cedar St,POB 208023, New Haven, CT 06520 USA. EM david.rimm@yale.edu RI Andrulis, Irene/E-7267-2013 FU Breast Cancer Research Foundation FX The authors of the study thank Pei Chao and Michael Stagner from Information Management Services (Silver Spring, MD) for data management support; the participants, physicians, pathologists, nurses, and interviewers from participating centers in Poland for their efforts during field-work; and Drs. Montserrat Garcia-Closas, Louise Brinton, Jolanta Lissowska, B. Peplonska for their contributions to the PBCS study design. Funding for this study was partially provided by the Breast Cancer Research Foundation. NR 31 TC 12 Z9 14 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD AUG PY 2014 VL 146 IS 3 BP 657 EP 667 DI 10.1007/s10549-014-3050-3 PG 11 WC Oncology SC Oncology GA AM4KV UT WOS:000339824300020 PM 25007965 ER PT J AU Thottassery, JV Sambandam, V Allan, PW Maddry, JA Maxuitenko, YY Tiwari, K Hollingshead, M Parker, WB AF Thottassery, Jaideep V. Sambandam, Vijaya Allan, Paula W. Maddry, Joseph A. Maxuitenko, Yulia Y. Tiwari, Kamal Hollingshead, Melinda Parker, William B. TI Novel DNA methyltransferase-1 (DNMT1) depleting anticancer nucleosides, 4 '-thio-2 '-deoxycytidine and 5-aza-4 '-thio-2 '-deoxycytidine SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE DNMT1; DNA methyltransferase; Decitabine; Azacytidine; Zebularine; Deoxycytidine ID CPG ISLAND; PROTEASOMAL DEGRADATION; HISTONE DEACETYLATION; BREAST-CANCER; METHYLATION; CELLS; INHIBITION; STABILITY; 4'-THIO-BETA-D-ARABINOFURANOSYLCYTOSINE; IDENTIFICATION AB Currently approved DNA hypomethylating nucleosides elicit their effects in part by depleting DNA methyltransferase I (DNMT1). However, their low response rates and adverse effects continue to drive the discovery of newer DNMT1 depleting agents. Herein, we identified two novel 2'-deoxycytidine (dCyd) analogs, 4'-thio-2'-deoxycytidine (T-dCyd) and 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd) that potently deplete DNMT1 in both in vitro and in vivo models of cancer and concomitantly inhibit tumor growth. DNMT1 protein levels in in vitro and in vivo cancer models were determined by Western blotting and antitumor efficacy was evaluated using xenografts. Effects on CpG methylation were evaluated using methylation-specific PCR. T-dCyd metabolism was evaluated using radiolabeled substrate. T-dCyd markedly depleted DNMT1 in CCRF-CEM and KG1a leukemia and NCI-H23 lung carcinoma cell lines, while it was ineffective in the HCT-116 colon or IGROV-1 ovarian tumor lines. On the other hand, aza-T-dCyd potently depleted DNMT1 in all of these lines indicating that dCyd analogs with minor structural dissimilarities induce different DNMT1 turnover mechanisms. Although T-dCyd was deaminated to 4'-thio-2'-deoxyuridine, very little was converted to 4'-thio-thymidine nucleotides, suggesting that inhibition of thymidylate synthase would be minimal with 4'-thio dCyd analogs. Both T-dCyd and aza-T-dCyd also depleted DNMT1 in human tumor xenografts and markedly reduced in vivo tumor growth. Interestingly, the selectivity index of aza-T-dCyd was at least tenfold greater than that of decitabine. Collectively, these data show that 4'-thio modified dCyd analogs, such as T-dCyd or aza-T-dCyd, could be a new source of clinically effective DNMT1 depleting anticancer compounds with less toxicity. C1 [Thottassery, Jaideep V.; Sambandam, Vijaya; Allan, Paula W.; Maddry, Joseph A.; Maxuitenko, Yulia Y.; Tiwari, Kamal; Parker, William B.] So Res Inst, Drug Discovery Div, Birmingham, AL 35205 USA. [Thottassery, Jaideep V.; Parker, William B.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Hollingshead, Melinda] NCI, Biol Testing Branch, Frederick, MD 21701 USA. RP Thottassery, JV (reprint author), So Res Inst, Drug Discovery Div, 2000 Ninth Ave South, Birmingham, AL 35205 USA. EM thottassery@southernresearch.org; parker@southernresearch.org FU NIH [P01 CA34200]; NCI [N01-CO-12400]; ADDA (Alabama Drug Discovery Alliance); UAB Center for Clinical and Translational Science [5UL1 RR025777] FX We thank Dr. Mark Suto for careful review of the manuscript. We also thank Dr. Joel Morris for T-dCyd synthesis and Dr. Robert J. Kinders for providing tumor lysates from T-dCyd-treated mice. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. NCI-Frederick and Southern Research Institute are accredited by AALAC International and follows the Public Health Service Policy for the Care and Use of Laboratory Animals. Animal care was provided in accordance with the procedures outlined in the "Guide for Care and Use of Laboratory Animals" (National Research Council; 2010; National Academy Press; Washington, D. C.). Work described in this report was funded by NIH Grant # P01 CA34200, NCI contract N01-CO-12400, the ADDA (Alabama Drug Discovery Alliance) and the UAB Center for Clinical and Translational Science under 5UL1 RR025777. NR 37 TC 7 Z9 10 U1 0 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD AUG PY 2014 VL 74 IS 2 BP 291 EP 302 DI 10.1007/s00280-014-2503-z PG 12 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA AM4LC UT WOS:000339825000009 PM 24908436 ER PT J AU Harford, TC Yi, HY Grant, BF AF Harford, Thomas C. Yi, Hsiao-ye Grant, Bridget F. TI Associations between childhood abuse and interpersonal aggression and suicide attempt among U.S. adults in a national study SO CHILD ABUSE & NEGLECT LA English DT Article DE Childhood physical abuse; Emotional abuse; Sexual abuse; Interpersonal aggression; Suicide attempt; Violence; Psychiatric disorder; Childhood adversity ID PSYCHIATRIC DIAGNOSTIC MODULES; ENVIRONMENTAL RISK-FACTORS; GENERAL-POPULATION SAMPLE; COMMON MENTAL-DISORDERS; SUBSTANCE USE DISORDERS; ALCOHOL-USE-DISORDER; IV AUDADIS-IV; SEXUAL-ABUSE; VIOLENT BEHAVIOR; EXTERNALIZING PSYCHOPATHOLOGY AB The aim of this study is to examine associations among childhood physical, emotional, or sexual abuse and violence toward self (suicide attempts [SA]) and others (interpersonal aggression [IA]). Data were obtained from the National Epidemiologic Survey on Alcohol and Related Conditions Waves 1 and 2 (n = 34,653). Multinomial logistic regression examined associations between type of childhood abuse and violence categories, adjusting for demographic variables, other childhood adversity, and DSM-IV psychiatric disorders. The prevalence of reported childhood abuse was 4.60% for physical abuse. 7.83% for emotional abuse, and 10.20% for sexual abuse. Approximately 18% of adults reported some form of violent behavior, distributed as follows: IA, 13.37%; SA, 2.64%; and SA with IA, 1.85%. After adjusting for demographic variables, other childhood adversity, and psychiatric disorders, each type of childhood abuse was significantly related to increased risk for each violence category as compared with the no violence category. Furthermore, the odds ratio of childhood physical abuse was significantly higher for SA with IA when compared with IA, and the odds ratio of childhood sexual abuse was significantly higher for SA and SA with IA when compared with IA. Childhood physical, emotional, and sexual abuse is directly related to the risk for violent behaviors to self and others. Both internalizing and externalizing psychiatric disorders impact the association between childhood abuse and violence. The inclusion of suicidal behaviors and interpersonal aggression and internalizing/externalizing psychiatric disorders within an integrated conceptual framework will facilitate more effective interventions for long-lasting effects of child abuse. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Harford, Thomas C.; Yi, Hsiao-ye] CSR Inc, Arlington, VA 22201 USA. [Grant, Bridget F.] NIAAA, Bethesda, MD 20892 USA. RP Yi, HY (reprint author), CSR Inc, Alcohol Epidemiol Data System, 2107 Wilson Blvd,Suite 1000, Arlington, VA 22201 USA. FU Intramural NIH HHS; NIAAA NIH HHS [HHSN267200800023C] NR 54 TC 18 Z9 19 U1 4 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2134 EI 1873-7757 J9 CHILD ABUSE NEGLECT JI Child Abuse Negl. PD AUG PY 2014 VL 38 IS 8 BP 1389 EP 1398 DI 10.1016/j.chiabu.2014.02.011 PG 10 WC Family Studies; Psychology, Social; Social Work SC Family Studies; Psychology; Social Work GA AM4YV UT WOS:000339863000012 PM 24656711 ER PT J AU Shin, DW Cho, J Roter, DL Kim, SY Park, JH Cho, B Eom, HS Chung, JS Yang, HK Park, JH AF Shin, D. W. Cho, J. Roter, D. L. Kim, S. Y. Park, Ji. H. Cho, B. Eom, H. -S. Chung, J. -S. Yang, H. -K. Park, Jo. -H. TI Attitudinal concordance toward uptake and disclosure of genetic testing for cancer susceptibility in patient-family member dyads SO CLINICAL GENETICS LA English DT Review DE cancer; communication; disclosure; family; genetic ID NONPOLYPOSIS COLORECTAL-CANCER; BREAST-CANCER; OVARIAN-CANCER; RISK; COMMUNICATION; INFORMATION; RELATIVES; CONFIDENTIALITY; RESPONSIBILITY; MUTATION AB Decisions for cancer susceptibility genetic testing (CSGT) uptake and dissemination of results occur within the family context. A national survey was performed with 990 patient-family member dyads (participation rate: 76.2%), with paired questionnaires examining attitudes toward CSGT uptake and disclosure of results in response to a hypothetical scenario in which a reliable CSGT was available for the specific cancer a patient was being treated. While most patients and family members responded they would uptake or recommend CSGT if available, concordance between the dyads was poor for both patient's testing (agreement rate 77.5%, weighted kappa = 0.09) and first-degree relatives' testing(agreement rate 78.0%, weighted kappa = 0.09). Most patients (93.2%) and family members (92.9%) indicated that patients should disclose positive CSGT results to family members, with dyadic agreement of 89.1% (kappa = 0.15). However, there were substantial disagreement regarding when disclosure should take place, who should make the disclosure (the patient or the health care professionals), and to whom the results should be disclosed. Patients and family members may hold different attitudes toward CSGT uptake of and disclosure of results within the family. Our findings reinforce the need for a family system approach to incorporate perspectives of patients as well as their family members. C1 [Shin, D. W.; Park, Ji. H.; Cho, B.] Seoul Natl Univ Hosp, Dept Family Med, Seoul 110744, South Korea. [Shin, D. W.; Park, Ji. H.; Cho, B.] Seoul Natl Univ Hosp, Hlth Promot Ctr, Seoul 110744, South Korea. [Shin, D. W.; Cho, B.] Seoul Natl Univ, Canc Hosp, Canc Survivorship Clin, Seoul, South Korea. [Shin, D. W.; Park, Ji. H.; Cho, B.] Seoul Natl Univ, Coll Med, Dept Family Med, Seoul, South Korea. [Shin, D. W.] Seoul Natl Univ, Coll Med, JW Lee Ctr Global Med, Seoul, South Korea. [Cho, J.] Sungkyunkwan Univ, Sch Med, Dept Hlth Sci & Technol, Seoul, South Korea. [Cho, J.] Sungkyunkwan Univ, Samsung Adv Inst Hlth Sci & Technol, Seoul, South Korea. [Cho, J.] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Canc Educ Ctr,Samsung Comprehens Canc Ctr, Seoul, South Korea. [Cho, J.; Roter, D. L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Behav & Soc, Baltimore, MD USA. [Cho, J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Roter, D. L.] Johns Hopkins Univ, Natl Human Genome Res Inst, Baltimore, MD USA. [Yang, H. -K.; Park, Jo. -H.] Natl Canc Ctr, Natl Canc Control Res Inst, Canc Policy Branch, Goyang, South Korea. [Park, Ji. H.] Boston Childrens Hosp, Dept Med, Boston, MA USA. [Park, Ji. H.] Boston Childrens Hosp, Div Hlth Sci & Technol, Boston, MA USA. [Eom, H. -S.] Natl Canc Ctr, Res Inst, Hematol Malignancy branch, Goyang, South Korea. [Chung, J. -S.] Pusan Natl Univ Hosp, Res Inst, Pusan, South Korea. RP Park, JH (reprint author), Natl Canc Ctr, Natl Canc Control Inst, Canc Policy Branch, 323 Ilsan Ro, Goyang Si 410769, Gyeonggi Do, South Korea. EM whitemiso@ncc.re.kr RI Roter, Debra/N-8830-2014 FU National R&D Program for Cancer Control [1210150] FX This work was supported by a grant of the National R&D Program for Cancer Control, No (1210150). The following 10 Korean institutions (regional cancer centers) participated in this study and data collection (in alphabetical order): National Cancer Center (Goyang), Busan Regional Cancer Center, Chungbuk Regional Cancer Center, Daegu-Gyeongbuk Regional Cancer Center, Daejeon Regional Cancer Center, Gangwon Regional Cancer Center, Gyeongnam Regional Cancer Center, Jeju Regional Cancer Center, Jeonbuk Regional Cancer Center, and Jeonnam Regional Cancer Center. NR 46 TC 0 Z9 0 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9163 EI 1399-0004 J9 CLIN GENET JI Clin. Genet. PD AUG PY 2014 VL 86 IS 2 BP 112 EP 120 DI 10.1111/cge.12343 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA AM6FS UT WOS:000339959400002 PM 24400667 ER PT J AU Deyo, RA Dworkin, SF Amtmann, D Andersson, G Borenstein, D Carragee, E Carrino, J Chou, R Cook, K DeLitto, A Goertz, C Khalsa, P Loeser, J Mackey, S Panagis, J Rainville, J Tosteson, T Turk, D Von Korff, M Weiner, DK AF Deyo, Richard A. Dworkin, Samuel F. Amtmann, Dagmar Andersson, Gunnar Borenstein, David Carragee, Eugene Carrino, John Chou, Roger Cook, Karon DeLitto, Anthony Goertz, Christine Khalsa, Partap Loeser, John Mackey, Sean Panagis, James Rainville, James Tosteson, Tor Turk, Dennis Von Korff, Michael Weiner, Debra K. TI Focus Article Report of the NIH Task Force on Research Standards for Chronic Low Back Pain SO CLINICAL JOURNAL OF PAIN LA English DT Article DE low back pain; chronic low back pain; research standards; minimum dataset; NIH Task Force ID CLINICAL-PRACTICE GUIDELINE; DEFINING CHRONIC PAIN; INFORMATION-SYSTEM PROMIS; FUNCTION ITEM BANK; QUALITY-OF-LIFE; PRIMARY-CARE; PROGNOSTIC APPROACH; SCREENING TOOL; START BACK; OUTCOME MEASURES AB Background: Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Methods: The NIH Pain Consortium therefore charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel developed a 3-stage process, each with a 2-day meeting. Results: The panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. Conclusions: The RTF believes these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement. C1 [Deyo, Richard A.; Chou, Roger] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Dworkin, Samuel F.; Amtmann, Dagmar; Loeser, John; Turk, Dennis] Univ Washington, Seattle, WA 98195 USA. [Andersson, Gunnar] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Borenstein, David] George Washington Univ, Washington, DC USA. [Carragee, Eugene; Mackey, Sean] Stanford Univ, Stanford, CA 94305 USA. [Carrino, John] Johns Hopkins Univ, Baltimore, MD USA. [Cook, Karon] Northwestern Univ, Evanston, IL USA. [DeLitto, Anthony; Weiner, Debra K.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [DeLitto, Anthony; Weiner, Debra K.] Univ Pittsburgh, Pittsburgh, PA USA. [Goertz, Christine] Palmer Coll Chiropract, Davenport, IA USA. [Khalsa, Partap] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. [Panagis, James] NIAMSD, Bethesda, MD 20892 USA. [Rainville, James] New England Baptist Hosp, Roxbury Crossing, MA USA. [Tosteson, Tor] Dartmouth Coll, Hanover, NH USA. [Von Korff, Michael] Grp Hlth Res Inst, Seattle, WA USA. RP Deyo, RA (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd,Mail Code FM, Portland, OR 97239 USA. EM deyor@ohsu.edu FU National Center for Complementary and Alternative Medicine; National Institute for Arthritis, Musculoskeletal, and Skin Diseases FX This study was supported by the National Center for Complementary and Alternative Medicine and the National Institute for Arthritis, Musculoskeletal, and Skin Diseases. The authors declare no conflict of interest. NR 124 TC 3 Z9 4 U1 9 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0749-8047 EI 1536-5409 J9 CLIN J PAIN JI Clin. J. Pain PD AUG PY 2014 VL 30 IS 8 BP 701 EP 712 PG 12 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA AM2DI UT WOS:000339658900008 PM 24988192 ER PT J AU Anver, S Roguev, A Zofall, M Krogan, NJ Grewal, SIS Harmer, SL AF Anver, Shajahan Roguev, Assen Zofall, Martin Krogan, Nevan J. Grewal, Shiv I. S. Harmer, Stacey L. TI Yeast X-chromosome-associated protein 5 (Xap5) functions with H2A.Z to suppress aberrant transcripts SO EMBO REPORTS LA English DT Article DE aberrant transcripts; chromatin modification; long terminal repeats; transcriptional repression; transposable elements ID FISSION YEAST; SCHIZOSACCHAROMYCES-POMBE; ANTISENSE TRANSCRIPTION; CHROMATIN; GENOME; RNA; HETEROCHROMATIN; ORGANIZATION; EXPRESSION; COMPLEXES AB Chromatin regulatory proteins affect diverse developmental and environmental response pathways via their influence on nuclear processes such as the regulation of gene expression. Through a genome-wide genetic screen, we implicate a novel protein called X-chromosome-associated protein 5 (Xap5) in chromatin regulation. We show that Xap5 is a chromatin-associated protein acting in a similar manner as the histone variant H2A.Z to suppress expression of antisense and repeat element transcripts throughout the fission yeast genome. Xap5 is highly conserved across eukaryotes, and a plant homolog rescues xap5 mutant yeast. We propose that Xap5 likely functions as a chromatin regulator in diverse organisms. C1 [Anver, Shajahan; Harmer, Stacey L.] Univ Calif Davis, Coll Biol Sci, Dept Plant Biol, Davis, CA 95616 USA. [Roguev, Assen; Krogan, Nevan J.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. [Zofall, Martin; Grewal, Shiv I. S.] NCI, Lab Biochem & Mol Biol, Ctr Canc Res, Bethesda, MD 20892 USA. RP Harmer, SL (reprint author), Univ Calif Davis, Coll Biol Sci, Dept Plant Biol, Davis, CA 95616 USA. EM slharmer@ucdavis.edu FU National Institutes of Health [R01 GM069418] FX We thank Dr. Nicholas R. Rhind (University of Massachusetts) for initial assistance and advice; Dr. Kaz Shiozaki and Dr. Hisashi Tatebe (NAIST, Japan) for the wild-type strain and expert advice; and Dr. Julin Maloof (University of California Davis) for assistance with RNA-seq data analysis. This work was supported by National Institutes of Health Grant R01 GM069418 to SLH. NR 32 TC 3 Z9 3 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1469-221X EI 1469-3178 J9 EMBO REP JI EMBO Rep. PD AUG PY 2014 VL 15 IS 8 BP 894 EP 902 DI 10.15252/embr.201438902 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AM6CC UT WOS:000339947900014 PM 24957674 ER PT J AU Ma, WL Gao, C Bell, EM Druschel, CM Caggana, M Aldous, KM Louis, GMB Kannan, K AF Ma, Wan-Li Gao, Chongjing Bell, Erin M. Druschel, Charlotte M. Caggana, Michele Aldous, Kenneth M. Louis, Germaine M. Buck Kannan, Kurunthachalam TI Analysis of polychlorinated biphenyls and organochlorine pesticides in archived dried blood spots and its application to track temporal trends of environmental chemicals in newborns SO ENVIRONMENTAL RESEARCH LA English DT Article DE PCBs; OCPs; Dried blood spot; Temporal trend; Infants ID PERSISTENT ORGANIC POLLUTANTS; POLYBROMINATED DIPHENYL ETHERS; NUTRITION EXAMINATION SURVEY; TANDEM MASS-SPECTROMETRY; NEW-YORK-STATE; CORD SERUM; SCREENING-PROGRAM; NATIONAL-HEALTH; MATERNAL SERUM; UMBILICAL-CORD AB Dried blood spots (DBS) collected from infants shortly after birth for the newborn screening program (NSP) in the United States are valuable resources for the assessment of exposure to environmental chemicals in newborns. The NSP was debuted as a public health program in the United States in the 1960s; and the DBS samples collected over a period of time can be used in tracking temporal trends in exposure to environmental chemicals by newborns. In this study, polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) were measured in DBS samples collected from newborns in Upstate New York from 1997 to 2011 by gas chromatography high resolution mass spectrometry (GC-HRMS). Twelve PCBs and two OCPs were found in DBS samples at a detection rate above 50% (n=51). The mean whole blood concentration of Sigma PCBs (sum of 12 congeners) over the 15-year period was 1.06 ng/mL, followed by p,p'-DDE (0.421 ng/mL) and HCB (0.065 ng/mL). The measured concentrations of PCBs and p,p'-DDE in infants' blood were comparable to those reported in cord blood, suggesting maternal/transplacental transfer of these compounds from mothers to fetuses. The concentrations of Sigma PCBs and p,p'-DDE in blood samples of infants decreased significantly between 1997 and 2001, and no significant reduction was found thereafter. This observation is consistent with the trends reported for these chemicals in other human tissues in the United States. (C) 2014 Elsevier Inc. All rights reserved. C1 [Ma, Wan-Li; Gao, Chongjing; Caggana, Michele; Aldous, Kenneth M.; Kannan, Kurunthachalam] SUNY Albany, New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12201 USA. [Ma, Wan-Li; Gao, Chongjing; Caggana, Michele; Aldous, Kenneth M.; Kannan, Kurunthachalam] SUNY Albany, Sch Publ Hlth, Dept Environm Hlth Sci, Albany, NY 12201 USA. [Ma, Wan-Li; Gao, Chongjing; Kannan, Kurunthachalam] Harbin Inst Technol, State Key Lab Urban Water Resource & Environm, Int Joint Res Ctr Persistent Toxic Subst, Harbin 150090, Peoples R China. [Bell, Erin M.] SUNY Albany, Sch Publ Hlth, Dept Environm Hlth Sci, Albany, NY 12201 USA. [Druschel, Charlotte M.] Bur Environm & Occupat Epidemiol, New York State Dept Hlth, Albany, NY 12237 USA. [Druschel, Charlotte M.] SUNY Albany, Sch Publ Hlth, Dept Epidemiol & Biostat, Albany, NY 12201 USA. [Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Kannan, Kurunthachalam] King Abdulaziz Univ, King Fand Med Res Ctr, Expt Biochem Unit, Jeddah 21589, Saudi Arabia. RP Kannan, K (reprint author), SUNY Albany, New York State Dept Hlth, Wadsworth Ctr, POB 509, Albany, NY 12201 USA. EM kkannan@wadsworth.org OI Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HHSN275201200005C, HHSN267200700019C] FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Contracts #HHSN275201200005C and #HHSN267200700019C to New York State Department of Health. NR 36 TC 10 Z9 10 U1 3 U2 26 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD AUG PY 2014 VL 133 BP 204 EP 210 DI 10.1016/j.envres.2014.05.029 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA AM2UI UT WOS:000339705900027 PM 24968082 ER PT J AU Jones, RR Yu, CL Nuckols, JR Cerhan, JR Airola, M Ross, JA Robien, K Ward, MH AF Jones, Rena R. Yu, Chu-Ling Nuckols, John R. Cerhan, James R. Airola, Matthew Ross, Julie A. Robien, Kim Ward, Mary H. TI Farm residence and lymphohematopoietic cancers in the Iowa Women's Health Study SO ENVIRONMENTAL RESEARCH LA English DT Article DE Farm residence; Pesticides; Iowa Women's Health Study; GIS; Land use ID NON-HODGKINS-LYMPHOMA; MALE PESTICIDE APPLICATORS; AGRICULTURAL HEALTH; UNITED-STATES; OCCUPATIONAL-EXPOSURE; OLDER WOMEN; RISK; MORTALITY; COHORT; PROXIMITY AB Background: Cancer incidence in male farmers has been studied extensively; however, less is known about risk among women residing on farms or in agricultural areas, who may be exposed to pesticides by their proximity to crop fields. We extended a previous follow-up of the Iowa Women's Health Study cohort to examine farm residence and the incidence of lymphohematopoietic cancers. Further, we investigated crop acreage within 750 m of residences, which has been associated with higher herbicide levels in Iowa homes. Methods: We analyzed data for a cohort of 37,099 Iowa women aged 55-69 years who reported their residence location (farm, rural (not a farm), town size based on population) at enrollment in 1986. We identified incident lymphohematopoietic cancers (1986-2009) by linkage with the Iowa Cancer Registry. Using a geographic information system, we geocoded addresses and calculated acreage of pasture and row crops within 750 m of homes using the 1992 National Land Cover Database. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) in multivariate analyses of cancer risk in relation to both residence location and crop acreage. Results: As found in an earlier analysis of residence location, risk of acute myeloid leukemia (AML) was higher among women living on farms (HR=2.23, 95%CI: 1.25-3.99) or rural areas (but not on a farm) (HR=1.95, 95%CI: 0.89-4.29) compared with women living in towns of > 10,000 population. We observed no association between farm or rural residence and non-Hodgkin lymphoma (NHL; overall or for major subtypes) or multiple myeloma. In analyses of crop acreage, we observed no association between pasture or row crop acreage within 750 m of homes and risk of leukemia overall or for the AML subtype. Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) risk was nonsignificantly elevated among women with pasture acreage within 750 m of their home (HRs for increasing tertiles=1.8, 1.8 and 1.5) and with row crop acreage within 750 m (HRs for increasing tertiles of acreage=1.4, 1.5 and 1.6) compared to women with no pasture or row crop acreage, respectively. Conclusions: Iowa women living on a farm or in a rural area were at increased risk of developing AML, which was not related to crop acreage near the home. Living near pasture or row crops may confer an increased risk of CLL/SLL regardless of residence location. Further investigation of specific farm-related exposures and these cancers among women living on farms and in agricultural areas is warranted. (C) 2014 Published by Elsevier Inc. C1 [Jones, Rena R.; Yu, Chu-Ling; Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Yu, Chu-Ling] Kaiser Permanente, Mid Atlantic Permanente Res Inst, Rockville, MD USA. [Nuckols, John R.] Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. [Nuckols, John R.] JRN Environm Hlth Sci, North Bethesda, MD USA. [Cerhan, James R.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Airola, Matthew] Westat Corp, Rockville, MD USA. [Ross, Julie A.] Univ Minnesota, Dept Pediat, Div Epidemiol & Clin Res, Minneapolis, MN 55455 USA. [Robien, Kim] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Epidemiol & Biostat, Washington, DC 20052 USA. RP Jones, RR (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Med Ctr Dr,Rm 6E116, Bethesda, MD 20892 USA. OI Cerhan, James/0000-0002-7482-178X FU Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI) [R01-CA39742, K05-CA157439, IR01-CA92674, N02-CP-11015]; NCI Division of Cancer Epidemiology and Genetics; Colorado State University FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI) extramural Grants R01-CA39742, K05-CA157439, IR01-CA92674, and Contract N02-CP-11015. J.R. Nuckols was supported, in part, through an Intergovernmental Personnel Agreement between the NCI Division of Cancer Epidemiology and Genetics and Colorado State University. This study was approved by the Institutional Review Boards of the University of Minnesota and the NCI. Participants' informed consent was implied by their returning the enrollment questionnaire. NR 47 TC 5 Z9 5 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD AUG PY 2014 VL 133 BP 353 EP 361 DI 10.1016/j.envres.2014.05.028 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA AM2UI UT WOS:000339705900046 PM 25038451 ER PT J AU Deziel, NC Rull, RP Colt, JS Reynolds, P Whitehead, TP Gunier, RB Month, SR Taggart, DR Buffler, P Ward, MH Metayer, C AF Deziel, N. C. Rull, R. P. Colt, J. S. Reynolds, P. Whitehead, T. P. Gunier, R. B. Month, S. R. Taggart, D. R. Buffler, P. Ward, M. H. Metayer, C. TI Polycyclic aromatic hydrocarbons in residential dust and risk of childhood acute lymphoblastic leukemia SO ENVIRONMENTAL RESEARCH LA English DT Article DE Polycyclic aromatic hydrocarbons; Childhood leukemia; Dust; Environmental exposures; Environmental epidemiology ID VOLUME SURFACE SAMPLER; IN-HOUSE DUST; CHROMOSOMAL-ABERRATIONS; PARENTAL SMOKING; TRAFFIC DENSITY; CANCER; EXPOSURE; CHILDREN; COLLECTION AB Several polycyclic aromatic hydrocarbons (PAHs) are known or probable human carcinogens. We evaluated the relationship between PAH exposure and risk of childhood acute lymphoblastic leukemia (ALL) using concentrations in residential dust as an exposure indicator. We conducted a population-based case-control study (251 ALL cases, 306 birth-certificate controls) in Northern and Central California from 2001 to 2007. We collected residential dust using a high volume small surface sampler (HVS3) (n=185 cases, 212 controls) or by sampling from participants' household vacuum cleaners (n=66 cases, 94 controls). We evaluated log-transformed concentrations of 9 individual PAHs, the summed PAHs, and the summed PAHs weighted by their carcinogenic potency (the toxic equivalence). We calculated odds ratios (ORs) and 95% confidence intervals (CI) using logistic regression adjusting for demographic characteristics and duration between diagnosis/reference date and dust collection. Among participants with HVS3 dust, risk of ALL was not associated with increasing concentration of any PAHs based on OR per ln (ng/g). Among participants with vacuum dust, we observed positive associations between ALL risk and increasing concentrations of benzo[a]pyrene (OR per In [ng/g]=1.42, 95% CI=0.95, 2.12), dibenzo[a,h]anthracene (OR=1.98, 95% CI=1.11, 3.55), benzo[k]fluoranthene (OR=1.71, 95% CI=0.91, 3.22), indeno[1,2,3-cd]pyrene (OR=1.81, 95% CI=1.04, 3.16), and the toxic equivalence (OR=2.35, 95% CI=1.18, 4.69). The increased ALL risk among participants with vacuum dust suggests that PAH exposure may increase the risk of childhood ALL; however, reasons for the different results based on HVS3 dust samples deserve further study. (C) 2014 Elsevier Inc. All rights reserved. C1 [Deziel, N. C.; Colt, J. S.; Ward, M. H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Rull, R. P.] Univ Nevada, Sch Community Hlth Sci, Reno, NV 89557 USA. [Reynolds, P.] Canc Prevent Inst Calif, Berkeley, CA USA. [Whitehead, T. P.; Gunier, R. B.; Buffler, P.; Metayer, C.] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Month, S. R.] Kaiser Permanente, Oakland, CA USA. [Taggart, D. R.] Kaiser Permanente, Santa Clara, CA USA. RP Deziel, NC (reprint author), Yale Univ, Sch Publ Hlth, 60 Coll St, New Haven, CT 06510 USA. EM nicole.deziel@yale.edu OI Gunier, Robert/0000-0001-5485-9919 FU National Institute of Environmental Health Sciences [R01 ES09137, P42-ES04705]; Intramural Research Program of the National Cancer Institute and the National Institutes of Health [7590-S-04, 7590-S-01]; National Cancer Institute [N02-CP-11015] FX This work was financially supported by the National Institute of Environmental Health Sciences, Grants R01 ES09137 and P42-ES04705; the Intramural Research Program of the National Cancer Institute and the National Institutes of Health (Subcontracts 7590-S-04 and 7590-S-01); and the National Cancer Institute (Contract N02-CP-11015). NR 39 TC 10 Z9 11 U1 5 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD AUG PY 2014 VL 133 BP 388 EP 395 DI 10.1016/j.envres.2014.04.033 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA AM2UI UT WOS:000339705900050 PM 24948546 ER PT J AU Wul, JW Boudreau, DM Park, Y Simonds, NI Freedman, AN AF Wul, Jennifer W. Boudreau, Denise M. Park, Yikyung Simonds, Naoko I. Freedman, Andrew N. TI Commonly used diabetes and cardiovascular medications and cancer recurrence and cancer-specific mortality: a review of the literature SO EXPERT OPINION ON DRUG SAFETY LA English DT Review DE cancer recurrence; cardiovascular disease; diabetes; medications; mortality ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; CONVERTING-ENZYME-INHIBITORS; CALCIUM-CHANNEL BLOCKERS; HMG-COA REDUCTASE; NATIONWIDE PROSPECTIVE COHORT; NEGATIVE BREAST-CANCER; CARCINOMA-CELL-LINE; COLORECTAL-CANCER; PROSTATE-CANCER; ASPIRIN USE AB Introduction: Cancer most commonly arises in the elderly who are often burdened with comorbidities. Medications used for treating these comorbidities may alter cancer prognosis. Understanding the impact of these medications on cancer is important in order to make effective evidence-based decisions about managing comorbidities while improving cancer outcomes. Areas covered: The evidence on diabetes, statins, antihypertensive and anti-inflammatory medications and their association with cancer recurrence and cancer-specific mortality are reviewed. The strengths and limitations of the existing literature, the current state of the field and future directions are discussed. Expert opinion: Metformin and aspirin were associated with a reduced risk of cancer recurrence and cancer-specific mortality. The evidence for statins and antihypertensive medications on cancer survival was inconsistent. There were few studies to suggest that any of the medication classes of interest were associated with negative effects on cancer survival. Methodological shortcomings within observational studies, such as confounding, distinguishing between use of medications pre-cancer versus post-cancer diagnosis/treatment, misclassification of exposures/outcomes, informative censoring and competing risks, must be considered. New observational studies addressing these limitations are essential. Some clinical trials are underway to further investigate the beneficial effects of these drugs and completed trials have confirmed results demonstrated in observational studies. C1 [Wul, Jennifer W.] McGill Univ, Montreal, PQ H3A 1A2, Canada. [Wul, Jennifer W.] McGill Univ, Jewish Gen Hosp, Ctr Clin Epidemiol, Montreal, PQ H3T 1E2, Canada. [Boudreau, Denise M.] Grp Hlth Res Inst, Seattle, WA USA. [Park, Yikyung; Simonds, Naoko I.; Freedman, Andrew N.] Natl Canc Inst, Rockville, MD 20850 USA. RP Freedman, AN (reprint author), Natl Canc Inst, 9609 Med Ctr Dr, Rockville, MD 20850 USA. OI Park, Yikyung/0000-0002-6281-489X NR 155 TC 0 Z9 0 U1 0 U2 14 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1474-0338 EI 1744-764X J9 EXPERT OPIN DRUG SAF JI Expert Opin. Drug Saf. PD AUG PY 2014 VL 13 IS 8 BP 1071 EP 1099 DI 10.1517/14740338.2014.926887 PG 29 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AM4YM UT WOS:000339862100008 ER PT J AU Kumar, A Chen, SH Kadiiska, MB Hong, JS Zielonka, J Kalyanaraman, B Mason, RP AF Kumar, Ashutosh Chen, Shih-Heng Kadiiska, Maria B. Hong, Jau-Shyong Zielonka, Jacek Kalyanaraman, Balaraman Mason, Ronald P. TI Inducible nitric oxide synthase is key to peroxynitrite-mediated, LPS-induced protein radical formation in murine microglial BV2 cells SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Lipopolysaccharide; Nitrone adducts; Protein radical; Peroxynitrite; Microglia; Inducible nitric oxide synthase; Parkinson disease; Free radicals ID LIPOPOLYSACCHARIDE-ACTIVATED MICROGLIA; NADPH OXIDASE; OXIDATIVE STRESS; REACTIVE OXYGEN; TYROSINE NITRATION; KAPPA-B; PARKINSONS-DISEASE; INOS EXPRESSION; MACROPHAGES; GENERATION AB Microglia are the resident immune cells in the brain. Microglial activation is characteristic of several inflammatory and neurodegenerative diseases including Alzheimer's disease, multiple sclerosis, and Parkinson's disease. Though lipopolysaccharide (LPS)-induced microglial activation in models of Parkinson's disease is well documented, the free radical-mediated protein radical formation and its underlying mechanism during LPS-induced microglial activation are not known. Here we have used immuno-spin trapping and RNA interference to investigate the role of inducible nitric oxide synthase (iNOS) in peroxynitrite-mediated protein radical formation in murine microglial BV2 cells treated with LPS. Treatment of BV2 cells with LPS resulted in morphological changes, induction of iNOS, and increased protein radical formation. Pretreatments with FeTPPS (a peroxynitrite decomposition catalyst), L-NAME (total NOS inhibitor), 1400W (iNOS inhibitor), and apocynin significantly attenuated LPS-induced protein radical formation and tyrosine nitration. Results obtained with coumarin-7-boronic acid, a highly specific probe for peroxynitrite detection, correlated with LPS-induced tyrosine nitration, which demonstrated involvement of peroxynitrite in protein radical formation. A similar degree of protection conferred by 1400W and L-NAME led us to conclude that only iNOS, and no other forms of NOS, is involved in LPS-induced peroxynitrite formation. Subsequently, siRNA for iNOS, the iNOS-specific inhibitor 1400W, the NF-kappa B inhibitor PDTC, and the p38 MAPK inhibitor SB202190 was used to inhibit iNOS directly or indirectly. Inhibition of iNOS precisely correlated with decreased protein radical formation in LPS-treated BV2 cells. The time course of protein radical formation also matched the time course of iNOS expression. Taken together, these results prove the role of iNOS in peroxynitrite-mediated protein radical formation in LPS-treated microglial BV2 cells. (C) 2014 Elsevier Inc. All rights reserved. C1 [Kumar, Ashutosh; Kadiiska, Maria B.; Mason, Ronald P.] NIEHS, Free Rad Metab Grp, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Chen, Shih-Heng; Hong, Jau-Shyong] NIEHS, Neuropharmacol Grp, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Zielonka, Jacek; Kalyanaraman, Balaraman] Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA. [Zielonka, Jacek; Kalyanaraman, Balaraman] Med Coll Wisconsin, Free Rad Res Ctr, Milwaukee, WI 53226 USA. RP Kumar, A (reprint author), NIEHS, Free Rad Metab Grp, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM kumara10@niehs.nih.gov RI Zielonka, Jacek/N-9546-2014 OI Zielonka, Jacek/0000-0002-2524-0145 FU Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences FX The authors gratefully acknowledge Dr. Ann Motten, Jean Corbett, and Mary Mason for their valuable help in the preparation of the manuscript. We are very thankful to Dr. Douglas Ganini and Dr. Thomas van't Erve for reviewing the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences. NR 50 TC 24 Z9 24 U1 2 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG PY 2014 VL 73 BP 51 EP 59 DI 10.1016/j.freeradbiomed.2014.04.014 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA AM2QJ UT WOS:000339695600006 PM 24746617 ER PT J AU Shvedova, AA Kisin, ER Murray, AR Mouithys-Mickalad, A Stadler, K Mason, RP Kadiiska, M AF Shvedova, A. A. Kisin, E. R. Murray, A. R. Mouithys-Mickalad, A. Stadler, K. Mason, R. P. Kadiiska, M. TI ESR evidence for in vivo formation of free radicals in tissue of mice exposed to single-walled carbon nanotubes SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Free radicals; Carbon nanotubes; in vivo; Tissues; Oxidative stress; Inflammation ID REACTIVE OXYGEN; OXIDATIVE STRESS; ENERGY-STORAGE; C57BL/6 MICE; LIFE-CYCLE; RAT LUNG; INHALATION; GENERATION; TRANSLOCATION; PARTICLES AB Nanomaterials are being utilized in an increasing variety of manufactured goods. Because of their unique physicochemical, electrical, mechanical, and thermal properties, single-walled carbon nanotubes (SWCNTs) have found numerous applications in the electronics, aerospace, chemical, polymer, and pharmaceutical industries. Previously, we have reported that pharyngeal exposure of C57BL/6 mice to SWCNTs caused dose-dependent formation of granulomatous bronchial interstitial pneumonia, fibrosis, oxidative stress, acute inflammatory/cytokine responses, and a decrease in pulmonary function. In the current study, we used electron spin resonance (ESR) to directly assess whether exposure to respirable SWCNTs caused formation of free radicals in the lungs and in two distant organs, the heart and liver. Here we report that exposure to partially purified SWCNTs (HiPco technique, Carbon Nanotechnologies, Inc., Houston, TX, USA) resulted in the augmentation of oxidative stress as evidenced by ESR detection of alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone spin-trapped carbon-centered lipid-derived radicals recorded shortly after the treatment. This was accompanied by a significant depletion of antioxidants and elevated biomarkers of inflammation presented by recruitment of inflammatory cells and an increase in proinflammatory cytokines in the lungs, as well as development of multifocal granulomatous pneumonia, interstitial fibrosis, and suppressed pulmonary function. Moreover, pulmonary exposure to SWCNTs also caused the formation of carbon-centered lipid-derived radicals in the heart and liver at later time points (day 7 postexposure). Additionally, SWCNTs induced a significant accumulation of oxidatively modified proteins, increase in lipid peroxidation products, depletion of antioxidants, and inflammatory response in both the heart and the liver. Furthermore, the iron chelator deferoxamine noticeably reduced lung inflammation and oxidative stress, indicating an important role for metal-catalyzed species in lung injury caused by SWCNTs. Overall, we provide direct evidence that lipid-derived free radicals are a critical contributor to tissue damage induced by SWCNTs not only in the lungs, but also in distant organs. Published by Elsevier Inc. C1 [Shvedova, A. A.; Kisin, E. R.; Murray, A. R.] NIOSH, Pathol & Physiol Res Branch, HELD, Morgantown, WV 26505 USA. [Shvedova, A. A.; Murray, A. R.] W Virginia Univ, Morgantown, WV 26506 USA. [Mouithys-Mickalad, A.] Univ Liege, B-4000 Liege, Belgium. [Stadler, K.; Mason, R. P.; Kadiiska, M.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Shvedova, AA (reprint author), NIOSH, Pathol & Physiol Res Branch, Hlth Effects Lab Div, 1095 Willowdale Rd, Morgantown, WV 26505 USA. EM ats1@cdc.gov FU NIOSH [OH008282]; NORA [92700Y]; NIH [RO1 HL-070755]; Intramural Program of the NIH, National Institute of Environmental Health Sciences FX This work was supported by NIOSH OH008282, NORA 92700Y, and NIH RO1 HL-070755. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health. Part of the research was supported by the Intramural Program of the NIH, National Institute of Environmental Health Sciences. NR 57 TC 11 Z9 11 U1 2 U2 28 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG PY 2014 VL 73 BP 154 EP 165 DI 10.1016/j.freeradbiomed.2014.05.010 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA AM2QJ UT WOS:000339695600017 PM 24863695 ER PT J AU Donko, A Morand, S Korzeniowska, A Boudreau, HE Zana, M Hunyady, L Geiszt, M Leto, TL AF Donko, Agnes Morand, Stanislas Korzeniowska, Agnieszka Boudreau, Howard E. Zana, Melinda Hunyady, Laszlo Geiszt, Miklos Leto, Thomas L. TI Hypothyroidism-associated missense mutation impairs NADPH oxidase activity and intracellular trafficking of Duox2 SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Duox; Mutation; Hypothyroidism; NADPH oxidase; Free radicals ID HYDROGEN-PEROXIDE PRODUCTION; AIRWAY EPITHELIAL-CELLS; DUAL OXIDASE; CONGENITAL HYPOTHYROIDISM; MATURATION FACTOR; JAPANESE PATIENTS; TH2 CYTOKINES; HOST-DEFENSE; GENE; EXPRESSION AB In the thyroid gland Duox2-derived H2O2 is essential for thyroid hormone biosynthesis. Several patients were identified with partial or severe iodide organification defects caused by mutation in the gene for Duox2 or its maturation factor, DuoxA2. A Duox2-deficient (Duox2(thyd)) mouse model enabled in vivo investigation of its critical function in thyroid tissues, but its roles proposed in host defense or other innate responses in nonthyroid tissues remain less certain. These mice carry a spontaneous DUOX2 missense mutation, a T -> G transversion, in exon 16 that changes the highly conserved valine 674 to glycine and results in severe congenital hypothyroidism. The exact mechanism underlying the effects of the V674G mutation has not been elucidated at the molecular or cellular level. To determine how the V674G mutation leads to congenital hypothyroidism, we introduced the same mutation into human Duox2 or Duox1 cDNAs and expressed them in HEK-293 cells stably expressing the corresponding DuoxA proteins. We found that the valine -> glycine mutant Duox proteins fail to produce H2O2, lose their plasma membrane localization pattern, and are retained within the endoplasmic reticulum. The Duox2 mutant binds to DuoxA2, but appears to be unstable owing to this retention. Immunohistochemical staining of Duox2 in murine salivary gland ducts showed that Duox2 in mutant mice loses its condensed apical plasma membrane localization pattern characteristic of wild-type Duox2 and accumulates in punctate vesicular structures within cells. Our findings demonstrate that changing the highly conserved valine 674 in Duox2 leads to impaired subcellular targeting and reactive oxygen species release required for hormonogenesis, resulting in congenital hypothyroidism. Published by Elsevier Inc. C1 [Donko, Agnes; Morand, Stanislas; Korzeniowska, Agnieszka; Boudreau, Howard E.; Leto, Thomas L.] NIAID, Lab Host Defenses, NIH, Rockville, MD 20852 USA. [Donko, Agnes; Zana, Melinda; Hunyady, Laszlo; Geiszt, Miklos] Semmelweis Univ, Dept Physiol, H-1085 Budapest, Hungary. [Donko, Agnes; Zana, Melinda; Geiszt, Miklos] Semmelweis Univ, Lendulet Peroxidase Enzyme Res Grp, H-1085 Budapest, Hungary. [Donko, Agnes; Zana, Melinda; Geiszt, Miklos] Hungarian Acad Sci, Budapest, Hungary. RP Leto, TL (reprint author), NIAID, Lab Host Defenses, NIH, Rockville, MD 20852 USA. EM tleto@nih.gov FU Hungarian Research Fund [OTKA PD103960, OTKA K106138]; Hungarian Academy of Sciences ("Lendulet" Program); Intramural Research Program of the National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health FX We are grateful to Beata Molnar and Tunde Szosznyak for technical assistance. We thank Dr. Laszlo Szidonya for critically reading the manuscript and Dr. Xavier de Deken for generously providing the anti-Duox antibody. This work was supported by grants from the Hungarian Research Fund (OTKA PD103960, OTKA K106138) and the Hungarian Academy of Sciences ("Lendulet" Program) and funds from the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health. NR 48 TC 3 Z9 3 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG PY 2014 VL 73 BP 190 EP 200 DI 10.1016/j.freeradbiomed.2014.05.006 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA AM2QJ UT WOS:000339695600020 PM 24853759 ER PT J AU Li, JE Ma, WZ Wang, PY Hurley, PJ Bunz, F Hwang, PM AF Li, Jie Ma, Wenzhe Wang, Ping-Yuan Hurley, Paula J. Bunz, Fred Hwang, Paul M. TI Polo-like kinase 2 activates an antioxidant pathway to promote the survival of cells with mitochondrial dysfunction SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Polo-like kinase 2; Antioxidant; Mitochondrial dysfunction; Oxidative stress; GSK3; NRF2; p53; Necrosis; Free radicals ID GLYCOGEN-SYNTHASE KINASE-3-BETA; OXIDATIVE STRESS; STRUCTURAL BASIS; DNA-DAMAGE; P53; PHOSPHORYLATION; SYNUCLEIN; CANCER; OXYGEN; GENE AB We previously reported that Polo-like kinase 2 (PLK2) is highly expressed in cells with defective mitochondrial respiration and is essential for their survival. Although PLK2 has been widely studied as a cell cycle regulator, we have uncovered an antioxidant function for this kinase that activates the GSK3- NRF2 signaling pathway. Here, we report that the expression of PLK2 is responsive to oxidative stress and that PLK2 mediates antioxidant signaling by phosphorylating GSK3, thereby promoting the nuclear translocation of NRF2. We further show that the antioxidant activity of PLK2 is essential for preventing p53-dependent necrotic cell death. Thus, the regulation of redox homeostasis by PLK2 promotes the survival of cells with dysfunctional mitochondria, which may have therapeutic implications for cancer and neurodegenerative diseases. Published by Elsevier Inc. C1 [Li, Jie; Ma, Wenzhe; Wang, Ping-Yuan; Hwang, Paul M.] Natl Heart Lung & Blood Inst, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Ma, Wenzhe] Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Macao, Peoples R China. [Hurley, Paula J.] Johns Hopkins Sch Med, Dept Urol, Baltimore, MD 21287 USA. [Bunz, Fred] Johns Hopkins Sch Med, Radiat Oncol & Mol Radiat Sci, Baltimore, MD 21287 USA. RP Hwang, PM (reprint author), Natl Heart Lung & Blood Inst, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. EM hwangp@mail.nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH FX This research was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH. We thank Jie Zhuang and Xinglu Huang for excellent assistance with confocal microscopy, the NHLBI FACS Core facility, Cory Lago for helpful discussions, and Ju-Gyeong Kang for advice and assistance. NR 41 TC 5 Z9 5 U1 3 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG PY 2014 VL 73 BP 270 EP 277 DI 10.1016/j.freeradbiomed.2014.05.022 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA AM2QJ UT WOS:000339695600027 PM 24887096 ER PT J AU Samuni, Y Wink, DA Krishna, MC Mitchell, JB Goldstein, S AF Samuni, Yuval Wink, David A. Krishna, Murali C. Mitchell, James B. Goldstein, Sara TI Suberoylanilide hydroxamic acid radiosensitizes tumor hypoxic cells in vitro through the oxidation of nitroxyl to nitric oxide SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE SAHA; Valproic acid; Tempol; Pulse radiolysis; HNO; NO; Nitroxide; Kinetics; Free radicals ID HISTONE DEACETYLASE INHIBITOR; VALPROIC ACID; IONIZING-RADIATION; PROSTATE-CANCER; HNO; VORINOSTAT; HYDROXYUREA; OXYGEN; ENHANCEMENT; GENERATION AB The pharmacological effects of hydroxamic acids are partially attributed to their ability to serve as HNO and/or NO donors under oxidative stress. Previously, it was concluded that oxidation of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) by the metmyoglobin/H2O2 reaction system releases NO, which was based on spin trapping of NO and accumulation of nitrite. Reinvestigation of this system demonstrates the accumulation of N2O, which is a marker of HNO formation, at similar rates under normoxia and anoxia. In addition, the yields of nitrite that accumulated in the absence and the presence of 02 did not differ, implying that the. source of nitrite is other than autoxidation of NO. In this system metmyoglobin is instantaneously and continuously converted into compound II, leading to one-electron oxidation of SAHA to its respective transient nitroxide radical. Studies using pulse radiolysis show that one-electron oxidation of SAHA (pK(a) = 9.56 +/- 0.04) yields the respective nitroxide radical (pK(a) = 9.1 +/- 0.2), which under all experimental conditions decomposes bimolecularly to yield HNO. The proposed mechanism suggests that compound I oxidizes SAHA to the respective nitroxide radical, which decomposes bimolecularly in competition with its oxidation by compound II to form HNO. Compound II also oxidizes HNO to NO and NO to nitrite. Given that NO, but not HNO, is an efficient hypoxic cell radiosensitizer, we hypothesized that under an oxidizing environment SAHA might act as a NO donor and radiosensitize hypoxic cells. Preincubation of A549 and HT29 cells with 2.5 mu M SAHA for 24 h resulted in a sensitizer enhancement ratio at 0.01 survival levels (SER0.01) of 1.33 and 1.59, respectively. Preincubation of A549 cells with oxidized SAHA had hardly any effect and, with 2 mM valproic acid, which lacks the hydroxamate group, resulted in SER0.01 = 1.17. Preincubation of HT29 cells with SAHA and Tempol, which readily oxidizes HNO to NO, enhanced the radiosensitizing effect of SAHA. Pretreatment with SAHA blocked A549 cells at the G1 stage of the cell cycle and upregulated gamma-H2AX after irradiation. Overall, we conclude that SAHA enhances tumor radioresponse by multiple mechanisms that might also involve its ability to serve as a NO donor under oxidizing environments. (C) 2014 Elsevier Inc. All rights reserved. C1 [Samuni, Yuval] Deakin Univ, Sch Med, IMPACT Strateg Res Ctr, Geelong, Vic 3220, Australia. [Samuni, Yuval] Barzilai Govt Hosp, Dept Oral & Maxillofacial Surg, IL-78278 Ashqelon, Israel. [Wink, David A.; Krishna, Murali C.; Mitchell, James B.] Natl Canc Inst, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Goldstein, Sara] Hebrew Univ Jerusalem, Inst Chem, Accelerator Lab, IL-91904 Jerusalem, Israel. RP Goldstein, S (reprint author), Hebrew Univ Jerusalem, Inst Chem, Accelerator Lab, IL-91904 Jerusalem, Israel. EM sara.goldstein1@mail.huji.ac.il FU Israel Science Foundation FX This work has been supported by the Israel Science Foundation. NR 43 TC 6 Z9 6 U1 1 U2 21 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG PY 2014 VL 73 BP 291 EP 298 DI 10.1016/j.freeradbiomed.2014.05.019 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA AM2QJ UT WOS:000339695600029 PM 24880052 ER PT J AU Manolio, TA Murray, MF AF Manolio, Teri A. Murray, Michael F. CA Intersoc Coordinating Comm Practi TI The growing role of professional societies in educating clinicians in genomics SO GENETICS IN MEDICINE LA English DT Editorial Material ID PHYSICIANS C1 [Manolio, Teri A.] NHGRI, Div Genom Med, Bethesda, MD 20892 USA. [Murray, Michael F.] Geisinger Med Ctr, Genom Med Inst, Danville, PA 17822 USA. RP Manolio, TA (reprint author), NHGRI, Div Genom Med, Bethesda, MD 20892 USA. EM manolio@nih.gov NR 10 TC 15 Z9 15 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD AUG PY 2014 VL 16 IS 8 BP 571 EP 572 DI 10.1038/gim.2014.6 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA AM7DI UT WOS:000340024500001 PM 24503779 ER PT J AU Wang, YJ Abu-Asab, MS Shen, DF Zhuang, ZP Chew, EY Chan, CC AF Wang, Yujuan Abu-Asab, Mones S. Shen, Defen Zhuang, Zhengping Chew, Emily Y. Chan, Chi-Chao TI Upregulation of hypoxia-inducible factors and autophagy in von Hippel-Lindau-associated retinal hemangioblastoma SO GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY LA English DT Article DE von Hippel-Lindau; Retina; Hemangioblastoma; Hypoxia-inducible factors; Autophagy; Inflammation ID RENAL-CELL CARCINOMA; ANTI-VEGF THERAPY; DISEASE; CANCER; INFILTRATION; INFLAMMATION; HIF-2-ALPHA; HIF-1-ALPHA; EXPRESSION; PHENOTYPE AB To describe pathological and molecular changes of three patients with clinically severe von Hippel-Lindau (VHL)-associated retinal hemangioblastoma (RH) with rapid progression. Medical records, ocular histopathology, and transmission electron microscopy from three cases of VHL-associated RHs at the National Eye Institute were retrospectively reviewed. One eye of each patient was enucleated. Hypoxia-inducible factor (HIF) 1 alpha and HIF2 alpha expressions were identified by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry. All three cases had rapidly growing RHs that were resistant to multiple conventional therapies and two (patients 1 and 2) were also resistant to multiple intravitreal anti-vascular endothelial growth factor (VEGF) treatments. Macroscopically, all the enucleated eyes had multiple RHs, serous retinal detachment, severe retinal disorganization and focal hemorrhages. Histopathology showed typical RHs composed of vacuolated foamy VHL cells and capillary networks. Retinal gliosis and hemorrhages were also presented. Additionally, T lymphocytes and macrophages infiltrated in the tumors of two patients resistant to anti-VEGF therapy. Immunohistochemistry, and qRT-PCR found upregulation of HIF1 alpha in the retinal lesions of all eyes. Importantly, upregulation of HIF2 alpha was exclusively detected in the two cases with inflammatory infiltration and resistance to anti-VEGF therapy. Ultrastructural images showed autophagy, lipid droplets, glycogen aggregations, and cytoplasmic degeneration in many VHL cells. Based on the histopathological and molecular pathological findings, autophagy, inflammation, and/or upregulation of HIF2 alpha could potentially contribute to the aggressive course of RHs, resulting in the resistance to multiple anti-VEGF and radiation therapies in these patients. C1 [Wang, Yujuan; Shen, Defen; Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Wang, Yujuan] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou 510060, Guangdong, Peoples R China. [Abu-Asab, Mones S.; Chan, Chi-Chao] NEI, Histopathol Core, NIH, Bethesda, MD 20892 USA. [Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Chan, CC (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, 10 Ctr Dr,10-10N103, Bethesda, MD 20892 USA. EM yujuanwang2013@gmail.com; mones@nei.nih.gov; shend@nei.nih.gov; zhuangp@ninds.nih.gov; echew@nei.nih.gov; chanc@nei.nih.gov RI wang, yujuan/C-8428-2016 FU National Eye Institute Intramural Research Program FX The National Eye Institute Intramural Research Program supported the study. NR 40 TC 2 Z9 2 U1 0 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0721-832X EI 1435-702X J9 GRAEF ARCH CLIN EXP JI Graefes Arch. Clin. Exp. Ophthalmol. PD AUG PY 2014 VL 252 IS 8 BP 1319 EP 1327 DI 10.1007/s00417-014-2660-0 PG 9 WC Ophthalmology SC Ophthalmology GA AM4MX UT WOS:000339829900019 PM 24859386 ER PT J AU Roukos, V Misteli, T AF Roukos, Vassilis Misteli, Tom TI Deep Imaging: the next frontier in microscopy SO HISTOCHEMISTRY AND CELL BIOLOGY LA English DT Review DE High-throughput imaging; Deep Imaging; High-content screening ID RECURRENT CHROMOSOMAL TRANSLOCATIONS; HUMAN GENOME; CELLS; ORGANIZATION; REPAIR; LOCALIZATION; PROTEINS; DYNAMICS; SITES AB The microscope is the quintessential tool for discovery in cell biology. From its earliest incarnation as a tool to make the unseen visible, microscopes have been at the center of most revolutionizing developments in cell biology, histology and pathology. Major quantum leaps in imaging involved the dramatic improvements in resolution to see increasingly smaller structures, methods to visualize specific molecules inside of cells and tissues, and the ability to peer into living cells to study dynamics of molecules and cellular structures. The latest revolution in microscopy is Deep Imaging-the ability to look at very large numbers of samples by high-throughput microscopy at high spatial and temporal resolution. This approach is rooted in the development of fully automated high-resolution microscopes and the application of advanced computational image analysis and mining methods. Deep Imaging is enabling two novel, powerful approaches in cell biology: the ability to image thousands of samples with high optical precision allows every discernible morphological pattern to be used as a read-out in large-scale imaging-based screens, particularly in conjunction with RNAi-based screening technology; in addition, the capacity to capture large numbers of images, combined with advanced computational image analysis methods, has also opened the door to detect and analyze very rare cellular events. These two applications of Deep Imaging are revolutionizing cell biology. C1 [Roukos, Vassilis; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov RI Roukos, Vassilis/K-6248-2012 FU National Institutes of Health (NIH), NCI, Center for Cancer Research FX We thank Gianluca Pegoraro and Sigal Shachar for Fig. 1. Work in the Misteli laboratory is supported by the Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research. NR 32 TC 3 Z9 3 U1 4 U2 27 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0948-6143 EI 1432-119X J9 HISTOCHEM CELL BIOL JI Histochem. Cell Biol. PD AUG PY 2014 VL 142 IS 2 BP 125 EP 131 DI 10.1007/s00418-014-1239-5 PG 7 WC Cell Biology; Microscopy SC Cell Biology; Microscopy GA AM6HA UT WOS:000339963300001 PM 24989801 ER PT J AU Ellis, J Lange, EM Li, J Dupuis, J Baumert, J Walston, JD Keating, BJ Durda, P Fox, ER Palmer, CD Meng, YA Young, T Farlow, DN Schnabel, RB Marzi, CS Larkin, E Martin, LW Bis, JC Auer, P Ramachandran, VS Gabriel, SB Willis, MS Pankow, JS Papanicolaou, GJ Rotter, JI Ballantyne, CM Gross, MD Lettre, G Wilson, JG Peters, U Koenig, W Tracy, RP Redline, S Reiner, AP Benjamin, EJ Lange, LA AF Ellis, Jaclyn Lange, Ethan M. Li, Jin Dupuis, Josee Baumert, Jens Walston, Jeremy D. Keating, Brendan J. Durda, Peter Fox, Ervin R. Palmer, Cameron D. Meng, Yan A. Young, Taylor Farlow, Deborah N. Schnabel, Renate B. Marzi, Carola S. Larkin, Emma Martin, Lisa W. Bis, Joshua C. Auer, Paul Ramachandran, Vasan S. Gabriel, Stacey B. Willis, Monte S. Pankow, James S. Papanicolaou, George J. Rotter, Jerome I. Ballantyne, Christie M. Gross, Myron D. Lettre, Guillaume Wilson, James G. Peters, Ulrike Koenig, Wolfgang Tracy, Russell P. Redline, Susan Reiner, Alex P. Benjamin, Emelia J. Lange, Leslie A. TI Large multiethnic Candidate Gene Study for C-reactive protein levels: identification of a novel association at CD36 in African Americans SO HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; QUANTITATIVE TRAIT LOCI; INSULIN-RESISTANCE; METABOLIC SYNDROME; MOLECULAR CLOCK; BLOOD-PRESSURE; HEART-DISEASE; LINKAGE SCAN; RISK-FACTORS; POPULATION AB C-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Large-scale genetic association studies for CRP have largely focused on individuals of European descent. We sought to uncover novel genetic variants for CRP in a multiethnic sample using the ITMAT Broad-CARe (IBC) array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate CVD genes. We performed analyses on 7,570 African Americans (AA) from the Candidate gene Association Resource (CARe) study and race-combined meta-analyses that included 29,939 additional individuals of European descent from CARe, the Women's Health Initiative (WHI) and KORA studies. We observed array-wide significance (p < 2.2 x 10(-6)) for four loci in AA, three of which have been reported previously in individuals of European descent (IL6R, p = 2.0 x 10(-6); CRP, p = 4.2 x 10(-71); APOE, p = 1.6 x 10(-6)). The fourth significant locus, CD36 (p = 1.6 x 10(-6)), was observed at a functional variant (rs3211938) that is extremely rare in individuals of European descent. We replicated the CD36 finding (p = 1.8 x 10(-5)) in an independent sample of 8,041 AA women from WHI; a meta-analysis combining the CARe and WHI AA results at rs3211938 reached genome-wide significance (p = 1.5 x 10(-10)). In the race-combined meta-analyses, 13 loci reached significance, including ten (CRP, TOMM40/APOE/APOC1, HNF1A, LEPR, GCKR, IL6R, IL1RN, NLRP3, HNF4A and BAZ1B/BCL7B) previously associated with CRP, and one (ARNTL) previously reported to be nominally associated with CRP. Two novel loci were also detected (RPS6KB1, p = 2.0 x 10(-6); CD36, p = 1.4 x 10(-6)). These results highlight both shared and unique genetic risk factors for CRP in AA compared to populations of European descent. C1 [Ellis, Jaclyn; Lange, Ethan M.; Li, Jin; Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Lange, Ethan M.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Dupuis, Josee; Benjamin, Emelia J.] NHLBI, Framingham, MA 01702 USA. [Dupuis, Josee; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA 01702 USA. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Baumert, Jens; Marzi, Carola S.] German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, D-23538 Euherberg, Germany. [Walston, Jeremy D.] Johns Hopkins Univ, Sch Med, Div Geriatr Med & Gerontol, Baltimore, MD 21205 USA. [Keating, Brendan J.] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Durda, Peter; Tracy, Russell P.] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Durda, Peter; Tracy, Russell P.] Univ Vermont, Coll Med, Dept Biochem, Burlington, VT 05405 USA. [Fox, Ervin R.; Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Palmer, Cameron D.; Meng, Yan A.; Young, Taylor; Farlow, Deborah N.; Gabriel, Stacey B.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Palmer, Cameron D.] Childrens Hosp Boston, Div Genet, Boston, MA 02115 USA. [Palmer, Cameron D.] Childrens Hosp Boston, Div Endocrinol, Boston, MA 02115 USA. [Palmer, Cameron D.] Childrens Hosp Boston, Program Genom, Boston, MA 02115 USA. [Schnabel, Renate B.] Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, D-21046 Hamburg, Germany. [Larkin, Emma] Vanderbilt Univ, Med Ctr, Dept Med, Div Allergy Pulm & Crit Care, Nashville, TN 37232 USA. [Martin, Lisa W.] George Washington Sch Med, Div Cardiol, Washington, DC 20037 USA. [Bis, Joshua C.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Bis, Joshua C.] Univ Washington, Dept Med, Seattle, WA 98101 USA. [Auer, Paul] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53206 USA. [Ramachandran, Vasan S.] Boston Univ, Dept Med, Sch Med, Boston, MA 02118 USA. [Willis, Monte S.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Pankow, James S.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Papanicolaou, George J.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Rotter, Jerome I.] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90095 USA. [Rotter, Jerome I.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. [Rotter, Jerome I.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Los Angeles, CA USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Div Genom Outcomes, Los Angeles, CA USA. [Ballantyne, Christie M.] Ctr Dis Control & Prevent, Sect Cardiovasc Res, Baylor Coll Med, Methodist DeBakey Heart Ctr, Houston, TX 77030 USA. [Gross, Myron D.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H3A 2T5, Canada. [Lettre, Guillaume] Univ Montreal, Dept Med, Montreal, PQ H3A 2T5, Canada. [Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-07304 Ulm, Germany. [Redline, Susan] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Redline, Susan] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. RP Lange, LA (reprint author), Univ N Carolina, Dept Genet, 5112 Genet Med Bldg, Chapel Hill, NC 27599 USA. EM leslie_lange@med.unc.edu OI Martin, Lisa Warsinger/0000-0003-4352-0914; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health (NIH)/National Heart Lung and Blood Institute (NHLBI) [HHSN268200625226C]; NHLBI [N01 HC-55015, N01 HC-55016, N01HC-55017, N01 HC-55018, N01 HC-55019, N01 HC-55020, N01 HC-55021, N01-HC-85239, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083]; NINDS; NIA [AG-023629, AG-15928, AG-20098, AG-027058, AG08122, AG033193]; National Institute on Minority Health and Health Disparities [N01 HC-95170, N01 HC-95171, N01 HC-95172]; German Research Center for Environmental Health, Neuherberg, Germany; German Federal Ministry of Education and Research; German National Genome Research Network [01GS0834]; German Research Foundation [TH-784/2-1, TH-784/2-2]; European Foundation; Helmholtz Zentrum Munchen; German Diabetes Center; University of Ulm; Munich Center of Health Sciences as part of the Ludwig Maximilians University innovative; National Heart, Lung, and Blood Institute (NHLBI) [CD36 rs3211938]; NHLBI. [N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HL080295, HHSN268201200036C]; The NHLBI [N01-HC95095, N01-HC48047, N01-HC48048, N01-HC48049, N01-HC48050, N01-HC-25195, R01 NS17950, N01-HC-65226, R01 HL071862, RC2 HL-103010, RC2 HL-102923, RC2 HL-102924, RC2 HL-102925, RC2 HL-102926]; [N01 HC-95159]; [N01-HC-95160]; [N01-HC-95161]; [N01-HC-95162]; [N01-HC-95163]; [N01-HC-95164]; [N01-HC-95165]; [N01-HC-95166]; [N01-HC-95167]; [N01-HC-95168]; [N01-HC-95169]; [RR-024156] FX CARe is supported by contract number HHSN268200625226C from the National Institutes of Health (NIH)/National Heart Lung and Blood Institute (NHLBI). Sources of funding for individual CARe cohorts: Atherosclerosis Risk in Communities (ARIC): NHLBI (N01 HC-55015, N01 HC-55016, N01HC-55017, N01 HC-55018, N01 HC-55019, N01 HC-55020, N01 HC-55021); Cardiovascular Health Study (CHS): NHLBI (N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant HL080295 and contract HHSN268201200036C), with additional support from NINDS and from NIA (AG-023629, AG-15928, AG-20098, and AG-027058); Coronary Artery Risk Development in Young Adults (CARDIA): NHLBI (N01-HC95095 & N01-HC48047, N01-HC48048, N01-HC48049, and N01-HC48050); Framingham Heart Study (FHS): NHLBI (N01-HC-25195 and grant R01 NS17950) with additional support from NIA (AG08122 and AG033193); Jackson Heart Study (JHS): NHLBI and the National Institute on Minority Health and Health Disparities (N01 HC-95170, N01 HC-95171 and N01 HC-95172); MultiEthnic Study of Atherosclerosis (MESA): N01 HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and RR-024156. Funding for CARe genotyping was provided by NHLBI Contract N01-HC-65226. Additional financial support was provided by NHLBI grant R01 HL071862. The MONICA/KORA Augsburg studies were financed by the Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany and supported by grants from the German Federal Ministry of Education and Research. Part of this work was financed by the German National Genome Research Network (project number 01GS0834), by the German Research Foundation (TH-784/2-1 and TH-784/2-2), by the European Foundation for the Study of Diabetes and through additional funds from the Helmholtz Zentrum Munchen, the German Diabetes Center and the University of Ulm. Furthermore, the research was supported within the Munich Center of Health Sciences as part of the Ludwig Maximilians University innovative. The authors wish to thank the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project for providing a reference panel for CD36 rs3211938 imputation. Funding for GO ESP was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO) and RC2 HL-102924 (WHISP). The exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). NR 63 TC 6 Z9 6 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD AUG PY 2014 VL 133 IS 8 BP 985 EP 995 DI 10.1007/s00439-014-1439-z PG 11 WC Genetics & Heredity SC Genetics & Heredity GA AM4FQ UT WOS:000339809200004 PM 24643644 ER PT J AU Lee, JJ Chow, CC AF Lee, James J. Chow, Carson C. TI Conditions for the validity of SNP-based heritability estimation SO HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; COMMON SNPS; MISSING HERITABILITY; POPULATION-STRUCTURE; LARGE PROPORTION; COMPLEX TRAIT; HUMAN HEIGHT; ARCHITECTURE; VARIANTS; EXPLAIN AB The heritability of a trait (h (2)) is the proportion of its population variance caused by genetic differences, and estimates of this parameter are important for interpreting the results of genome-wide association studies (GWAS). In recent years, researchers have adopted a novel method for estimating a lower bound on heritability directly from GWAS data that uses realized genetic similarities between nominally unrelated individuals. The quantity estimated by this method is purported to be the contribution to heritability that could in principle be recovered from association studies employing the given panel of SNPs (). Thus far, the validity of this approach has mostly been tested empirically. Here, we provide a mathematical explication and show that the method should remain a robust means of obtaining under circumstances wider than those under which it has so far been derived. C1 [Lee, James J.] Univ Minnesota Twin Cities, Dept Psychol, Minneapolis, MN 55455 USA. [Lee, James J.] BGI Cognit Genom Lab, Shenzhen 518083, Peoples R China. [Lee, James J.; Chow, Carson C.] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Lee, JJ (reprint author), Univ Minnesota Twin Cities, Dept Psychol, Minneapolis, MN 55455 USA. EM leex2293@umn.edu; carsonc@mail.nih.gov FU NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX We thank Doug Speed and Xiang Zhou for answering our queries. This work was supported by the Intramural Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies, GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. NR 42 TC 9 Z9 9 U1 0 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD AUG PY 2014 VL 133 IS 8 BP 1011 EP 1022 DI 10.1007/s00439-014-1441-5 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA AM4FQ UT WOS:000339809200006 PM 24744256 ER PT J AU Olaniyan, SA Amodu, OK Yindom, LM Conway, DJ Aka, P Bakare, AA Omotade, OO AF Olaniyan, Subulade A. Amodu, Olukemi K. Yindom, Louis-Marie Conway, David J. Aka, Peter Bakare, Adekunle A. Omotade, Olayemi O. TI Killer-cell immunoglobulin-like receptors and falciparum malaria in southwest Nigeria SO HUMAN IMMUNOLOGY LA English DT Article DE KIR genes; Severe malaria; Genotyping; Disease association study; West Africa ID HUMAN NK CELLS; HLA CLASS-I; PLASMODIUM-FALCIPARUM; HETEROZYGOTE ADVANTAGE; INFECTED ERYTHROCYTES; ASSOCIATION ANALYSIS; WEST-AFRICA; KIR; SELECTION; DISEASE AB Killer-cell immunoglobulin-like receptors (KIRs) are a group of natural killer cell receptors (NKRs) that regulate NK-cell-mediated production of interferon gamma (IFN-gamma) in response to infection. These receptors have recently been suggested to influence the severity of clinical Plasmodium falciparum malaria infection. We examined the KIR locus in relation to malaria in children from southwest Nigeria. Sequence specific priming (SSP)-PCR was used to detect the KIR genes. The presence or absence of fifteen different KIR genes was determined in each individual and the proportions compared across 3 clinical groups: asymptomatic malaria, uncomplicated clinical malaria and severe clinical malaria. The genes KIR2DL5, KIR2DS3 and KIR2DS5 were present in a significantly higher proportion of individuals in the asymptomatic control group than in the malaria cases. Furthermore, KIR2DS3 and KIR2DS5 were present in a higher proportion of uncomplicated malaria cases than severe malaria cases. Carriage c-AB2 genotype (which comprises all centromeric KIR genes including KIR2DL5, KIR2DS3 and KIR2DS5) decreases with severity of the disease suggesting that the KIR AB profile might be associated with protection from severe malaria infection in this population in Nigeria. (C) 2014 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. C1 [Olaniyan, Subulade A.; Amodu, Olukemi K.; Omotade, Olayemi O.] Univ Ibadan, Inst Child Hlth, Coll Med, Ibadan, Nigeria. [Yindom, Louis-Marie; Conway, David J.] MRC Labs, Banjul, Gambia. [Conway, David J.] London Sch Hyg & Trop Med, London WC1, England. [Aka, Peter] NIH, Bethesda, MD 20892 USA. [Yindom, Louis-Marie] Univ Oxford, Nuffield Dept Med, Oxford, England. [Bakare, Adekunle A.] Univ Ibadan, Dept Zool, Ibadan, Nigeria. RP Amodu, OK (reprint author), Univ Ibadan, Inst Child Hlth, Coll Med, Ibadan, Nigeria. EM subulade.olaniyan@yahoo.com; amkemi@hotmail.com; louis-marie.yindom@ndm.ox.ac.uk; David.Conway@lshtm.ac.uk; peter.aka@nih.gov; adebakar19@yahoo.com; edjohnade@gmail.com OI Conway, David/0000-0002-8711-3037; Amodu, Olukemi/0000-0003-1477-4229 FU European Community [LSHP-CT-2004-503578]; Seventh Framework Programme [242095] FX We are grateful to all study participants and their parents/guardians. We appreciate all the field and laboratory staff of the malaria pathogenesis unit, Institute Child Health, University of lbadan. We acknowledge Omar janha and Fanta Conteh for their assistance with KIR typing. The research leading to these results has received funding from the European Community under grant agreement LSHP-CT-2004-503578 and Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 242095. NR 38 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0198-8859 EI 1879-1166 J9 HUM IMMUNOL JI Hum. Immunol. PD AUG PY 2014 VL 75 IS 8 BP 816 EP 821 DI 10.1016/j.humimm.2014.06.002 PG 6 WC Immunology SC Immunology GA AM7CN UT WOS:000340022400017 PM 24929143 ER PT J AU Schwandt, A von Gruenigen, VE Wenham, RM Frasure, H Eaton, S Fusco, N Fu, PF Wright, JJ Dowlati, A Waggoner, S AF Schwandt, Anita von Gruenigen, Vivian E. Wenham, Robert M. Frasure, Heidi Eaton, Susan Fusco, Nancy Fu, Pingfu Wright, John J. Dowlati, Afshin Waggoner, Steven TI Randomized phase II trial of sorafenib alone or in combination with carboplatin/paclitaxel in women with recurrent platinum sensitive epithelial ovarian, peritoneal, or fallopian tube cancer SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Sorafenib; Ovarian cancer; Gynecologic malignancies; Chemotherapy; Tyrosine kinase inhibitors (TKI); Molecular targeted agents (MTA) ID SQUAMOUS-CELL CARCINOMAS; CLINICAL-TRIALS; BEVACIZUMAB; THERAPY; KERATOACANTHOMAS; CHEMOTHERAPY; MUTATIONS; TOXICITY; TUMORS; SKIN AB Background/Purpose This study was designed to evaluate the response and toxicity of sorafenib alone or when combined with carboplatin and paclitaxel in patients with platinum-sensitive, recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer (EOC). Methods Patients with recurrent platinum-sensitive EOC with no more than 2 prior courses of chemotherapy were randomized to single-agent sorafenib 400 mg twice daily or combination sorafenib 400 mg bid (days 2-19) with IV carboplatin (AUC 6) and IV paclitaxel 175 mg/m(2) (S+C/T) every 3 weeks. Single agent sorafenib could cross over to combination upon progression. Results Patients were initially randomized to either arm, however, due to poor accrual, sorafenib arm was prematurely closed. A total of 13 patients were evaluable for response to sorafenib and 23 patients were evaluable for response to S+C/T. Objective response rate (RR) was 15 % for patients on sorafenib vs. 61 % for patients on S+C/T (p = 0.014); stable disease was seen in 62 % and 35 %, respectively. Clinical benefit rate (CBR) at 4 months (mos.) was 69 % for S and 65 % for S+C/T. The median progression free survival was 5.6 months on sorafenib vs. 16.8 months on S+C/T (p = 0.012) and there was no significant difference of overall survival between two arms (p = 0.974) with median overall survival 25.6 months under sorafenib vs. 25.9 months on S+C/T. Patients remained on trial for a median of 7.8 cycles on sorafenib and 5.4 cycles on S+C/T. Conclusion Sorafenib, alone or in combination with carboplatin and paclitaxel, has activity in patients with platinum-sensitive EOC. Sorafenib in combination with carboplatin and paclitaxel improved RR and PFS; however, there were increased grade and frequencies of toxicities. C1 [Schwandt, Anita] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [von Gruenigen, Vivian E.] Summa Akron City Hosp, Akron, OH USA. [Wenham, Robert M.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Frasure, Heidi; Eaton, Susan; Fusco, Nancy; Waggoner, Steven] Univ Hosp Case Med Ctr, Dept Obstet & Gynecol, Cleveland, OH 44106 USA. [Frasure, Heidi; Eaton, Susan; Fusco, Nancy; Waggoner, Steven] Case Western Reserve Univ, Sch Med, Dept Reprod Biol, Cleveland, OH 44106 USA. [Fu, Pingfu; Dowlati, Afshin] Case Comprehens Canc Ctr, Cleveland, OH USA. [Wright, John J.] NCI, Canc Therapeut Evaluat Program, Bethesda, MD 20892 USA. [Waggoner, Steven] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Dept Obstet & Gynecol, Cleveland, OH 44106 USA. RP Waggoner, S (reprint author), Univ Hosp Case Med Ctr, Seidman Canc Ctr, Dept Obstet & Gynecol, Mac 7128,11100 Euclid Ave, Cleveland, OH 44106 USA. EM steven.waggoner@uhhospitals.org FU National Institutes of Health [U01-CA62502] FX Supported by grant U01-CA62502 (PI: A. Dowlati) from the National Institutes of Health. NR 27 TC 8 Z9 8 U1 0 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD AUG PY 2014 VL 32 IS 4 BP 729 EP 738 DI 10.1007/s10637-014-0078-5 PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA AM4IS UT WOS:000339817800018 PM 24619298 ER PT J AU Meissner, EG Wu, D Osinusi, A Bon, D Virtaneva, K Sturdevant, D Porcella, S Wang, HH Herrmann, E McHutchison, J Suffredini, AF Polis, M Hewitt, S Prokunina-Olsson, L Masur, H Fauci, AS Kottilil, S AF Meissner, Eric G. Wu, David Osinusi, Anu Bon, Dimitra Virtaneva, Kimmo Sturdevant, Dan Porcella, Steve Wang, Honghui Herrmann, Eva McHutchison, John Suffredini, Anthony F. Polis, Michael Hewitt, Stephen Prokunina-Olsson, Ludmila Masur, Henry Fauci, Anthony S. Kottilil, Shyamasundaran TI Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID HEPATITIS-C VIRUS; INTERFERON-LAMBDA; SPONTANEOUS CLEARANCE; GENETIC-VARIATION; STIMULATED GENES; VIRAL CLEARANCE; GENOTYPE 1; INFECTION; SOFOSBUVIR; RIBAVIRIN AB BACKGROUND. Hepatitis C virus (HCV) infects approximately 170 million people worldwide and may lead to cirrhosis and hepatocellular carcinoma in chronically infected individuals. Treatment is rapidly evolving from IFN-alpha-based therapies to IFN-alpha-free regimens that consist of directly acting antiviral agents (DAAs), which demonstrate improved efficacy and tolerability in clinical trials. Virologic relapse after DAA therapy is a common cause of treatment failure; however, it is not clear why relapse occurs or whether certain individuals are more prone to recurrent viremia. METHODS. We conducted a clinical trial using the DAA sofosbuvir plus ribavirin (SOF/RBV) and performed detailed mRNA expression analysis in liver and peripheral blood from patients who achieved either a sustained virologic response (SVR) or relapsed. RESULTS. On-treatment viral clearance was accompanied by rapid downregulation of IFN-stimulated genes (ISGs) in liver and blood, regardless of treatment outcome. Analysis of paired pretreatment and end of treatment (EOT) liver biopsies from SVR patients showed that viral clearance was accompanied by decreased expression of type II and III IFNs, but unexpectedly increased expression of the type I IFN IFNA2. mRNA expression of ISGs was higher in EOT liver biopsies of patients who achieved SVR than in patients who later relapsed. CONCLUSION. These results suggest that restoration of type I intrahepatic IFN signaling by EOT may facilitate HCV eradication and prevention of relapse upon withdrawal of SOF/RBV. C1 [Meissner, Eric G.; Wu, David; Osinusi, Anu; Polis, Michael; Fauci, Anthony S.; Kottilil, Shyamasundaran] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Osinusi, Anu] Univ Maryland, Sch Med, Div Infect Dis, Inst Human Virol, Baltimore, MD 21201 USA. [Bon, Dimitra; Herrmann, Eva] Goethe Univ Frankfurt, Inst Biostat & Math Modeling, D-60054 Frankfurt, Germany. [Virtaneva, Kimmo; Sturdevant, Dan; Porcella, Steve] NIAID, Genom Unit, Res Technol Sect, Rocky Mt Labs,NIH, Hamilton, MT USA. [Wang, Honghui; Suffredini, Anthony F.; Masur, Henry] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [McHutchison, John] Gilead Sci Inc, Foster City, CA 94404 USA. [Hewitt, Stephen] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Kottilil, S (reprint author), NIAID, NIH, 10 Ctr Dr,Bldg 10 Room 11N204, Bethesda, MD 20892 USA. EM SKottilil@niaid.nih.gov OI Wu, David/0000-0002-9030-3667; Prokunina-Olsson, Ludmila/0000-0002-9622-2091; Hewitt, Stephen/0000-0001-8283-1788 FU Intramural Programs of the National Institute of Allergy and Infectious Diseases, National Institutes of Health Clinical Center; National Cancer Institute; German Research Foundation FX Intramural Programs of the National Institute of Allergy and Infectious Diseases, National Institutes of Health Clinical Center, and National Cancer Institute; German Research Foundation. NR 50 TC 49 Z9 49 U1 0 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 2014 VL 124 IS 8 BP 3352 EP 3363 DI 10.1172/JCI75938 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AM6OH UT WOS:000339984000012 PM 24983321 ER PT J AU Araya, N Sato, T Ando, H Tomaru, U Yoshida, M Coler-Reilly, A Yagishita, N Yamauchi, J Hasegawa, A Kannagi, M Hasegawa, Y Takahashi, K Kunitomo, Y Tanaka, Y Nakajima, T Nishioka, K Utsunomiya, A Jacobson, S Yamano, Y AF Araya, Natsumi Sato, Tomoo Ando, Hitoshi Tomaru, Utano Yoshida, Mari Coler-Reilly, Ariella Yagishita, Naoko Yamauchi, Junji Hasegawa, Atsuhiko Kannagi, Mari Hasegawa, Yasuhiro Takahashi, Katsunori Kunitomo, Yasuo Tanaka, Yuetsu Nakajima, Toshihiro Nishioka, Kusuki Utsunomiya, Atae Jacobson, Steven Yamano, Yoshihisa TI HTLV-1 induces a Th1-like state in CD4(+)CCR4(+) T cells SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID MYELOPATHY/TROPICAL SPASTIC PARAPARESIS; I-ASSOCIATED MYELOPATHY; SCURFY MOUSE MUTANT; LEUKEMIA-VIRUS; NEUROINFLAMMATORY DISEASE; CEREBROSPINAL-FLUID; PROVIRAL LOAD; TAX PROTEIN; EXPRESSION; LYMPHOMA AB Human T-Iymphotropic virus type 1 (HTLV-1) is linked to multiple diseases, including the neuroinflammatory disease HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T cell leukemia/lymphoma. Evidence suggests that HTLV-1, via the viral protein Tax, exploits CD4(+)T cell plasticity and induces transcriptional changes in infected T cells that cause suppressive CD4(+)CD25(+)CCR4(+) Tregs to lose expression of the transcription factor FOXP3 and produce IFN-gamma, thus promoting inflammation. We hypothesized that transformation of HTLV-1 infected CCR4(+)T cells into Th1-like cells plays a key role in the pathogenesis of HAM/TSP. Here, using patient cells and cell lines, we demonstrated that Tax, in cooperation with specificity protein 1 (Sp1), boosts expression of the Th1 master regulator T box transcription factor (T-bet) and consequently promotes production of IFN-gamma. Evaluation of CSF and spinal cord lesions of HAM/TSP patients revealed the presence of abundant CD4(+)CCR4(+)T cells that coexpressed the Th1 marker CXCR3 and produced T-bet and IFN-gamma. Finally, treatment of isolated PBMCs and CNS cells from HAM/TSP patients with an antibody that targets CCR+T cells and induces cytotoxicity in these cells reduced both viral load and IFN-gamma production, which suggests that targeting CCR4(+)T cells may be a viable treatment option for HAM/TSP. C1 [Araya, Natsumi; Sato, Tomoo; Ando, Hitoshi; Coler-Reilly, Ariella; Yagishita, Naoko; Yamauchi, Junji; Takahashi, Katsunori; Kunitomo, Yasuo; Yamano, Yoshihisa] St Marianna Univ, Sch Med, Inst Med Sci, Dept Rare Dis Res, Kawasaki, Kanagawa 2168512, Japan. [Tomaru, Utano] Hokkaido Univ, Grad Sch Med, Dept Pathol, Sapporo, Hokkaido 060, Japan. [Yoshida, Mari] Aichi Med Univ, Inst Med Sci Aging, Nagakute, Aichi, Japan. [Hasegawa, Atsuhiko; Kannagi, Mari] Tokyo Med & Dent Univ, Grad Sch, Dept Immunotherapeut, Tokyo, Japan. [Hasegawa, Atsuhiko] St Marianna Univ, Sch Med, Dept Neurol, Kawasaki, Kanagawa 2168512, Japan. [Tanaka, Yuetsu] Univ Ryukyus, Grad Sch Med, Dept Immunol, Nishihara, Okinawa 90301, Japan. [Nakajima, Toshihiro; Nishioka, Kusuki] Tokyo Med Univ, Inst Med Sci, Tokyo 1608402, Japan. [Nakajima, Toshihiro] Tokyo Med Univ, Clin Res Ctr, Tokyo 1608402, Japan. [Utsunomiya, Atae] Imamura Bun In Hosp, Dept Hematol, Kagoshima, Japan. [Jacobson, Steven] NIH, Viral Immunol Sect, Neuroimmunol Branch, Bethesda, MD 20892 USA. RP Yamano, Y (reprint author), St Marianna Univ, Sch Med, Inst Med Sci, Dept Rare Dis Res,Miyamae Ku, 2-16-1 Sugao, Kawasaki, Kanagawa 2168512, Japan. EM yyamano@marianna-u.ac.jp FU JSPS KAKENHI [24790898, 25461294, 25461293]; Takeda Science Foundation; Daiichi Sankyo Foundation of Life Science FX The authors acknowledge the excellent technical assistance provided by Yumiko Hasegawa, M. Koike, Y. Suzuki-Ishikura, and Y. Saito. This work was partly supported by project "Research on Measures for Intractable Disease"; by a matching fund subsidy from the Ministry of Health Labour and Welfare; by JSPS KAKENHI grant nos. 24790898, 25461294, and 25461293; by the Takeda Science Foundation; and by the Daiichi Sankyo Foundation of Life Science. NR 61 TC 15 Z9 16 U1 0 U2 4 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 2014 VL 124 IS 8 BP 3431 EP 3442 DI 10.1172/JCI75250 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AM6OH UT WOS:000339984000018 PM 24960164 ER PT J AU Veerapu, NS Park, SH Tully, DC Allen, TM Rehermann, B AF Veerapu, Naga Suresh Park, Su-Hyung Tully, Damien C. Allen, Todd M. Rehermann, Barbara TI Trace amounts of sporadically reappearing HCV RNA can cause infection SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID HEPATITIS-C VIRUS; T-CELL RESPONSES; SUSTAINED VIROLOGICAL RESPONSE; INJECTION-DRUG USERS; IMMUNE-RESPONSES; FOLLOW-UP; INTERFERON; THERAPY; SEROCONVERSION; REEMERGENCE AB Successful hepatitis C virus (HCV) treatment is defined as the absence of viremia 6 months after therapy cessation. We previously reported that trace amounts of HCV RNA, below the sensitivity of the standard clinical assay, can reappear sporadically in treatment responders. Here, we assessed the infectivity of this RNA and infused 3 chimpanzees sequentially at 9-week intervals with plasma or PBMCs from patients who tested positive for trace amounts of HCV RNA more than 6 months after completing pegylated IFN-alpha/ribavirin therapy. A fourth chimpanzee received HCV RNA-negative plasma and PBMCs from healthy blood donors. The 3 experimental chimpanzees, but not the control chimpanzee, generated HCV-specific T cell responses against nonstructural and structural HCV sequences 6-10 weeks after the first infusion of patient plasma and during subsequent infusions. In 1 chimpanzee, T cell responses declined, and this animal developed high-level viremia at week 27. Deep sequencing of HCV demonstrated transmission of a minor HCV variant from the first infusion donor that persisted in the chimpanzee for more than 6 months despite undetectable systemic viremia. Collectively, these results demonstrate that trace amounts of HCV RNA, which appear sporadically in successfully treated patients, can be infectious; furthermore, transmission can be masked in the recipient by an extended eclipse phase prior to establishing high-level viremia. C1 [Veerapu, Naga Suresh; Park, Su-Hyung; Rehermann, Barbara] NIDDK, Immunol Sect, Liver Dis Branch, NIH,DHHS, Bethesda, MD 20892 USA. [Tully, Damien C.; Allen, Todd M.] Ragon Inst MGH MIT & Harvard, Boston, MA USA. RP Rehermann, B (reprint author), NIDDK, Immunol Sect, Liver Dis Branch, NIH, 10 Ctr Dr,Bldg 10,Room 9B16C, Bethesda, MD 20892 USA. EM Rehermann@nih.gov RI Allen, Todd/F-5473-2011; Park, Su-Hyung/N-3514-2014 FU NIDDK, NIH; NIAID [U19-AI082630] FX We thank T.J. Rowell, J. Fontenot, and the staff at New Iberia Research Center for the care of the chimpanzees and technical support; T. Jake Liang, Marc Ghany, and Theo Heller at the Liver Diseases Branch, NIDDK, NIH for patient samples and clinical information; and Colin Ogilvie and Karen Power at the Ragon Institute for technical support with 454 pyrosequencing. This work was supported by the intramural research program of the NIDDK, NIH (to B. Rehermann) and NIAID grant U19-AI082630 (to T.M. Allen). NR 41 TC 8 Z9 8 U1 0 U2 5 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 2014 VL 124 IS 8 BP 3469 EP 3478 DI 10.1172/JC173104 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AM6OH UT WOS:000339984000021 PM 25003189 ER PT J AU Lau, AF Wang, HH Weingarten, RA Drake, SK Suffredini, AF Garfield, MK Chen, Y Gucek, M Youn, JH Stock, F Tso, H DeLeo, J Cimino, JJ Frank, KM Dekker, JP AF Lau, Anna F. Wang, Honghui Weingarten, Rebecca A. Drake, Steven K. Suffredini, Anthony F. Garfield, Mark K. Chen, Yong Gucek, Marjan Youn, Jung-Ho Stock, Frida Tso, Hanna DeLeo, Jim Cimino, James J. Frank, Karen M. Dekker, John P. TI A Rapid Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry-Based Method for Single-Plasmid Tracking in an Outbreak of Carbapenem-Resistant Enterobacteriaceae SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID COMPLETE NUCLEOTIDE-SEQUENCE; NEW-YORK HOSPITALS; KLEBSIELLA-PNEUMONIAE; STAPHYLOCOCCUS-AUREUS; NEW-JERSEY; IDENTIFICATION; STRAINS; PKPQIL; KPC-3; BACTERIA AB Carbapenem-resistant Enterobacteriaceae (CRE) have spread globally and represent a serious and growing threat to public health. Rapid methods for tracking plasmids carrying carbapenemase genes could greatly benefit infection control efforts. Here, we demonstrate that real-time, direct tracking of a single plasmid in a bacterial strain responsible for an outbreak is possible using a commercial matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) system. In this case, we retrospectively tracked the bla(KPC) carbapenemase gene-bearing pKpQIL plasmid responsible for a CRE outbreak that occurred at the NIH Clinical Center in 2011. An similar to 11,109-Da MS peak corresponding to a gene product of the bla(KPC) pKpQIL plasmid was identified and characterized using a combination of proteomics and molecular techniques. This plasmid peak was present in spectra from retrospectively analyzed K. pneumoniae outbreak isolates, concordant with results from whole-genome sequencing, and absent from a diverse control set of bla(KPC)-negative clinical Enterobacteriaceae isolates. Notably, the gene characterized here is located adjacent to the bla(KPC) Tn4401 transposon on the pKpQIL plasmid. Sequence analysis demonstrates the presence of this gene in other bla(KPC) Tn4401-containing plasmids and suggests that this signature MS peak may be useful in tracking other plasmids conferring carbapenem resistance. Plasmid identification using this MALDI-TOF MS method was accomplished in as little as 10 min from isolated colonies and 30 min from positive (spiked) blood cultures, demonstrating the potential clinical utility for real-time plasmid tracking in an outbreak. C1 [Lau, Anna F.; Weingarten, Rebecca A.; Youn, Jung-Ho; Stock, Frida; Frank, Karen M.; Dekker, John P.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Honghui; Drake, Steven K.; Suffredini, Anthony F.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Garfield, Mark K.] NIAID, Res Technol Branch, NIH, Bethesda, MD 20892 USA. [Chen, Yong; Gucek, Marjan] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. [Tso, Hanna; DeLeo, Jim; Cimino, James J.] NIH, Lab Informat Dev, Ctr Clin, Bethesda, MD 20892 USA. RP Dekker, JP (reprint author), NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM john.dekker@nih.gov RI chen, yong/E-2432-2011; OI Cimino, James/0000-0003-4101-1622 FU Intramural Research Program of the National Institutes of Health FX The work was supported by the Intramural Research Program of the National Institutes of Health. NR 45 TC 23 Z9 26 U1 3 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD AUG PY 2014 VL 52 IS 8 BP 2804 EP 2812 DI 10.1128/JCM.00694-14 PG 9 WC Microbiology SC Microbiology GA AM0OF UT WOS:000339544200010 PM 24850353 ER PT J AU Wentzensen, N Follansbee, S Borgonovo, S Tokugawa, D Sahasrabuddhe, VV Chen, J Lorey, TS Gage, JC Fetterman, B Boyle, S Sadorra, M Tang, SD Darragh, TM Castle, PE AF Wentzensen, Nicolas Follansbee, Stephen Borgonovo, Sylvia Tokugawa, Diane Sahasrabuddhe, Vikrant V. Chen, Jie Lorey, Thomas S. Gage, Julia C. Fetterman, Barbara Boyle, Sean Sadorra, Mark Tang, Scott Dahai Darragh, Teresa M. Castle, Philip E. TI Analytic and Clinical Performance of cobas HPV Testing in Anal Specimens from HIV-Positive Men Who Have Sex with Men SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID HUMAN-PAPILLOMAVIRUS; CERVICAL-CANCER; INTRAEPITHELIAL NEOPLASIA; INFECTED MEN; RISK; CYTOLOGY; WOMEN; METAANALYSIS; GUIDELINES; PRECURSORS AB Anal human papillomavirus (HPV) infections are common, and the incidence of anal cancer is high in HIV-infected men who have sex with men (MSM). To evaluate the performance of HPV assays in anal samples, we compared the cobas HPV test (cobas) to the Roche Linear Array HPV genotyping assay (LA) and cytology in HIV-infected MSM. Cytology and cobas and LA HPV testing were conducted for 342 subjects. We calculated agreement between the HPV assays and the clinical performance of HPV testing and HPV genotyping alone and in combination with anal cytology. We observed high agreement between cobas and LA, with cobas more likely than LA to show positive results for HPV16, HPV18, and other carcinogenic types. Specimens testing positive in cobas but not in LA were more likely to be positive for other markers of HPV-related disease compared to those testing negative in both assays, suggesting that at least some of these were true positives for HPV. cobas and LA showed high sensitivities but low specificities for the detection of anal intraepithelial neoplasia grade 2/3 (AIN2/3) in this population (100% sensitivity and 26% specificity for cobas versus 98.4% sensitivity and 28.9% specificity for LA). A combination of anal cytology and HPV genotyping provided the highest accuracy for detecting anal precancer. A higher HPV load was associated with a higher risk of AIN2/3 with HPV16 (P-trend < 0.001), HPV18 (P-trend = 0.07), and other carcinogenic types (P-trend < 0.001). We demonstrate that cobas can be used for HPV detection in anal cytology specimens. Additional tests are necessary to identify men at the highest risk of anal cancer among those infected with high-risk HPV. C1 [Wentzensen, Nicolas; Sahasrabuddhe, Vikrant V.; Chen, Jie; Gage, Julia C.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Follansbee, Stephen; Borgonovo, Sylvia] Kaiser Permanente Med Ctr, San Francisco, CA USA. [Tokugawa, Diane; Lorey, Thomas S.; Fetterman, Barbara] Kaiser Permanente TPMG Reg Lab, Berkeley, CA USA. [Boyle, Sean; Sadorra, Mark; Tang, Scott Dahai] Roche Mol Syst, Pleasanton, CA USA. [Darragh, Teresa M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Castle, Philip E.] Global Canc Initiat, Chestertown, MD USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM wentzenn@mail.nih.gov FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health; Roche; BD; GE Healthcare; Cepheid; Gen-Probe/Hologic; OncoHealth FX This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. Roche Molecular Systems provided the HPV genotyping assays and testing without charge.; P.E.C. is compensated for serving on a Merck data and safety monitoring board for HPV vaccines and has served as a paid consultant to Roche, BD, GE Healthcare, Cepheid, and Gen-Probe/Hologic. T.M.D. has served as a paid consultant to Roche and OncoHealth and has received research supplies for anal cytology from Hologic at no charge. S.B., M.S., and S.D.T. are employees of Roche Molecular Systems. The other authors have no potential conflicts of interests to declare. NR 19 TC 7 Z9 7 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD AUG PY 2014 VL 52 IS 8 BP 2892 EP 2897 DI 10.1128/JCM.03517-13 PG 6 WC Microbiology SC Microbiology GA AM0OF UT WOS:000339544200022 PM 24899025 ER PT J AU van Berkel, A Rao, JU Kusters, B Demir, T Visser, E Mensenkamp, AR van der Laak, JAWM Oosterwijk, E Lenders, JWM Sweep, FCGJ Wevers, RA Hermus, AR Langenhuijsen, JF Kunst, DPM Pacak, K Gotthardt, M Timmers, HJLM AF van Berkel, Anouk Rao, Jyotsna U. Kusters, Benno Demir, Tuna Visser, Eric Mensenkamp, Arjen R. van der Laak, Jeroen A. W. M. Oosterwijk, Egbert Lenders, Jacques W. M. Sweep, Fred C. G. J. Wevers, Ron A. Hermus, Ad R. Langenhuijsen, Johan F. Kunst, Dirk P. M. Pacak, Karel Gotthardt, Martin Timmers, Henri J. L. M. TI Correlation Between In Vivo F-18-FDG PET and Immunohistochemical Markers of Glucose Uptake and Metabolism in Pheochromocytoma and Paraganglioma SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE pheochromocytoma; paraganglioma; succinate dehydrogenase; Warburg effect; F-18-fluorodeoxyglucose positron emission tomography ID POSITRON-EMISSION-TOMOGRAPHY; HYPOXIA-INDUCIBLE FACTORS; FLUORODEOXYGLUCOSE UPTAKE; CELL-LINES; FDG UPTAKE; CANCER; SDHB; HEREDITARY; EXPRESSION; PROFILES AB Pheochromocytomas and paragangliomas (PPGLs) can be localized by F-18-FDG PET. The uptake is particularly high in tumors with an underlying succinate dehydrogenase (SDH) mutation. SDHx-related PPGLs are characterized by compromised oxidative phosphorylation and a pseudohypoxic response, which mediates an increase in aerobic glycolysis, also known as the Warburg effect. The aim of this study was to explore the hypothesis that increased uptake of F-18-FDG in SDHx-related PPGLs is reflective of increased glycolytic activity and is correlated with expression of different proteins involved in glucose uptake and metabolism through the glycolytic pathway. Methods: Twenty-seven PPGLs collected from patients with hereditary mutations in SDHB (n = 2), SDHD (n = 3), RET(n = 5), neurofibromatosis 1 (n = 1), and myc-associated factor X (n = 1) and sporadic patients (n = 15) were investigated. Preoperative F-18-FDG PET/CT studies were analyzed; mean and maximum standardized uptake values (SUVs) in manually drawn regions of interest were calculated. The expression of proteins involved in glucose uptake (glucose transporters types 1 and 3 [GLUT-1 and -3, respectively]), phosphorylation (hexokinases 1, 2, and 3 [HK-1, -2, and -3, respectively]), glycolysis (monocarboxylate transporter type 4 [MCT-4]), and angiogenesis (vascular endothelial growth factor [VEGF], CD34) were examined in paraffin-embedded tumor tissues using immunohistochemical staining with peroxidase-catalyzed polymerization of diaminobenzidine as a read-out. The expression was correlated with corresponding SUVs. Results: Both maximum and mean SUVs for SDHx-related tumors were significantly higher than those for sporadic and other hereditary tumors (P < 0.01). The expression of HK-2 and HK-3 was significantly higher in SDHx-related PPGLs than in sporadic PPGLs (P = 0.022 and 0.025, respectively). The expression of HK-2 and VEGF was significantly higher in SDHx-related PPGLs than in other hereditary PPGLs (P = 0.039 and 0.008, respectively). No statistical differences in the expression were observed for GLUT-1, GLUT-3, and MCT-4. The percentage anti-CD 34 staining and mean vessel perimeter were significantly higher in SDHx-related PPGLs than in sporadic tumors (P = 0.050 and 0.010, respectively). Mean SUVs significantly correlated with the expression of HK-2 (P = 0.027), HK-3 (P = 0.013), VEGF (P = 9.049), and MCT-4 (P = 0.020). Conclusion: The activation of aerobic glycolysis in SDHx-related PPGLs is associated with increased F-18-FDG accumulation due to accelerated glucose phosphorylation by hexokinases rather than increased expression of glucose transporters. C1 [van Berkel, Anouk; Rao, Jyotsna U.; Demir, Tuna; Lenders, Jacques W. M.; Hermus, Ad R.; Timmers, Henri J. L. M.] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6500 HB Nijmegen, Netherlands. [Rao, Jyotsna U.; Demir, Tuna; Sweep, Fred C. G. J.; Wevers, Ron A.] Radboud Univ Nijmegen, Med Ctr, Lab Genet Endocrine & Metab Dis, Dept Lab Med, NL-6500 HB Nijmegen, Netherlands. [Kusters, Benno; van der Laak, Jeroen A. W. M.] Radboud Univ Nijmegen, Med Ctr, Dept Pathol, NL-6500 HB Nijmegen, Netherlands. [Kusters, Benno] Maastricht Univ, Med Ctr, Dept Pathol, Maastricht, Netherlands. [Visser, Eric; Gotthardt, Martin] Radboud Univ Nijmegen, Med Ctr, Dept Nucl Med, NL-6500 HB Nijmegen, Netherlands. [Mensenkamp, Arjen R.] Radboud Univ Nijmegen, Med Ctr, Dept Genet, NL-6500 HB Nijmegen, Netherlands. [Oosterwijk, Egbert; Langenhuijsen, Johan F.] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6500 HB Nijmegen, Netherlands. [Lenders, Jacques W. M.] Univ Hosp Carl Gustav Carus, Dept Med, Dresden, Germany. [Lenders, Jacques W. M.] Univ Hosp Carl Gustav Carus, Inst Clin Chem & Lab Med, Dresden, Germany. [Kunst, Dirk P. M.] Radboud Univ Nijmegen, Med Ctr, Dept Otolaryngol, NL-6500 HB Nijmegen, Netherlands. [Pacak, Karel] NICHD, NIH, Bethesda, MD USA. RP Timmers, HJLM (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, POB 9101, NL-6500 HB Nijmegen, Netherlands. EM Henri.Timmers@radboudumc.nl RI Kusters, B./L-4465-2015; Sweep, C.G.J./H-8096-2014; Langenhuijsen, J.F./L-4472-2015; Lenders, J.W.M./L-4487-2015; Mensenkamp, A.R./L-4520-2015; Visser, Eric/L-4719-2015; Oosterwijk, Egbert/P-5466-2014; Wevers, Ron/H-8116-2014; Hermus, A.R.M.M./H-8043-2014; Gotthardt, M./H-8037-2014; van der Laak, Jeroen/D-3057-2015 OI Visser, Eric/0000-0003-3672-5882; Wevers, Ron/0000-0003-2278-9746; van der Laak, Jeroen/0000-0001-7982-0754 FU European Union [259735] FX The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. Financial support was granted by the European Union Seventh Framework Programme (FP712007-2013) under grant agreement no. 259735 (ENSAT CANCER). No other potential conflict of interest relevant to this article was reported. NR 34 TC 12 Z9 12 U1 0 U2 5 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD AUG PY 2014 VL 55 IS 8 BP 1253 EP 1259 DI 10.2967/jnumed.114.137034 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AM7CM UT WOS:000340022300012 PM 24925884 ER PT J AU Suzuki, A Leland, P Kobayashi, H Choyke, PL Jagoda, EM Inoue, T Joshi, BH Puri, RK AF Suzuki, Akiko Leland, Pamela Kobayashi, Hisataka Choyke, Peter L. Jagoda, Elaine M. Inoue, Tomio Joshi, Bharat H. Puri, Raj K. TI Analysis of Biodistribution of Intracranially Infused Radio labeled Interleukin-13 Receptor-Targeted Immunotoxin IL-13PE by SPECT/CT in an Orthotopic Mouse Model of Human Glioma SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE SPECT; brain tumor; convection-enhanced delivery; biodistribution; IL-13PE; radioiodination ID CONVECTION-ENHANCED DELIVERY; RECURRENT MALIGNANT GLIOMA; GLIOBLASTOMA; THERAPY; CYTOTOXIN; PATIENT; TRIAL AB Interleukin-13 Pseudomonas exotoxin (IL-13PE), a targeted agent for interleukin-13 receptor alpha 2 (IL-13R alpha 2)-expressing tumors, has been administered intracranially by convection-enhanced delivery (CED) for glioma therapy in several clinical trials including a randomized phase 3 clinical trial. However, its intracranial distribution was not optimally evaluated. We investigated the intracranial distribution of radiolabeled IL-13PE after CED in a murine model of glioblastoma multiforme. Methods: IL-13PE was radiolabeled with (NaI)-I-125 and evaluated for its activity in vitro in receptor-positive U251 or -negative T98G human glioma cell lines. Gliomas were grown in nude mice after intracranial implantation with U251 cells, and I-125-IL-13PE was stereotactically administered by bolus or CED for 3 d, followed by micro-SPECT/CT imaging. SPECT images were evaluated quantitatively and compared with histology and autoradiography results. Results: The radioiodination technique resulted in a specific and biologically active I-125-IL-13PE, which bound and was cytotoxic to IL-13R alpha 2-positive but not to IL-13R alpha 2-negative tumor cells. Both the binding and the cytotoxic activities were blocked by a 100-fold excess of IL-13, which indicated the specificity of binding and cytotoxicity. SPECT/CT imaging revealed retention of I-125-IL-13PE administered by CED in U251 tumors and showed significantly higher volumes of distribution and maintained detectable drug levels for a longer period of time than the bolus route. These results were confirmed by autoradiography. Conclusion: IL-13PE can be radioiodinated without the loss of specificity, binding, or cytotoxic activity. Intracranial CEO administration produces a higher volume of distribution for a longer period of time than,the bolus route. Thus, CED of IL-13PE is superior to bolus injection in delivering the drug to the entire tumor. C1 [Suzuki, Akiko; Leland, Pamela; Joshi, Bharat H.; Puri, Raj K.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Kobayashi, Hisataka; Choyke, Peter L.; Jagoda, Elaine M.] NCI, NIH, Bethesda, MD 20892 USA. [Inoue, Tomio] Yokohama City Univ, Dept Radiol, Yokohama, Kanagawa 232, Japan. RP Puri, RK (reprint author), NIH, Div Cellular & Gene Therapy, Ctr Biol Evaluat & Res, Food & Drug Adm, Bldg 29B,Rm 2NN20,29 Lincoln Dr, Bethesda, MD 20892 USA. EM raj.puri@fda.hhs.gov FU Akiko Suzuki to the Research Participation Program at the Center for Biologics Evaluation and Research FX The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. This project was supported by an appointment of Akiko Suzuki to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education. No other potential conflict of interest relevant to this article was reported. NR 18 TC 7 Z9 8 U1 1 U2 9 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD AUG PY 2014 VL 55 IS 8 BP 1323 EP 1329 DI 10.2967/jnumed.114.138404 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AM7CM UT WOS:000340022300023 PM 24947060 ER PT J AU Nansel, TR Lipsky, LM Liu, AY Laffel, LMB Mehta, SN AF Nansel, Tonja R. Lipsky, Leah M. Liu, Aiyi Laffel, Lori M. B. Mehta, Sanjeev N. TI Contextual Factors Are Associated with Diet Quality in Youth with Type 1 Diabetes Mellitus SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE Type 1 diabetes mellitus; Diet; Children; Adolescents; Contextual factors ID CARDIOVASCULAR RISK-FACTORS; PUBLIC-SCHOOL CHILDREN; ENERGY-INTAKE; NUTRITIONAL QUALITY; GLYCEMIC CONTROL; GLUCOSE CONTROL; UNITED-STATES; FOOD-INTAKE; US; ADOLESCENTS AB This study examined differences in diet quality by meal type, location, and time of week in youth with type 1 diabetes mellitus. A sample of youth with type 1 diabetes mellitus (n=252; 48% female) age 8 to 18 years (mean +/- standard deviation=13.2 +/- 2.8 years) with diabetes duration >= 1 year (mean +/- standard deviation=6.3 +/- 3.4 years) completed 3-day diet records. Multilevel linear regression models tested for differences in diet quality indicators by meal type, location, and time of week (weekdays vs weekends). Participants showed greater energy intake and poorer diet quality on weekends relative to weekdays, with lower intake of fruit and vegetables, and higher intake of total and saturated fat. Differences in diet quality were seen across meal types, with higher nutrient density at breakfast and dinner than at lunch and snacks. Participants reported the highest whole-grain and lowest fat intake at breakfast, but higher added sugar than at lunch or dinner. Dinner was characterized by the highest fruit intake, lowest added sugar, and lowest glycemic load, but also the highest sodium intake. The poorest nutrient density and highest added sugar occurred during snacks. Diet quality was poorer for meals consumed away from home than those consumed at home for breakfast, dinner, and snacks. Findings regarding lunch meal location were mixed, with higher nutrient density, lower glycemic load, and less added sugar at home lunches, and lower total fat, saturated fat, and sodium at lunches away from home. Findings indicate impacts of meal type, location, and time of week on diet quality, suggesting targets for nutrition education and behavioral interventions. C1 [Nansel, Tonja R.; Liu, Aiyi; Laffel, Lori M. B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Lipsky, Leah M.] Joslin Diabet Ctr, Pediat Adolescent & Young Adult Sect, Boston, MA 02215 USA. [Mehta, Sanjeev N.] Joslin Diabet Ctr, Sect Genet & Epidemiol, Boston, MA 02215 USA. RP Nansel, TR (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Dept Hlth & Human Serv, 6100 Execut Blvd,Room 7B13R,MSC 7510, Bethesda, MD 20892 USA. EM nanselt@mail.nih.gov OI Nansel, Tonja/0000-0002-8298-7595; Liu, Aiyi/0000-0002-6618-5082; Lipsky, Leah/0000-0003-2645-4388 FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN267200703434C] FX This research was supported by the intramural research program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, contract no. HHSN267200703434C. NR 36 TC 1 Z9 1 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD AUG PY 2014 VL 114 IS 8 BP 1223 EP 1229 DI 10.1016/j.jand.2014.01.012 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AM6YS UT WOS:000340012500011 PM 24651028 ER PT J AU McGrath, LM Yu, DM Marshall, C Davis, LK Thiruvahindrapuram, B Li, BB Cappi, C Gerber, G Wolf, A Schroeder, FA Osiecki, L O'Dushlaine, C Kirby, A Illmann, C Haddad, S Gallagher, P Fagerness, JA Barr, CL Bellodi, L Benarroch, F Bienvenu, OJ Black, DW Bloch, MH Bruun, RD Budman, CL Camarena, B Cath, DC Cavallini, MC Chouinard, S Coric, V Cullen, B Delorme, R Denys, D Derks, EM Dion, Y Rosario, MC Eapen, V Evans, P Falkai, P Fernandez, TV Garrido, H Geller, D Grabe, HJ Grados, MA Greenberg, BD Gross-Tsur, V Gruenblatt, E Heiman, GA Hemmings, SMJ Herrera, LD Hounie, AG Jankovic, J Kennedy, JL King, RA Kurlan, R Lanzagorta, N Leboyer, M Leckman, JF Lennertz, L Lochner, C Lowe, TL Lyon, GJ Macciardi, F Maier, W McCracken, JT McMahon, W Murphy, DL Naarden, AL Neale, BM Nurmi, E Pakstis, AJ Pato, MT Pato, CN Piacentini, J Pittenger, C Pollak, Y Reus, VI Richter, MA Riddle, M Robertson, MM Rosenberg, D Rouleau, GA Ruhrmann, S Sampaio, AS Samuels, J Sandor, P Sheppard, B Singer, HS Smit, JH Stein, DJ Tischrield, JA Vallada, H Veenstra-VanderWeele, J Walitza, S Wang, Y Wendfand, JR Shugart, YY Miguel, EC Nicolini, H Oostra, BA Moessner, R Wagner, M Ruiz-Linares, A Heutink, P Nestadt, G Freimer, N Petryshen, T Posthuma, D Jenike, MA Cox, NJ Hanna, GL Brentani, H Scherer, SW Arnold, PD Stewart, SE Mathews, CA Knowles, JA Cook, EH Pauls, DL Wang, K Scharf, JM AF McGrath, Lauren M. Yu, Dongmei Marshall, Christian Davis, Lea K. Thiruvahindrapuram, Bhooma Li, Bingbin Cappi, Carolina Gerber, Gloria Wolf, Aaron Schroeder, Frederick A. Osiecki, Lisa O'Dushlaine, Colm Kirby, Andrew Illmann, Cornelia Haddad, Stephen Gallagher, Patience Fagerness, Jesen A. Barr, Cathy L. Bellodi, Laura Benarroch, Fortu Bienvenu, O. Joseph Black, Donald W. Bloch, Michael H. Bruun, Ruth D. Budman, Cathy L. Camarena, Beatriz Cath, Danielle C. Cavallini, Maria C. Chouinard, Sylvain Coric, Vladimir Cullen, Bernadette Delorme, Richard Denys, Damiaan Derks, Eske M. Dion, Yves Rosario, Maria C. Eapen, Valsama Evans, Patrick Falkai, Peter Fernandez, Thomas V. Garrido, Helena Geller, Daniel Grabe, Hans J. Grados, Marco A. Greenberg, Benjamin D. Gross-Tsur, Varda Gruenblatt, Edna Heiman, Gary A. Hemmings, Sian M. J. Herrera, Luis D. Hounie, Ana G. Jankovic, Joseph Kennedy, James L. King, Robert A. Kurlan, Roger Lanzagorta, Nuria Leboyer, Marion Leckman, James F. Lennertz, Leonhard Lochner, Christine Lowe, Thomas L. Lyon, Gholson J. Macciardi, Fabio Maier, Wolfgang McCracken, James T. McMahon, William Murphy, Dennis L. Naarden, Allan L. Neale, Benjamin M. Nurmi, Erika Pakstis, Andrew J. Pato, Michele T. Pato, Carlos N. Piacentini, John Pittenger, Christopher Pollak, Yehuda Reus, Victor I. Richter, Margaret A. Riddle, Mark Robertson, Mary M. Rosenberg, David Rouleau, Guy A. Ruhrmann, Stephan Sampaio, Aline S. Samuels, Jack Sandor, Paul Sheppard, Brooke Singer, Harvey S. Smit, Jan H. Stein, Dan J. Tischrield, Jay A. Vallada, Homero Veenstra-VanderWeele, Jeremy Walitza, Susanne Wang, Ying Wendfand, Jens R. Shugart, Yin Yao Miguel, Euripedes C. Nicolini, Humberto Oostra, Ben A. Moessner, Rainald Wagner, Michael Ruiz-Linares, Andres Heutink, Peter Nestadt, Gerald Freimer, Nelson Petryshen, Tracey Posthuma, Danielle Jenike, Michael A. Cox, Nancy J. Hanna, Gregory L. Brentani, Helena Scherer, Stephen W. Arnold, Paul D. Stewart, S. Evelyn Mathews, Carol A. Knowles, James A. Cook, Edwin H. Pauls, David L. Wang, Kai Scharf, Jeremiah M. TI Copy Number Variation in Obsessive-Compulsive Disorder and Tourette Syndrome: A Cross-Disorder Study SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE Tourette syndrome; obsessive-compulsive disorder; copy number variation; genetics; 16p13.11 ID RARE CHROMOSOMAL DELETIONS; GENOME-WIDE ASSOCIATION; DE-NOVO CNVS; DEVELOPMENTAL-DISABILITIES; 16P13.11 PREDISPOSE; VARIANTS; DUPLICATIONS; AUTISM; SCHIZOPHRENIA; GENETICS AB Objective: Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date. Method: The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios. Results: Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p = .09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p = .08 in the current study, p = .025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%). Conclusion: Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes. C1 [Haddad, Stephen; Fagerness, Jesen A.; Petryshen, Tracey] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Stewart, S. Evelyn] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [McGrath, Lauren M.] Amer Univ, Washington, DC 20016 USA. [Scharf, Jeremiah M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [McGrath, Lauren M.; O'Dushlaine, Colm; Neale, Benjamin M.] Harvard Brood Inst, Boston, MA USA. [Marshall, Christian; Barr, Cathy L.] Univ Toronto, Toronto, ON, Canada. [Marshall, Christian; Barr, Cathy L.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Schroeder, Frederick A.; Barr, Cathy L.] Univ Hlth Network, Toronto Western Res Inst, Toronto, ON, Canada. [Kennedy, James L.] Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Davis, Lea K.; Evans, Patrick] Univ Chicago, Chicago, IL 60637 USA. [Vallada, Homero; Miguel, Euripedes C.] Univ Sao Paulo, Med School, BR-05508 Sao Paulo, Brazil. [Bellodi, Laura] Univ Vita Salute Son Raffaele, Milan, Italy. [Benarroch, Fortu] Hadassah Hebrew Univ, Med Ctr, Jerusalem, Israel. [Bienvenu, O. Joseph; Cullen, Bernadette; Grados, Marco A.; Samuels, Jack; Singer, Harvey S.; Nestadt, Gerald] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Black, Donald W.] Univ Iowa, Coll Med, Iowa City, IA USA. [Bloch, Michael H.; Coric, Vladimir; Fernandez, Thomas V.; Leckman, James F.; Pakstis, Andrew J.; Pittenger, Christopher] Yale Univ, Sch Med, New Haven, CT USA. [Bruun, Ruth D.; Budman, Cathy L.] North Shore Long Isl Jewish Med Ctr, New Hyde Pk, NY USA. [Budman, Cathy L.] Hofstra Univ, Sch Med, Hempstead, NY USA. [Bruun, Ruth D.] NYU, Med Ctr, New York, NY 10016 USA. [Camarena, Beatriz] Inst Nacl Psiquiatria Ramon Fuente Muniz, Mexico City, DF, Mexico. [Cath, Danielle C.] Univ Utrecht, Amsterdam, Netherlands. [Cath, Danielle C.] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Smit, Jan H.] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Cavallini, Maria C.] Osped San Raffoe, Milan, Italy. [Chouinard, Sylvain; Dion, Yves] Univ Montreal, Montreal, PQ H3C 3J7, Canada. [Delorme, Richard; Leboyer, Marion] Robert Debre Univ Hosp, Paris, France. [Delorme, Richard; Dion, Yves] French Notional Sci Fdn, Creteil, France. [Delorme, Richard] Inst Pasteur, Paris, France. [Leboyer, Marion] Inst Mondor Rech Biomed, Creteil, France. [Denys, Damiaan] Netherlands Inst Neurosci, Amsterdam, Netherlands. [Denys, Damiaan; Derks, Eske M.] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Sampaio, Aline S.] Univ Fed Sao Paulo, Sao Paulo, Brazil. [Sampaio, Aline S.] Univ Fed Bahia, Salvador, BA, Brazil. [Eapen, Valsama] Univ New S Wales, Sydney, NSW 2052, Australia. [Falkai, Peter] Univ Munich, D-81377 Munich, Germany. [Garrido, Helena] Hosp Nacl Ninos Dr Carlos Saenz Herrera, San Jose, Costa Rica. [Garrido, Helena] Clin Herrera Amighetti, San Jose, Costa Rica. [Grabe, Hans J.] Univ Med Greifswald, Greifswold, Germany. [Greenberg, Benjamin D.] Brown Med Sch, Providence, RI USA. [Gross-Tsur, Varda; Pollak, Yehuda] Shoare Zedek Med Ctr, Jerusalem, Israel. [Gruenblatt, Edna] Univ Zurich, CH-8006 Zurich, Switzerland. [Walitza, Susanne] Univ Wurzburg, Wurzburg, Germany. [Heiman, Gary A.] Rutgers State Univ, Piscataway Township, NJ USA. [Jankovic, Joseph] Baylor Coll Med, Houston, TX 77030 USA. [Kurlan, Roger] Atlant Neurosci Inst, Summit, NJ USA. [Lanzagorta, Nuria] Corracci Med Grp, Mexico City, DF, Mexico. [Lennertz, Leonhard; Maier, Wolfgang; Wagner, Michael] Univ Bonn, Bonn, Germany. [Hemmings, Sian M. J.] Univ Stellenbosch, ZA-7600 Stellenbosch, South Africa. [Lowe, Thomas L.; Sheppard, Brooke] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Lyon, Gholson J.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [McCracken, James T.] Univ Calif Irvine, Irvine, CA USA. [Freimer, Nelson] Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. [Freimer, Nelson] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [McMahon, William] Univ Utah, Salt Lake City, UT USA. [Murphy, Dennis L.; Wendfand, Jens R.] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. [Naarden, Allan L.] Med City Dallas Hosp, Dallas, TX USA. [Pato, Michele T.; Pato, Carlos N.; Wang, Ying] Zilkho Neurogenet Inst, Los Angeles, CA USA. [Richter, Margaret A.] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Robertson, Mary M.] UCL, London, England. [Rosenberg, David] Wayne State Univ, Detroit, MI USA. [Rosenberg, David] Detroit Med Ctr, Detroit, MI USA. [Rouleau, Guy A.] Montreal Neurol Inst, Montreal, PQ, Canada. [Ruhrmann, Stephan] Univ Cologne, Cologne, Germany. [Smit, Jan H.] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Stein, Dan J.] Univ Cape Town, Rondebosch, South Africa. [Veenstra-VanderWeele, Jeremy] Vanderbilt Univ, Nashville, TN 37235 USA. [Oostra, Ben A.] Erasmus MC, Rotterdam, Netherlands. [Heutink, Peter] German Ctr Neurodegenerat Dis, Bonn, Germany. [Heutink, Peter] VU Med Ctr Amsterdam, Amsterdam, Netherlands. [Posthuma, Danielle] VU Amsterdam & Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Hanna, Gregory L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Cook, Edwin H.] Univ Illinois, Chicago, IL USA. RP Scharf, JM (reprint author), Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, 185 Cambridge St, Boston, MA 02114 USA. EM ischarf@partners.org RI Brentani, Helena/G-6839-2011; Fernandez, Thomas/D-4295-2009; Vallada, Homero/D-1333-2014; Stein, Dan/A-1752-2008; Scherer, Stephen /B-3785-2013; Stewart, Evelyn/K-6961-2014; Nurmi, Erika/P-4627-2014; reus, victor/I-7923-2015; Veenstra-VanderWeele, Jeremy/K-1935-2015; Grunblatt, Edna/A-6762-2016; Macciardi, Fabio/N-3768-2014; Wagner, Michael/E-2325-2011; Derks, Eske/A-1652-2017; OI Brentani, Helena/0000-0001-5192-4682; Fernandez, Thomas/0000-0003-0830-022X; Vallada, Homero/0000-0001-5123-8295; Stein, Dan/0000-0001-7218-7810; Scherer, Stephen /0000-0002-8326-1999; Nurmi, Erika/0000-0003-4893-8957; reus, victor/0000-0002-8193-5697; Veenstra-VanderWeele, Jeremy/0000-0002-6349-1076; Grunblatt, Edna/0000-0001-8505-7265; Macciardi, Fabio/0000-0003-0537-4266; Wagner, Michael/0000-0003-2589-6440; Derks, Eske/0000-0002-6292-6883; Walitza, Susanne/0000-0002-8161-8683; Hanna, Gregory/0000-0002-0742-6990; Samuels, Jack/0000-0002-6715-7905; Barr, Cathy/0000-0003-0361-0106; Tischfield, Jay/0000-0003-3217-8287; Hemmings, Sian/0000-0001-8461-1017; Lanzagorta, Nuria/0000-0001-6769-6813; Stewart, S. Evelyn/0000-0002-0994-6383 FU David Judah Fund; Tourette Syndrome Association; International OCD Foundation; National Institutes of Health [TSA International Consortium for Genetics] [U01NS40024, R01NS16648, R01MH079489, MH073250, K23MH085057, T32MH16259, NS037484, P30NS062691, K20MH01065, R01MH58376, R01MH092293]; American Recovery and Re-investment Act (ARRA) awards [NS40024-07S1, NS16648-29S1]; New Jersey Center for Tourette Syndrome and Associated Disorders; German Research Foundation (DFG) [Fa 241/6-1]; Ontario Mental Health Foundation; NIH Genes, Environment and Health Initiative (GEI) [U01 HG004422]; Gene Environment Association Studies (GENEVA) under GEI; NIH GEI [U01HG004438]; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; NIH contract "High throughput genotyping for studying the genetic contributions to human disease" [HHSN268200782096C]; [T32MH018268] FX This work was supported by grants from the David Judah Fund, the Tourette Syndrome Association, the International OCD Foundation, and National Institutes of Health (U01NS40024: [D.L.P./J.M.S/TSA International Consortium for Genetics]; R01NS16648, R01MH079489, and MH073250 [D.L.P.]; K23MH085057 [J.M.S.]; T32MH16259 [L.M.M.]; NS037484 and P30NS062691 [N.B.F.]; K20MH01065 and R01MH58376 (G.L.H.); R01MH092293 [G.A.H./R.A.K./J.A.T.]). Support also came from American Recovery and Re-investment Act (ARRA) awards NS40024-07S1 and NS16648-29S1 (D.L.P.). This work was also supported by grants from the New Jersey Center for Tourette Syndrome and Associated Disorders, the German Research Foundation (Fa 241/6-1; DFG), the Ontario Mental Health Foundation (M.A.R. and J.L.K.), and T32MH018268 (J.F.L.). Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative (GEI; U01 HG004422). SAGE is 1 of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10M008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392), and the Family Study of Cocaine Dependence (FSCD; R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease" (HHSN268200782096C) The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nlh.gov/projects/gap/cgibin/study.cgi?study_id=phs00 0092.vl.pl through dbGaP accession number phs000092.vl p None of the funding agencies for this protect had any influence on the design or conduct of the study; the management, analysis, or interpretation of the data; or the preparation, review, or approval of the manuscript. NR 40 TC 18 Z9 18 U1 5 U2 28 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD AUG PY 2014 VL 53 IS 8 BP 910 EP 919 DI 10.1016/j.jaac.2014.04.022 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA AM5WY UT WOS:000339932900011 PM 25062598 ER PT J AU Xie, XF Colberg-Poley, AM Das, JR Li, JL Zhang, AP Tang, PT Jerebtsova, M Gutkind, JS Ray, PE AF Xie, Xuefang Colberg-Poley, Anamaris M. Das, Jharna R. Li, Jinliang Zhang, Aiping Tang, Pingtao Jerebtsova, Marina Gutkind, J. Silvio Ray, Patricio E. TI The Basic Domain of HIV-Tat Transactivating Protein Is Essential for Its Targeting to Lipid Rafts and Regulating Fibroblast Growth Factor-2 Signaling in Podocytes Isolated from Children with HIV-1-Associated Nephropathy SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEMOLYTIC-UREMIC SYNDROME; MEDIATED GENE-TRANSFER; FACTOR-BINDING-PROTEIN; ACTIN CYTOSKELETON; ENDOTHELIAL-CELLS; EPITHELIAL-CELLS; KAPOSIS-SARCOMA; FUSION PROTEINS; KIDNEY-DISEASE AB Podocyte injury has a critical role in the pathogenesis of HIV-associated nephropathy (HIVAN). The HIV-1 transactivator of transcription (Tat), combined with fibroblast growth factor-2 (FGF-2), can induce the dedifferentiation and proliferation of cultured human podocytes. Cellular internalization of Tat requires interactions with heparan sulfate proteoglycans and cholesterol-enriched lipid rafts (LRs). However, the specific distribution of Tat in human podocytes and its ability to associate with LRs have not been documented. Here, we found that Tat is preferentially recruited to LRs in podocytes isolated from children with HIVAN. Furthermore, we identified arginines in the basic domain (RKKRRQRRR) of Tat as essential for (1) targeting Tat to LRs, (2) Tat-mediated increases in the expression of Rho-A and matrix metalloproteinase-9 in LRs, and (3) Tat-mediated enhancement of FGF-2 signaling in human podocytes and HIV-transgenic mouse kidneys and the exacerbation of renal lesions in these mice. Tat carrying alanine substitutions in the basic domain (AKKAAQAAA) remained localized in the cytosol and did not associate with LRs or enhance FGF-2 signaling in cultured podocytes. These results show the specific association of Tat with LRs in podocytes isolated from children with HIVAN, confirm Tat as a regulator of FGF-2 signaling in LRs, and identify the key domain of Tat responsible for promoting these effects and aggravating renal injury in HIV-transgenic mice. Moreover, these results provide a molecular framework for developing novel therapies to improve the clinical outcome of children with HIVAN. C1 [Xie, Xuefang; Colberg-Poley, Anamaris M.; Das, Jharna R.; Li, Jinliang; Zhang, Aiping; Tang, Pingtao; Jerebtsova, Marina; Ray, Patricio E.] Childrens Natl Med Ctr, Ctr Genet Med Res, Washington, DC 20010 USA. [Ray, Patricio E.] Childrens Natl Med Ctr, Div Nephrol, Washington, DC 20010 USA. [Colberg-Poley, Anamaris M.; Tang, Pingtao; Jerebtsova, Marina; Ray, Patricio E.] George Washington Univ, Dept Pediat, Washington, DC 20052 USA. [Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Ray, PE (reprint author), Childrens Natl Med Ctr, Ctr Genet Med Res, 111 Michigan Ave NW, Washington, DC 20010 USA. EM Pray@childrensnational.org FU National Institutes of Health [R01-HL55605, R01-HL102497, R01-DK049419] FX This study was supported, in part, by National Institutes of Health Grants R01-HL55605, R01-HL102497, and R01-DK049419. NR 70 TC 7 Z9 7 U1 0 U2 4 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD AUG PY 2014 VL 25 IS 8 BP 1800 EP 1813 DI 10.1681/ASN.2013070710 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA AM2MV UT WOS:000339686400021 PM 24578133 ER PT J AU Haynes, R Lewis, D Emberson, J Reith, C Agodoa, L Cass, A Craig, JC de Zeeuw, D Feldt-Rasmussen, B Fellstrom, B Levin, A Wheeler, DC Walker, R Herrington, WG Baigent, C Landray, MJ AF Haynes, Richard Lewis, David Emberson, Jonathan Reith, Christina Agodoa, Lawrence Cass, Alan Craig, Jonathan C. de Zeeuw, Dick Feldt-Rasmussen, Bo Fellstrom, Bengt Levin, Adeera Wheeler, David C. Walker, Rob Herrington, William G. Baigent, Colin Landray, Martin J. CA SHARP Collaborative Grp TI Effects of Lowering LDL Cholesterol on Progression of Kidney Disease SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GLOMERULAR-FILTRATION-RATE; RENAL-DISEASE; METAANALYSIS; PROTECTION; TRIAL; HEART AB Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily or matching placebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared with placebo. There was a nonsignificant 3% reduction in the incidence of ESRD (1057 [33.9%] cases with simvastatin plus ezetimibe versus 1084 [34.6%] cases with placebo; rate ratio, 0.97; 95% confidence interval [95% CI], 0.89 to 1.05; P=0.41). Similarly, allocation to simvastatin plus ezetimibe had no significant effect on the prespecified tertiary outcomes of ESRD or death (1477 [47.4%] events with treatment versus 1513 [48.3%] events with placebo; rate ratio, 0.97; 95% CI, 0.90 to 1.04; P=0.34) or ESRD or doubling of baseline creatinine (1189 [38.2%] events with treatment versus 1257 [40.2%] events with placebo; rate ratio, 0.93; 95% CI, 0.86 to 1.01; P=0.09). Exploratory analyses also showed no significant effect on the rate of change in eGFR. Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD. C1 [Haynes, Richard; Lewis, David; Emberson, Jonathan; Reith, Christina; Herrington, William G.; Baigent, Colin; Landray, Martin J.] Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England. [Haynes, Richard; Lewis, David; Emberson, Jonathan; Reith, Christina; Herrington, William G.; Baigent, Colin; Landray, Martin J.] Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford, England. [Agodoa, Lawrence] NIDDKD, NIH, Bethesda, MD USA. [Cass, Alan] Charles Darwin Univ, Menzies Sch Hlth Res, Darwin, NT 0909, Australia. [Craig, Jonathan C.] Univ Sydney, Childrens Hosp Westmead, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia. [de Zeeuw, Dick] Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands. [Feldt-Rasmussen, Bo] Univ Copenhagen, Rigshosp, DK-2100 Copenhagen, Denmark. [Fellstrom, Bengt] Univ Uppsala Hosp, Uppsala, Sweden. [Levin, Adeera] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Wheeler, David C.] UCL, London, England. [Walker, Rob] Univ Otago, Dunedin Sch Med, Otago, New Zealand. RP Landray, MJ (reprint author), Clin Trial Serv Unit, Richard Doll Bldg,Old Rd Campus,Roosevelt Dr, Oxford OX3 7LF, England. EM sharpclinical@ctsu.ox.ac.uk RI Craig, Jonathan/E-2813-2013; de Zeeuw, Dick/E-9080-2014; OI Craig, Jonathan/0000-0002-2548-4035; de Zeeuw, Dick/0000-0003-3434-7777; Emberson, Jonathan/0000-0001-7792-9422; Herrington, Will/0000-0003-1172-8243 FU Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council FX The study was funded by Merck/Schering-Plough Pharmaceuticals, with additional support from the Australian National Health and Medical Research Council, the British Heart Foundation, and the UK Medical Research Council. NR 18 TC 38 Z9 41 U1 1 U2 7 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD AUG PY 2014 VL 25 IS 8 BP 1825 EP 1833 DI 10.1681/ASN.2013090965 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA AM2MV UT WOS:000339686400023 PM 24790178 ER PT J AU Porter, A Fischer, MJ Wang, XL Brooks, D Bruce, M Charleston, J Cleveland, WH Dowie, D Faulkner, M Gassman, J Hiremath, L Kendrick, C Kusek, JW Norris, KC Thornley-Brown, D Greene, T Lash, JP AF Porter, Anna Fischer, Michael J. Wang, Xuelei Brooks, Deborah Bruce, Marino Charleston, Jeanne Cleveland, William H. Dowie, Donna Faulkner, Marquetta Gassman, Jennifer Hiremath, Leena Kendrick, Cindy Kusek, John W. Norris, Keith C. Thornley-Brown, Denyse Greene, Tom Lash, James P. CA AASK Study Grp TI Quality of Life and Outcomes in African Americans with CKD SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; HEALTH SURVEY SF-36; UNITED-STATES; CARDIOVASCULAR OUTCOMES; DIALYSIS OUTCOMES; PRACTICE PATTERNS; RISK-FACTORS; AASK TRIAL; MORTALITY AB Low health-related quality of life (HRQOL) has been associated with increased risk for hospitalization and death in ESRD. However, the relationship of HRQOL with outcomes in predialysis CKD is not well understood. We evaluated the association between HRQOL and renal and cardiovascular (CV) outcomes in 1091 African Americans with hypertensive CKD enrolled in the African American Study of Kidney Disease and Hypertension (AASK) trial and cohort studies. Outcomes included CKD progression (doubling of serum creatinine/ESRD), CV events/CV death, and a composite of CKD progression or death from any cause (CKD progression/death). We assessed HRQOL, including mental health composite (MHC) and physical health composite (PHC), using the Short Form-36 survey. Cox regression analyses were used to assess the relationship between outcomes and five-point decrements in MHC and PHC scores using measurements at baseline, at the most recent annual visit (time-varying), or averaged from baseline to the most recent visit (cumulative). During approximately 10 years of follow-up, lower mean PHC score was associated with increased risk of CV events/CV death and CKD progression/death across all analytic approaches, but only time-varying and cumulative decrements were associated with CKD progression. Similarly, lower mean MHC score was associated with increased risk of CV events/CV death regardless of analytic approach, while only time-varying and cumulative decrements in mean MHC score was associated with CKD progression and CKD progression or death. In conclusion, lower HRQOL is associated with a range of adverse outcomes in African Americans with hypertensive CKD. C1 [Porter, Anna; Fischer, Michael J.; Lash, James P.] Univ Illinois Hosp & Hlth Sci Syst, Dept Med, Chicago, IL USA. [Porter, Anna; Fischer, Michael J.; Lash, James P.] Jesse Brown Vet Affairs Med Ctr, Chicago, IL USA. [Fischer, Michael J.] Edward Hines Jr Vet Affairs Hosp, Ctr Management Complex Chron Care, Hines, IL USA. [Wang, Xuelei; Gassman, Jennifer; Kendrick, Cindy] Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. [Brooks, Deborah] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Bruce, Marino] Jackson State Univ, Jackson, MS USA. [Bruce, Marino] Univ Mississippi, Med Ctr, Ctr Hlth Minor Males, Jackson, MS 39216 USA. [Charleston, Jeanne] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Cleveland, William H.] Morehouse Sch Med, Multidisciplinary Res Ctr, Atlanta, GA 30310 USA. [Dowie, Donna] Columbia Univ, Dept Med, Med Ctr, Harlem Hosp, New York, NY USA. [Faulkner, Marquetta] Meharry Med Coll, Dept Med, Nashville, TN 37208 USA. [Hiremath, Leena] Ohio State Univ, Med Ctr, Dept Med, Columbus, OH 43210 USA. [Kusek, John W.] NIDDK, NIH, Bethesda, MD USA. [Norris, Keith C.] Charles R Drew Univ Med & Sci, Dept Med, Los Angeles, CA 90059 USA. [Thornley-Brown, Denyse] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Greene, Tom] Univ Utah, Dept Med, Salt Lake City, UT 84112 USA. RP Porter, A (reprint author), Dept Med, Nephrol Sect, 820 S Wood St M-C 793, Chicago, IL 60612 USA. EM aporte3@uic.edu FU National Center on Minority Health and Health Disparities; National Institutes of Health [M01-RR00080, M01-RR00071, M01-00032, P20-RR11145, M01-RR00827, M01-RR00052, 2P20-RR11104, RR029887, DK2818-02]; King Pharmaceuticals; NIDDK [K24-DK092290]; National Cancer Institute [KM1CA156717] FX AASK was supported by grants to each clinical center and the coordinating center from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). In addition, AASK was supported by the Office of Research in Minority Health (now the National Center on Minority Health and Health Disparities) and the following institutional grants from the National Institutes of Health: M01-RR00080, M01-RR00071, M01-00032, P20-RR11145, M01-RR00827, M01-RR00052, 2P20-RR11104, RR029887, and DK2818-02. King Pharmaceuticals provided monetary support and antihypertensive medications to each clinical center. Pfizer, Inc., AstraZeneca Pharmaceuticals, GlaxoSmithKline, Forest Laboratories, Pharmacia, and Upjohn also donated antihypertensive medications. J.P.L. was supported by NIDDK K24-DK092290. The project described was supported by Award Number KM1CA156717 (AR) from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 27 TC 8 Z9 8 U1 1 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD AUG PY 2014 VL 25 IS 8 BP 1849 EP 1855 DI 10.1681/ASN.2013080835 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AM2MV UT WOS:000339686400026 PM 24700865 ER PT J AU Olden, M Corre, T Hayward, C Toniolo, D Ulivi, S Gasparini, P Pistis, G Hwang, SJ Bergmann, S Campbell, H Cocca, M Gandin, I Girotto, G Glaudemans, B Hastie, ND Loffing, J Polasek, O Rampoldi, L Rudan, I Sala, C Traglia, M Vollenweider, P Vuckovic, D Youhanna, S Weber, J Wright, AF Kutalik, Z Bochud, M Fox, CS Devuyst, O AF Olden, Matthias Corre, Tanguy Hayward, Caroline Toniolo, Daniela Ulivi, Sheila Gasparini, Paolo Pistis, Giorgio Hwang, Shih-Jen Bergmann, Sven Campbell, Harry Cocca, Massimiliano Gandin, Ilaria Girotto, Giorgia Glaudemans, Bob Hastie, Nicholas D. Loffing, Johannes Polasek, Ozren Rampoldi, Luca Rudan, Igor Sala, Cinzia Traglia, Michela Vollenweider, Peter Vuckovic, Dragana Youhanna, Sonia Weber, Julien Wright, Alan F. Kutalik, Zoltan Bochud, Murielle Fox, Caroline S. Devuyst, Olivier TI Common Variants in UMOD Associate with Urinary Uromodulin Levels: A Meta-Analysis SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; TAMM-HORSFALL PROTEIN; GENOME-WIDE ASSOCIATION; RISK-FACTORS; CARDIOVASCULAR MORTALITY; BLOOD-PRESSURE; INCIDENT CKD; GENE; POPULATION; NEPHROPATHY AB Uromodulin is expressed exclusively in the thick ascending limb and is the most abundant protein excreted in normal urine. Variants in UMOD, which encodes uromodulin, are associated with renal function, and urinary uromodulin levels may be a biomarker for kidney disease. However, the genetic factors regulating uromodulin excretion are unknown. We conducted a meta-analysis of urinary uromodulin levels to identify associated common genetic variants in the general population. We included 10,884 individuals of European descent from three genetic isolates and three urban cohorts. Each study measured uromodulin indexed to creatinine and conducted linear regression analysis of approximately 2.5 million single nucleotide polymorphisms using an additive model. We also tested whether variants in genes expressed in the thick ascending limb associate with uromodulin levels. rs12917707, located near UMOD and previously associated with renal function and CKD, had the strongest association with urinary uromodulin levels (P<0.001). In all cohorts, carriers of a G allele of this variant had higher uromodulin levels than noncarriers did (geometric means 10.24, 14.05, and 17.67 mu g/g creatinine for zero, one, or two copies of the G allele). rs12446492 in the adjacent gene PDILT (protein disulfide isomerase-like, testis expressed) also reached genome-wide significance (P<0.001). Regarding genes expressed in the thick ascending limb, variants in KCNJ1, SORL1, and CAB39 associated with urinary uromodulin levels. These data indicate that common variants in the UMOD promoter region may influence urinary uromodulin levels. They also provide insights into uromodulin biology and the association of UMOD variants with renal function. C1 [Olden, Matthias; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Olden, Matthias] Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany. [Corre, Tanguy; Bergmann, Sven; Kutalik, Zoltan] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Corre, Tanguy; Bergmann, Sven; Kutalik, Zoltan] Swiss Inst Bioinformat, Lausanne, Switzerland. [Hayward, Caroline; Hastie, Nicholas D.; Wright, Alan F.] Western Gen Hosp, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Vollenweider, Peter] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Toniolo, Daniela; Pistis, Giorgio; Cocca, Massimiliano; Sala, Cinzia; Traglia, Michela] Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy. [Toniolo, Daniela] CNR, Inst Mol Genet, Pavia, Italy. [Ulivi, Sheila; Gasparini, Paolo; Gandin, Ilaria; Girotto, Giorgia; Vuckovic, Dragana] Burlo Garofolo Pediat Inst Trieste, Inst Maternal & Child Hlth, Trieste, Italy. [Gasparini, Paolo; Gandin, Ilaria; Girotto, Giorgia; Vuckovic, Dragana] Univ Trieste, Dept Med Sci, Trieste, Italy. [Campbell, Harry; Rampoldi, Luca] Ist Sci San Raffaele, Dulbecco Telethon Inst, I-20132 Milan, Italy. [Glaudemans, Bob; Youhanna, Sonia; Weber, Julien; Devuyst, Olivier] Univ Zurich, Inst Physiol, Zurich Ctr Integrat Human Physiol, Zurich, Switzerland. [Loffing, Johannes] Univ Zurich, Inst Anat, Zurich, Switzerland. [Youhanna, Sonia; Weber, Julien; Devuyst, Olivier] Catholic Univ Louvain Med Sch, Div Nephrol, Brussels, Belgium. [Polasek, Ozren] Univ Split, Fac Med, Dept Publ Hlth, Split, Croatia. [Vollenweider, Peter] Univ Lausanne Hosp, Dept Internal Med, Lausanne, Switzerland. [Kutalik, Zoltan; Bochud, Murielle] Univ Lausanne Hosp, Inst Social & Prevent Med, Lausanne, Switzerland. [Fox, Caroline S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. RP Devuyst, O (reprint author), Univ Zurich, Zurich Ctr Integrat Human Physiol, Inst Physiol, Winterthurerstr 190, CH-8057 Zurich, Switzerland. EM olivier.devuyst@uzh.ch RI Colaus, PsyColaus/K-6607-2013; Polasek, Ozren/B-6002-2011; Rudan, Igor/I-1467-2012; Bochud, Murielle/A-3981-2010; OI Polasek, Ozren/0000-0002-5765-1862; Rudan, Igor/0000-0001-6993-6884; Bochud, Murielle/0000-0002-5727-0218; Rampoldi, Luca/0000-0002-0544-7042; Cocca, Massimiliano/0000-0002-1127-7596; youhanna, sonia/0000-0002-9376-8478; Girotto, Giorgia/0000-0003-4507-6589; Vuckovic, Dragana/0000-0001-9343-6142 FU NHLBI Framingham Heart Study [N01-HC-25195]; Swiss National Science Foundation [33CSCO-122661, 3200BO-111361/2, 3100AO-116323/1, 310000-112552, 310030-146490]; Swiss School of Public Health Plus; United Kingdom Medical Research Council; European Commission [LSHG-CT-2006-018947, 246539, 305608]; Republic of Croatia Ministry of Science, Education, and Sports [108-1080315-0302]; Regione FVG [L.26.2008]; Compagnia di San Paolo (Torino, Italy); Fondazione Cariplo; Ministry of Health (Ricerca Finalizzata); Action de Recherche Concertee [ARC10/15-029]; Fonds de la Recherche Scientifique; Fonds de la Recherche Scientifique Medicale, Belgium Federal Government Inter-University Attraction Pole, Gebert Ruf Stiftung [GRS-038/12] FX This research was conducted in part using data and resources from the Framingham Heart Study of the National Institutes of Health National Heart Lung and Blood Institute (NHLBI) and Boston University School of Medicine. This work was partially supported by the NHLBI Framingham Heart Study (Contract N01-HC-25195). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (33CSCO-122661, 3200BO-111361/2, 3100AO-116323/1, and 310000-112552). The computations for CoLius imputation were performed in part at the Vital-IT center for high-performance computing of the Swiss Institute of Bioinformatics. M.B. is supported by the Swiss School of Public Health Plus. The Croatia-Korcula and Croatia-Split studies were funded by grants from the United Kingdom Medical Research Council, the European Commission Framework EUROSPAN 6 Project (Contract LSHG-CT-2006-018947), and the Republic of Croatia Ministry of Science, Education, and Sports (Grant 108-1080315-0302 to I.R.). The SNP genotyping for the Croatia-Korcula cohort was performed by Helmholtz Zentrum Munchen (Neuherberg, Germany). The SNP genotyping for the Croatia-Split cohort was performed by AROS Applied Biotechnology (Aarhus, Denmark). The INGI-Carlantino study. was funded by Regione FVG (L.26.2008). The INGI-Val Borbera study was supported by funds from Compagnia di San Paolo (Torino, Italy), Fondazione Cariplo, and the Ministry of Health (Ricerca Finalizzata 2008 to D.T.). Other funding sources for this study include the European Commission Seventh Framework Programme (FP7/2007-2013 under Grant 246539 of the Marie Curie Actions Programme and Grant 305608 of the EURenOmics project), Action de Recherche Concertee (ARC10/15-029, Communaute Francaise de Belgique), Fonds de la Recherche Scientifique and Fonds de la Recherche Scientifique Medicale, Belgium Federal Government Inter-University Attraction Pole, Gebert Ruf Stiftung (Project GRS-038/12), and the Swiss National Science Foundation (Grant 310030-146490 and the NCCR Kidney. CH program). NR 50 TC 17 Z9 17 U1 2 U2 17 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD AUG PY 2014 VL 25 IS 8 BP 1869 EP 1882 DI 10.1681/ASN.2013070781 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA AM2MV UT WOS:000339686400028 PM 24578125 ER PT J AU Memon, AA Shaikh, QN Kamal, AK AF Memon, Adeel Ali Shaikh, Quratulain Nauman Kamal, Ayeesha Kamran TI Depression and risk of stroke in middle aged women SO JOURNAL OF THE PAKISTAN MEDICAL ASSOCIATION LA English DT Editorial Material ID EPIDEMIOLOGY C1 [Memon, Adeel Ali] Stroke Res Stroke Serv, London, England. [Shaikh, Quratulain Nauman] NIH, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Bethesda, MD USA. [Kamal, Ayeesha Kamran] Aga Khan Univ, Neurol Stroke Serv, Karachi, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ, Neurol Stroke Serv, Karachi, Pakistan. FU FIC NIH HHS [D43TW008660] NR 5 TC 0 Z9 0 U1 0 U2 3 PU PAKISTAN MEDICAL ASSOC PI KARACHI PA PMA HOUSE, AGA KHAN III RD, KARACHI, 00000, PAKISTAN SN 0030-9982 J9 J PAK MED ASSOC JI J. Pak. Med. Assoc. PD AUG PY 2014 VL 64 IS 8 BP 969 EP 969 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA AL9MZ UT WOS:000339466700026 PM 25252532 ER PT J AU Wang, C Yolitz, J Alberico, T Laslo, M Sun, YN Wheeler, CT Sun, XP Zou, SG AF Wang, Cecilia Yolitz, Jason Alberico, Thomas Laslo, Mara Sun, Yaning Wheeler, Charles T. Sun, Xiaoping Zou, Sige TI Cranberry Interacts With Dietary Macronutrients to Promote Healthy Aging in Drosophila SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Aging; Dietary intervention; Nutraceutical; Diet composition; Oxidative stress ID LIFE-SPAN EXTENSION; CAENORHABDITIS-ELEGANS; SUPEROXIDE-DISMUTASE; CALORIC RESTRICTION; ANASTREPHA-LUDENS; IMPROVES HEALTH; RHESUS-MONKEYS; FRUIT-FLY; IN-VITRO; MELANOGASTER AB Botanicals possess numerous bioactivities, and some promote healthy aging. Dietary macronutrients are major determinants of life span. The interaction between botanicals and macronutrients that modulates life span is not well understood. Here, we investigated the effect of a cranberry-containing botanical on life span and the influence of macronutrients on the longevity-related effect of cranberry in Drosophila. Flies were supplemented with cranberry on three dietary conditions: standard, high sugar-low protein, and low sugar-high protein diets. We found that cranberry slightly extended life span in males fed with the low sugar-high protein diet but not with other diets. Cranberry extended life span in females fed with the standard diet and more prominently the high sugar-low protein diet but not with the low sugar-high protein diet. Life-span extension was associated with increased reproduction and higher expression of oxidative stress and heat shock response genes. Moreover, cranberry improved survival of sod1 knockdown and dfoxo mutant flies but did not increase wild-type fly's resistance to acute oxidative stress. Cranberry slightly extended life span in flies fed with a high-fat diet. These findings suggest that cranberry promotes healthy aging by increasing stress responsiveness. Our study reveals an interaction of cranberry with dietary macronutrients and stresses the importance of considering diet composition in designing interventions for promoting healthy aging. C1 [Wang, Cecilia; Yolitz, Jason; Alberico, Thomas; Laslo, Mara; Sun, Yaning; Wheeler, Charles T.; Sun, Xiaoping; Zou, Sige] NIA, Funct Genom Unit, Translat Gerontol Branch, Baltimore, MD 21224 USA. RP Zou, SG (reprint author), NIA, Funct Genom Unit, Translat Gerontol Branch, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM zous@mail.nih.gov FU Intramural Research Program of the National Institute on Aging, National Institutes of Health [Z01-AG000366-06] FX This work was supported by funding from the Intramural Research Program of the National Institute on Aging, National Institutes of Health (Z01-AG000366-06 to S.Z). NR 51 TC 3 Z9 3 U1 3 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD AUG PY 2014 VL 69 IS 8 BP 945 EP 954 DI 10.1093/gerona/glt161 PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AM2GS UT WOS:000339668700004 PM 24149429 ER PT J AU Schrack, JA Zipunnikov, V Goldsmith, J Bai, JW Simonsick, EM Crainiceanu, C Ferrucci, L AF Schrack, Jennifer A. Zipunnikov, Vadim Goldsmith, Jeff Bai, Jiawei Simonsick, Eleanor M. Crainiceanu, Ciprian Ferrucci, Luigi TI Assessing the "Physical Cliff": Detailed Quantification of Age-Related Differences in Daily Patterns of Physical Activity SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Epidemiology; Functional performance; Physical activity; Public health ID UNITED-STATES; OLDER-ADULTS; HEART-RATE; ACCELEROMETER AB In spite of evidence that physical activity has beneficial effects on health and age-related functional decline, there is a scarcity of detailed and accurate information on objectively measured daily activity and patterns of such activity in older adults. Participants in the Baltimore Longitudinal Study of Aging (n = 611, 50% male, mean age 67, range 32-93) wore the Actiheart portable activity monitor for 7 days in the free-living environment. The association between activity and age was modeled using a continuous log-linear regression of activity counts on age with sex, body mass index, employment status, functional performance, and comorbid conditions as covariates. In the fully adjusted model, continuous analyses demonstrated that overall physical activity counts were 1.3% lower for each year increase in age. Although there were no differences among morning levels of activity, there was significantly lower afternoon and evening activity in older individuals (p < .01). After adjusting for age, poor functional performance, nonworking status, and higher body mass index were independently associated with less physical activity (p < .001). The use of accelerometers to characterize minute-by-minute intensity, cumulative physical activity counts, and daily activity patterns provides detailed data not gathered by traditional subjective methods, particularly at low levels of activity. The findings of a 1.3% decrease per year in activity from mid-to-late life, and the corresponding drop in afternoon and evening activity, provide new information that may be useful when targeting future interventions. Further, this methodology addresses essential gaps in understanding activity patterns and trends in more sedentary sectors of the population. C1 [Schrack, Jennifer A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Schrack, Jennifer A.; Simonsick, Eleanor M.; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Zipunnikov, Vadim; Bai, Jiawei; Crainiceanu, Ciprian] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Goldsmith, Jeff] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA. RP Schrack, JA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, 615 N Wolfe St,E6137, Baltimore, MD 21205 USA. EM jschrack@jhsph.edu FU Intramural Research Program of the NIH, National Institute on Aging; National Institute of Neurological Disorders and Stroke [R01NS060910] FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. Data for these analyses were obtained from the Baltimore Longitudinal Study of Aging, a study performed by the National Institute on Aging. Crainiceanu's research was supported by the National Institute of Neurological Disorders and Stroke (R01NS060910). NR 18 TC 25 Z9 25 U1 0 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD AUG PY 2014 VL 69 IS 8 BP 973 EP 979 DI 10.1093/gerona/glt199 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AM2GS UT WOS:000339668700007 PM 24336819 ER PT J AU Nadkarni, NK Nunley, KA Aizenstein, H Harris, TB Yaffe, K Satterfield, S Newman, AB Rosano, C AF Nadkarni, Neelesh K. Nunley, Karen A. Aizenstein, Howard Harris, Tamara B. Yaffe, Kristine Satterfield, Suzanne Newman, Anne B. Rosano, Caterina CA Hlth ABC Study TI Association Between Cerebellar Gray Matter Volumes, Gait Speed, and Information-Processing Ability in Older Adults Enrolled in the Health ABC Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Gait; Brain aging; Cognition; Imaging ID BRAIN ACTIVATION; SLOWER GAIT; ATROPHY; MOTOR; HYPERINTENSITIES; DISTURBANCES; EXECUTION; MOVEMENT; PATTERNS; DEFICITS AB The cerebellum plays an important role in mobility and cognition. However, it is unclear which regions of the cerebellum are associated with gait speed and information-processing ability in older adults without overt brain damage. Cross-sectional associations between cerebellar gray matter volumes (GMV), gait speed, and information-processing ability were explored in 231 community-dwelling adults (mean age: 83 years, 48% black, 58% female). We measured gait speed on an automated walkway and information-processing ability on the Digit Symbol Substitution test (DSST). Total and regional cerebellar GMV was measured on 3T-magnetic resonance imaging. Lobar GMV of the cerebellum, obtained by an automated parcellation process, were aggregated based on the cognitive (lobules VI, VII, VIII and crus I, II), sensorimotor (lobules II, IV, V), and vestibular (lobules IX and X) functions ascribed to the cerebellar regions. Larger cerebellar GMV correlated with faster gait speed and superior DSST scores (both p < .001) independent of age, gender, atrophy, and small vessel disease. After adjusting for age, gender, and atrophy, larger cognitive cerebellar GMV correlated with both faster gait speed (p = .04) and higher DSST scores (p < .001), larger sensorimotor cerebellar GMV correlated significantly with DSST alone (p = .02), and the vestibular cerebellar GMV with neither. The association between cognitive cerebellar GMV and gait speed was no longer significant after adjusting for DSST score in the linear regression models. The relationship between gait speed and cerebellar GMV is influenced by information-processing ability, and this relationship is stronger in subregions ascribed to cognitive than vestibular or sensorimotor functions. C1 [Nadkarni, Neelesh K.] Univ Pittsburgh, Div Geriatr Med, Dept Med, Pittsburgh, PA 15213 USA. [Nunley, Karen A.; Newman, Anne B.; Rosano, Caterina] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15213 USA. [Aizenstein, Howard] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. [Harris, Tamara B.] NIA, Bethesda, MD 20892 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. RP Nadkarni, NK (reprint author), Univ Pittsburgh, Div Geriatr Med, Dept Med, Suite 500,3471 Fifth Ave, Pittsburgh, PA 15213 USA. EM nadkarnink@upmc.edu RI Newman, Anne B./C-6408-2013; OI , Karen/0000-0001-5848-7673; Newman, Anne B./0000-0002-0106-1150; Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010 FU Intramural Research Program of the National Institutes of Health, National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; Pittsburgh Claude D. Pepper Older American's Independence Center [P30 AG024827]; Intramural Research Program of the National Institutes of Health, National Institute on Aging (National Institure of Nursing Research (NINR)) [R01-NR012459] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, National Institute on Aging grant R01-AG028050, National Institure of Nursing Research (NINR) grant R01-NR012459) and the Pittsburgh Claude D. Pepper Older American's Independence Center (P30 AG024827). NR 48 TC 15 Z9 15 U1 3 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD AUG PY 2014 VL 69 IS 8 BP 996 EP 1003 DI 10.1093/gerona/glt151 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AM2GS UT WOS:000339668700010 PM 24170673 ER PT J AU Lin, YH Hanson, JA Strandjord, SE Salem, NM Dretsch, MN Haub, MD Hibbeln, JR AF Lin, Yu Hong Hanson, Jennifer A. Strandjord, Sarah E. Salem, Nicholas M. Dretsch, Michael N. Haub, Mark D. Hibbeln, Joseph R. TI Fast Transmethylation of Total Lipids in Dried Blood by Microwave Irradiation and its Application to a Population Study SO LIPIDS LA English DT Article DE Finger pricked blood; Filter paper; Dried blood spot; Microwave reaction system; PUFA; Omega-3; Omega-6 ID POLYUNSATURATED FATTY-ACIDS; GAS-CHROMATOGRAPHY; MASS-SPECTROMETRY; FINGERTIP; SUPPLEMENTATION; DROP; OMEGA-3-FATTY-ACIDS; TRANSESTERIFICATION; PEROXIDATION; VALIDATION AB A methodology combining finger-pricked blood sampling, microwave accelerated fatty acid assay, fast gas chromatography data acquisition, and automated data processing was developed, evaluated and applied to a population study. Finger-pricked blood was collected on filter paper previously impregnated with 0.05 mg of the antioxidant butylated hydroxytoluene and air-dried at room temperature. Transmethylation was accelerated by microwave irradiation in an explosion-proof multimode microwave reaction system. The chemical procedure was based on a one-step direct transmethylation procedure catalyzed by acetyl chloride. The short-term stability of PUFA in blood dried on filter paper and storage at room temperature was examined using venous blood. The recoveries ranged from 97 to 101 % for the categorized fatty acids as well as the ratios of n-6 to n-3 PUFA and the n-3 % highly unsaturated fatty acid. Specifically, recoveries were 99, 98, 97, and 97 % for linoleic acid (18:2n-6), arachidonic acid (ARA), alpha-linolenic acid (ALA), and docosahexaenoic acid (DHA), respectively. The mol% (mean +/- A SD, 95 % confidence interval) of fatty acid composition in subjects from the population study was determined as 36.2 +/- A 3.8 (35.8, 36.7), 23.2 +/- A 3.0 (22.8, 23.5), 36.8 +/- A 3.5 (36.4, 37.2) and 3.79 +/- A 1.0 (3.68, 3.91) for the saturated, monounsaturated, n-6 and n-3 PUFA, respectively. Individually, the mean mol% (95 % CI) was 22.6 (22.3, 22.9) for 18:2n-6, 9.5 (9.3, 9.7) for ARA, 0.51 (0.49, 0.53) for ALA, 0.42 (0.38, 0.47) for eicosapentaenoic acid (EPA), and 1.67 (1.61, 1.73) for DHA. This methodology provides an accelerated yet high-efficiency, chemically safe, and temperature-controlled transmethylation, with diverse laboratory applications including population studies. C1 [Lin, Yu Hong; Strandjord, Sarah E.; Salem, Nicholas M.; Hibbeln, Joseph R.] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Hanson, Jennifer A.] Louisiana Tech Univ, Sch Human Ecol, Ruston, LA 71270 USA. [Hanson, Jennifer A.] Kansas State Univ, Dept Hospitality Management & Dietet, Manhattan, KS 66506 USA. [Dretsch, Michael N.] Walter Reed Natl Mil Med Ctr, Natl Intrepid Ctr Excellence, Bethesda, MD USA. [Dretsch, Michael N.] US Army Aeromed Res Lab, Ft Rucker, AL USA. [Haub, Mark D.] Kansas State Univ, Dept Human Nutr, Manhattan, KS 66506 USA. RP Lin, YH (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. EM yulin@mail.nih.gov OI Hanson, Jennifer /0000-0003-0437-6489 FU National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health FX The authors wish to acknowledge the service members who took part in the study as well as Dr. Norman Salem Jr. and Dr. Charlie N. Serhan for the valuable advice and discussion on the method development. The authors thank Mr. Brian Brown, NIH Library Writing Center, for manuscript editing assistance. This project was partially funded by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. NR 42 TC 7 Z9 7 U1 2 U2 8 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0024-4201 EI 1558-9307 J9 LIPIDS JI Lipids PD AUG PY 2014 VL 49 IS 8 BP 839 EP 851 DI 10.1007/s11745-014-3918-3 PG 13 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA AM4NP UT WOS:000339831800010 PM 24986160 ER PT J AU Molina, JR Foster, NR Reungwetwattana, T Nelson, GD Grainger, AV Steen, PD Stella, PJ Marks, R Wright, J Adjei, AA AF Molina, Julian R. Foster, Nathan R. Reungwetwattana, Thanyanan Nelson, Garth D. Grainger, Andrew V. Steen, Preston D. Stella, Philip J. Marks, Randolph Wright, John Adjei, Alex A. TI A phase II trial of the Src-kinase inhibitor saracatinib after four cycles of chemotherapy for patients with extensive stage small cell lung cancer: NCCTG trial N-0621 SO LUNG CANCER LA English DT Article DE Small cell lung cancer; Extensive stage; Maintenance; Saracatinib; C-Src ID FAMILY KINASES; CISPLATIN; ETOPOSIDE; ACTIVATION; CARBOPLATIN; IMATINIB; CYCLOPHOSPHAMIDE; METAANALYSIS; VINCRISTINE; IRRADIATION AB Introduction: To assess the efficacy and the Src-kinase inhibitor saracatinib (AZD-0530) after four cycles of platinum-based chemotherapy for extensive stage small cell lung cancer (SCLC). Methods: Patients with at least stable disease received saracatinib at a dose of 175 mg/day by mouth until disease progression, unacceptable toxicity, or patient refusal. The primary endpoint was the 12-week progression-free survival (PFS) rate from initiation of saracatinib treatment. Planned interim analysis in first 20 patients, where 13 or more patients alive and progression-free at 12-weeks would allow continued enrollment to 40 total patients. Results: All 23 evaluable patients received platinum based standard chemotherapy. Median age was 58 years (range: 48-82). 96% of patients had a performance status of 0/1. Median of two cycles given (range: 1-34). All 23 (100%) patients have ended treatment, most for disease progression (19/23). The 12-week PFS rate was 26% (6/23; 95% CI: 10-48%). From start of standard chemotherapy, median PFS was 4.7 months (95% CI: 4.5-5.1) and median OS was 11.2 months (95% CI: 9.9-13.8). Eight (35%) and three (13%) patients experienced at least one grade 3/4 or grade 4 AE, respectively. Commonly occurring grade 3/4 adverse events were thrombocytopenia (13%), fatigue (9%), nausea (9%), and vomiting (9%). Conclusions: Saracatinib at a dose of 175 mg/day by mouth is well tolerated. However, the PFS rate observed at the pre-planned interim analysis did not meet the criteria for additional enrollment. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Molina, Julian R.; Marks, Randolph] Mayo Clin, Div Med Oncol, Rochester, MN 55905 USA. [Foster, Nathan R.; Nelson, Garth D.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Grainger, Andrew V.] Columbus Oncol & Hematol Inc, Columbus, OH USA. [Steen, Preston D.] MeritCare Hosp CCOP, Fargo, ND 58102 USA. [Stella, Philip J.] St Joseph Mercy Canc Ctr, Ypsilanti, MI 48197 USA. [Wright, John] NCI, CTEP Program, Rockville, MD 20852 USA. [Adjei, Alex A.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Reungwetwattana, Thanyanan] Ramathibodi Hosp, Dept Internal Med, Div Med Oncol, Bangkok, Thailand. RP Molina, JR (reprint author), Mayo Clin, Dept Oncol, 200 First St SW, Rochester, MN 55905 USA. EM molina.julian@mayo.edu FU NCI NIH HHS [U10 CA180866] NR 38 TC 10 Z9 10 U1 2 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD AUG PY 2014 VL 85 IS 2 BP 245 EP 250 DI 10.1016/j.lungcan.2014.03.004 PG 6 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AM6ZO UT WOS:000340014700023 PM 24957683 ER PT J AU Lionakis, MS AF Lionakis, Michail S. TI New insights into innate immune control of systemic candidiasis SO MEDICAL MYCOLOGY LA English DT Review DE systemic candidiasis; innate immunity; neutrophils; monocytes/macrophages ID PATTERN-RECOGNITION RECEPTOR; CHRONIC GRANULOMATOUS-DISEASE; EXTRACELLULAR TRAP FORMATION; INVASIVE FUNGAL-INFECTION; NATURAL-KILLER-CELLS; C-TYPE LECTIN; HOST-DEFENSE; MYELOPEROXIDASE DEFICIENCY; FLUCONAZOLE PROPHYLAXIS; SPORADIC MONOCYTOPENIA AB Systemic infection caused by Candida species is the fourth leading cause of nosocomial bloodstream infection in modern hospitals and carries high morbidity and mortality despite antifungal therapy. A recent surge of immunological studies in the mouse models of systemic candidiasis and the parallel discovery and phenotypic characterization of inherited genetic disorders in antifungal immune factors that are associated with enhanced susceptibility or resistance to the infection have provided new insights into the cellular and molecular basis of protective innate immune responses against Candida. In this review, the new developments in our understanding of how the mammalian immune system responds to systemic Candida challenge are synthesized and important future research directions are highlighted. C1 NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Lionakis, MS (reprint author), NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike,Bldg 10,Room 11C102, Bethesda, MD 20892 USA. EM lionakism@mail.nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 105 TC 25 Z9 25 U1 0 U2 15 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1369-3786 EI 1460-2709 J9 MED MYCOL JI Med. Mycol. PD AUG PY 2014 VL 52 IS 6 BP 555 EP 564 DI 10.1093/mmy/myu029 PG 10 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA AM5QP UT WOS:000339915400001 PM 25023483 ER PT J AU Birn, RM Shackman, AJ Oler, JA Williams, LE McFarlin, DR Rogers, GM Shelton, SE Alexander, AL Pine, DS Slattery, MJ Davidson, RJ Fox, AS Kalin, NH AF Birn, R. M. Shackman, A. J. Oler, J. A. Williams, L. E. McFarlin, D. R. Rogers, G. M. Shelton, S. E. Alexander, A. L. Pine, D. S. Slattery, M. J. Davidson, R. J. Fox, A. S. Kalin, N. H. TI Extreme early-life anxiety is associated with an evolutionarily conserved reduction in the strength of intrinsic functional connectivity between the dorsolateral prefrontal cortex and the central nucleus of the amygdala SO MOLECULAR PSYCHIATRY LA English DT Editorial Material C1 [Birn, R. M.; Alexander, A. L.] Univ Wisconsin, Dept Med Phys, Madison, WI 53706 USA. [Birn, R. M.; Oler, J. A.; Williams, L. E.; McFarlin, D. R.; Rogers, G. M.; Shelton, S. E.; Slattery, M. J.; Davidson, R. J.; Fox, A. S.; Kalin, N. H.] Univ Wisconsin, Dept Psychiat, Madison, WI 53706 USA. [Birn, R. M.; Oler, J. A.; Williams, L. E.; McFarlin, D. R.; Davidson, R. J.; Fox, A. S.; Kalin, N. H.] Univ Wisconsin, HealthEmot Res Inst, Madison, WI USA. [Birn, R. M.; Oler, J. A.; Williams, L. E.; McFarlin, D. R.; Fox, A. S.; Kalin, N. H.] Univ Wisconsin, Lane Neuroimaging Lab, Madison, WI USA. [Birn, R. M.; McFarlin, D. R.; Alexander, A. L.; Davidson, R. J.; Fox, A. S.; Kalin, N. H.] Univ Wisconsin, Waisman Lab Brain Imaging & Behav, Madison, WI USA. [Shackman, A. J.] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. [Shackman, A. J.] Univ Maryland, Neurosci & Cognit Sci Program, College Pk, MD 20742 USA. [Shackman, A. J.] Univ Maryland, Maryland Neuroimaging Ctr, College Pk, MD 20742 USA. [Pine, D. S.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Davidson, R. J.; Fox, A. S.; Kalin, N. H.] Univ Wisconsin, Dept Psychol, Madison, WI 53706 USA. [Davidson, R. J.; Fox, A. S.] Univ Wisconsin, Ctr Investigating Hlth Minds, Madison, WI USA. RP Birn, RM (reprint author), Univ Wisconsin, Dept Med Phys, 1530 Med Sci Ctr, Madison, WI 53706 USA. FU NCRR NIH HHS [P51 RR000167]; NICHD NIH HHS [P30 HD003352]; NIH HHS [P51 OD011106]; NIMH NIH HHS [R21 MH091550, P50 MH084051, R01 MH046729, R01 MH081884, T32 MH018931] NR 1 TC 7 Z9 7 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD AUG PY 2014 VL 19 IS 8 BP 853 EP 853 DI 10.1038/mp.2014.85 PG 1 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA AM7IR UT WOS:000340040200001 PM 25055941 ER PT J AU Birn, R Shackman, AJ Oler, JA Williams, LE McFarlin, DR Rogers, GM Shelton, SE Alexander, AL Pine, DS Slattery, MJ Davidson, RJ Fox, AS Kalin, NH AF Birn, R. M. Shackman, A. J. Oler, J. A. Williams, L. E. McFarlin, D. R. Rogers, G. M. Shelton, S. E. Alexander, A. L. Pine, D. S. Slattery, M. J. Davidson, R. J. Fox, A. S. Kalin, N. H. TI Evolutionarily conserved prefrontal-amygdalar dysfunction in early-life anxiety SO MOLECULAR PSYCHIATRY LA English DT Article ID INFANT RHESUS-MONKEYS; FUNCTIONAL CONNECTIVITY; ANXIOUS TEMPERAMENT; INTERNALIZING SYMPTOMS; AFFECTIVE-DISORDERS; CENTRAL NUCLEUS; MEDIATING FEAR; BRAIN ACTIVITY; CORTEX; PRIMATES AB Some individuals are endowed with a biology that renders them more reactive to novelty and potential threat. When extreme, this anxious temperament (AT) confers elevated risk for the development of anxiety, depression and substance abuse. These disorders are highly prevalent, debilitating and can be challenging to treat. The high-risk AT phenotype is expressed similarly in children and young monkeys and mechanistic work demonstrates that the central (Ce) nucleus of the amygdala is an important substrate. Although it is widely believed that the flow of information across the structural network connecting the Ce nucleus to other brain regions underlies primates' capacity for flexibly regulating anxiety, the functional architecture of this network has remained poorly understood. Here we used functional magnetic resonance imaging (fMRI) in anesthetized young monkeys and quietly resting children with anxiety disorders to identify an evolutionarily conserved pattern of functional connectivity relevant to early-life anxiety. Across primate species and levels of awareness, reduced functional connectivity between the dorsolateral prefrontal cortex, a region thought to play a central role in the control of cognition and emotion, and the Ce nucleus was associated with increased anxiety assessed outside the scanner. Importantly, high-resolution 18-fluorodeoxyglucose positron emission tomography imaging provided evidence that elevated Ce nucleus metabolism statistically mediates the association between prefrontal-amygdalar connectivity and elevated anxiety. These results provide new clues about the brain network underlying extreme early-life anxiety and set the stage for mechanistic work aimed at developing improved interventions for pediatric anxiety. C1 [Birn, R. M.; Alexander, A. L.] Univ Wisconsin, Dept Med Phys, Madison, WI 53706 USA. [Birn, R. M.; Oler, J. A.; Williams, L. E.; McFarlin, D. R.; Rogers, G. M.; Shelton, S. E.; Slattery, M. J.; Davidson, R. J.; Fox, A. S.; Kalin, N. H.] Univ Wisconsin, Dept Psychiat, Madison, WI 53706 USA. [Birn, R. M.; Oler, J. A.; Williams, L. E.; McFarlin, D. R.; Davidson, R. J.; Fox, A. S.; Kalin, N. H.] Univ Wisconsin, Wisconsin Psychiat Inst & Clin, HealthEmot Res Inst, Madison, WI 53719 USA. [Birn, R. M.; Oler, J. A.; Williams, L. E.; McFarlin, D. R.; Fox, A. S.; Kalin, N. H.] Univ Wisconsin, Lane Neuroimaging Lab, Madison, WI 53719 USA. [Birn, R. M.; McFarlin, D. R.; Alexander, A. L.; Davidson, R. J.; Fox, A. S.; Kalin, N. H.] Univ Wisconsin, Waisman Lab Brain Imaging & Behav, Madison, WI 53719 USA. [Shackman, A. J.] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. [Shackman, A. J.] Univ Maryland, Neurosci & Cognit Sci Program, College Pk, MD 20742 USA. [Shackman, A. J.] Univ Maryland, Maryland Neuroimaging Ctr, College Pk, MD 20742 USA. [Pine, D. S.] NIMH, Bethesda, MD 20892 USA. [Davidson, R. J.; Fox, A. S.; Kalin, N. H.] Univ Wisconsin, Dept Psychiat, Madison, WI 53706 USA. [Davidson, R. J.; Fox, A. S.] Univ Wisconsin, Ctr Investigating Hlth Minds, Madison, WI 53719 USA. RP Kalin, NH (reprint author), Univ Wisconsin, Wisconsin Psychiat Inst & Clin, HealthEmot Res Inst, 6001 Res Pk Blvd, Madison, WI 53719 USA. EM nkalin@wisc.edu FU National Institutes of Health (NIH) [HD003352, HD008352, MH018931, MH046729, MH081884, MH084051, MH090912, MH091550, OD011106, RR000167]; HERI; Meriter Hospital; University of Maryland FX We acknowledge the assistance of E Ahlers, V Balchen, B Christian, A Converse, L Friedman, M Jesson, E Larson, K Mayer, T Oakes, M Riedel, P Roseboom, J Storey, D Tromp, N Vack, H Van Valkenberg and the staffs of the Harlow Center for Biological Psychology, HealthEmotions Research Institute (HERI), Waisman Center, Waisman Laboratory for Brain Imaging and Behavior and Wisconsin National Primate Center. We thank Julie Fudge, Luiz Pessoa, and several anonymous reviewers for critical feedback. This work was supported by the National Institutes of Health (NIH; Intramural Research Program and extramural grants HD003352, HD008352, MH018931, MH046729, MH081884, MH084051, MH090912, MH091550, OD011106 and RR000167), HERI, Meriter Hospital and the University of Maryland. NR 74 TC 26 Z9 26 U1 12 U2 34 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD AUG PY 2014 VL 19 IS 8 BP 915 EP 922 DI 10.1038/mp.2014.46 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA AM7IR UT WOS:000340040200013 PM 24863147 ER PT J AU Arking, DE Pulit, SL Crotti, L Van der Harst, P Munroe, PB Koopmann, TT Sotoodehnia, N Rossin, EJ Morley, M Wang, X Johnson, AD Lundby, A Gudbjartsson, DF Noseworthy, PA Eijgelsheim, M Bradford, Y Tarasov, KV Dorr, M Miiller-Nurasyid, M Lahtinen, AM Nolte, IM Smith, AV Bis, JC Isaacs, A Newhouse, SJ Evans, DS Post, WS Waggott, D Lyytikainen, LP Hicks, AA Eisele, L Ellinghaus, D Hayward, C Navarro, P Ulivi, S Tanaka, T Tester, DJ Chatel, S Gustafsson, S Kumari, M Morris, RW Naluai, AT Padmanabhan, S Kluttig, A Strohmer, B Panayiotou, AG Torres, M Knoflach, M Hubacek, JA Slowikowski, K Raychaudhuri, S Kumar, RD Harris, TB Launer, LJ Shuldiner, AR Alonso, A Bader, JS Ehret, G Huang, H Kao, WHL Strait, JB Macfarlane, PW Brown, M Caulfield, MJ Samani, NJ Kronenberg, F Willeit, J Smith, JG Greiser, KH Schwabedissen, HMZ Werdan, K Carella, M Zelante, L Heckbert, SR Psaty, BM Rotter, JI Kolcic, I Poagek, O Wright, AF Griffin, M Daly, MJ Arnar, DO Holm, H Thorsteinsdottir, U Denny, JC Roden, DM Zuvich, RL Emilsson, V Plump, AS Larson, MG O'Donnell, CJ Yin, X Bobboll, M D'Adamo, AP Iorio, A Sinagra, G Carracedo, A Cummings, SR Nalls, MA Jula, A Kontula, KK Marjamaa, A Oikarinen, L Perola, M Porthan, K Erbe, R Hoffmann, P Jockel, KH Kalsch, H Nothen, MM Den Hoed, M Loos, RJF Thelle, DS Gieger, C Meitinger, T Perz, S Peters, A Pruchal, H Sinner, MF Waldenberger, M De Boer, RA Franke, L Van der Vleuten, PA Beckmann, BM Martens, E Bardail, A Hofman, N Wilde, AAM Behr, ER Dalageorgou, C Giudicessi, JR Medeiros-Domingo, A Barc, J Kyndt, F Probst, V Ghidoni, A Insolia, R Hamilton, RM Scherer, SW Brandimarto, J Margulies, K Moravec, CE Del Greco, F Fuchsberger, C O'Connell, JR Lee, WK Watt, GCM Campbell, H Wild, SH El Mokhtari, NE Frey, N Asselbergs, FW Leach, IM Navis, G Van den Berg, MP Van Veldhuisen, DJ Kellis, M Krijthe, BP Franco, OH Hofman, A Kors, JA Uitterlinden, AG Witteman, JCM Kedenko, L Lamina, C Oostra, BA Abecasis, GR Lakatta, EG Mulas, A Orru, M Schlessinger, D Uda, M Markus, MRP Volker, U Snieder, H Spector, TD Arnlov, J Lind, L Sundstrom, J Syvanen, AC Kivimaki, M Kahonen, M Mononen, N Raitakari, IT Viikari, JS Adamkova, V Kiech, S Brion, M Nicolaides, AN Paulweber, B Haerting, J Dominiczak, AF Nyberg, F Whincup, PH Hingorani, AD Schott, JJ Bezzina, CR Ingelsson, E Ferrucci, L Gaspariniin, P Wilson, JF Rudan, I Franke, A Miihleisen, TW Pramstaller, PP Lehtimaki, TJ Paterson, AD Parsa, A Liu, Y Van Duijn, CM Siscovick, DS Gudnason', V Jamshidi, Y Salomaa, V Felix, SB Sanna, S Ritchie, MD Stricker, BH Stefansson, K Boyer, LA Cappola, TP Olsen, JV Lage, K Schwartz, PJ Kaab, S Chakravarti, A Ackerman, MJ Pfeufer, A De Bakker, PIW Newton-Cheh, C AF Arking, Dan E. Pulit, Sara L. Crotti, Lia Van der Harst, Pim Munroe, Patricia B. Koopmann, Tamara T. Sotoodehnia, Nona Rossin, Elizabeth J. Morley, Michael Wang, Xinchen Johnson, Andrew D. Lundby, Alicia Gudbjartsson, Daniel F. Noseworthy, Peter A. Eijgelsheim, Mark Bradford, Yuki Tarasov, Kirill V. Dorr, Marcus Miiller-Nurasyid, Martina Lahtinen, Annukka M. Nolte, Ilja M. Smith, Albert Vernon Bis, Joshua C. Isaacs, Aaron Newhouse, Stephen J. Evans, Daniel S. Post, Wendy S. Waggott, Daryl Lyytikainen, Leo-Pekka Hicks, Andrew A. Eisele, Lewin Ellinghaus, David Hayward, Caroline Navarro, Pau Ulivi, Sheila Tanaka, Toshiko Tester, David J. Chatel, Stephanie Gustafsson, Stefan Kumari, Meena Morris, Richard W. Naluai, Asa T. Padmanabhan, Sandosh Kluttig, Alexander Strohmer, Bernhard Panayiotou, Andrie G. Torres, Maria Knoflach, Michael Hubacek, Jaroslav A. Slowikowski, Kamil Raychaudhuri, Soumya Kumar, Runjun D. Harris, Tamara B. Launer, Lenore J. Shuldiner, Alan R. Alonso, Alvaro Bader, Joel S. EhreT, Georg Huang, Hailiang Kao, W. H. Linda Strait, James B. Macfarlane, Peter W. Brown, Morris Caulfield, Mark J. Samani, Nilesh J. Kronenberg, Florian Willeit, Johann Smith, J. Gustav Greiser, Karin H. Schwabedissen, Henriette Meyer Zu Werdan, Karl Carella, Massimo Zelante, Leopoldo Heckbert, Susan R. Psaty, Bruce M. Rotter, Jerome I. Kolcic, Ivana Poagek, Ozren Wright, Alan F. Griffin, Maura Daly, Mark J. Arnar, David O. Holm, Hilma Thorsteinsdottir, Unnur Denny, Joshua C. Roden, Dan M. Zuvich, Rebecca L. Emilsson, Valur Plump, Andrew S. Larson, Martin G. O'Donnell, Christopher J. Yin, Xiaoyan Bobboll, Marco D'Adamo, Adamo P. Iorio, Annamaria Sinagra, Gianfranco Carracedo, Angel Cummings, Steven R. Nalls, Michael A. Jula, Antti Kontula, Kimmo K. Marjamaa, Annukka Oikarinen, Lasse Perola, Markus Porthan, Kimmo Erbe, Raimund Hoffmann, Per Jockel, Karl-Heinz Kalsch, Hagen Nothen, Markus M. Den Hoed, Marcel Loos, Ruth J. F. Thelle, Dag S. Gieger, Christian Meitinger, Thomas Perz, Siegfried Peters, Annette Pruchal, Hanna Sinner, Moritz F. Waldenberger, Melanie De Boer, Rudolf A. Franke, Lude Van der Vleuten, Pieter A. Beckmann, Britt Maria Martens, Eimo Bardail, Abdennasser Hofman, Nynke Wilde, Arthur A. M. Behr, Elijah R. Dalageorgou, Chrysoula Giudicessi, John R. Medeiros-Domingo, Argelia Barc, Julien Kyndt, Florence Probst, Vincent Ghidoni, Alice Insolia, Roberto Hamilton, Robert M. Scherer, Stephen W. Brandimarto, Jeffrey Margulies, Kenneth Moravec, Christine E. Del Greco, Fabiola Fuchsberger, Christian O'Connell, Jeffrey R. Lee, Wai K. Watt, Graham C. M. Campbell, Harry Wild, Sarah H. El Mokhtari, Nour E. Frey, Norbert Asselbergs, Folkert W. Leach, Irene Mateo Navis, Gerjan Van den Berg, Maarten P. Van Veldhuisen, Dirk J. Kellis, Manolis Krijthe, Bouwe P. Franco, Oscar H. Hofman, Albert Kors, Jan A. Uitterlinden, Andre G. Witteman, Jacqueline C. M. Kedenko, Lyudmyla Lamina, Claudia Oostra, Ben A. Abecasis, Goncalo R. Lakatta, Edward G. Mulas, Antonella Orru, Marco Schlessinger, David Uda, Manuela Markus, Marcello R. P. Volker, Uwe Snieder, Harold Spector, Timothy D. Arnlov, Johan Lind, Lars Sundstrom, Johan Syvanen, Ann-Christine Kivimaki, Mika Kahonen, Mika Mononen, Nina Raitakari, I. T. Viikari, Jorma S. Adamkova, Vera Kiech, Stefan Brion, Maria Nicolaides, Andrew N. Paulweber, Bernhard Haerting, Johannes Dominiczak, Anna F. Nyberg, Fredrik Whincup, Peter H. Hingorani, Aroon D. Schott, Jean-Jacques Bezzina, Connie R. Ingelsson, Erik Ferrucci, Luigi Gaspariniin, Paolo Wilson, James F. Rudan, Igor Franke, Andre Miihleisen, Thomas W. Pramstaller, Peter P. Lehtimaki, Terho J. Paterson, Andrew D. Parsa, Afshin Liu, Yongmei Van Duijn, Cornelia M. Siscovick, David S. Gudnason, Vilmundur Jamshidi, Yalda Salomaa, Veikko Felix, Stephan B. Sanna, Serena Ritchie, Marylyn D. Stricker, Bruno H. Stefansson, Karl Boyer, Laurie A. Cappola, Thomas P. Olsen, Jesper V. Lage, Kasper Schwartz, Peter J. Kaab, Stefan Chakravarti, Aravinda Ackerman, Michael J. Pfeufer, Arne De Bakker, Paul I. W. Newton-Cheh, Christopher CA CARe Consortium COGENT Consortium DCCT EDIC eMERGE Consortium HRGEN Consortium TI Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CHRONIC HEART-FAILURE; COMMON VARIANTS; CARDIAC REPOLARIZATION; SARCOPLASMIC-RETICULUM; QRS DURATION; PR INTERVAL; LOCI; TRPM7; MODEL AB The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain similar to 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. C1 [Arking, Dan E.; EhreT, Georg; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD 21218 USA. [Pulit, Sara L.; Noseworthy, Peter A.; Smith, J. Gustav; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Pulit, Sara L.; Lundby, Alicia; Noseworthy, Peter A.; Raychaudhuri, Soumya; Huang, Hailiang; Smith, J. Gustav; Daly, Mark J.; Lage, Kasper; Newton-Cheh, Christopher] Harvard & MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Pulit, Sara L.; De Bakker, Paul I. W.] Univ Med Ctr Utrecht, Ctr Mol Med, Dept Med Genet, Utrecht, Netherlands. [Crotti, Lia; Ghidoni, Alice; Insolia, Roberto] Univ Pavia, Cardiol Sect, Dept Mol Med, I-27100 Pavia, Italy. [Crotti, Lia; Ghidoni, Alice; Insolia, Roberto; Schwartz, Peter J.] Ist Ric & Cura Carattere Sci, Ctr Cardiac Arrhythmias Genet Origin, Milan, Italy. [Crotti, Lia] Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Van der Harst, Pim; De Boer, Rudolf A.; Van der Vleuten, Pieter A.; Leach, Irene Mateo; Van den Berg, Maarten P.; Van Veldhuisen, Dirk J.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Van der Harst, Pim; Franke, Lude; Van der Vleuten, Pieter A.] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Munroe, Patricia B.; Newhouse, Stephen J.; Caulfield, Mark J.] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, London, England. [Munroe, Patricia B.] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, Barts & London Genome Ctr, London, England. [Koopmann, Tamara T.; Bardail, Abdennasser; Wilde, Arthur A. M.; Bezzina, Connie R.] Acad Med Ctr, Dept Clin & Expt Cardiol, Heart Failure Res Ctr, Amsterdam, Netherlands. [Sotoodehnia, Nona; Bis, Joshua C.; Heckbert, Susan R.; Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Sotoodehnia, Nona] Univ Washington, Div Cardiol, Seattle, WA 98195 USA. [Rossin, Elizabeth J.; Huang, Hailiang; Daly, Mark J.; Lage, Kasper] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Rossin, Elizabeth J.; Huang, Hailiang; Newton-Cheh, Christopher] Harvard Univ, Sch Med, Boston, MA USA. [Morley, Michael; Brandimarto, Jeffrey; Margulies, Kenneth; Moravec, Christine E.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Wang, Xinchen; Kellis, Manolis] MIT & Harvard, Broad Inst, Cambridge, MA USA. [Wang, Xinchen; Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Wang, Xinchen] MIT, Dept Biol, Cambridge, MA USA. [Johnson, Andrew D.; Larson, Martin G.; O'Donnell, Christopher J.; Yin, Xiaoyan] NHLBI, Framingham, MA USA. [Lundby, Alicia; Lage, Kasper] Univ Copenhagen, Fac Hlth Sci, Novo Nordisk Fdn, Ctr Prot Res, Copenhagen, Denmark. [Lundby, Alicia] Univ Copenhagen, Danish Natl Res Fdn Ctr Cardiac Arrhythmia, Copenhagen, Denmark. [Gudbjartsson, Daniel F.; Holm, Hilma; Thorsteinsdottir, Unnur] deCODE Genet, Reykjavik, Iceland. [Noseworthy, Peter A.; Smith, J. Gustav; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Eijgelsheim, Mark; Krijthe, Bouwe P.; Franco, Oscar H.; Hofman, Albert; Uitterlinden, Andre G.; Witteman, Jacqueline C. M.; Oostra, Ben A.; Van Duijn, Cornelia M.; Stricker, Bruno H.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Bradford, Yuki; Zuvich, Rebecca L.] Vanderbilt Univ, Sch Med, Ctr Human Genet Res, Nashville, TN 37212 USA. [Tarasov, Kirill V.; Strait, James B.; Lakatta, Edward G.] Natl Inst Aging, US Natl Inst Hlth, Human Cardiovasc Studies Unit, Lab Cardiovasc Sci, Baltimore, MD USA. [Dorr, Marcus; Felix, Stephan B.] Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany. [Dorr, Marcus; Volker, Uwe; Felix, Stephan B.] DZHK, Greifswald, Germany. [Miiller-Nurasyid, Martina; Sinner, Moritz F.; Beckmann, Britt Maria; Martens, Eimo; Kaab, Stefan] Univ Munich, Univ Hosp Munich, Dept Med 1, Munich, Germany. [Miiller-Nurasyid, Martina] Univ Munich, Chair Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Miiller-Nurasyid, Martina; Gieger, Christian] Helmholtz Zentrum Munich, German Res Ctr Environm Hlth, Inst Genet Epidemiol, Neuherberg, Germany. [Miiller-Nurasyid, Martina] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Miiller-Nurasyid, Martina; Meitinger, Thomas; Peters, Annette; Kaab, Stefan] DZHK German Ctr Cardiovasc Res, Munich, Germany. [Lahtinen, Annukka M.; Marjamaa, Annukka] Univ Helsinki, Res Programs Unit, Helsinki, Finland. [Lahtinen, Annukka M.; Marjamaa, Annukka] Univ Helsinki, Cent Hosp, Dept Med, Helsinki, Finland. [Nolte, Ilja M.; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Smith, Albert Vernon; Emilsson, Valur; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert Vernon; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Isaacs, Aaron] Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Evans, Daniel S.; Cummings, Steven R.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Post, Wendy S.] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD USA. [Post, Wendy S.; Kao, W. H. Linda] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Waggott, Daryl] Ontario Inst Canc Res, Toronto, ON, Canada. [Lyytikainen, Leo-Pekka; Mononen, Nina; Lehtimaki, Terho J.] Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Lyytikainen, Leo-Pekka; Mononen, Nina; Lehtimaki, Terho J.] Univ Tampere, Sch Med, Tampere, Finland. [Hicks, Andrew A.; Del Greco, Fabiola; Pramstaller, Peter P.; Pfeufer, Arne] Med Univ Lubeck, European Acad Bozen Bolzano EURAC, Ctr Biomed, Lubeck, Germany. [Eisele, Lewin; Jockel, Karl-Heinz] Univ Duisburg Essen, Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Ellinghaus, David; Franke, Andre] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany. [Hayward, Caroline; Navarro, Pau; Wright, Alan F.] MRC, Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Ulivi, Sheila; D'Adamo, Adamo P.; Gaspariniin, Paolo] Inst Maternal & Child Hlth, Trieste, Italy. [Tanaka, Toshiko; Strait, James B.; Ferrucci, Luigi] Natl Inst Aging, Translat Gerontol Branch, Baltimore, MD USA. [Tester, David J.; Ackerman, Michael J.] Mayo Clin, Div Pediat Cardiol, Dept Pediat, Rochester, MN USA. [Isaacs, Aaron; Tester, David J.; Giudicessi, John R.; Medeiros-Domingo, Argelia; Ackerman, Michael J.] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Windland Smith Rice Sudden Death Genom Lab, Rochester, MN USA. [Chatel, Stephanie; Kyndt, Florence; Probst, Vincent; Schott, Jean-Jacques] Univ Nantes, Inst Throax, Ctr Hosp, Nantes, France. [Chatel, Stephanie; Barc, Julien; Kyndt, Florence; Probst, Vincent; Schott, Jean-Jacques] Univ Nantes, INSERM UMR1087, CNRS, UMR 6291,Inst Thorax, Nantes, France. [Gustafsson, Stefan] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Gustafsson, Stefan; Arnlov, Johan; Syvanen, Ann-Christine; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden. [Kumari, Meena; Kivimaki, Mika; Hingorani, Aroon D.] UCL, Inst Cardiovasc Sci, London, England. [Morris, Richard W.] UCL, Dept Primary Care & Populat Hlth, London, England. [Naluai, Asa T.] Univ Gothenburg, Sahlgrenska Acad, Dept Med & Clin Genet, Gothenburg, Sweden. [Naluai, Asa T.] BBMRI, Gothenburg, Sweden. [Padmanabhan, Sandosh; Lee, Wai K.; Dominiczak, Anna F.] Univ Glasgow, Coll Med Vet & Life Sci, Inst Cardiovasc & Med Sci, BHF Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Kluttig, Alexander; Greiser, Karin H.; Haerting, Johannes] Univ Halle Wittenberg, Inst Med Epidemiol Biostat & Informat, D-06108 Halle, Germany. [Strohmer, Bernhard] Paracelsus Med Univ, Dept Internal Med 2, Salzburg, Austria. [Panayiotou, Andrie G.] Cyprus Univ Technol, Harvard Sch Publ Hlth, Cyprus Int Inst Environm & Publ Hlth Assoc, Limassol, Cyprus. [Panayiotou, Andrie G.; Raitakari, I. T.; Nicolaides, Andrew N.] Cyprus Cardiovascular & Educ Res Trust, Nicosia, Cyprus. [Torres, Maria; Carracedo, Angel; Brion, Maria] Univ Santiago Compostela, Ctr Invest Biomed Red Enfermedades Raras, Santiago De Compostela, Spain. [Knoflach, Michael; Willeit, Johann; Kiech, Stefan] Med Univ Innsbruck, Dept Neurol, A-6020 Innsbruck, Austria. [Hubacek, Jaroslav A.; Adamkova, Vera] Inst Clin & Expt Med, Ctr Med Expt, Prague, Czech Republic. [Slowikowski, Kamil; Raychaudhuri, Soumya] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet,Dep Med, Boston, MA USA. [Slowikowski, Kamil] Harvard Bioinformat & Integrat Gen, Boston, MA USA. [Raychaudhuri, Soumya] Partners HealthCare Ctr Personalized Genet Med, Boston, MA USA. [Raychaudhuri, Soumya] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Raychaudhuri, Soumya] Univ Manchester, Fac Med & Human Sci, Manchester, Lancs, England. [Kumar, Runjun D.] Washington Univ, Div Biol & Biomed Sci, Computat & Syst Biol Program, St Louis, MO USA. [Kumar, Runjun D.] Washington Univ, Sch Med, Div Oncol, Dept Med, St Louis, MO USA. [Harris, Tamara B.; Launer, Lenore J.] Natl Inst Aging, Lab Epidemiol Demog & Biometry, Bethesda, MD USA. [Shuldiner, Alan R.; O'Connell, Jeffrey R.; Parsa, Afshin] Univ Maryland, Sch Med, Dept Med, Baltimore, MD USA. [Shuldiner, Alan R.; O'Connell, Jeffrey R.; Parsa, Afshin] Univ Maryland, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA. [Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Bader, Joel S.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. [Macfarlane, Peter W.] Univ Glasgow, Inst Cardiovasc & Med Sci, Royal Infirm, Glasgow, Lanark, Scotland. [Brown, Morris] Univ Cambridge, Addenbrookes Hosp, Cambridge, England. [Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England. [Kronenberg, Florian; Lamina, Claudia] Med Univ Innsbruck, Div Genet Epidemiol, A-6020 Innsbruck, Austria. [Smith, J. Gustav] Lund Univ, Dept Cardiol, Lund, Sweden. [Greiser, Karin H.] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Schwabedissen, Henriette Meyer Zu] Ernst Moritz Arndt Univ Greifswald, Dept Pharmacol, Greifswald, Germany. [Werdan, Karl] Univ Halle Wittenberg, Dept Med 3, D-06108 Halle, Germany. [Carella, Massimo; Zelante, Leopoldo] Med Genet Unit, San Giovanni Rotondo, Italy. [Heckbert, Susan R.; Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Washington, DC USA. [Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Med, Seattle, WA USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA USA. [Kolcic, Ivana; Poagek, Ozren] Univ Split, Fac Med, Dept Publ Hlth, Split, Croatia. [Griffin, Maura; Nicolaides, Andrew N.] Vasc Screening & Diagnost Ctr, London, England. [Arnar, David O.] Landspitali Univ Hosp, Div Cardiol, Dept Med, Reykjavik, Iceland. [Denny, Joshua C.] Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN USA. [Denny, Joshua C.; Roden, Dan M.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN USA. [Roden, Dan M.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN USA. [Roden, Dan M.] Vanderbilt Univ, Off Personalized Med, Nashville, TN USA. [Plump, Andrew S.] Sanofi Res & Dev, Paris, France. [Larson, Martin G.; Yin, Xiaoyan] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA USA. [Bobboll, Marco; Iorio, Annamaria; Sinagra, Gianfranco] Osped Riuniti, Dept Cardiovasc, Trieste, Italy. [D'Adamo, Adamo P.; Gaspariniin, Paolo] Univ Trieste, Clin Dept Med, Trieste, Italy. [Carracedo, Angel] Fdn Publ Galega Medicina Xenom, Santiago De Compostela, Spain. [Carracedo, Angel] King Abdulaziz Univ, Ctr Excellence Genom Med Res, Jeddah, Saudi Arabia. [Nalls, Michael A.] US Natl Inst Hlth, Natl Inst Aging, Neurogenet Lab, Bethesda, MD USA. [Jula, Antti; Salomaa, Veikko] Natl Inst Hlth & Welf, Chron Dis Epidemiol & Prevent Unit, Helsinki, Finland. [Kontula, Kimmo K.] Univ Helsinki, Dept Med, Helsinki, Finland. [Oikarinen, Lasse; Porthan, Kimmo] Univ Helsinki, Cent Hosp, Div Cardiol, Dept Med, Helsinki, Finland. [Perola, Markus] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland. [Perola, Markus] Univ Helsinki, FIMM, Helsinki, Finland. [Perola, Markus] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Erbe, Raimund; Kalsch, Hagen] Univ Duisburg Essen, Univ Hosp Essen, Dept Cardiol, Essen, Germany. [Hoffmann, Per; Nothen, Markus M.; Miihleisen, Thomas W.] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany. [Hoffmann, Per; Nothen, Markus M.; Miihleisen, Thomas W.] Univ Bonn, Inst Human Genet, Bonn, Germany. [Hoffmann, Per] Univ Basel Hosp, Div Med Genet, CH-4031 Basel, Switzerland. [Hoffmann, Per] Univ Basel, Dept Biomed, Basel, Switzerland. [Den Hoed, Marcel; Loos, Ruth J. F.] Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY USA. [Loos, Ruth J. F.] Icahn Sch Med, Charles Bronfman Inst Personalized Med, New York, NY USA. [Thelle, Dag S.] Univ Oslo, Inst Basic Med Sci, Dept Biostat, Oslo, Norway. [Thelle, Dag S.; Nyberg, Fredrik] Univ Gothenburg, Inst Med, Sahlgrenska Acad, Dept Publ Hlth & Community Med, Gothenburg, Sweden. [Meitinger, Thomas; Pfeufer, Arne] Univ Munich, Inst Human Genet, Munich, Germany. [Meitinger, Thomas; Waldenberger, Melanie] Helmholtz Zentrum Munchen German Res Ctr Environm, Res Unit Mol Epidemiol, Neuherberg, Germany. [Perz, Siegfried] Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Biol & Med Imaging, Neuherberg, Germany. [Peters, Annette] Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Epidemiol 2, Neuherberg, Germany. [Pruchal, Hanna] Christine Kuhne Ctr Allergy & Educ, Munich, Germany. [Pruchal, Hanna] Tech Univ Munich, Dept Dermatol, D-80290 Munich, Germany. [Martens, Eimo] Hosp Friedberg, Dept Med, Friedberg, Germany. [Hofman, Nynke] Acad Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. [Wilde, Arthur A. M.] Princess AI Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia. [Behr, Elijah R.] St Georges Univ London, Cardiovasc & Cell Sci Inst, London, England. [Dalageorgou, Chrysoula] St Georges Univ London, London, England. [Hamilton, Robert M.] Hosp Sick Children, Labatt Family Heart Ctr, Toronto, ON, Canada. [Hamilton, Robert M.] Hosp Sick Children, Dept Pediat, Toronto, ON, Canada. [Scherer, Stephen W.] Hosp Sick Children, Ctr Appl Genom, Toronto, ON, Canada. [Fuchsberger, Christian; Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI USA. [Watt, Graham C. M.] Univ Glasgow, Glasgow, Lanark, Scotland. [Campbell, Harry; Wild, Sarah H.; Wilson, James F.; Rudan, Igor] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [El Mokhtari, Nour E.; De Bakker, Paul I. W.] Univ Kiel, Inst Expt Med, Biobank PopGen, Kiel, Germany. [Frey, Norbert] Univ Med Ctr Schleswig Holstein, Dept Internal Med 2, Kiel, Germany. [Asselbergs, Folkert W.] Interunivers Cardiol Inst Netherlands, Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands. [Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands. [Asselbergs, Folkert W.] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England. [Navis, Gerjan] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Groningen, Netherlands. [Krijthe, Bouwe P.; Franco, Oscar H.; Hofman, Albert; Uitterlinden, Andre G.; Witteman, Jacqueline C. M.; Stricker, Bruno H.] NCHA, Leiden, Netherlands. [Kors, Jan A.; Stricker, Bruno H.] Erasmus MC, Dept Med Informat, Rotterdam, Netherlands. [Uitterlinden, Andre G.; Stricker, Bruno H.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Kedenko, Lyudmyla; Paulweber, Bernhard] Paracelsus Med Univ, Dept Internal Med 1, Salzburg, Austria. [Mulas, Antonella; Orru, Marco; Uda, Manuela; Sanna, Serena] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. [Schlessinger, David] US Natl Inst Hlth, Natl Inst Aging, Intramural Res Program, Genet Lab, Baltimore, MD USA. [Markus, Marcello R. P.] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Volker, Uwe] Ernst Moritz Arndt Univ Greifswald, Interfaculty Inst Genet & Funct Gen, Greifswald, Germany. [Spector, Timothy D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Arnlov, Johan] Dalarna Univ, Sch Hlth & Social Sci, Falun, Sweden. [Krijthe, Bouwe P.; Franco, Oscar H.; Hofman, Albert; Uitterlinden, Andre G.; Witteman, Jacqueline C. M.; Stricker, Bruno H.] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland. [Kahonen, Mika] Univ Tampere, Sch Med, Tampere, Finland. [Raitakari, I. T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland. [Raitakari, I. T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Viikari, Jorma S.] Turku Univ Hosp, Dept Med, FIN-20520 Turku, Finland. [Viikari, Jorma S.] Univ Turku, Turku, Finland. [Brion, Maria] Univ Santiago Compostela, Santiago De Compostela, Spain. [Nyberg, Fredrik] AstraZeneca Res & Dev, Molndal, Sweden. [Whincup, Peter H.] St Georges Univ London, Div Populat Hlth Sci & Educ, London, England. [Ingelsson, Erik] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Miihleisen, Thomas W.] Res Ctr Juelich, Inst Neurosci & Med INM1, Julich, Germany. [Pramstaller, Peter P.] Med Univ Lubeck, Dept Neurol, Lubeck, Germany. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, Bolzano, Italy. [Paterson, Andrew D.] Hosp Sick Children Res Inst, Genet & Genome Biol Program, Toronto, ON, Canada. [Liu, Yongmei] Wake Forest Univ, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Jamshidi, Yalda] St Georges Univ London, Human Genet Res Ctr, London, England. [Ritchie, Marylyn D.] Penn State Univ, Ctr Syst Genom, University Pk, PA 16802 USA. [Stricker, Bruno H.] Inspectorate Hlth Care, The Hague, Netherlands. [Lage, Kasper] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Lage, Kasper] Massachusetts Gen Hosp, Mass Gen Hosp Children, Pediat Surg Res Labs, Boston, MA USA. [Ackerman, Michael J.] Mayo Clin, Div Cardiovasc Dis, Dept Med, Rochester, MN USA. [Pfeufer, Arne] Helmholtz Zentrum, Inst Bioinformat & Syst Biol, Munich, Germany. [De Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, Utrecht, Netherlands. RP Newton-Cheh, C (reprint author), Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD 21218 USA. EM cnewtoncheh@mgh.harvard.edu RI Hayward, Caroline/M-8818-2016; Newhouse, Stephen/C-9330-2011; Johnson, Andrew/G-6520-2013; Franke, Lude/P-7036-2016; Ellinghaus, David/G-4467-2012; Padmanabhan, Sandosh/S-3963-2016; Franke, Andre/B-2151-2010; Kolcic, Ivana/E-2713-2017; Hicks, Andrew/E-9518-2017; Paterson, Andrew/A-4088-2011; Polasek, Ozren/B-6002-2011; Meitinger, Thomas/O-1318-2015; probst, vincent/D-4996-2015; Torinsson Naluai, Asa/P-3269-2015; Alonso, Alvaro/A-4917-2010; Kronenberg, Florian/B-1736-2008; Sundstrom, Johan/A-6286-2009; Peters, Annette/A-6117-2011; Lyytikainen, Leo-Pekka/C-8544-2016; Brion, Maria/J-8059-2014; Rudan, Igor/I-1467-2012; Smith, Albert/K-5150-2015; Schwartz, Peter/J-4267-2016; barc, julien/K-5495-2014; Scherer, Stephen /B-3785-2013; Pfeufer, Arne/B-6634-2013; d'Adamo, Adamo Pio/G-4064-2011; Wilson, James F/A-5704-2009; EHRET, Georg/A-9532-2009; de Bakker, Paul/B-8730-2009; CHATEL, Stephanie/D-2536-2015; KYNDT, Florence/D-6370-2015; Schott, jean-Jacques/F-8842-2013; Lundby, Alicia/H-3322-2013; Frey, Norbert/A-9695-2010; Gudnason, Vilmundur/K-6885-2015 OI Morris, Richard/0000-0001-7240-4563; Kumari, Meena/0000-0001-9716-1035; Nothen, Markus/0000-0002-8770-2464; Markus, Marcello Ricardo Paulista/0000-0002-6234-4955; Navarro, Pau/0000-0001-5576-8584; SINAGRA, GIANFRANCO/0000-0003-2700-8478; sanna, serena/0000-0002-3768-1749; Kivimaki, Mika/0000-0002-4699-5627; Whincup, Peter/0000-0002-5589-4107; Jamshidi, Yalda/0000-0003-0151-6482; Olsen, Jesper/0000-0002-4747-4938; Carracedo, Angel/0000-0003-1085-8986; Gieger, Christian/0000-0001-6986-9554; crotti, lia/0000-0001-8739-6527; Huang, Hailiang/0000-0003-1461-5762; Fuchsberger, Christian/0000-0002-5918-8947; Tuiskula, Annukka/0000-0002-6538-635X; Padmanabhan, Sandosh/0000-0003-3869-5808; den Hoed, Marcel/0000-0001-8081-428X; Hayward, Caroline/0000-0002-9405-9550; Newhouse, Stephen/0000-0002-1843-9842; Franke, Lude/0000-0002-5159-8802; Franke, Andre/0000-0003-1530-5811; Kolcic, Ivana/0000-0001-7918-6052; Hicks, Andrew/0000-0001-6320-0411; Paterson, Andrew/0000-0002-9169-118X; Mulas, Antonella/0000-0002-6856-1483; Polasek, Ozren/0000-0002-5765-1862; Torinsson Naluai, Asa/0000-0002-0504-6492; Alonso, Alvaro/0000-0002-2225-8323; Kronenberg, Florian/0000-0003-2229-1120; Sundstrom, Johan/0000-0003-2247-8454; Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Brion, Maria/0000-0001-7463-2148; Rudan, Igor/0000-0001-6993-6884; Smith, Albert/0000-0003-1942-5845; Schwartz, Peter/0000-0003-0367-1048; barc, julien/0000-0003-4106-5946; Scherer, Stephen /0000-0002-8326-1999; d'Adamo, Adamo Pio/0000-0001-9367-4909; Wilson, James F/0000-0001-5751-9178; EHRET, Georg/0000-0002-5730-0675; de Bakker, Paul/0000-0001-7735-7858; CHATEL, Stephanie/0000-0003-0677-5627; Gudnason, Vilmundur/0000-0001-5696-0084 FU British Heart Foundation [PG/12/38/29615, RG/10/12/28456, RG/13/16/30528]; Chief Scientist Office [CZB/4/710]; Medical Research Council [G0701863, G9521010, MC_PC_U127561128, MC_PC_U127592696, MC_U106179471, MC_UU_12015/1, MR/K006584/1, MR/K013351/1]; NCATS NIH HHS [UL1 TR000114, UL1 TR000124, UL1 TR000142]; NHGRI NIH HHS [T32 HG002295, R01 HG004037]; NHLBI NIH HHS [K23 HL080025, R01 HL098283, R01 HL105756, R01 HL111267, R01 HL113933, R01 HL117626, R01 HL120393]; NIDDK NIH HHS [P30 DK063491, P30 DK072488, U01 DK094176]; NIGMS NIH HHS [T32 GM007753] NR 49 TC 34 Z9 34 U1 0 U2 45 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD AUG PY 2014 VL 46 IS 8 BP 826 EP 836 DI 10.1038/ng.3014 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA AM2TT UT WOS:000339704400010 PM 24952745 ER PT J AU Petrini, I Meltzer, PS Kim, IK Lucchi, M Park, KS Fontanini, G Gao, J Zucali, PA Calabrese, F Favaretto, A Rea, F Rodriguez-Canales, J Walker, RL Pineda, M Zhu, YLJ Lau, C Killian, KJ Bilke, S Voeller, D Dakshanamurthy, S Wang, YS Giaccone, G AF Petrini, Iacopo Meltzer, Paul S. Kim, In-Kyu Lucchi, Marco Park, Kang-Seo Fontanini, Gabriella Gao, James Zucali, Paolo A. Calabrese, Fiorella Favaretto, Adolfo Rea, Federico Rodriguez-Canales, Jaime Walker, Robert L. Pineda, Marbin Zhu, Yuelin J. Lau, Christopher Killian, Keith J. Bilke, Sven Voeller, Donna Dakshanamurthy, Sivanesan Wang, Yisong Giaccone, Giuseppe TI A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors SO NATURE GENETICS LA English DT Article ID FACTOR TFII-I; CELL-CYCLE; GENOME; BIOCHEMISTRY; MANAGEMENT; BIOLOGY; PROTEIN; GENES; KIT AB We analyzed 28 thymic epithelial tumors (TETs) using next-generation sequencing and identified a missense mutation (chromosome 7 c.74146970T>A) in GTF2I at high frequency in type A thymomas, a relatively indolent subtype. In a series of 274 TETs, we detected the GTF2I mutation in 82% of type A and 74% of type AB thymomas but rarely in the aggressive subtypes, where recurrent mutations of known cancer genes have been identified. Therefore, GTF2I mutation correlated with better survival. GTF2I beta and delta isoforms were expressed in TETs, and both mutant isoforms were able to stimulate cell proliferation in vitro. Thymic carcinomas carried a higher number of mutations than thymomas (average of 43.5 and 18.4, respectively). Notably, we identified recurrent mutations of known cancer genes, including TP53, CYLD, CDKN2A, BAP1 and PBRM1, in thymic carcinomas. These findings will complement the diagnostic assessment of these tumors and also facilitate development of a molecular classification and assessment of prognosis and treatment strategies. C1 [Petrini, Iacopo; Gao, James; Voeller, Donna; Wang, Yisong; Giaccone, Giuseppe] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Meltzer, Paul S.; Walker, Robert L.; Pineda, Marbin; Zhu, Yuelin J.; Lau, Christopher; Killian, Keith J.; Bilke, Sven] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Kim, In-Kyu; Park, Kang-Seo; Dakshanamurthy, Sivanesan; Wang, Yisong; Giaccone, Giuseppe] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Lucchi, Marco; Fontanini, Gabriella] Pisa Univ Hosp, Pisa, Italy. [Zucali, Paolo A.] Humanitas Clin & Res Ctr, Milan, Italy. [Calabrese, Fiorella; Favaretto, Adolfo; Rea, Federico] Padua Univ Hosp, Padua, Italy. [Rodriguez-Canales, Jaime] NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, Bethesda, MD 20892 USA. EM gg496@georgetown.edu RI Fontanini, Gabriella/O-7636-2015; Petrini, Iacopo/K-7316-2016; Giaccone, Giuseppe/E-8297-2017; OI Fontanini, Gabriella/0000-0003-1957-2052; Petrini, Iacopo/0000-0002-7752-6866; Giaccone, Giuseppe/0000-0002-5023-7562; LUCCHI, MARCO/0000-0001-9909-6820 FU US National Institutes of Health National Cancer Institute; Georgetown University Lombardi Cancer Center FX This work was supported by a US National Institutes of Health National Cancer Institute intramural program and the Georgetown University Lombardi Cancer Center. We thank A. Proietti for her help in reviewing pathology slides. NR 23 TC 23 Z9 24 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD AUG PY 2014 VL 46 IS 8 BP 844 EP 849 DI 10.1038/ng.3016 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA AM2TT UT WOS:000339704400012 PM 24974848 ER PT J AU Li, ML Zhang, Z Li, XG Ye, JY Wu, XS Tan, ZJ Liu, C Shen, BY Wang, XA Wu, WG Zhou, DZ Zhang, D Wang, T Liu, BY Qu, K Ding, QC Weng, H Ding, Q Mu, JS Shu, YJ Bao, RF Cao, Y Chen, PZ Liu, TY Jiang, L Hu, YP Dong, P Gu, J Lu, W Shi, WB Lu, JH Gong, W Tang, ZH Zhang, Y Wang, XF Chin, YE Weng, XL Zhang, H Tang, W Zheng, YL He, L Wang, H Liu, Y Liu, YB AF Li, Maolan Zhang, Zhou Li, Xiaoguang Ye, Junyi Wu, Xiangsong Tan, Zhujun Liu, Chang Shen, Baiyong Wang, Xu-An Wu, Wenguang Zhou, Daizhan Zhang, Di Wang, Ting Liu, Bingya Qu, Kai Ding, Qichen Weng, Hao Ding, Qian Mu, Jiasheng Shu, Yijun Bao, Runfa Cao, Yang Chen, Peizhan Liu, Tianyu Jiang, Lin Hu, Yunping Dong, Ping Gu, Jun Lu, Wei Shi, Weibin Lu, Jianhua Gong, Wei Tang, Zhaohui Zhang, Yong Wang, Xuefeng Chin, Y. Eugene Weng, Xiaoling Zhang, Hong Tang, Wei Zheng, Yonglan He, Lin Wang, Hui Liu, Yun Liu, Yingbin TI Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway SO NATURE GENETICS LA English DT Article ID BILIARY-TRACT; HUMAN CANCERS; MUTAGENESIS; GENOME AB Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR) <0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P = 0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis. C1 [Li, Maolan; Zhang, Zhou; Wu, Xiangsong; Tan, Zhujun; Wang, Xu-An; Wu, Wenguang; Ding, Qichen; Weng, Hao; Ding, Qian; Mu, Jiasheng; Shu, Yijun; Bao, Runfa; Cao, Yang; Liu, Tianyu; Jiang, Lin; Hu, Yunping; Dong, Ping; Gu, Jun; Lu, Wei; Shi, Weibin; Lu, Jianhua; Gong, Wei; Tang, Zhaohui; Zhang, Yong; Wang, Xuefeng; Liu, Yingbin] Shanghai Jiao Tong Univ, Xinhua Hosp, Sch Med, Dept Gen Surg, Shanghai, Peoples R China. [Li, Maolan; Zhang, Zhou; Wu, Xiangsong; Tan, Zhujun; Wang, Xu-An; Wu, Wenguang; Ding, Qichen; Weng, Hao; Ding, Qian; Mu, Jiasheng; Shu, Yijun; Bao, Runfa; Cao, Yang; Liu, Tianyu; Jiang, Lin; Hu, Yunping; Dong, Ping; Gu, Jun; Lu, Wei; Shi, Weibin; Lu, Jianhua; Gong, Wei; Tang, Zhaohui; Zhang, Yong; Wang, Xuefeng; Liu, Yingbin] Shanghai Jiao Tong Univ, Sch Med, Inst Biliary Tract Dis, Shanghai, Peoples R China. [Zhang, Zhou; Zhou, Daizhan; Zhang, Di; Wang, Ting; He, Lin] Shanghai Jiao Tong Univ, BioX Ctr, Key Lab Genet Dev & Neuropsychiat Disorders, Minist Educ, Shanghai, Peoples R China. [Li, Xiaoguang; Chen, Peizhan; Wang, Hui] Chinese Acad Sci, Univ Chinese Acad Sci, Inst Nutr Sci, Shanghai Inst Biol Sci,Key Lab Food Safety Res, Shanghai, Peoples R China. [Ye, Junyi; Weng, Xiaoling; Zhang, Hong; He, Lin; Liu, Yun] Fudan Univ, Inst Biomed Sci, Shanghai 200433, Peoples R China. [Liu, Chang; Qu, Kai] Xi An Jiao Tong Univ, Affiliated Hosp 1, Coll Med, Dept Hepatobiliary Surg, Xian, Peoples R China. [Shen, Baiyong; Liu, Bingya] Shanghai Jiao Tong Univ, Ruijin Hosp, Sch Med, Dept Gen Surg, Shanghai, Peoples R China. [Chin, Y. Eugene] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Shanghai, Peoples R China. [Tang, Wei] NCI, Lab Human Carcinogenesis, Ctr Canc Res, US NIH, Bethesda, MD 20892 USA. [Zheng, Yonglan] Univ Chicago, Dept Med, Chicago, IL USA. [He, Lin] Zhejiang Univ, Sch Med, Womens Hosp, Hangzhou 310003, Zhejiang, Peoples R China. [Wang, Hui] Minist Hlth, Key Lab Food Safety Risk Assessment, Beijing, Peoples R China. RP Liu, YB (reprint author), Shanghai Jiao Tong Univ, Xinhua Hosp, Sch Med, Dept Gen Surg, Shanghai, Peoples R China. EM huiwang@sibs.ac.cn; superliuyun@fudan.edu.cn; liuybphd@126.com FU National Natural Science Foundation of China [81172026, 81272402, 81301816, 81172029, 81370728, 81125020, 81328022, 81302507]; National High-Technology Research and Development Program (863 Program) [2012AA022606, 2012BAK01B00]; Foundation for Interdisciplinary Research of Shanghai Jiao Tong University [YG2011ZD07]; Shanghai Science and Technology Commission Intergovernmental International Cooperation Project [12410705900]; Shanghai Science and Technology Commission Medical-Guiding Project [12401905800]; China Postdoctoral Science Foundation [2013M541513]; Program for Changjiang Scholars; Leading Talent program of Shanghai FX This study was supported by the National Natural Science Foundation of China (81172026, 81272402, 81301816, 81172029, 81370728, 81125020, 81328022 and 81302507), the National High-Technology Research and Development Program (863 Program, 2012AA022606; 2012BAK01B00), the Foundation for Interdisciplinary Research of Shanghai Jiao Tong University (YG2011ZD07), the Shanghai Science and Technology Commission Intergovernmental International Cooperation Project (12410705900), the Shanghai Science and Technology Commission Medical-Guiding Project (12401905800), the China Postdoctoral Science Foundation (2013M541513), the Program for Changjiang Scholars and the Leading Talent program of Shanghai. NR 26 TC 62 Z9 69 U1 7 U2 31 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD AUG PY 2014 VL 46 IS 8 BP 872 EP 876 DI 10.1038/ng.3030 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA AM2TT UT WOS:000339704400016 PM 24997986 ER PT J AU Cai, QY Zhang, B Sung, H Low, SK Kweon, SS Lu, W Shi, JJ Long, JR Wen, WQ Choi, JY Noh, DY Shen, CY Matsuo, K Teo, SH Kim, MK Khoo, US Iwasaki, M Hartman, M Takahashi, A Ashikawa, K Matsuda, K Shin, MH Park, MH Zheng, Y Xiang, YB Ji, BT Park, SK Wu, PE Hsiung, CN Ito, H Kasuga, YS Kang, P Mariapun, S Ahn, SH Kang, HS Chan, KYK Man, EPS Iwata, H Tsugane, SC Miao, H Liao, JM Nakamura, YS Kubo, M Delahanty, RJ Zhang, YF Li, BS Li, C Gao, YT Shu, XO Kang, D Zheng, W AF Cai, Qiuyin Zhang, Ben Sung, Hyuna Low, Siew-Kee Kweon, Sun-Seog Lu, Wei Shi, Jiajun Long, Jirong Wen, Wanqing Choi, Ji-Yeob Noh, Dong-Young Shen, Chen-Yang Matsuo, Keitaro Teo, Soo-Hwang Kim, Mi Kyung Khoo, Ui Soon Iwasaki, Motoki Hartman, Mikael Takahashi, Atsushi Ashikawa, Kyota Matsuda, Koichi Shin, Min-Ho Park, Min Ho Zheng, Ying Xiang, Yong-Bing Ji, Bu-Tian Park, Sue K. Wu, Pei-Ei Hsiung, Chia-Ni Ito, Hidemi Kasuga, Yoshio Kang, Peter Mariapun, Shivaani Ahn, Sei Hyun Kang, Han Sung Chan, Kelvin Y. K. Man, Ellen P. S. Iwata, Hiroji Tsugane, Shoichiro Miao, Hui Liao, Jiemin Nakamura, Yusuke Kubo, Michiaki Delahanty, Ryan J. Zhang, Yanfeng Li, Bingshan Li, Chun Gao, Yu-Tang Shu, Xiao-Ou Kang, Daehee Zheng, Wei CA DRIVE GAME-ON Consortium TI Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1 SO NATURE GENETICS LA English DT Article ID RISK VARIANT; METAANALYSIS; CYTOKINESIS; PRC1 AB In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified 3 genetic loci newly associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H1 IA gene; P = 8.82 x 10(-9)), rs10474352 at 5q14.3 (near the ARRDC3 gene; P = 1.67 x 10(-9)) and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene; P= 4.25 x 10(-8)). We replicated these associations in 16,003 cases and 41,335 controls of European ancestry (P = 0.030, 0.004 and 0.010, respectively). Data from the ENCODE Project suggest that variants rs4951011 and rs10474352 might be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer. C1 [Cai, Qiuyin; Zhang, Ben; Shi, Jiajun; Long, Jirong; Wen, Wanqing; Delahanty, Ryan J.; Zhang, Yanfeng; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr, Sch Med,Dept Med,Div Epidemiol, Nashville, TN 37212 USA. [Sung, Hyuna; Choi, Ji-Yeob; Park, Sue K.; Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea. [Sung, Hyuna] NCI, Div Epidemiol & Genet, Genet Epidemiol Branch, Rockville, MD USA. [Low, Siew-Kee; Takahashi, Atsushi] RIKEN, Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa, Japan. [Kweon, Sun-Seog; Shin, Min-Ho] Chonnam Natl Univ, Sch Med, Dept Prevent Med, Kwangju, South Korea. [Kweon, Sun-Seog] Chonnam Natl Univ, Hwasun Hosp, Jeonnam Reg Canc Ctr, Hwasun, South Korea. [Lu, Wei; Zheng, Ying] Shanghai Municipal Ctr Dis Control & Prevent, Shanghai, Peoples R China. [Choi, Ji-Yeob; Noh, Dong-Young; Park, Sue K.; Kang, Daehee] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea. [Noh, Dong-Young] Seoul Natl Univ, Coll Med, Dept Surg, Seoul, South Korea. [Shen, Chen-Yang; Wu, Pei-Ei; Hsiung, Chia-Ni] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Shen, Chen-Yang; Wu, Pei-Ei; Hsiung, Chia-Ni] Acad Sinica, Taiwan Biobank, Taipei, Taiwan. [Shen, Chen-Yang] China Med Univ, Coll Publ Hlth, Dept Publ Hlth, Taichung, Taiwan. [Matsuo, Keitaro] Kyushu Univ, Fac Med Sci, Dept Prevent Med, Fukuoka, Japan. [Teo, Soo-Hwang; Kang, Peter; Mariapun, Shivaani] Sime Darby Med Ctr, Cancer Res Initiat Fdn, Subang Jaya, Malaysia. [Teo, Soo-Hwang; Mariapun, Shivaani] Univ Malaya, Fac Med, Univ Malaya Canc Res Inst, Kuala Lumpur, Malaysia. [Kim, Mi Kyung] Natl Canc Ctr, Div Canc Epidemiol & Management, Gyeonggi Do, South Korea. [Khoo, Ui Soon; Chan, Kelvin Y. K.; Man, Ellen P. S.] Univ Hong Kong, Li Ka Shing Fac Med, Dept Pathol, Hong Kong, Peoples R China. [Iwasaki, Motoki] Natl Canc Ctr, Epidemiol Div,Res Ctr Canc Prevent & Screen, Tokyo, Japan. [Hartman, Mikael] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Hartman, Mikael; Miao, Hui] Natl Univ Singapore, Dept Surg, Singapore, Singapore. [Hartman, Mikael] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Hartman, Mikael] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Ashikawa, Kyota] RIKEN, Ctr Integrat Med Sci, Lab Genotyping Dev, Yokohama, Kanagawa, Japan. [Matsuda, Koichi] Univ Tokyo, Ctr Human Genome, Inst Med Sci, Mol Med Lab, Tokyo, Japan. [Park, Min Ho] Chonnam Natl Univ, Sch Med, Dept Surg, Kwangju, South Korea. [Xiang, Yong-Bing; Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Ji, Bu-Tian] US Dept Hlth & Human Serv, US Natl Inst Hlth, Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Park, Sue K.; Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Ito, Hidemi] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan. [Kasuga, Yoshio] Nagano Matsushiro Gen Hosp, Dept Surg, Nagano, Japan. [Ahn, Sei Hyun] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Surg, Seoul, South Korea. [Kang, Han Sung] Natl Canc Ctr, Ctr Breast Canc, Gyeonggi Do, South Korea. [Chan, Kelvin Y. K.] Univ Hong Kong, Queen Mary Hosp, Li Ka Shing Fac Med, Dept Obstet & Gynaecol, Hong Kong, Hong Kong, Peoples R China. [Iwata, Hiroji] Aichi Canc Ctr Cent Hosp, Dept Breast Oncol, Nagoya, Aichi, Japan. [Tsugane, Shoichiro] Natl Canc Ctr, Res Ctr Canc Prevent & Screening, Tokyo, Japan. [Liao, Jiemin] Singapore Eye Res Inst, Singapore, Singapore. [Liao, Jiemin] Natl Univ Singapore, Dept Ophthalmol, Singapore 117548, Singapore. [Liao, Jiemin] Natl Univ Hlth Syst, Singapore, Singapore. [Nakamura, Yusuke] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Li, Bingshan] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37235 USA. [Li, Chun] Vanderbilt Univ, Sch Med, Dept Biostat, Nashville, TN 37212 USA. RP Cai, QY (reprint author), Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr, Sch Med,Dept Med,Div Epidemiol, Nashville, TN 37212 USA. EM qiuyin.cai@vanderbilt.edu RI zhang, yanfeng/E-6971-2016; Teo, Soo-hwang/H-2353-2014; Hartman, Mikael/B-4324-2011; Tsugane, Shocichiro/A-2424-2015; Kubo, Michiaki/N-7947-2015; OI zhang, yanfeng/0000-0002-3859-3839; Low, Siew-Kee/0000-0003-2386-0698; Matsuda, Koichi/0000-0001-7292-2686; Matsuo, Keitaro/0000-0003-1761-6314 FU US National Institutes of Health grants [R01CA124558, R01CA148667, R37CA070867, R01CA118229, R01CA092585, R01CA064277, R01CA122756, R01CA137013]; US Department of Defense Idea Awards [BC011118, BC050791]; Ingram Professorship and Research Reward funds; Vanderbilt-Ingram Cancer Center [P30CA068485]; BRL (Basic Research Laboratory) program through the National Research Foundation of Korea - Ministry of Education, Science and Technology [2011-0001564]; National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea [1020350]; Shanghai Breast Cancer Study [R01CA064277]; Shanghai Women's Health Study [R37CA070867]; Shanghai Breast Cancer Survival Study [R01CA118229]; Shanghai Endometrial Cancer Study [R01CA092585]; Seoul Breast Cancer Study (BRL program through the National Research Foundation of Korea - Ministry of Education, Science and Technology) [2012-0000347]; BioBank Japan Project (Ministry of Education, Culture, Sports, Science and Technology of Japan); Hwasun Cancer Epidemiology Study-Breast (National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea) [1020010]; Taiwan Study (Institute of Biomedical Sciences, Academia Sinica, Taiwan and National Science Council) [DOH97-01]; Hong Kong Study (Research Grant Council, Hong Kong, China) [HKU 7520/05M, 76730M]; Korean-NCC Study (Korea National Cancer Center) [NCC-0910310]; Nagano Breast Cancer Study (Ministry of Health, Labor and Welfare of Japan, for Scientific Research on Priority Areas) [17015049]; Nagano Breast Cancer Study (Ministry of Education, Culture, Sports, Science and Technology of Japan) [221S0001]; Hospital-Based Epidemiologic Research Program at the Aichi Cancer Center (Ministry of Education, Culture, Sports, Science and Technology of Japan) [221S0001, 24590776, 17015018]; Malaysian Breast Cancer Genetic Study (Malaysian Ministry of Science, Technology and Innovation, Malaysian Ministry of Higher Education) [UM.C/H1R/MOHE/06]; Cancer Research Initiatives Foundation; Yayasan Sime Darby LPGA; Singapore Breast Cancer Study (National Medical Research Council Start-Up Grant and Centre Grant ) [NMRC/CG/NCIS/2010]; Biomedical Research Council [05/1/21/19/425]; US NIH grant [U19CA148065] FX This research was supported in part by US National Institutes of Health grants R01CA124558, R01CA148667 and R37CA070867 (to W.Z.); R01CA118229, R01CA092585 and R01CA064277 (to X.-O.S.); R01CA122756 (to Q.C.); and R01CA137013 (to J. Long), US Department of Defense Idea Awards BC011118 (to X.-O.S.) and BC050791 (to Q.C.), and Ingram Professorship and Research Reward funds (to W.Z.). Sample preparation and genotyping assays at Vanderbilt were conducted at the Survey and Biospecimen Shared Resources and the Vanderbilt Microarray Shared Resource, which are supported in part by the Vanderbilt-Ingram Cancer Center (P30CA068485). SeBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2011-0001564). KOHBRA/KOGES was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1020350).; Studies participating in the ABCC include (principal investigator, grant support) the Shanghai Breast Cancer Study (W.Z. and X.-O.S., R01CA064277), the Shanghai Women's Health Study (W.Z., R37CA070867), the Shanghai Breast Cancer Survival Study (X.-O.S., R01CA118229), the Shanghai Endometrial Cancer Study (X.-O.S., R01CA092585, controls only), the Seoul Breast Cancer Study (D.K., BRL program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347)), the BioBank Japan Project (S.-K.L., the Ministry of Education, Culture, Sports, Science and Technology of Japan), the Hwasun Cancer Epidemiology Study-Breast (S.-S.K., the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea, 1020010), the Taiwan Study (C.-Y.S., Institute of Biomedical Sciences, Academia Sinica, Taiwan and National Science Council, DOH97-01), the Hong Kong Study (U.S.K., Research Grant Council, Hong Kong, China, HKU 7520/05M and 76730M), the Korean-NCC Study (M.K.K., grant-in-aid from the Korea National Cancer Center, NCC-0910310), the Nagano Breast Cancer Study (S.T., Grants-in-Aid for the Third-Term Comprehensive Ten-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan, for Scientific Research on Priority Areas, 17015049 and for Scientific Research on Innovative Areas, 221S0001, from the Ministry of Education, Culture, Sports, Science and Technology of Japan), the Hospital-Based Epidemiologic Research Program at the Aichi Cancer Center (K. Tajima, Grant-in-Aid for Scientific Research (C) (24590776) and Grant-in-Aid for Scientific Research on Priority Areas of Cancer (17015018) and Scientific Research on Innovative Areas (221S0001) from the Ministry of Education, Culture, Sports, Science and Technology of Japan), the Malaysian Breast Cancer Genetic Study (S.-H.T., the Malaysian Ministry of Science, Technology and Innovation, Malaysian Ministry of Higher Education (UM.C/H1R/MOHE/06) and the Cancer Research Initiatives Foundation; controls were recruited by the Malaysian More than a Mammo Programme, which was supported by a grant from Yayasan Sime Darby LPGA) and the Singapore Breast Cancer Study (M.H., National Medical Research Council Start-Up Grant and Centre Grant (NMRC/CG/NCIS/2010); additional controls were recruited by the Singapore Consortium of Cohort Studies Multi-Ethnic Cohort (SCCS-MEC), which was funded by the Biomedical Research Council, grant 05/1/21/19/425). The DRIVE GAME-ON Consortium is funded by US NIH grant U19CA148065 (D. Hunter). We thank I. Soong, A. Chan and T.Y. Leung for their assistance in facilitating recruitment of the breast cancer cases included in the Hong Kong Study. NR 25 TC 34 Z9 35 U1 1 U2 30 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD AUG PY 2014 VL 46 IS 8 BP 886 EP 890 DI 10.1038/ng.3041 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA AM2TT UT WOS:000339704400019 PM 25038754 ER PT J AU Choi, KY Silvestre, OF Huang, XL Hida, N Liu, G Ho, DN Lee, S Lee, SW Hong, JI Chen, XY AF Choi, Ki Young Silvestre, Oscar F. Huang, Xinglu Hida, Naoki Liu, Gang Ho, Don N. Lee, Seulki Lee, Sang Wook Hong, Jong In Chen, Xiaoyuan TI A nanoparticle formula for delivering siRNA or miRNAs to tumor cells in cell culture and in vivo SO NATURE PROTOCOLS LA English DT Article ID PEGYLATED HYALURONIC-ACID; THERANOSTIC AGENTS; RNA INTERFERENCE; DRUG-RESISTANCE; CANCER-THERAPY; THERAPEUTICS; NANOCARRIERS; STRATEGIES; MOLECULE; RECEPTOR AB To improve RNA delivery, we present a protocol to produce an RNA carrier based on a Zn(II)-dipicolylamine (Zn-DPA) analog, which is an artificial receptor for phosphate anion derivatives. We further functionalized this Zn-DPA analog to hyaluronic acid (HA)-based self-assembled nanoparticles (HA-NPs) with a hydrodynamic diameter of 100 nm by conjugating amine-functionalized Zn-DPA molecules onto the HA-NPs through amide formation, resulting in efficient tumor-targeted delivery of RNAs (siRNAs, miRNA or other short oligoribonucleotides) and small-molecule drugs. The functional group of Zn-DPA can be converted into other groups such as a carboxylic or thiol group, and the DPA analog can be covalently attached to a variety of existing and novel platforms or formulations for the development of multifunctional materials via standard bioconjugation techniques. Protocols for RNA formulation and delivery into tumor tissues and tumor cells are also described. Our design strategy offers a versatile and practical method for delivering both RNA and chemotherapeutics to tumor cells and expands existing nanomaterial capabilities to further the field of drug and gene delivery. C1 [Choi, Ki Young; Silvestre, Oscar F.; Huang, Xinglu; Hida, Naoki; Liu, Gang; Ho, Don N.; Lee, Seulki; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, US Natl Inst Hlth NIH, Bethesda, MD 20892 USA. [Choi, Ki Young] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Choi, Ki Young] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Liu, Gang] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen, Fujian, Peoples R China. [Lee, Seulki] Johns Hopkins Univ, Sch Med, Dept Radiol, Ctr Nanomed, Baltimore, MD 21205 USA. [Lee, Seulki] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Lee, Sang Wook; Hong, Jong In] Seoul Natl Univ, Dept Chem, Seoul, South Korea. RP Chen, XY (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, US Natl Inst Hlth NIH, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov RI CHOI, KI YOUNG/Q-7177-2016; OI Silvestre, Oscar/0000-0002-3750-4187 FU National Basic Research Program of China (973 program) [2013CB733802, 2014CB744503]; National Science Foundation of China [51273165, 81101101, 81371596]; AXA Research Fund Postdoctoral Fellowship; National Research Foundation of Korea (NRF) Postdoctoral Fellowship [2013R1A6A3A03]; NRF from the Ministry of Education, Science and Technology (MEST, Korea) [2009-0080734]; Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), US National Institutes of Health (NIH) FX This work was supported in part by the National Basic Research Program of China (973 program nos. 2013CB733802 and 2014CB744503), the National Science Foundation of China (nos. 51273165, 81101101 and 81371596), an AXA Research Fund Postdoctoral Fellowship, the National Research Foundation of Korea (NRF) Postdoctoral Fellowship (no. 2013R1A6A3A03) and NRF grant (2009-0080734) from the Ministry of Education, Science and Technology (MEST, Korea), and the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), US National Institutes of Health (NIH). NR 35 TC 11 Z9 11 U1 6 U2 105 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 EI 1750-2799 J9 NAT PROTOC JI Nat. Protoc. PD AUG PY 2014 VL 9 IS 8 BP 1900 EP 1915 DI 10.1038/nprot.2014.128 PG 16 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AM7IN UT WOS:000340039700009 PM 25033207 ER PT J AU Stepanov, I Biener, L Yershova, K Nyman, AL Bliss, R Parascandola, M Hatsukami, DK AF Stepanov, Irina Biener, Lois Yershova, Katrina Nyman, Amy L. Bliss, Robin Parascandola, Mark Hatsukami, Dorothy K. TI Monitoring Tobacco-Specific N-Nitrosamines and Nicotine in Novel Smokeless Tobacco Products: Findings From Round II of the New Product Watch SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID PUBLIC-HEALTH; CIGARETTE-SMOKING; HARM REDUCTION; UNITED-STATES; RISK-FACTOR; SNUS; SWEDEN; COHORT; SURVEILLANCE; MOISTURE AB Introduction: Analysis of novel smokeless tobacco products purchased in Round I of the New Product Watch (NPW)-a national tobacco monitoring network-demonstrated that some tobacco constituents vary not only across various brands but also regionally and over time within the same product. In this study, we analyzed snus and dissolvable tobacco products that were purchased in Round II of the NPW. Methods: We analyzed tobacco-specific N-nitrosamines (TSNA) and nicotine in snus and dissolvable tobacco products that were purchased in various regions of the country during the spring and summer of 2011. The results were compared against the Round I data, across different U. S. regions, and among products. Results: A total of 216 samples were received from different states representing 6 regions of the country. Compared with the previous analyses, TSNA levels increased significantly in Marlboro and Camel Snus and some dissolvable Camel products. The levels of unprotonated nicotine in Marlboro Snus and Camel Snus in this study were not different from Round I but varied significantly by regions; the differences between the highest and the lowest average regional levels were similar to 3.2-fold in Marlboro Snus similar to 1.7-fold in Camel Snus. Conclusions: Our results indicate that some novel smokeless tobacco products contain TSNA at the levels found in the conventional moist snuff. Observation of regional variations in unprotonated nicotine content in both Round I and Round II of NPW suggest that manufacturers may tailor the levels of this constituent consistently to different regions. C1 [Stepanov, Irina] Univ Minnesota, Div Environm Hlth Sci, Minneapolis, MN 55455 USA. [Stepanov, Irina; Yershova, Katrina; Bliss, Robin; Hatsukami, Dorothy K.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Biener, Lois; Nyman, Amy L.] Univ Massachusetts, Survey Res Ctr, Boston, MA 02125 USA. [Parascandola, Mark] NCI, Tobacco Control Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Hatsukami, Dorothy K.] Univ Minnesota, Tobacco Res Programs, Minneapolis, MN 55455 USA. RP Stepanov, I (reprint author), Univ Minnesota, Masonic Canc Ctr, 420 Delaware St,SE MMC 806, Minneapolis, MN 55455 USA. EM stepa011@umn.edu OI Stepanov, Irina/0000-0001-5140-8944 FU National Cancer Institute [HHSN261201100513P]; National Institutes of Health [R01-CA141631, R01-CA135884]; Masonic Cancer Center, University of Minnesota FX This study was supported by National Cancer Institute contract HHSN261201100513P, by grants R01-CA141631 and R01-CA135884 from the National Institutes of Health, and by the startup funds from the Masonic Cancer Center, University of Minnesota, to IS. NR 32 TC 8 Z9 8 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD AUG PY 2014 VL 16 IS 8 BP 1070 EP 1078 DI 10.1093/ntr/ntu026 PG 9 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA AM6CQ UT WOS:000339949600006 PM 24604020 ER PT J AU Dalal, M Casady, M Moriarty, E Faia, L Nussenblatt, R Chan, CC Sen, HN AF Dalal, Monica Casady, Megan Moriarty, Emily Faia, Lisa Nussenblatt, Robert Chan, Chi-Chao Sen, H. Nida TI Diagnostic Procedures in Vitreoretinal Lymphoma SO OCULAR IMMUNOLOGY AND INFLAMMATION LA English DT Article DE Biopsy; diagnosis; masquerade; vitrectomy; vitreoretinal lymphoma ID PRIMARY INTRAOCULAR LYMPHOMA; CENTRAL-NERVOUS-SYSTEM; PRIMARY CNS LYMPHOMA; RETICULUM-CELL SARCOMA; OCULAR LYMPHOMA; CLINICAL-FEATURES; AQUEOUS-HUMOR; MENINGEAL DISSEMINATION; VITRECTOMY SPECIMENS; IL-10 MEASUREMENT AB Purpose: To evaluate the type and number of diagnostic interventions needed to confirm the presence of vitreoretinal lymphoma. Method: Chart review of interventions performed for diagnosis of vitreoretinal lymphoma. Results: Of the 27 cases, diagnosis was made by pars plana vitrectomy in 13 (48.1%), vitreous tap in 2 (7.4%), anterior chamber tap in 1 (3.7%), chorioretinal biopsy in 2 (7.4%), brain biopsy in 5 (18.5%), and cerebrospinal fluid cytology via lumbar puncture in 4 (14.8%). Ten (37%) had definitive results on the first procedure, and 17 (63%) had at least one false negative. Vitrectomy was the most common procedure performed. Patients required a mean of 2.1 procedures. Average time from onset of symptoms to confirmed histopathologic diagnosis was 13.9 months. Conclusion: Vitreoretinal lymphoma is difficult to recognize and requires a high degree of clinical suspicion. It often takes more than one invasive procedure to make the diagnosis. C1 [Dalal, Monica; Casady, Megan; Nussenblatt, Robert; Chan, Chi-Chao; Sen, H. Nida] NEI, NIH, Bethesda, MD 20892 USA. [Moriarty, Emily] Maimonides Hosp, Div Ophthalmol, Brooklyn, NY 11219 USA. [Faia, Lisa] Associated Retinal Consultants PC, Royal Oak, MI USA. RP Sen, HN (reprint author), NEI, NIH, 10 Ctr Dr,10-10N109, Bethesda, MD 20892 USA. EM senh@nei.nih.gov NR 37 TC 4 Z9 4 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0927-3948 EI 1744-5078 J9 OCUL IMMUNOL INFLAMM JI Ocul. Immunol. Inflamm. PD AUG PY 2014 VL 22 IS 4 BP 270 EP 276 DI 10.3109/09273948.2013.848905 PG 7 WC Ophthalmology SC Ophthalmology GA AM4ER UT WOS:000339806300005 PM 24377379 ER PT J AU Ni, CP Ma, LH Wang, B Yan, YP Huang, YQ Wallen, GR Li, L Lang, HJ Hua, QZ AF Ni, Chunping Ma, Lihua Wang, Bo Yan, Yongping Huang, Yueqin Wallen, Gwenyth R. Li, Lu Lang, Hongjuan Hua, Qianzhen TI Neurotic Disorders of General Medical Outpatients in Xi'an, China: Knowledge, Attitudes, and Help-Seeking Preferences SO PSYCHIATRIC SERVICES LA English DT Article ID MENTAL-HEALTH LITERACY; PSYCHIATRIC-TREATMENT; SPEAKING AUSTRALIANS; ANXIETY DISORDERS; ASIAN-AMERICANS; HONG-KONG; SCHIZOPHRENIA; DEPRESSION; PREVALENCE; INSIGHT AB Objective: This study assessed knowledge of neurotic disorders, and attitudes and preferences toward professional help and treatment for them, among general medical outpatients in general hospitals in Xi'an, China. Methods: General medical outpatients (N=372) from general hospitals in China were recruited by using a stratified cluster sampling method between June and September 2010. In face-to-face interviews, participants age 16 years or older were assessed for their knowledge, attitudes, and help-seeking preferences in regard to neurotic disorders (obsessive-compulsive disorder, social phobia, and panic disorder). Demographic data were also collected. Results: Lack of insight into neurotic disorders was common among medical outpatients in general hospitals of Xi'an, China. Twenty-four percent to 58% of the outpatients had some knowledge of the symptoms and treatment of neurotic disorders. Only 11% of the outpatients would reveal to others that they or a family member suffered from neurotic disorders. When faced with the problem of neurotic disorders, the preference of the respondents was to visit a psychiatrist in a general hospital (44%), and only 17% would visit a physician in a psychiatric hospital. Major ways for the outpatients to obtain knowledge regarding neurotic disorders were via radio and television (36%), and only 18%-23% of outpatients obtained knowledge about neurotic disorders through printed public health materials and by attending lectures. Conclusions: Study results underscore the need for information campaigns aimed at improving the mental health literacy of general medical outpatients. Such campaigns must consider culturally relevant beliefs to facilitate the development of specific educational programs. C1 [Ni, Chunping; Hua, Qianzhen] Fourth Mil Med Univ, Dept Nursing, Xian 710032, Peoples R China. [Wang, Bo; Yan, Yongping] Fourth Mil Med Univ, Dept Epidemiol, Xian 710032, Peoples R China. [Li, Lu] Fourth Mil Med Univ, Dept Polit Theories Teaching Res, Xian 710032, Peoples R China. [Ma, Lihua] Lanzhou Univ, Hosp 1, Lanzhou 730000, Gansu, Peoples R China. [Huang, Yueqin] Peking Univ, Inst Mental Hlth, Beijing 100871, Peoples R China. [Wallen, Gwenyth R.] NIH, Dept Nursing, Bethesda, MD 20892 USA. [Lang, Hongjuan] Fourth Mil Med Univ, Tangdu Hosp, Xian 710032, Peoples R China. RP Lang, HJ (reprint author), Fourth Mil Med Univ, Tangdu Hosp, Xian 710032, Peoples R China. EM jhfmmu@163.com FU Ministry of Science and Technology of the People's Republic of China [2007BAI17B01]; Department of Science and Technology of Shaanxi Province of China [2010K16-02-01]; National Natural Science Foundation of China [71373281]; Chinese Scholarship Council FX This study was supported by grants 2007BAI17B01 from the Ministry of Science and Technology of the People's Republic of China, 2010K16-02-01 from the Department of Science and Technology of Shaanxi Province of China, and 71373281 from the National Natural Science Foundation of China and Chinese Scholarship Council. The funding sources had no role in the study design, data collection, data analyses, data interpretation, or writing of the paper. NR 38 TC 0 Z9 0 U1 0 U2 9 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 EI 1557-9700 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD AUG PY 2014 VL 65 IS 8 BP 1047 EP 1053 DI 10.1176/appi.ps.201300071 PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA AM3TU UT WOS:000339776500014 PM 24733481 ER PT J AU Soto, PL Hiranita, T Grandy, DK Katz, JL AF Soto, Paul L. Hiranita, Takato Grandy, David K. Katz, Jonathan L. TI Choice for response alternatives differing in reinforcement frequency in dopamine D-2 receptor mutant and Swiss-Webster mice SO PSYCHOPHARMACOLOGY LA English DT Article DE Dopamine; D-2 receptor; Knockout mice; Choice; Generalized matching law; Eticlopride; D-2 antagonist ID LOCOMOTOR-ACTIVITY; DEFICIENT MICE; COCAINE; SENSITIVITY AB A previous study showed that dopamine (DA) D-2 receptors (D(2)Rs) are involved in the reinforcing effectiveness of food, but the specific involvement of DA D(2)Rs in choice among food reinforcers remains unclear. The current study used genetic and pharmacological approaches to assess the role of D(2)Rs in choice among food-reinforcement frequencies using the generalized matching law (GML), which specifies that logged response and time allocation ratios vary linearly with logged reinforcer ratios. Congenic D2R knockout (KO) and wild-type (WT) mice were exposed to concurrent variable-interval schedules of reinforcement with scheduled relative-reinforcement rates from 4:1 to 1:4. Effects of the D2R antagonist (-)-eticlopride (0.1-1.0 mg/kg) were assessed in Swiss-Webster mice. Response and time allocation ratios were related to obtained reinforcement ratios as predicted by the GML. GML fits accounted for a parts per thousand yen92 % of the variance in allocation ratios and did not differ in D2R KO and WT mice. Similarly, there were no significant effects of (-)-eticlopride dose on GML fits, despite effects on overall response rates. The current results demonstrate that neither deletion nor acute blockade of D(2)Rs affects choice among response alternatives varying in food-reinforcement frequencies. Because previously published results suggest a role of D(2)Rs in choice between response alternatives differing in reinforcer magnitude and delay or magnitude and probability, the current findings suggest that D(2)Rs play a role in choice only among certain parameters of reinforcement. Furthermore, these findings suggest parameters of reinforcement may only be fungible in a complex manner. C1 [Soto, Paul L.] Texas Tech Univ, Dept Educ Psychol & Leadership, Lubbock, TX 79410 USA. [Hiranita, Takato; Katz, Jonathan L.] NIDA, Mol Targets & Medicat Discovery Branch, Psychobiol Sect, Biomed Res Ctr,Intramural Res Program, Baltimore, MD 21224 USA. [Grandy, David K.] Oregon Hlth & Sci Univ, Sch Med, Dept Physiol & Pharmacol, Portland, OR 97239 USA. RP Soto, PL (reprint author), Texas Tech Univ, Dept Educ Psychol & Leadership, Lubbock, TX 79410 USA. EM paul.soto@ttu.edu FU National Institute on Drug Abuse Intramural Program FX These studies were conducted with support of the National Institute on Drug Abuse Intramural Program. We also gratefully acknowledge the contributions of Dawn French-Evans in conducting these studies, and W. M. Baum and L. Green for comments on an earlier version of the manuscript. NR 21 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD AUG PY 2014 VL 231 IS 16 BP 3169 EP 3177 DI 10.1007/s00213-014-3495-4 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AM5MP UT WOS:000339904200009 PM 24682471 ER PT J AU George, RT Mehra, VC Chen, MY Kitagawa, K Arbab-Zadeh, A Miller, JM Matheson, MB Vavere, AL Kofoed, KF Rochitte, CE Dewey, M Yaw, TS Niinuma, H Brenner, W Cox, C Clouse, ME Lima, JAC Di Carli, M AF George, Richard T. Mehra, Vishal C. Chen, Marcus Y. Kitagawa, Kakuya Arbab-Zadeh, Armin Miller, Julie M. Matheson, Matthew B. Vavere, Andrea L. Kofoed, Klaus F. Rochitte, Carlos E. Dewey, Marc Yaw, Tan S. Niinuma, Hiroyuki Brenner, Winfried Cox, Christopher Clouse, Melvin E. Lima, Joao A. C. Di Carli, Marcelo TI Myocardial CT Perfusion Imaging and SPEC T for the Diagnosis of Coronary Artery Disease: A Head-to-Head Comparison from the CORE320 Multicenter Diagnostic Performance Study SO RADIOLOGY LA English DT Article ID EMISSION-COMPUTED-TOMOGRAPHY; BLOOD-FLOW; MAGNETIC-RESONANCE; ANGIOGRAPHY; STENOSIS; SEVERITY; ISCHEMIA; EXTENT; UNDERESTIMATION; RESERVE AB Purpose: To compare the diagnostic performance of myocardial computed tomographic (CT) perfusion imaging and single photon emission computed tomography (SPECT) perfusion imaging in the diagnosis of anatomically significant coronary artery disease (CAD) as depicted at invasive coronary angiography. Materials and Methods: This study was approved by the institutional review board. Written informed consent was obtained from all patients. Sixteen centers enrolled 381 patients from November 2009 to July 2011. Patients underwent rest and adenosine stress CT perfusion imaging and rest and either exercise or pharmacologic stress SPECT before and within 60 days of coronary angiography. Images from CT perfusion imaging, SPECT, and coronary angiography were interpreted at blinded, independent core laboratories. The primary diagnostic parameter was the area under the receiver operating characteristic curve (A(z)). Sensitivity and specificity were calculated with use of prespecified cutoffs. The reference standard was a stenosis of at least 50% at coronary angiography as determined with quantitative methods. Results: CAD was diagnosed in 229 of the 381 patients (60%). The per-patient sensitivity and specificity for the diagnosis of CAD (stenosis. 50%) were 88% (202 of 229 patients) and 55% (83 of 152 patients), respectively, for CT perfusion imaging and 62% (143 of 229 patients) and 67% (102 of 152 patients) for SPECT, with A(z) values of 0.78 (95% confidence interval: 0.74, 0.82) and 0.69 (95% confidence interval: 0.64, 0.74) (P =.001). The sensitivity of CT perfusion imaging for single-and multivessel CAD was higher than that of SPECT, with sensitivities for left main, three-vessel, two-vessel, and one-vessel disease of 92%, 92%, 89%, and 83%, respectively, for CT perfusion imaging and 75%, 79%, 68%, and 41%, respectively, for SPECT. Conclusion: The overall performance of myocardial CT perfusion imaging in the diagnosis of anatomic CAD (stenosis. 50%), as demonstrated with the A(z), was higher than that of SPECT and was driven in part by the higher sensitivity for left main and multivessel disease. (C) RSNA, 2014 C1 [George, Richard T.; Mehra, Vishal C.; Arbab-Zadeh, Armin; Miller, Julie M.; Vavere, Andrea L.; Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21287 USA. [Matheson, Matthew B.; Cox, Christopher] Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Di Carli, Marcelo] Brigham & Womens Hosp, Dept Nucl Med & Cardiovasc Imaging, Boston, MA USA. [Rochitte, Carlos E.] Univ Sao Paulo, Inst Heart Incor, Sch Med, Dept Cardiol, Sao Paulo, Brazil. [Mehra, Vishal C.; Chen, Marcus Y.] NHLBI, NIH, Bethesda, MD 20892 USA. [Niinuma, Hiroyuki] Iwate Med Univ, Dept Radiol, Morioka, Iwate 020, Japan. [Niinuma, Hiroyuki] St Lukes Int Hosp, Dept Radiol, Tokai, Ibaraki, Japan. [Kitagawa, Kakuya] Mie Univ Hosp, Dept Radiol, Tsu, Mie, Japan. [Clouse, Melvin E.] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02115 USA. [Kofoed, Klaus F.] Univ Copenhagen, Rigshosp, Dept Radiol, DK-2100 Copenhagen, Denmark. [Yaw, Tan S.] Natl Heart Ctr, Dept Cardiol, Singapore, Singapore. [Di Carli, Marcelo] Charite, Dept Radiol, D-13353 Berlin, Germany. [Brenner, Winfried] Charite, Dept Nucl Med, D-13353 Berlin, Germany. RP George, RT (reprint author), Johns Hopkins Univ, Sch Med, 600 N Wolfe St,Blalock 524D2, Baltimore, MD 21287 USA. EM rgeorge3@jhmi.edu OI Dewey, Marc/0000-0002-4402-2733 FU Toshiba Medical Systems; Toshiba; GE Healthcare; Siemens; Bayer; Bracco; Guerbet; Bayer-Schering FX R. T. G. Financial activities related to the present article: institution received a grant from Toshiba Medical Systems; received grants from Toshiba and GE Healthcare; is a paid consultant for ICON Medical Imaging. Financial activities not related to the present article: none to disclose. Other relationships: has patents issued. V. C. M. Financial activities related to the present article: institution received a grant from Toshiba Medical Systems. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. M. Y. C. No relevant conflicts of interest to disclose. K. K. Financial activities related to the present article: institution received a grant from Toshiba Medical Systems. Financial activities not related to the present article: institution has grants/grants pending from Siemens and Bayer; receives payment for relationships: none to disclose. M. E. C. No relevant conflicts of interest to disclose. J.A.C.L. Financial activities related to the present article: institution received a grant from Toshiba Medical Systems. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. M. D. C. Financial activities related to the present article: institution received a grant from Toshiba Medical Systems; institution received support for travel to meetings for the study or other purposes from Toshiba Medical Systems. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. lectures including service on speakers bureaus from Siemens. Other relationships: none to disclose. A. A. Financial activities related to the present article: institution received a grant from Toshiba Medical Systems; institution receives support for travel to meetings for study or other purposes from Toshiba Medical Systems. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. J. M. M. Financial activities related to the present article: institution received a grant from Toshiba Medical Systems. Financial activities not related to the present article: received a grant through the university for study services. Other relationships: none to disclose. M. B. M. Financial activities related to the present article: institution received a grant from Toshiba Medical Systems. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. A. L. V. Financial activities related to the present article: institution received a grant from Toshiba Medical Systems. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. K. F. K. Financial activities related to the present article: institution received a grant from Toshiba Medical Systems; institution received support for travel to meetings for the study or other purposes from Toshiba Medical Systems. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. C. E. R. Financial activities related to the present article: received support for travel to meetings for the study or other purposes from Toshiba Medical Systems. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. M. D. Financial activities related to the present article: institution received a grant from Toshiba Medical Systems.; Financial activities not related to the present article: is a paid consultant for Guerbet; institution has grants/ grants pending from GE Healthcare, Bracco, Guerbet, and Toshiba Medical Systems; receives payment for development of educational presentations including service on speakers bureaus from Toshiba Medical Systems, Bayer-Schering, and Guerbet; institution receives travel/accommodations expenses from Toshiba Medical Systems and Guerbet; receives royalties from Springer. Other relationships: none to disclose. T. S. Y. Financial activities related to the present article: institution received a grant from Toshiba Medical Systems; receives payment for service on speakers bureau from Toshiba Medical Systems none to disclose. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. H. N. Financial activities related to the present article: institution received a grant from Toshiba Medical Systems. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. W. B. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: is on the advisory board for Bayer. Other relationships: none to disclose. C. C. Financial activities related to the present article: institution received a grant from Toshiba Medical Systems. Financial activities not related to the present article: none to disclose. Other NR 32 TC 30 Z9 30 U1 1 U2 7 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2014 VL 272 IS 2 BP 407 EP 416 DI 10.1148/radiol.14140806 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AM7HA UT WOS:000340035100010 PM 24865312 ER PT J AU Jain, R Poisson, LM Gutman, D Scarpace, L Hwang, SN Holder, CA Wintermark, M Rao, A Colen, RR Kirby, J Freymann, J Jaffe, CC Mikkelsen, T Flanders, A AF Jain, Rajan Poisson, Laila M. Gutman, David Scarpace, Lisa Hwang, Scott N. Holder, Chad A. Wintermark, Max Rao, Arvind Colen, Rivka R. Kirby, Justin Freymann, John Jaffe, C. Carl Mikkelsen, Tom Flanders, Adam TI Outcome Prediction in Patients with Glioblastoma by Using Imaging, Clinical, and Genomic Biomarkers: Focus on the Nonenhancing Component of the Tumor SO RADIOLOGY LA English DT Article ID HIGH-GRADE GLIOMAS; MOLECULAR SUBCLASSIFICATION; 5-AMINOLEVULINIC ACID; SOLITARY METASTASES; ROC CURVES; SURVIVAL; MULTIFORME; RESECTION; PERFUSION; TEMOZOLOMIDE AB Purpose: To correlate patient survival with morphologic imaging features and hemodynamic parameters obtained from the nonenhancing region (NER) of glioblastoma (GBM), along with clinical and genomic markers. Materials and Methods: An institutional review board waiver was obtained for this HIPAA-compliant retrospective study. Forty-five patients with GBM underwent baseline imaging with contrast material-enhanced magnetic resonance (MR) imaging and dynamic susceptibility contrast-enhanced T2*-weighted perfusion MR imaging. Molecular and clinical predictors of survival were obtained. Single and multivariable models of overall survival (OS) and progression- free survival (PFS) were explored with Kaplan-Meier estimates, Cox regression, and random survival forests. Results: Worsening OS (log-rank test, P = .0103) and PFS (log-rank test, P = .0223) were associated with increasing relative cerebral blood volume of NER (rCBV(NER)), which was higher with deep white matter involvement (t test, P = .0482) and poor NER margin definition (t test, P = .0147). NER crossing the midline was the only morphologic feature of NER associated with poor survival (log-rank test, P = .0125). Preoperative Karnofsky performance score (KPS) and resection extent (n = 30) were clinically significant OS predictors (log-rank test, P = .0176 and P = .0038, respectively). No genomic alterations were associated with survival, except patients with high rCBV(NER) and wild-type epidermal growth factor receptor (EGFR) mutation had significantly poor survival (log-rank test, P = .0306; area under the receiver operating characteristic curve = 0.62). Combining resection extent with rCBV(NER) marginally improved prognostic ability (permutation, P = .084). Random forest models of presurgical predictors indicated rCBV(NER) as the top predictor; also important were KPS, age at diagnosis, and NER crossing the midline. A multivariable model containing rCBV(NER), age at diagnosis, and KPS can be used to group patients with more than 1 year of difference in observed median survival (0.49-1.79 years). Conclusion: Patients with high rCBV(NER) and NER crossing the midline and those with high rCBV(NER) and wild-type EGFR mutation showed poor survival. In multivariable survival models, however, rCBV(NER) provided unique prognostic information that went above and beyond the assessment of all NER imaging features, as well as clinical and genomic features. (C) RSNA, 2014 C1 [Jain, Rajan] Henry Ford Hlth Syst, Div Neuroradiol, Dept Radiol, Detroit, MI 48202 USA. [Poisson, Laila M.] Henry Ford Hlth Syst, Ctr Informat Biol, Dept Publ Hlth Sci, Detroit, MI 48202 USA. [Jain, Rajan; Scarpace, Lisa; Mikkelsen, Tom] Henry Ford Hlth Syst, Dept Neurosurg, Detroit, MI 48202 USA. [Gutman, David; Holder, Chad A.] Emory Univ, Dept Radiol, Atlanta, GA 30322 USA. [Hwang, Scott N.] St Jude Childrens Res Hosp, Dept Radiol, Memphis, TN 38105 USA. [Wintermark, Max] Univ Virginia, Dept Radiol, Charlottesville, VA USA. [Rao, Arvind] MD Anderson Canc Ctr, Dept Radiol, Houston, TX USA. [Colen, Rivka R.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Kirby, Justin; Freymann, John] NCI Frederick, SAIC Frederick, CMRP, Clin Res Directorate, Frederick, MD USA. [Jaffe, C. Carl] Boston Univ, Dept Radiol, Boston, MA 02215 USA. [Flanders, Adam] Thomas Jefferson Univ Hosp, Dept Radiol, Philadelphia, PA 19107 USA. RP Jain, R (reprint author), Henry Ford Hlth Syst, Div Neuroradiol, Dept Radiol, 2799 West Grand Blvd, Detroit, MI 48202 USA. EM rajan.jain@nyumc.org OI Hwang, Scott/0000-0002-6496-2087; Wintermark, Max/0000-0002-6726-3951 FU National Institutes of Health [HHSN261200800001E] FX This research was supported by the National Institutes of Health (grant HHSN261200800001E). NR 39 TC 29 Z9 29 U1 0 U2 9 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2014 VL 272 IS 2 BP 484 EP 493 DI 10.1148/radiol.14131691 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AM7HA UT WOS:000340035100018 PM 24646147 ER PT J AU Ward, MM AF Ward, Michael M. TI Recent Clinical Trials in Lupus Nephritis SO RHEUMATIC DISEASE CLINICS OF NORTH AMERICA LA English DT Article DE Lupus nephritis; Randomized controlled trial; Cyclophosphamide; Mycophenolate mofetil; Azathioprine; Cyclosporine; Rituximab ID RANDOMIZED CONTROLLED-TRIAL; PULSE INTRAVENOUS CYCLOPHOSPHAMIDE; MYCOPHENOLATE-MOFETIL; MEMBRANOUS NEPHROPATHY; SINGLE-CENTER; MAINTENANCE THERAPY; INDUCTION TREATMENT; PROGNOSTIC-FACTORS; ERYTHEMATOSUS; COHORT AB Recent clinical trials have provided evidence for the efficacy of low-dose intravenous cyclophosphamide and mycophenolate mofetil as induction treatment for patients with proliferative lupus nephritis in comparative trials with standard-dose intravenous cyclophosphamide. Trials of maintenance treatments have had more variable results, but suggest that the efficacy of mycophenolate mofetil may be similar to that of quarterly standard-dose intravenous cyclophosphamide and somewhat more efficacious than azathioprine. Differential responses to mycophenolate mofetil based on ethnicity suggest that it may be more effective in black and Hispanic patients. Rituximab was not efficacious as an adjunct to induction treatment with mycophenolate mofetil. C1 NIAMSD, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMSD, Intramural Res Program, NIH, Bldg 10CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. NR 55 TC 4 Z9 6 U1 0 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-857X EI 1558-3163 J9 RHEUM DIS CLIN N AM JI Rheum. Dis. Clin. North Am. PD AUG PY 2014 VL 40 IS 3 BP 519 EP + DI 10.1016/j.rdc.2014.05.001 PG 18 WC Rheumatology SC Rheumatology GA AM2PZ UT WOS:000339694600010 PM 25034160 ER PT J AU Arimbasseri, AG Kassavetis, GA Maraia, RJ AF Arimbasseri, Aneeshkumar G. Kassavetis, George A. Maraia, Richard J. TI Comment on "Mechanism of eukaryotic RNA polymerase III transcription termination" SO SCIENCE LA English DT Editorial Material ID SACCHAROMYCES-CEREVISIAE AB Nielsen et al. (Reports, 28 June 2013, p. 1577) characterized their RNA polymerase III (Pol III) preparation and concluded that it requires an RNA hairpin/duplex structure for terminating transcription. We could not corroborate their findings using bona fide Pol III from two laboratory sources. We show that Pol III efficiently terminates transcription in the absence of a hairpin/duplex in vitro and in vivo. C1 [Arimbasseri, Aneeshkumar G.; Maraia, Richard J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program, NIH, Bethesda, MD 20847 USA. [Kassavetis, George A.] Univ Calif San Diego, Div Biol Sci, San Diego, CA 92103 USA. [Maraia, Richard J.] US PHS, Commissioned Corps, Washington, DC 20201 USA. RP Maraia, RJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program, NIH, Bethesda, MD 20847 USA. EM maraiar@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999, ZIA HD000412-25, ZIA HD000412-26] NR 15 TC 9 Z9 9 U1 0 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD AUG 1 PY 2014 VL 345 IS 6196 DI 10.1126/science.1253783 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM2AU UT WOS:000339651300034 PM 25082694 ER PT J AU Carragher, N Krueger, RF Eaton, NR Markon, KE Keyes, KM Blanco, C Saha, TD Hasin, DS AF Carragher, Natacha Krueger, Robert F. Eaton, Nicholas R. Markon, Kristian E. Keyes, Katherine M. Blanco, Carlos Saha, Tulshi D. Hasin, Deborah S. TI ADHD and the externalizing spectrum: direct comparison of categorical, continuous, and hybrid models of liability in a nationally representative sample SO SOCIAL PSYCHIATRY AND PSYCHIATRIC EPIDEMIOLOGY LA English DT Article DE Externalizing; Comorbidity; ADHD; Classification; DSM-5 ID SUBSTANCE USE DISORDERS; ALCOHOL-USE-DISORDER; PSYCHIATRIC DIAGNOSTIC MODULES; INTERVIEW SCHEDULE AUDADIS; GENERAL-POPULATION SAMPLE; COMMON MENTAL-DISORDERS; FACTOR MIXTURE-MODELS; DSM-IV; PERSONALITY-DISORDER; FIT INDEXES AB Alcohol use disorders, substance use disorders, and antisocial personality disorder share a common externalizing liability, which may also include attention-deficit hyperactivity disorder (ADHD). However, few studies have compared formal quantitative models of externalizing liability, with the aim of delineating the categorical and/or continuous nature of this liability in the community. This study compares categorical, continuous, and hybrid models of externalizing liability. Data were derived from the 2004-2005 National Epidemiologic Survey on Alcohol and Related Conditions (N = 34,653). Seven disorders were modeled: childhood ADHD and lifetime diagnoses of antisocial personality disorder (ASPD), nicotine dependence, alcohol dependence, marijuana dependence, cocaine dependence, and other substance dependence. The continuous latent trait model provided the best fit to the data. Measurement invariance analyses supported the fit of the model across genders, with females displaying a significantly lower probability of experiencing externalizing disorders. Cocaine dependence, marijuana dependence, other substance dependence, alcohol dependence, ASPD, nicotine dependence, and ADHD provided the greatest information, respectively, about the underlying externalizing continuum. Liability to externalizing disorders is continuous and dimensional in severity. The findings have important implications for the organizational structure of externalizing psychopathology in psychiatric nomenclatures. C1 [Carragher, Natacha] Univ New S Wales, Natl Drug & Alcohol Res Ctr, Sydney, NSW 2052, Australia. [Krueger, Robert F.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Eaton, Nicholas R.] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Markon, Kristian E.] Univ Iowa, Dept Psychol, Iowa City, IA 52242 USA. [Keyes, Katherine M.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Blanco, Carlos] Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, New York, NY 10032 USA. [Saha, Tulshi D.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD USA. [Hasin, Deborah S.] Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York, NY 10032 USA. RP Carragher, N (reprint author), Univ New S Wales, Natl Drug & Alcohol Res Ctr, Sydney, NSW 2052, Australia. EM n.carragher@unsw.edu.au FU NIH [U01AA018111, K05AA014223]; New York State Psychiatric Institute FX This work was funded by NIH grants U01AA018111 and K05AA014223 and the New York State Psychiatric Institute (Dr. Hasin). NR 57 TC 11 Z9 11 U1 0 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0933-7954 EI 1433-9285 J9 SOC PSYCH PSYCH EPID JI Soc. Psychiatry Psychiatr. Epidemiol. PD AUG PY 2014 VL 49 IS 8 BP 1307 EP 1317 DI 10.1007/s00127-013-0770-3 PG 11 WC Psychiatry SC Psychiatry GA AM5JS UT WOS:000339894400014 PM 24081325 ER PT J AU Shrestha, S Bjornstad, ON King, AA AF Shrestha, Sourya Bjornstad, Ottar N. King, Aaron A. TI Evolution of acuteness in pathogen metapopulations: conflicts between "classical" and invasion-persistence trade-offs SO THEORETICAL ECOLOGY LA English DT Article DE Evolution of infectious pathogens; Invasion-persistence trade-off; Metapopulation model; Acute infections; Individual-based model; Bordetellae ID STRUCTURED POPULATIONS; WITHIN-HOST; VIRULENCE; SELECTION; EPIDEMICS; DYNAMICS; MODEL; TIME; MICROPARASITES; TRANSMISSION AB Classical life-history theory predicts that acute, immunizing pathogens should maximize between-host transmission. When such pathogens induce violent epidemic outbreaks, however, a pathogen's short-term advantage at invasion may come at the expense of its ability to persist in the population over the long term. Here, we seek to understand how the classical and invasion-persistence trade-offs interact to shape pathogen life-history evolution as a function of the size and structure of the host population. We develop an individual-based infection model at three distinct levels of organization: within an individual host, among hosts within a local population, and among local populations within a metapopulation. We find a continuum of evolutionarily stable pathogen strategies. At one end of the spectrum-in large well-mixed populations-pathogens evolve to greater acuteness to maximize between-host transmission: the classical trade-off theory applies in this regime. At the other end of the spectrum-when the host population is broken into many small patches-selection favors less acute pathogens, which persist longer within a patch and thereby achieve enhanced between-patch transmission: the invasion-persistence trade-off dominates in this regime. Between these extremes, we explore the effects of the size and structure of the host population in determining pathogen strategy. In general, pathogen strategies respond to evolutionary pressures arising at both scales. C1 [Shrestha, Sourya; King, Aaron A.] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Shrestha, Sourya; King, Aaron A.] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Bjornstad, Ottar N.] Penn State Univ, Dept Entomol & Biol, University Pk, PA 16802 USA. [King, Aaron A.] Univ Michigan, Dept Math, Ann Arbor, MI 48109 USA. [Bjornstad, Ottar N.; King, Aaron A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Shrestha, S (reprint author), Johns Hopkins Sch Publ Hlth, Baltimore, MD 21205 USA. EM sourya@umich.edu OI Shrestha, Sourya/0000-0002-6106-6834 FU Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, US Department of Homeland Security; Fogarty International Center, US National Institutes of Health; National Institutes of Health [1-R01-AI-101155] FX Financial support was provided by the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, US Department of Homeland Security, and the Fogarty International Center, US National Institutes of Health. AAK acknowledges the support of the National Institutes of Health (grant # 1-R01-AI-101155). NR 31 TC 1 Z9 1 U1 3 U2 7 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1874-1738 EI 1874-1746 J9 THEOR ECOL-NETH JI Theor. Ecol. PD AUG PY 2014 VL 7 IS 3 BP 299 EP 311 DI 10.1007/s12080-014-0219-7 PG 13 WC Ecology SC Environmental Sciences & Ecology GA AM4JN UT WOS:000339820000007 PM 25214895 ER PT J AU Gray, K Elghadban, S Thongyoo, P Owen, KA Szabo, R Bugge, TH Tate, EW Leatherbarrow, RJ Ellis, V AF Gray, Kelly Elghadban, Salma Thongyoo, Panumart Owen, Kate A. Szabo, Roman Bugge, Thomas H. Tate, Edward W. Leatherbarrow, Robin J. Ellis, Vincent TI Potent and specific inhibition of the biological activity of the type-II transmembrane serine protease matriptase by the cyclic microprotein MCoTI-II SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Serine protease; protease inhibitor; hepatocyte growth factor; epithelial cell; tight junctions; matriptase; cyclotide ID HEPATOCYTE GROWTH-FACTOR; PROSTASIN PROTEOLYTIC CASCADE; FACTOR ACTIVATOR INHIBITOR-1; EPIDERMAL DIFFERENTIATION; PLASMINOGEN-ACTIVATOR; ZYMOGEN ACTIVATION; CANCER; CARCINOGENESIS; AFFINITY; SURFACE AB Matriptase is a type-II transmembrane serine protease involved in epithelial homeostasis in both health and disease, and is implicated in the development and progression of a variety of cancers. Matriptase mediates its biological effects both via as yet undefined substrates and pathways, and also by proteolytic cleavage of a variety of well-defined protein substrates, several of which it shares with the closely-re-lated protease hepsin. Development of targeted therapeutic strategies will require discrimination between these proteases. Here we have investigated cyclic microproteins of the squash Momordica cochinchinensis trypsin-inhibitor family (generated by total chemical synthesis) and found MCoTI-II to be a high-affinity (K-I 9 nM) and highly selective (> 1,000-fold) inhibitor of matriptase. MCoTI-II efficiently inhibited 1 the proteolytic activation of pro-hepatocyte growth factor (HGF) by matriptase but not by hepsin, in both purified and cell-based systems,, and inhibited HGF-dependent cell scattering. MCoTI-II also selectively inhibited the invasion of matriptase-expressing prostate cancer cells. Using a model of epithelial cell tight junction assembly, we also found that MCoTI-II could effectively inhibit the re-establishment of tight junctions and epithelial barrier function in MDCK-I cells after disruption, consistent with the role of matriptase in regulating epithelial integrity. Surprisingly, MCoTI-II was unable to inhibit matriptasedependent proteolytic activation of prostasin, a GPI-anchored serine protease also implicated in epithelial homeostasis. These observations suggest that the unusually high selectivity afforded by MCoTI-II and its biological effectiveness might represent a useful starting point for the development of therapeutic inhibitors, and further highlight the role of matriptase in epithelial maintenance. C1 [Gray, Kelly; Elghadban, Salma; Owen, Kate A.; Ellis, Vincent] Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England. [Thongyoo, Panumart; Tate, Edward W.; Leatherbarrow, Robin J.] Univ London Imperial Coll Sci Technol & Med, Biol & Biophys Chem Sect, Dept Chem, London SW7 2AZ, England. [Szabo, Roman; Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Ellis, V (reprint author), Univ E Anglia, Sch Biol Sci, Norwich Res Pk, Norwich NR4 7TJ, Norfolk, England. EM v.ellis@uea.ac.uk RI Ellis, Vincent/D-1860-2009; OI Ellis, Vincent/0000-0003-1956-073X; Thongyoo, Panumart/0000-0001-9918-8805 FU Norfolk and Waveney Big C Cancer Charity; John and Pamela Salter Charitable Trust; European Union FX This study was supported by the Norfolk and Waveney Big C Cancer Charity, the John and Pamela Salter Charitable Trust and by European Union FP6 (Cancerdegradome) project. NR 52 TC 9 Z9 9 U1 1 U2 14 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD AUG PY 2014 VL 112 IS 2 BP 402 EP 411 DI 10.1160/TH13-11-0895 PG 10 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AM4YH UT WOS:000339861600019 PM 24696092 ER PT J AU Ferraz, RRN Fonseca, JM Germino, GG Onuchic, LF Heilberg, IP AF Nogueira Ferraz, Renato Ribeiro Fonseca, Jonathan Mackowiak Germino, Gregory George Onuchic, Luiz Fernando Heilberg, Ita Pfeferman TI Determination of urinary lithogenic parameters in murine models orthologous to autosomal dominant polycystic kidney disease SO UROLITHIASIS LA English DT Article DE ADPKD; Nephrolithiasis; Pkd1 haploinsufficiency; Renal cysts; Uric acid; Urinary analytes ID CYSTIC-DISEASE; NEPHROLITHIASIS; OXALATE; PKD1; PROGRESSION; STONES; MICE AB Autosomal dominant polycystic kidney disease (ADPKD), a genetic disease caused by mutations in PKD1 or PKD2 genes, is associated with a high prevalence of nephrolithiasis. The underlying mechanisms may encompass structural abnormalities resulting from cyst growth, urinary metabolic abnormalities or both. An increased frequency of hypocitraturia has been described in ADPKD even in the absence of nephrolithiasis, suggesting that metabolic alterations may be associated with ADPKD per se. We aimed to investigate whether non-cystic Pkd1-haploinsufficient (Pkd1 (+/-)) and/or nestin-Cre Pkd1-targeted cystic (Pkd1 (cond/cond):Nestin(cre)) mouse models develop urinary metabolic abnormalities potentially related to nephrolithiasis in ADPKD. 24-h urine samples were collected during three non-consecutive days from 10-12 and 18-20 week-old animals. At 10-12 weeks of age, urinary oxalate, calcium, magnesium, citrate and uric acid did not differ between test and their respective control groups. At 18-20 weeks, Pkd1 (+/-) showed slightly but significantly higher urinary uric acid vs. controls while cystic animals did not. The absence of hypocitraturia, hyperoxaluria and hyperuricosuria in the cystic model at both ages and the finding of hyperuricosuria in the 18-20 week-old animals suggest that anatomic cystic distortions per se do not generate the metabolic disturbances described in human ADPKD-related nephrolithiasis, while Pkd1 haploinsufficiency may contribute to this phenotype in this animal model. C1 [Nogueira Ferraz, Renato Ribeiro; Heilberg, Ita Pfeferman] Univ Fed Sao Paulo, Div Nephrol, BR-04023900 Sao Paulo, Brazil. [Fonseca, Jonathan Mackowiak; Onuchic, Luiz Fernando] Univ Sao Paulo, Sch Med, Div Nephrol, Sao Paulo, Brazil. [Fonseca, Jonathan Mackowiak; Onuchic, Luiz Fernando] Ctr Cellular & Mol Studies & Therapy NETCEM, Sao Paulo, Brazil. [Germino, Gregory George] NIDDK, Bethesda, MD USA. RP Heilberg, IP (reprint author), Univ Fed Sao Paulo, Div Nephrol, Rua Botucatu,740 Vila Clementino, BR-04023900 Sao Paulo, Brazil. EM ita.heilberg@gmail.com RI Onuchic, Luiz/H-1589-2012 FU Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [150638/2009-4]; Fundacao Oswaldo Ramos; Fundacao de Amparo a Pesquisa (FAPESP) [2010/17424-0] FX This research was supported by Grants from the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Grant 150638/2009-4, Fundacao Oswaldo Ramos, and Fundacao de Amparo a Pesquisa (FAPESP) Grant 2010/17424-0. NR 33 TC 1 Z9 1 U1 3 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 2194-7228 EI 2194-7236 J9 UROLITHIASIS JI Urolithiasis PD AUG PY 2014 VL 42 IS 4 BP 301 EP 307 DI 10.1007/s00240-014-0664-1 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AM4DR UT WOS:000339803400003 PM 24817661 ER PT J AU Sadri, N Barroeta, J Pack, SD Abdullaev, Z Chatterjee, B Puthiyaveettil, R Brooks, JS Barr, FG Zhang, PJ AF Sadri, Navid Barroeta, Julieta Pack, Svetlana D. Abdullaev, Zied Chatterjee, Bishwanath Puthiyaveettil, Raghunath Brooks, John S. Barr, Frederic G. Zhang, Paul J. TI Malignant round cell tumor of bone with EWSR1-NFATC2 gene fusion SO VIRCHOWS ARCHIV LA English DT Article DE EWSR1-NFATc2 fusion gene; EWSR1; Ewing's sarcoma; Osteosarcoma ID EWINGS-SARCOMA TRANSLOCATION; SOFT-TISSUE TUMORS; EWS GENE; CHROMOSOME-TRANSLOCATION; EWSR1-ATF1 FUSION; OSTEOSARCOMA; FAMILY; FLI-1; CHONDROSARCOMA; EWSR1-CREB1 AB Gene rearrangements involving the Ewing sarcoma breakpoint region 1 (EWSR1) gene are seen in a broad range of sarcomas and some nonmesenchymal neoplasms. Ewing sarcoma is molecularly defined by a fusion of the EWSR1 gene (or rarely the related FUS gene) to a member of the E26 transformation-specific (ETS) family of transcription factors, frequently the EWSR1-FLI1 fusion. More recently, EWSR1 gene fusion to non-ETS family members, including the nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 2 (NFATC2) gene, has been reported in a histological variant of Ewing sarcoma. Here, we report a malignant round cell tumor of bone with an EWSR1-NFATC2 fusion gene. This report builds upon the unusual morphological and clinical presentation of bone neoplasms containing an EWSR1-NFATC2 fusion gene. C1 [Sadri, Navid; Puthiyaveettil, Raghunath; Zhang, Paul J.] Hosp Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Barroeta, Julieta; Brooks, John S.] Penn Hosp, Dept Pathol & Lab Med, Philadelphia, PA 19107 USA. [Pack, Svetlana D.; Abdullaev, Zied; Chatterjee, Bishwanath; Barr, Frederic G.] Natl Canc Inst, Pathol Lab, Bethesda, MD 20892 USA. RP Sadri, N (reprint author), Hosp Univ Penn, Dept Pathol & Lab Med, 3400 Spruce St, Philadelphia, PA 19104 USA. EM sadrin@mskcc.org; barrfg@mail.nih.gov; pjz@mail.med.upenn.edu NR 43 TC 3 Z9 3 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0945-6317 EI 1432-2307 J9 VIRCHOWS ARCH JI Virchows Arch. PD AUG PY 2014 VL 465 IS 2 BP 233 EP 239 DI 10.1007/s00428-014-1613-7 PG 7 WC Pathology SC Pathology GA AM6CX UT WOS:000339950400013 PM 24993903 ER PT J AU Phillips, JE Stallknecht, DE Perkins, TA McClure, NS Mead, DG AF Phillips, J. E. Stallknecht, D. E. Perkins, T. A. McClure, N. S. Mead, D. G. TI Evolutionary dynamics of West Nile virus in Georgia, 2001-2011 SO VIRUS GENES LA English DT Article DE West Nile virus; Evolutionary analysis; Genetic surveillance; Mosquito-borne flavivirus ID UNITED-STATES; PHYLOGENETIC ANALYSIS; BLOOD-DONORS; USA; GENOTYPE; AMERICA; SPREAD AB From 1999-2001, West Nile virus (WNV) spread throughout the eastern United States (US) and was first detected in Georgia in 2001. To date, the virus has been detected in over 2,500 dead wild bird and mosquito samples from across Georgia. We sequenced the premembrane (preM) and envelope gene (E) (2004 bp) from 111 isolates collected from 2001 to 2011. To assess viral gene flow from other geographic regions in the US, we combined our data with WNV sequences available at the National Center for Biotechnology Information (NCBI) and performed phylogenetic analysis. We found evidence that WNV isolates detected in Chatham County Georgia most likely originated from the Northeastern United States. These results highlight the growing importance of adequate genetic surveillance for monitoring and controlling viruses of public health concern. C1 [Phillips, J. E.; Stallknecht, D. E.; Mead, D. G.] Univ Georgia, Dept Populat Hlth, Coll Vet Med, Southeastern Cooperat Wildlife Dis Study, Athens, GA 30602 USA. [Perkins, T. A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Perkins, T. A.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [McClure, N. S.] Queens Univ, Dept Biol, Kingston, ON K7L 3N6, Canada. RP Phillips, JE (reprint author), Univ Georgia, Dept Populat Hlth, Coll Vet Med, Southeastern Cooperat Wildlife Dis Study, 589 DW Brooks Dr, Athens, GA 30602 USA. EM jamiep44@gmail.com FU Georgia Department of Human Resources through the Centers for Disease Control and Prevention's "Epidemiology and Laboratory Capacity for Infectious Diseases'' Grant Program [42793-02241, 42793-35023, 42793-45142, 427930505084199, 42793-0606053599, 4279394848, 427930707111899, 427930909124499]; University of Georgia Provost's Office Competitive Research Grant; member states of the Southeastern Cooperative Wildlife Disease Study provided by the Federal Aid to Wildlife Restoration Act FX The authors thank Jennifer Abi Younes, all the Southeastern Cooperative Wildlife Disease Study diagnosticians for their diagnostic support, as well as other county level officials for collection and submission of mosquitoes and birds. Support for this project was provided by the Georgia Department of Human Resources through the Centers for Disease Control and Prevention's "Epidemiology and Laboratory Capacity for Infectious Diseases'' Grant Program (Contract Nos. 42793-02241, 42793-35023, 42793-45142, 427930505084199, 42793-0606053599, 4279394848, 427930707111899, 427930909124499, and 427930909124499), a University of Georgia Provost's Office Competitive Research Grant, and from the member states of the Southeastern Cooperative Wildlife Disease Study provided by the Federal Aid to Wildlife Restoration Act (50 Stat. 917). NR 17 TC 1 Z9 1 U1 0 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-8569 EI 1572-994X J9 VIRUS GENES JI Virus Genes PD AUG PY 2014 VL 49 IS 1 BP 132 EP 136 DI 10.1007/s11262-014-1061-0 PG 5 WC Genetics & Heredity; Virology SC Genetics & Heredity; Virology GA AM3DA UT WOS:000339731000015 PM 24691819 ER PT J AU Summers, RM AF Summers, Ronald M. TI Tumor Response Assessment Using Volumetric Doubling Time: Better Than RECIST? SO ACADEMIC RADIOLOGY LA English DT Editorial Material ID COMPUTED-TOMOGRAPHY; CRITERIA; CARCINOMA C1 NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bethesda, MD 20892 USA. RP Summers, RM (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bldg 10,Room 1C224D MSC 1182, Bethesda, MD 20892 USA. EM rms@nih.gov FU Intramural NIH HHS NR 14 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD AUG PY 2014 VL 21 IS 8 BP 947 EP 949 DI 10.1016/j.acra.2014.04.002 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AM1JY UT WOS:000339603400001 PM 25018066 ER PT J AU Wilkes, AL Jones, PL Morales-Reid, B Ramos, B Vega, MY Scholes, D Farrell, D Edwards, A Polk, L AF Wilkes, Aisha L. Jones, Patricia L. Morales-Reid, Bethsy Ramos, Bertha Vega, Miriam Y. Scholes, Delia Farrell, David Edwards, Arlene Polk, LaShaun TI LESSONS LEARNED WHILE PREPARING A TAILORED, SELF-HELP, TECHNOLOGY-DRIVEN INTERVENTION FOR NATIONAL DISSEMINATION SO AIDS EDUCATION AND PREVENTION LA English DT Article ID EFFECTIVE BEHAVIORAL INTERVENTIONS; HIV-PREVENTION INTERVENTIONS; HEALTH; IMPLEMENTATION; METAANALYSIS; PROGRAMS; MODEL AB Tailored health interventions have been found to be effective in various areas of health promotion because of their delivery of customized content, which focuses the prevention messages more closely on the individual's risk behavior. However, the use of tailored interventions in the prevention of STD/HIV has been limited, and there is a void in the literature on translating tailored interventions into practice. This paper discusses the process of translating a tailored, self-help, technology-driven STD/HIV prevention intervention from research-to-practice. Three agencies were selected during the translation process to test the intervention materials and provided valuable lessons learned for translating a tailored intervention into practice. A racially diverse group of more than 250 women in six states participated in the intervention during this pilot test. Lessons learned for research-to-practice efforts for tailored interventions are presented, including expanding the reach of such interventions by making them more compatible for mobile technology. C1 [Wilkes, Aisha L.; Edwards, Arlene; Polk, LaShaun] Ctr Dis Control & Prevent CDC, Atlanta, GA USA. [Jones, Patricia L.] NIH, Bethesda, MD USA. [Jones, Patricia L.] CDC, Atlanta, GA 30333 USA. [Morales-Reid, Bethsy; Ramos, Bertha; Vega, Miriam Y.] Latino Commiss AIDS, New York, NY USA. [Scholes, Delia] Grp Hlth Res Inst, Seattle, WA USA. [Farrell, David] People Designs Inc, Makati, Philippines. RP Wilkes, AL (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd NE,Mailstop E-37, Atlanta, GA 30329 USA. EM awilkes@cdc.gov NR 30 TC 1 Z9 1 U1 1 U2 5 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0899-9546 EI 1943-2755 J9 AIDS EDUC PREV JI Aids Educ. Prev. PD AUG PY 2014 VL 26 IS 4 BP 281 EP 295 PG 15 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA AM0WJ UT WOS:000339568000001 PM 25068177 ER PT J AU Vuittonet, CL Halse, M Leggio, L Fricchione, SB Brickley, M Haass-Koffler, CL Tavares, T Swift, RM Kenna, GA AF Vuittonet, Cynthia L. Halse, Michael Leggio, Lorenzo Fricchione, Samuel B. Brickley, Michael Haass-Koffler, Carolina L. Tavares, Tonya Swift, Robert M. Kenna, George A. TI Pharmacotherapy for alcoholic patients with alcoholic liver disease SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article ID PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED-TRIAL; DOUBLE-BLIND; UNITED-STATES; FATTY LIVER; NONALCOHOLIC STEATOHEPATITIS; CRYPTOGENIC CIRRHOSIS; EPIDEMIOLOGIC SURVEY; ETHNIC-DIFFERENCES; DEPENDENT PATIENTS AB Purpose. An update on pharmacotherapy for achieving and maintaining abstinence and mitigating hepatic damage in patients with alcoholic liver disease (ALD) is presented. Summary. Currently there are limited pharmacotherapy options for managing ALD, which encompasses a broad spectrum of disorders ranging from steatosis and alcoholic hepatitis to fibrosis, cirrhosis, and hepatocellular cancer. Individual variation in the severity, presentation, and complex pathologenesis of ALD defines barriers to effective treatment. Scoring of disease severity using validated assessment instruments should guide treatment approaches; abstinence and proper nutrition continue to be the cornerstones of management. A literature search (through December 31, 2013) identified no reports of randomized controlled trials using Food and Drug Administration (FDA)-approved medications for the treatment of alcohol dependence in ALD-spectrum disorders. Disulfiram, acamprosate, and naltrexone (oral and intramuscular), while approved by FDA for treatment of alcohol dependence, are not currently approved for use in patients with ALD. Baclofen (also not FDA-approved for use in ALD) is the only medication available in the United States with demonstrated safety and efficacy in reducing alcoholic behavior that has been formally tested in clinical trials in patients with ALD. Pharmacotherapy of alcoholic hepatitis using glucocorticoids or pentoxifylline has shown promise, but these options are reserved for severe ALD only. Conclusion. Although various treatments have been investigated for ALD in patients with alcoholism, complete abstinence from alcohol is currently the only recommended form of hepatoprotection for the entire spectrum of ALD diagnoses. C1 [Vuittonet, Cynthia L.] Brown Univ, Warren Alpert Med Sch, Dept Internal Med, Providence, RI 02912 USA. [Halse, Michael] South Cty Hosp, Wakefield, RI USA. [Leggio, Lorenzo] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Lab Clin & Translat Studies, NIH, Baltimore, MD USA. [Leggio, Lorenzo] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Leggio, Lorenzo; Fricchione, Samuel B.; Brickley, Michael; Haass-Koffler, Carolina L.; Tavares, Tonya; Swift, Robert M.; Kenna, George A.] Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [Swift, Robert M.] Providence Vet Affairs Med Ctr, Providence, RI USA. [Swift, Robert M.; Kenna, George A.] Brown Univ, Dept Psychiat & Human Behav, Warren Alpert Med Sch, Providence, RI 02912 USA. RP Kenna, GA (reprint author), Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. EM george_kenna@brown.edu RI Leggio, Lorenzo/M-2972-2016 FU National Institute on Alcohol Abuse and Alcoholism [R01-AA016079, R03AA020169, R21AA019709, R01-AA015753, R21AA019994, R21AA021128]; Laboratorio Farmaceutico CT Srl [GET73]; D A Pharma FX Drs. Kenna and Swift are currently receiving or have received support from the National Institute on Alcohol Abuse and Alcoholism from the following grants: R01-AA016079 (drugs under study, ondansetron and sertraline), R03AA020169 (baclofen), R21AA019709 (ghrelin), R01-AA015753 (aripiprazole and topiramate), R21AA019994 (doxazosin), and R21AA021128 (metadoxine). Drs. Kenna and Swift have received consultant fees from Laboratorio Farmaceutico CT Srl (drug under study, GET73). Dr. Swift has received fees from D & A Pharma. The other authors have declared no potential conflicts of interest. NR 81 TC 9 Z9 10 U1 0 U2 10 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 EI 1535-2900 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD AUG 1 PY 2014 VL 71 IS 15 BP 1265 EP 1276 DI 10.2146/ajhp140028 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AM1ZI UT WOS:000339647400010 PM 25027533 ER PT J AU Sorokin, Y Romero, R Mele, L Iams, JD Peaceman, AM Leveno, KJ Harper, M Caritis, SN Mercer, BM Thorp, JM O'Sullivan, MJ Ramin, SM Carpenter, MW Rouse, DJ Sibai, B AF Sorokin, Yoram Romero, Roberto Mele, Lisa Iams, Jay D. Peaceman, Alan M. Leveno, Kenneth J. Harper, Margaret Caritis, Steve N. Mercer, Brian M. Thorp, John M. O'Sullivan, Mary Jo Ramin, Susan M. Carpenter, Marshall W. Rouse, Dwight J. Sibai, Baha TI Umbilical Cord Serum Interleukin-6, C-Reactive Protein, and Myeloperoxidase Concentrations at Birth and Association with Neonatal Morbidities and Long-Term Neurodevelopmental Outcomes SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE umbilical cord serum; cytokines; preterm birth; neonatal morbidity; neurodevelopmental infant outcome ID FETAL INFLAMMATORY RESPONSE; TUMOR-NECROSIS-FACTOR; AMNIOTIC-FLUID INFECTION; CHRONIC LUNG-DISEASE; RESPIRATORY-DISTRESS-SYNDROME; BRONCHOPULMONARY DYSPLASIA; PRETERM INFANTS; CEREBRAL-PALSY; PERIVENTRICULAR LEUKOMALACIA; WEIGHT INFANTS AB Objective The aim of the study is to determine if umbilical cord serum concentrations of interleukin-6 (IL-6), C-reactive protein (CRP), and myeloperoxidase (MPO), in pregnancies at risk for preterm birth (PTB), are associated with neonatal morbidities and/or altered neurodevelopmental outcomes in the children. Study Design Umbilical cord serum samples were collected at birth from 400 newborns delivered within a multicenter randomized controlled trial of repeated versus single course of antenatal corticosteroids (ACs), in women at increased risk for PTB. Newborns were followed through discharge and were evaluated between 36 and 42 months corrected age with neurological examination and Bayley Scales of Infant Development. Umbilical cord serum concentrations of IL-6, CRP, and MPO were determined using enzyme-linked immunoassays. Multivariate logistic regression analyses explored the relationship between umbilical cord serum IL-6, CRP, and MPO levels, adverse newborn outcomes, and PTB < 32 weeks of gestational age (GA). Results Univariate analysis revealed that umbilical cord IL-6 above the 75th percentile was associated with increased respiratory distress syndrome (RDS) and chronic lung disease (CLD), but not with necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), or neonatal sepsis; however, this association was not significant after adjusting for GA at delivery and treatment group. No significant associations between CRP or MPO and RDS, CLD, NEC, sepsis, or IVH were evident. Regression analysis revealed that CRP above the 75th percentile was associated with a decreased risk of CLD (odds ratio, 0.10; 95% confidence interval, 0.02-0.41). No associations between umbilical cord IL-6, CRP, or MPO and MDI < 70 or PDI < 70 were evident. Umbilical cord serum concentrations of IL-6, CRP, and MPO, above the 75th percentile, were associated with more frequent PTB < 32 weeks of GA. Conclusion Elevated umbilical cord serum concentration of CRP is associated with reduced risk for CLD even after adjusting for GA at delivery. Occurrence of levels > 75th percentile of IL-6, CRP, and MPO in umbilical cord serum was associated with PTB < 32 weeks of GA. Elevated umbilical cord serum concentrations of IL-6, CRP, and MPO at birth were not associated with poor neurodevelopmental outcomes. C1 [Sorokin, Yoram] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Detroit, MI 48201 USA. [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Detroit, MI USA. [Mele, Lisa] George Washington Univ, Ctr Biostat, Washington, DC USA. [Iams, Jay D.] Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Peaceman, Alan M.] Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Leveno, Kenneth J.] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. [Harper, Margaret] Wake Forest Univ Hlth Sci, Dept Obstet & Gynecol, Winston Salem, NC USA. [Caritis, Steve N.] Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. [Mercer, Brian M.] Case Western Reserve Univ, Metrohlth Med Ctr, Dept Obstet & Gynecol, Cleveland, OH USA. [Thorp, John M.] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. [O'Sullivan, Mary Jo] Univ Miami, Dept Obstet & Gynecol, Miami, FL USA. [Ramin, Susan M.] Univ Texas Hlth Sci Ctr Houston, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Carpenter, Marshall W.] Brown Univ, Dept Obstet & Gynecol, Providence, RI 02912 USA. [Rouse, Dwight J.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Sibai, Baha] Univ Tennessee, Dept Obstet & Gynecol, Memphis, TN 38103 USA. RP Sorokin, Y (reprint author), Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Hutzel Womens Hosp,Div Maternal Fetal Med, 3990 John R,Mailbox 163, Detroit, MI 48201 USA. EM ysorokin@med.wayne.edu OI caritis, steve/0000-0002-2169-0712 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD21410, HD21414, HD27869, HD27917, HD27905, HD27860, HD27861, HD27915, HD34122, HD34116, HD34208, HD34136, HD40500, HD40485, HD40544, HD40545, HD40560, HD40512, HD36801]; National Center for Research Resources (NCRR) [M01-RR-000080] FX This study was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD21410, HD21414, HD27869, HD27917, HD27905, HD27860, HD27861, HD27915, HD34122, HD34116, HD34208, HD34136, HD40500, HD40485, HD40544, HD40545, HD40560, HD40512, HD36801) and M01-RR-000080 from the National Center for Research Resources (NCRR) and its content is solely the responsibility of the authors and does not necessarily represent the official views of the NICHD, the National Institutes of Health, and the NCRR. NR 62 TC 8 Z9 9 U1 0 U2 2 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 EI 1098-8785 J9 AM J PERINAT JI Am. J. Perinatol. PD AUG PY 2014 VL 31 IS 8 BP 717 EP 726 DI 10.1055/s-0033-1359723 PG 10 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA AL9JZ UT WOS:000339458700012 PM 24338120 ER PT J AU Yusen, RD Hong, BA Messersmith, EE Gillespie, BW Lopez, BM Brown, KL Odim, J Merion, RM Barr, ML AF Yusen, R. D. Hong, B. A. Messersmith, E. E. Gillespie, B. W. Lopez, B. M. Brown, K. L. Odim, J. Merion, R. M. Barr, M. L. CA RELIVE Study Grp TI Morbidity and Mortality of Live Lung Donation: Results From the RELIVE Study SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Live donors; lung transplantation; mortality; outcomes ID PERIOPERATIVE COMPLICATIONS; ORGAN DONOR; TRANSPLANTATION; GUIDELINES; STATEMENT AB The Renal and Lung Living Donors Evaluation Study assesses outcomes of live lung (lobectomy) donors. This is a retrospective cohort study at University of Southern California (USC) and Washington University (WASHU) Medical Centers (1993-2006), using medical records to assess morbidity and national databases to ascertain postdonation survival and lung transplantation. Serious complications were defined as those that required significant treatment, were potentially life-threatening or led to prolonged hospitalization. The 369 live lung donors (287 USC, 82 WASHU) were predominantly white, non-Hispanic and male; 72% had a biological relationship to the recipient, and 30% were recipient parents. Serious complications occurred in 18% of donors; 2.2% underwent reoperation and 6.5% had an early rehospitalization. The two centers had significantly different incidences of serious complications (p<0.001). No deaths occurred and no donors underwent lung transplantation during 4000+person-years of follow-up (death: minimum 4, maximum 17 years; transplant: minimum 5, maximum 19). Live lung donation remains a potential option for recipients when using deceased donor lungs lacks feasibility. However, the use of two live donors for each recipient and the risk of morbidity associated with live lung donation do not justify this approach when deceased lung donors remain available. Center effects and long-term live donor outcomes require further evaluation. C1 [Yusen, R. D.; Hong, B. A.] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Messersmith, E. E.; Merion, R. M.] Arbor Res Collaborat Hlth, Ann Arbor, MI USA. [Gillespie, B. W.; Merion, R. M.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Lopez, B. M.] Univ So Calif, Dept Cardiothorac Surg, Los Angeles, CA USA. [Brown, K. L.] Alternat Hosp, Fenton, MO USA. [Odim, J.] NIAID, NIH, Rockville, MD USA. RP Yusen, RD (reprint author), Washington Univ, Sch Med, St Louis, MO 63130 USA. EM ryusen@dom.wustl.edu FU National Institute of Allergy and Infectious Diseases (NIAID); Health Resources and Services Administration (HRSA); National Heart, Lung, and Blood Institute (NHLBI); National Institutes of Health (NIH), NIAID [U01AI069545, U01A169550, U01AI69491]; HRSA FX This research was performed as a project of the Renal and Lung Living Donors Evaluation Study (RELIVE), a collaborative clinical research project sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), Health Resources and Services Administration (HRSA) and National Heart, Lung, and Blood Institute (NHLBI). The Minneapolis Medical Research Foundation (MMRF), as the contractor for the US Scientific Registry of Transplant Recipients (SRTR), provided SRTR and/or Social Security Death Master File (SSDMF) data under a data use agreement. This study used data from the SRTR. The SRTR data system includes data on all donor, wait-listed candidates, and transplant recipients in the United States, submitted by the members of the Organ Procurement and Transplantation Network (OPTN), and has been described elsewhere. HRSA, US Department of Health and Human Services provides oversight to the activities of the OPTN and SRTR contractors. The data reported here have been supplied by MMRF as the contractor for the SRTR. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy of or interpretation by the SRTR or the US Government. This study was sponsored by the National Institutes of Health (NIH), NIAID, grants U01AI069545, U01A169550 and U01AI69491 and the HRSA. NR 24 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD AUG PY 2014 VL 14 IS 8 BP 1846 EP 1852 DI 10.1111/ajt.12771 PG 7 WC Surgery; Transplantation SC Surgery; Transplantation GA AL9AZ UT WOS:000339433100020 PM 25039865 ER PT J AU Ulrich, CM Zhou, QP Hanlon, A Danis, M Grady, C AF Ulrich, Connie M. Zhou, Qiuping (Pearl) Hanlon, Alexandra Danis, Marion Grady, Christine TI The impact of ethics and work-related factors on nurse practitioners' and physician assistants' views on quality of primary healthcare in the United States SO APPLIED NURSING RESEARCH LA English DT Article DE Ethics confidence; Ethics preparedness; Nurse practitioners; Physician assistants; Practice autonomy; Quality of care ID MEDICAL-ETHICS; EDUCATION AB Purpose: Nurse practitioners (NPs) and physician assistants (PAs) provide primary care services for many American patients. Ethical knowledge is foundational to resolving challenging practice issues, yet little is known about the importance of ethics and work-related factors in the delivery of quality care. The aim of this study was to quantitatively assess whether the quality of the care that practitioners deliver is influenced by ethics and work-related factors. Methods: This paper is a secondary data analysis of a cross-sectional self-administered mailed survey of 1,371 primary care NPs and PAs randomly selected from primary care and primary care subspecialties in the United States. Results: Ethics preparedness and confidence were significantly associated with perceived quality of care (p < 0.01) as were work-related characteristics such as percentage of patients with Medicare and Medicaid, patient demands, physician collegiality, and practice autonomy (p < 0.01). Forty-four percent of the variance in quality of care was explained by these factors. Conclusions: Investing in ethics education and addressing restrictive practice environments may improve collaborative practice, teamwork, and quality of care. (C) 2014 Elsevier Inc. All rights reserved. C1 [Ulrich, Connie M.] Univ Penn, Sch Nursing, Dept Med Eth & Hlth Policy, Philadelphia, PA 19104 USA. [Ulrich, Connie M.] Univ Penn, New Courtland Ctr Transit & Hlth, Philadelphia, PA 19104 USA. [Zhou, Qiuping (Pearl)] George Washington Univ, Ashburn, VA 20147 USA. [Hanlon, Alexandra] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Danis, Marion; Grady, Christine] NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Ulrich, CM (reprint author), Univ Penn, Sch Nursing, Dept Med Eth & Hlth Policy, Philadelphia, PA 19106 USA. EM culrich@nursing.upenn.edu FU Department of Clinical Bioethics, National Institutes of Health FX This research was supported by the Department of Clinical Bioethics, National Institutes of Health. NR 19 TC 0 Z9 0 U1 1 U2 14 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0897-1897 EI 1532-8201 J9 APPL NURS RES JI Appl. Nurs. Res. PD AUG PY 2014 VL 27 IS 3 BP 152 EP 156 DI 10.1016/j.apnr.2014.01.001 PG 5 WC Nursing SC Nursing GA AM1IP UT WOS:000339599900002 PM 24613597 ER PT J AU Hinkle, SN Albert, PS Mendola, P Sjaarda, LA Boghossian, NS Yeung, E Laughon, SK AF Hinkle, S. N. Albert, P. S. Mendola, P. Sjaarda, L. A. Boghossian, N. S. Yeung, E. Laughon, S. K. TI Differences in risk factors for incident and recurrent small-for-gestational-age birthweight: a hospital-based cohort study SO BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY LA English DT Article DE Fetal growth restriction; small-for-gestational-age ID FETAL-GROWTH RESTRICTION; UNITED-STATES; RECOMMENDATIONS; SMOKING; WOMEN; GAIN; CARE AB Objective Examine whether small-for-gestational-age (SGA) risk factors differed by prior SGA birth. Design Hospital-based cohort study. Setting Utah, USA. Population Electronic medical record data from 25 241 women who were nulliparous at study entry with >= 2 subsequent consecutive singleton deliveries (2002-2010). Methods Estimated adjusted relative risks (RR) and 95% confidence intervals (95% CI) for the association between second pregnancy characteristics and SGA risk. Tested for risk factor differences between recurrence and incidence (P-difference). Main outcome measures Second pregnancy incident (n = 1067) and recurrent SGA (n = 484) determined using a population-based reference. Results SGA complicated 20.3 and 4.5% of deliveries to women with and without a prior SGA birth, respectively. Young maternal age (P-difference = 0.01) and pregnancy hypertensive diseases (P-difference = 0.03) were associated with incident but not recurrent SGA. Significant risk factors for incidence and recurrence were smoking (incident RR = 1.64 [ 95% CI 1.22-2.19]; recurrent RR = 1.59 [ 95% CI 1.17-2.17]), short stature (incident RR = 1.34 [ 95% CI 1.16-1.54]; recurrent RR = 1.54 [ 95% CI 1.31-1.82]), prepregnancy underweight (incident RR = 1.32 [ 95% CI 1.071.64]; recurrent RR = 1.30 [ 95% CI 1.03-1.64]), and inadequate weight gain (incident RR = 1.41 [ 95% CI 1.22-1.64]; recurrent RR = 1.33 [ 95% CI 1.10-1.60]). Race-ethnicity, marital or insurance status, alcohol, diabetes, asthma, thyroid disease, depression, or interpregnancy interval were not associated with incidence or recurrence. Conclusion There was considerable overlap in the risk factors for SGA recurrence and incidence. Recurrence and incidence risk factors included smoking, short stature, underweight, and inadequate weight gain. Maternal age and hypertensive diseases increased the risk for incidence only. Regardless of the SGA definition, some potentially modifiable risk factors for recurrence were identified. C1 [Hinkle, S. N.; Albert, P. S.; Mendola, P.; Sjaarda, L. A.; Boghossian, N. S.; Yeung, E.; Laughon, S. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. RP Laughon, SK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd Room 7B03, Bethesda, MD 20892 USA. EM laughonsk@mail.nih.gov RI Yeung, Edwina/F-5992-2015; Hinkle, Stefanie/F-8253-2013; OI Yeung, Edwina/0000-0002-3851-2613; Hinkle, Stefanie/0000-0003-4312-708X; Sjaarda, Lindsey/0000-0003-0539-8110; Mendola, Pauline/0000-0001-5330-2844; Grantz, Katherine/0000-0003-0276-8534 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN275200800002I, HHSN27500004] FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contract numbers: HHSN275200800002I, HHSN27500004). NR 31 TC 8 Z9 9 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1470-0328 EI 1471-0528 J9 BJOG-INT J OBSTET GY JI BJOG PD AUG PY 2014 VL 121 IS 9 BP 1080 EP 1088 DI 10.1111/1471-0528.12628 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AL9TD UT WOS:000339483400006 PM 24702952 ER PT J AU van der Marel, J van Baars, R Quint, WGV Berkhof, J del Pino, M Torne, A Ordi, J Wentzensen, N Schiffman, M van de Sandt, MMV Lindeman, J Jenkins, D Helmerhorst, TJM Verheijen, RHM ter Harmsel, B Alonso, I AF van der Marel, J. van Baars, R. Quint, W. G. V. Berkhof, J. del Pino, M. Torne, A. Ordi, J. Wentzensen, N. Schiffman, M. van de Sandt, M. M. Lindeman, J. Jenkins, D. Helmerhorst, T. J. M. Verheijen, R. H. M. ter Harmsel, B. Alonso, I. TI The impact of human papillomavirus genotype on colposcopic appearance: a cross-sectional analysis SO BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY LA English DT Article DE Cervical intraepithelial neoplasia; colposcopy; genotyping; HPV16; human papillomavirus ID CERVICAL INTRAEPITHELIAL NEOPLASIA; HIGH-RISK HPV; INVASIVE CANCER; GENITAL WARTS; YOUNG-WOMEN; DIAGNOSIS; ACCURACY; GP5+/6+-PCR; INFECTIONS; LESIONS AB Objective To study colposcopic performance in diagnosing high-grade cervical intraepithelial neoplasia or cervical cancer (CIN2+ and CIN3+) using colposcopic characteristics and high-risk human papillomavirus (hrHPV) genotyping. Design Cross-sectional multicentre study. Setting Two colposcopy clinics in The Netherlands and Spain. Population Six hundred and ten women aged 17 years and older referred for colposcopy because of abnormal cytology. Methods A cervical smear was obtained. Colposcopists identified the worst lesion, graded their impression and scored the colposcopic characteristics of the lesions. Up to four biopsies were collected, including one biopsy from visually normal tissue. Main outcome measures CIN2+ and CIN3+, positive for HPV16 or other high-risk HPV types (non-16 hrHPV-positive). Results The mean age in HPV16-positive CIN2+ women was 35.1 years compared with 39.1 years in women with other hrHPV types (P = 0.002). Sensitivity for colposcopy to detect CIN2+ was 87.9% (95% CI 83.2-91.5), using colposcopic cut-off of 'any abnormality'. The remaining CIN2+ were found by a biopsy from visually normal tissue or endocervical curettage (ECC). Detection of CIN2+ by lesion-targeted biopsies was not different between HPV16-positive women [119/135; 88.1% (95% CI 81.2-92.9)] and non-16 hrHPV-positive women [100/115; 87.0% (95% CI 79.192.3); P = 0.776]. In multivariate analysis, 'cetowhitening' [odds ratio (OR) 1.91, 95% CI 1.56-3.17], 'ime of appearance' (OR 1.95, 95% CI 1.21-3.15) and 'esion >25% of visible cervix' (OR 2.25, 95% CI 1.44-3.51) were associated with CIN2+. Conclusions In this population following European screening practice, HPV16-related CIN2+ lesions were detected at younger age and showed similar colposcopic impression as non-16 hrHPV high-grade lesions. There was no relationship between any of the colposcopic characteristics and HPV16 status. C1 [van der Marel, J.; van Baars, R.; Quint, W. G. V.; van de Sandt, M. M.; Lindeman, J.; Jenkins, D.] DDL Diagnost Lab, Dept Res & Dev, NL-2288 ER Rijswijk, Netherlands. [Berkhof, J.] Vrije Univ Amsterdam, Dept Epidemiol & Biostat, Med Ctr, Amsterdam, Netherlands. [del Pino, M.; Torne, A.; Alonso, I.] Inst Invest Biomed August Pi & Sunyer IDIBAPS, Hosp Clin, Inst Clin Gynecol Obstet & Neonatol, Barcelona, Spain. [Ordi, J.] Hosp Clin Barcelona, CRESIB, Dept Pathol, Barcelona, Spain. [Wentzensen, N.; Schiffman, M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Helmerhorst, T. J. M.] Erasmus Univ, Med Ctr, Dept Obstet & Gynaecol, Rotterdam, Netherlands. [Verheijen, R. H. M.] Univ Med Ctr Utrecht, Div Woman & Baby, Utrecht, Netherlands. [ter Harmsel, B.] Reinier de Graaf Grp, Dept Obstet & Gynaecol, Delft, Netherlands. [ter Harmsel, B.] Roosevelt Klin, Dept Gynaecol, Leiden, Netherlands. RP van der Marel, J (reprint author), DDL Diagnost Lab, Visseringlaan 25, NL-2288 ER Rijswijk, Netherlands. EM Jacolien.van.der.marel@DDL.nl FU Stichting Pathologie Ontwikkeling en Onderzoek (SPOO) Foundation, The Netherlands FX This research was funded by the Stichting Pathologie Ontwikkeling en Onderzoek (SPOO) Foundation, The Netherlands. The sponsor had no involvement in study design, data interpretation, writing of the manuscript, or decision to submit the manuscript for publication. NR 36 TC 8 Z9 8 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1470-0328 EI 1471-0528 J9 BJOG-INT J OBSTET GY JI BJOG PD AUG PY 2014 VL 121 IS 9 BP 1117 EP 1126 DI 10.1111/1471-0528.12668 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AL9TD UT WOS:000339483400014 PM 24494663 ER PT J AU Fasano, RM Mamcarz, E Adams, S Jerussi, TD Sugimoto, K Tian, X Flegel, WA Childs, RW AF Fasano, Ross M. Mamcarz, Ewelina Adams, Sharon Jerussi, Theresa Donohue Sugimoto, Kyoko Tian, Xin Flegel, Willy A. Childs, Richard W. TI Persistence of recipient human leucocyte antigen (HLA) antibodies and production of donor HLA antibodies following reduced intensity allogeneic haematopoietic stem cell transplantation SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE HLA antibodies; platelets; allogeneic bone marrow transplantation ID PLATELET TRANSFUSION REFRACTORINESS; BONE-MARROW-TRANSPLANTATION; CORD BLOOD TRANSPLANTATION; GRAFT FAILURE; THROMBOCYTOPENIC PATIENTS; ALLOIMMUNIZATION; DESENSITIZATION; IMMUNOGLOBULIN; ENGRAFTMENT; REDUCTION AB The effects of reduced intensity conditioning (RIC) on human leucocyte antigen (HLA)-alloimmunization and platelet transfusion refractoriness (PTR) following allogeneic haematopoietic stem cell transplantation (Allo-HSCT) are unknown. We studied HLA-alloantibodies in a cohort of 16 patients (eight HLA-alloimmunized with pre-transplant histories of PTR and eight non-alloimmunized controls) undergoing Allo-HSCT using fludarabine/cyclophosphamide-based RIC. Pre- and post-transplant serum samples were analysed for HLA-antibodies and compared to myeloid, T-cell and bone marrow plasma cell chimaerism. Among alloimmunized patients, the duration that HLA-antibodies persisted post-transplant correlated strongly with pre-transplant HLA-antibody mean fluorescence intensity (MFI) and PRA levels (Spearman's rank correlation = 0.954 (P = 0.0048) and 0.865 (P = 0.0083) respectively). Pre-transplant MFI >10 000 was associated with post-transplant HLA antibody persistence >100 d (P = 0.029). HLA-antibodies persisted >= 100 d in 3/8 patients despite recipient chimaerism being undetectable in all lympho-haematopoietic lineages including plasma cells. Post-transplant de-novo HLA-antibodies developed in three control patients with two developing PTR; the donors for two of these patients demonstrated pre-existing HLA-antibodies of equivalent specificity to those in the patient, confirming donor origin. These data show HLA-antibodies may persist for prolonged periods following RIC. Further study is needed to determine the incidence of post-transplant PTR as a consequence of donor-derived HLA alloimmunization before recommendations on donor HLA-antibody screening can be made. C1 [Fasano, Ross M.; Mamcarz, Ewelina] Childrens Natl Med Ctr, Div Haematol Oncol, Washington, DC 20010 USA. [Mamcarz, Ewelina; Jerussi, Theresa Donohue; Sugimoto, Kyoko; Tian, Xin; Childs, Richard W.] NHLBI, Haematol Branch, Bethesda, MD 20892 USA. [Mamcarz, Ewelina; Jerussi, Theresa Donohue; Sugimoto, Kyoko; Tian, Xin; Childs, Richard W.] NIH, Bethesda, MD 20892 USA. [Adams, Sharon; Flegel, Willy A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Fasano, RM (reprint author), Childrens Natl Med Ctr, 111 Michigan Ave NW, Washington, DC 20010 USA. EM rfasano@childrensnational.org FU National Heart, Lung and Blood Institute; Department of Transfusion Medicine at the Clinical Center, National Institutes of Health FX This research was supported by the Intramural Research Programs of the National Heart, Lung and Blood Institute and the Department of Transfusion Medicine at the Clinical Center, National Institutes of Health. The authors would like to acknowledge the patients who participated in this trial, and Lisa Cook, Catalina Ramos, Patty Prince, Rob Reger, Maria Berg and Rose Goodwin for their critical support of the clinical study described in this manuscript. NR 31 TC 6 Z9 6 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD AUG PY 2014 VL 166 IS 3 BP 425 EP 434 DI 10.1111/bjh.12890 PG 10 WC Hematology SC Hematology GA AL9RQ UT WOS:000339478800015 PM 24750103 ER PT J AU White, RW Harpaz, R Shah, NH DuMouchel, W Horvitz, E AF White, R. W. Harpaz, R. Shah, N. H. DuMouchel, W. Horvitz, E. TI Toward Enhanced Pharmacovigilance Using Patient-Generated Data on the Internet SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID ADVERSE DRUG-REACTIONS; MEDICAL OUTCOMES PARTNERSHIP; EVENT REPORTING SYSTEM; HOSPITALIZED-PATIENTS; SAFETY; PERFORMANCE; FDA; INFORMATION; ALGORITHMS; DISCOVERY AB The promise of augmenting pharmacovigilance with patient-generated data drawn from the Internet was called out by a scientific committee charged with conducting a review of the current and planned pharmacovigilance practices of the US Food and Drug Administration (FDA).To this end, we present a study on harnessing behavioral data drawn from Internet search logs to detect adverse drug reactions (ADRs). By analyzing search queries collected from 80 million consenting users and by using a widely recognized benchmark of ADRs, we found that the performance of ADR detection via search logs is comparable and complementary to detection based on the FDA's adverse event reporting system (AERS).We show that by jointly leveraging data from the AERS and search logs, the accuracy of ADR detection can be improved by 19% relative to the use of each data source independently.The results suggest that leveraging nontraditional sources such as online search logs could supplement existing pharmacovigilance approaches. C1 [White, R. W.; Horvitz, E.] Microsoft Res, Redmond, WA USA. [Harpaz, R.; Shah, N. H.] Stanford Univ, Ctr Biomed Informat Res, Stanford, CA 94305 USA. [DuMouchel, W.] Oracle Hlth Sci, Burlington, MA USA. [DuMouchel, W.] Fdn Natl Inst Hlth, Observat Med Outcomes Partnership, Bethesda, MD USA. RP Harpaz, R (reprint author), Stanford Univ, Ctr Biomed Informat Res, Stanford, CA 94305 USA. EM rharpaz@stanford.edu FU National Institutes of Health [U54-HG004028]; National Institute of General Medical Sciences [GM101430-01A1] FX This research was supported by National Institutes of Health grant U54-HG004028 for the National Center for Biomedical Ontology and by National Institute of General Medical Sciences grant GM101430-01A1. We thank Paul Koch for assistance with access to and analysis of search log information. NR 37 TC 28 Z9 28 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD AUG PY 2014 VL 96 IS 2 BP 239 EP 246 DI 10.1038/clpt.2014.77 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AM1JT UT WOS:000339602900035 PM 24713590 ER PT J AU Turnbull, AE Ruhl, AP Needham, DM AF Turnbull, Alison E. Ruhl, A. Parker Needham, Dale M. TI Timing of Limitations in the ICU and Sequential Organ Failure Assessment Scores Reply SO CRITICAL CARE MEDICINE LA English DT Letter ID INJURY C1 [Turnbull, Alison E.; Ruhl, A. Parker; Needham, Dale M.] Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Baltimore, MD 21218 USA. [Turnbull, Alison E.; Ruhl, A. Parker; Needham, Dale M.] Outcomes Crit Illness & Surg OACIS Grp, Baltimore, MD USA. [Turnbull, Alison E.] Johns Hopkins Univ, Sch Med, Dept Epidemiol, Baltimore, MD USA. [Ruhl, A. Parker] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Needham, Dale M.] Johns Hopkins Univ, Sch Med, Dept Phys Med & Rehabil, Baltimore, MD USA. RP Turnbull, AE (reprint author), Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Baltimore, MD 21218 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD AUG PY 2014 VL 42 IS 8 BP E596 EP E596 DI 10.1097/CCM.0000000000000447 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA AL7QV UT WOS:000339330700007 PM 25674633 ER PT J AU Tronnes, H Wilcox, AJ Lie, RT Markestad, T Moster, D AF Tronnes, Havard Wilcox, Allen J. Lie, Rolv T. Markestad, Trond Moster, Dag TI Risk of cerebral palsy in relation to pregnancy disorders and preterm birth: a national cohort study SO DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY LA English DT Article ID GESTATIONAL-AGE; SURVEILLANCE; EPIDEMIOLOGY; INFANTS; NORWAY AB AIM To assess the risk of developing cerebral palsy in relation to pregnancy disorders and preterm birth. METHOD By linking the Medical Birth Registry of Norway to other national registries, we identified all live births in Norway from 1967 through to 2001. Risks of cerebral palsy (CP) after preterm delivery and pregnancy disorders were estimated in different gestational age groups. RESULT In total, 1 764 509 children delivered at 23 to 43 weeks' gestation were included. The prevalence of CP was 1.8 per 1000 births. Absolute risk of CP was 8.5% among children born at 23 to 27 weeks' gestation, 5.6% at 28 to 30 weeks, 2.0% at 31 to 33 weeks, 0.4% at 34 to 36 weeks, and 0.1% thereafter. Placental abruption, chorioamnionitis, prolonged rupture of membranes, intrauterine growth restriction, pre-eclampsia, multiple births, placenta previa, bleeding, cervical conization, and congenital malformation were all associated with CP. Before 32 weeks' gestation, absolute risk of CP was highest with chorioamnionitis (9.1%) and lowest with pre-eclampsia (3.1%). Among those born after 31 weeks, the absolute risk of CP was more consistently (but also more slightly) increased with a recorded pregnancy disorder. INTERPRETATION Early delivery and pregnancy disorders were both strong risk factors for CP. The added risks with recorded pregnancy disorders varied within categories of gestational age. C1 [Tronnes, Havard; Lie, Rolv T.; Moster, Dag] Univ Bergen, Dept Global Publ Hlth & Primary Care, N-5020 Bergen, Norway. [Tronnes, Havard; Markestad, Trond; Moster, Dag] Haukeland Hosp, Dept Pediat, N-5021 Bergen, Norway. [Wilcox, Allen J.] NIEHS, NIH, Epidemiol Branch, Durham, NC USA. [Lie, Rolv T.; Moster, Dag] Med Birth Registry Norway, Norwegian Inst Publ Hlth, Bergen, Norway. [Markestad, Trond] Univ Bergen, Dept Clin Med, Bergen, Norway. RP Tronnes, H (reprint author), Univ Bergen, Dept Global Publ Hlth & Primary Care, Kalfarveien 31, N-5020 Bergen, Norway. EM havard.tronnes@igs.uib.no OI Wilcox, Allen/0000-0002-3376-1311 FU Western Norwegian Regional Health Authority; NIH, National Institute of Environmental Health Sciences FX The study was funded by the Western Norwegian Regional Health Authority and by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. These organisations had no role in study design, data analysis, and interpretation of the results. The authors have stated that they had no interests that might be perceived as posing a conflict or bias. NR 22 TC 21 Z9 23 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1622 EI 1469-8749 J9 DEV MED CHILD NEUROL JI Dev. Med. Child Neurol. PD AUG PY 2014 VL 56 IS 8 BP 779 EP 785 DI 10.1111/dmcn.12430 PG 7 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA AL9VB UT WOS:000339489500017 PM 24621110 ER PT J AU Hunter, T Siess, F Colloca, L AF Hunter, T. Siess, F. Colloca, L. TI Socially induced placebo analgesia: A comparison of a pre-recorded versus live face-to-face observation SO EUROPEAN JOURNAL OF PAIN LA English DT Article ID RESPONSES; EMPATHY; PAIN; MECHANISMS; COLOR; FEAR AB Background: Recently, it has been shown that live, face-to-face social observation induces marked placebo analgesia. Despite the phenomenal growth of video sharing platforms, the potential analgesic effects of video-based social observation are largely unknown. This study compared video-based and live social observation induced placebo analgesia and whether there was a similar relationship between analgesic responses and empathy traits for both conditions. Methods: Here, we compared placebo analgesia in four groups: social observation through a video (SOV group), social observation in person (SOP group), verbal suggestion alone (VS group) and a natural history group (NH group). The SOV and SOP groups underwent a placebo treatment and painful stimuli following respectively a video-based and live observation of a demonstrator showing analgesic effects when the painful stimuli were paired to a green light but not a red light. The VS group received painful stimuli after they had been verbally instructed to expect less pain after the green light. The NH group received painful stimuli, but was told nothing about the meaning of the lights. Individual pain reports and empathy traits were measured. Results: We found that video-based observation induced substantial placebo analgesic responses that were of similar magnitude to live observation. Notably, the analgesic scores were strongly correlated with empathetic concern in the live observation group but not in the video replay group. Conclusions: These findings add evidence that placebo analgesia can be induced by social observation and that empathy interacts with these effects in a context-dependent manner. C1 [Hunter, T.; Siess, F.] Univ E London, Human Motor Performance Grp, London E15 4LZ, England. [Colloca, L.] NIMH, NCCAM, Bethesda, MD 20892 USA. [Colloca, L.] NIMH, Ctr Clin, NIH, Bethesda, MD 20892 USA. RP Hunter, T (reprint author), Univ E London, Human Motor Performance Grp, London E15 4LZ, England. EM t.hunter@uel.ac.uk; luana.colloca@nih.gov OI Colloca, Luana/0000-0002-6503-4709 FU UEL; NCCAM; NIMH FX This research was supported by UEL (T.H.) and NCCAM and NIMH Intramural Programs (L.C.). NR 28 TC 15 Z9 16 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1090-3801 EI 1532-2149 J9 EUR J PAIN JI Eur. J. Pain PD AUG PY 2014 VL 18 IS 7 BP 914 EP 922 DI 10.1002/j.1532-2149.2013.00436.x PG 9 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA AL9RL UT WOS:000339478300004 PM 24347563 ER PT J AU Thomas, A Jakopovic, M AF Thomas, Anish Jakopovic, Marko TI Immunotherapy for non-small-cell lung cancer SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Editorial Material DE immune checkpoint inhibitors; immunotherapy; non-small-cell lung cancer; vaccines ID 1ST-LINE TREATMENT; DOUBLE-BLIND; TRIAL; IPILIMUMAB; ANTIBODY; PLACEBO; AGONIST; SAFETY AB Activation of the host immune system represents an attractive treatment approach for cancers. In non-small-cell lung cancer (NSCLC), a variety of immunotherapies, including nonspecific immune stimulants, vaccines and checkpoint inhibitors, have been evaluated in clinical trials. Several randomized Phase III trials have failed to demonstrate clinical benefit from nonspecific immune stimulants and vaccines in the overall trial populations. Activity of vaccines in subsets of patients in these trials needs further evaluation. Unlike vaccines aimed at stimulating a cellular immune response to antigens differentially expressed in cancers, checkpoint inhibitors aim at overcoming immune inhibitory signals in the tumor microenvironment via pharmacological inhibition of immune checkpoints - a crucial tumoral immune escape mechanism. Early clinical trials of checkpoint inhibitors showed promising results with some durable responses. Better understanding of the mechanisms of immunosuppression specific to NSCLC will be crucial for successful patient selection for immunotherapy. C1 [Thomas, Anish] NCI, NIH, Ctr Canc Res Thorac, Bethesda, MD 20892 USA. [Thomas, Anish] NCI, NIH, GI Oncol Branch, Bethesda, MD 20892 USA. [Jakopovic, Marko] Univ Zagreb, Sch Med, Univ Hosp Ctr Zagreb, Dept Resp Dis, Zagreb 41001, Croatia. RP Thomas, A (reprint author), NCI, NIH, Ctr Canc Res Thorac, Bldg 10 CRC 4-5330, Bethesda, MD 20892 USA. OI Thomas, Anish/0000-0003-3293-3115 FU Intramural NIH HHS NR 16 TC 2 Z9 2 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1471-2598 EI 1744-7682 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD AUG PY 2014 VL 14 IS 8 BP 1061 EP 1064 DI 10.1517/14712598.2014.925874 PG 4 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA AL9UN UT WOS:000339487700003 PM 24878420 ER PT J AU Gao, W Kim, H Feng, MQ Phung, Y Xavier, CP Rubin, JS Ho, M AF Gao, Wei Kim, Heungnam Feng, Mingqian Phung, Yen Xavier, Charles P. Rubin, Jeffrey S. Ho, Mitchell TI Inactivation of Wnt Signaling by a Human Antibody That Recognizes the Heparan Sulfate Chains of Glypican-3 for Liver Cancer Therapy SO HEPATOLOGY LA English DT Article ID HEPATOCELLULAR-CARCINOMA CELLS; MONOCLONAL-ANTIBODIES; IN-VITRO; GROWTH; EXPRESSION; PROTEOGLYCANS; ANGIOGENESIS; INHIBITION; PROTEINS; PATHWAY AB Wnt signaling is important for cancer pathogenesis and is often up-regulated in hepatocellular carcinoma (HCC). Heparan sulfate proteoglycans (HSPGs) function as coreceptors or modulators of Wnt activation. Glypican-3 (GPC3) is an HSPG that is highly expressed in HCC, where it can attract Wnt proteins to the cell surface and promote cell proliferation. Thus, GPC3 has emerged as a candidate therapeutic target in liver cancer. While monoclonal antibodies to GPC3 are currently being evaluated in preclinical and clinical studies, none have shown an effect on Wnt signaling. Here, we first document the expression of Wnt3a, multiple Wnt receptors, and GPC3 in several HCC cell lines, and demonstrate that GPC3 enhanced the activity of Wnt3a/beta-catenin signaling in these cells. Then we report the identification of HS20, a human monoclonal antibody against GPC3, which preferentially recognized the heparan sulfate chains of GPC3, both the sulfated and nonsulfated portions. HS20 disrupted the interaction of Wnt3a and GPC3 and blocked Wnt3a/beta-catenin signaling. Moreover, HS20 inhibited Wnt3a-dependent cell proliferation in vitro and HCC xenograft growth in nude mice. In addition, HS20 had no detectable undesired toxicity in mice. Taken together, our results show that a monoclonal antibody primarily targeting the heparin sulfate chains of GPC3 inhibited Wnt/beta-catenin signaling in HCC cells and had potent antitumor activity in vivo. Conclusion: An antibody directed against the heparan sulfate of a proteoglycan shows efficacy in blocking Wnt signaling and HCC growth, suggesting a novel strategy for liver cancer therapy. C1 [Gao, Wei; Kim, Heungnam; Feng, Mingqian; Phung, Yen; Ho, Mitchell] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Xavier, Charles P.; Rubin, Jeffrey S.] NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Ho, M (reprint author), NCI, Antibody Therapy Sect, Mol Biol Lab, NIH, 37 Convent Dr,Rm 5002C, Bethesda, MD 20892 USA. EM homi@mail.nih.gov RI Ho, Mitchell/F-5059-2015 FU NIH, NCI, Center for Cancer Research [Z01 BC 010891, ZIA BC 010891]; NCI Director's Intramural Innovation Award FX Supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research (Z01 BC 010891 and ZIA BC 010891) and by the 2011 NCI Director's Intramural Innovation Award (Principal Investigator Award) to M. Ho. NR 44 TC 27 Z9 30 U1 1 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD AUG PY 2014 VL 60 IS 2 BP 576 EP 587 DI 10.1002/hep.26996 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AL9XT UT WOS:000339497600017 PM 24492943 ER PT J AU Li, WQ Park, Y McGlynn, KA Hollenbeck, AR Taylor, PR Goldstein, AM Freedman, ND AF Li, Wen-Qing Park, Yikyung McGlynn, Katherine A. Hollenbeck, Albert R. Taylor, Philip R. Goldstein, Alisa M. Freedman, Neal D. TI Index-Based Dietary Patterns and Risk of Incident Hepatocellular Carcinoma and Mortality From Chronic Liver Disease in a Prospective Study SO HEPATOLOGY LA English DT Article ID HEALTHY EATING INDEX; RETIRED-PERSONS DIET; UNITED-STATES; NATIONAL-INSTITUTES; NIH-AARP; CARDIOVASCULAR-DISEASE; AMERICAN-ASSOCIATION; MEDITERRANEAN DIET; QUALITY SCORES; LARGE COHORT AB The role of diet in hepatocellular carcinoma (HCC) and its typical precursor, chronic liver disease (CLD), is poorly understood. Following dietary recommendations has been shown to reduce risk of many cancers, but whether such diets are associated with HCC and CLD is unknown. We prospectively evaluated the association of two dietary indices, the Healthy Eating Index-2010 (HEI-2010) and the alternate Mediterranean Diet Score (aMED), with HCC incidence and CLD mortality in a large U.S. prospective cohort. We calculated the HEI-2010 and aMED scores for 494,942 participants in the National Institutes of Health-AARP Diet and Health study, based on typical diet assessed using a food frequency questionnaire FFQ between 1995 and 1996. Hazard ratios (HRs) and 95% confidence intervals (CIs) for quintiles of each index were estimated using Cox's proportional hazards regression, after adjusting for alcohol intake, smoking, body mass index, diabetes, and other covariates. A total of 509 HCC cases (1995-2006) and 1,053 CLD deaths (1995-2011) were documented during follow-up. Higher HEI-2010 scores, reflecting favorable adherence to dietary guidelines, were associated with lower risk of HCC (HR, 0.72, 95% CI: 0.53-0.97 for the highest quintile, compared to lowest; P trend = 0.03) and lower mortality resulting from CLD (HR, 0.57; 95% CI: 0.46-0.71; P trend < 0.0001). High aMED scores were also associated with lower risk of HCC (HR, 0.62; 95% CI: 0.47-0.84; P trend = 0.0002) and lower risk of CLD mortality (HR, 0.52; 95% CI: 0.42-0.65; P trend < 0.0001). Conclusions: Adhering to dietary recommendations may reduce the risk of developing HCC and dying of CLD. C1 [Li, Wen-Qing; Taylor, Philip R.; Goldstein, Alisa M.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Li, Wen-Qing] Brown Univ, Warren Alpert Med Sch, Dept Dermatol, Providence, RI 02906 USA. [Park, Yikyung; Freedman, Neal D.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [McGlynn, Katherine A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Li, WQ (reprint author), Brown Univ, Warren Alpert Med Sch, Dept Dermatol, 339 Eddy St, Providence, RI 02906 USA. EM wen-qing_li@brown.edu RI Li, Wenqing/N-2293-2014; Freedman, Neal/B-9741-2015; OI Li, Wenqing/0000-0002-1283-4091; Freedman, Neal/0000-0003-0074-1098; Park, Yikyung/0000-0002-6281-489X FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD FX This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD. NR 46 TC 14 Z9 15 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD AUG PY 2014 VL 60 IS 2 BP 588 EP 597 DI 10.1002/hep.27160 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AL9XT UT WOS:000339497600018 PM 24715615 ER PT J AU Russo, MW Hoofnagle, JH Gu, JZ Fontana, RJ Barnhart, H Kleiner, DE Chalasani, N Bonkovsky, HL AF Russo, Mark W. Hoofnagle, Jay H. Gu, Jiezhun Fontana, Robert J. Barnhart, Huiman Kleiner, David E. Chalasani, Naga Bonkovsky, Herbert L. TI Spectrum of Statin Hepatotoxicity: Experience of the Drug-Induced Liver Injury Network SO HEPATOLOGY LA English DT Article ID RANDOMIZED CONTROLLED TRIAL; ACUTE HEPATITIS; ATORVASTATIN; FAILURE; OUTCOMES; EVENTS AB The HMG-CoA reductase inhibitors (statins) are widely prescribed for patients with hyperlipidemia and are generally well tolerated. Mild elevations in serum aminotransferases arise in up to 3% of treated patients, but clinically apparent drug-induced liver injury is rare. The aim of this study is to report the presenting features and outcomes of 22 patients with clinically apparent liver injury due to statins. Among 1,188 cases of drug-induced liver injury enrolled between 2004 and 2012 in a prospective registry by the U.S. Drug Induced Liver Injury Network, 22 were attributed to a statin. All patients were evaluated in a standard fashion and followed for at least 6 months after onset. The median age was 60 years (range 41-80), and 15 (68%) were female. The latency to onset of liver injury ranged from 34 days to 10 years (median=155 days). Median peak levels were alanine aminotransferase 892 U/L, alkaline phosphatase 358 U/L, and total bilirubin 6.1 mg/dL. Nine patients presented with cholestatic hepatitis and 12 patients presented with hepatocellular injury, of which six had an autoimmune phenotype. Nine patients were hospitalized, four developed evidence of hepatic failure, and one died. All commonly used statins were implicated. Four patients developed chronic liver injury, of which three had an autoimmune phenotype of liver injury. Conclusion: Drug-induced liver injury from statins is rare and characterized by variable patterns of injury, a range of latencies to onset, autoimmune features in some cases, and persistent or chronic injury in 18% of patients, most of whom have an autoimmune phenotype. C1 [Russo, Mark W.] Carolinas Med Ctr, Transplant Ctr, Charlotte, NC 28204 USA. [Hoofnagle, Jay H.] NIDDK, NIH, Bethesda, MD 20892 USA. [Gu, Jiezhun; Barnhart, Huiman] Duke Univ, Duke Clin Res Inst, Durham, NC USA. [Fontana, Robert J.] Univ Michigan, Sch Med, Dept Med, Ann Arbor, MI 48104 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Chalasani, Naga] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Bonkovsky, Herbert L.] Carolinas Med Ctr, Dept Med, Charlotte, NC 28204 USA. RP Russo, MW (reprint author), Carolinas Med Ctr, Transplant Ctr, 6th Floor Morehead Med Plaza,1025 Morehead Med Dr, Charlotte, NC 28204 USA. EM mark.russo@carolinashealthcare.org FU National Institute of Diabetes and Digestive and Kidney Diseases [1UO1DK065201, 1UO1DK065193, 1UO1DKO65184, 1UO1DK065211, 1UO1DK065238, 1UO1DK06F5176]; NIH, National Cancer Institute FX DILIN is supported by the National Institute of Diabetes and Digestive and Kidney Diseases under the following cooperative agreements: 1UO1DK065201, 1UO1DK065193, 1UO1DKO65184, 1UO1DK065211, 1UO1DK065238, and 1UO1DK06F5176. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute. NR 20 TC 42 Z9 44 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD AUG PY 2014 VL 60 IS 2 BP 679 EP 686 DI 10.1002/hep.27157 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AL9XT UT WOS:000339497600026 PM 24700436 ER PT J AU Revell, AD Boyd, MA Wang, D Emery, S Gazzard, B Reiss, P van Sighem, A Montaner, JS Lane, HC Larder, BA AF Revell, A. D. Boyd, M. A. Wang, D. Emery, S. Gazzard, B. Reiss, P. van Sighem, Al Montaner, J. S. Lane, H. C. Larder, B. A. TI A comparison of computational models with and without genotyping for prediction of response to second-line HIV therapy SO HIV MEDICINE LA English DT Article DE antiretroviral; computational model; genotype; HIV; response prediction ID INFECTION; FAILURE AB Objectives We compared the use of computational models developed with and without HIV genotype vs. genotyping itself to predict effective regimens for patients experiencing first-line virological failure. Methods Two sets of models predicted virological response for 99 three-drug regimens for patients on a failing regimen of two nucleoside/nucleotide reverse transcriptase inhibitors and one nonnucleoside reverse transcriptase inhibitor in the Second-Line study. One set used viral load, CD4 count, genotype, plus treatment history and time to follow-up to make its predictions; the second set did not include genotype. Genotypic sensitivity scores were derived and the ranking of the alternative regimens compared with those of the models. The accuracy of the models and that of genotyping as predictors of the virological responses to second-line regimens were compared. Results The rankings of alternative regimens by the two sets of models were significantly correlated in 60-69% of cases, and the rankings by the models that use a genotype and genotyping itself were significantly correlated in 60% of cases. The two sets of models identified alternative regimens that were predicted to be effective in 97% and 100% of cases, respectively. The area under the receiver-operating curve was 0.72 and 0.74 for the two sets of models, respectively, and significantly lower at 0.55 for genotyping. Conclusions The two sets of models performed comparably well and significantly outperformed genotyping as predictors of response. The models identified alternative regimens predicted to be effective in almost all cases. It is encouraging that models that do not require a genotype were able to predict responses to common second-line therapies in settings where genotyping is unavailable. C1 [Revell, A. D.; Wang, D.; Larder, B. A.] HIV Resistance Response Database Initiat RDI, London, England. [Boyd, M. A.; Emery, S.] Univ New S Wales, Kirby Inst Infect & Immun Soc, Sydney, NSW, Australia. [Gazzard, B.] Chelsea & Westminster Hosp, London, England. [Reiss, P.] Univ Amsterdam, Acad Med Ctr, Amsterdam Inst Global Hlth & Dev, Dept Global Hlth, NL-1105 AZ Amsterdam, Netherlands. [Reiss, P.; van Sighem, Al] Stichting HIV Monitoring, Amsterdam, Netherlands. [Montaner, J. S.] BC Ctr Excellence HIV & AIDS, Vancouver, BC, Canada. [Lane, H. C.] NIAID, Bethesda, MD 20892 USA. RP Revell, AD (reprint author), 14 Union Sq, London N1 7DH, England. EM andrewrevell@hivrdi.org RI Emery, Sean/H-4920-2013 OI Emery, Sean/0000-0001-6072-8309 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. This research was supported by the National Institute of Allergy and Infectious Diseases. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 11 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-2662 EI 1468-1293 J9 HIV MED JI HIV Med. PD AUG PY 2014 VL 15 IS 7 BP 442 EP 448 DI 10.1111/hiv.12156 PG 7 WC Infectious Diseases SC Infectious Diseases GA AL9WZ UT WOS:000339495500007 PM 24735474 ER PT J AU Celeste, FV Vilboux, T Ciccone, C de Dios, JK Malicdan, MCV Leoyklang, P McKew, JC Gahl, WA Carrillo-Carrasco, N Huizing, M AF Celeste, Frank V. Vilboux, Thierry Ciccone, Carla de Dios, John Karl Malicdan, May Christine V. Leoyklang, Petcharat McKew, John C. Gahl, William A. Carrillo-Carrasco, Nuria Huizing, Marjan TI Mutation Update for GNE Gene Variants Associated with GNE Myopathy SO HUMAN MUTATION LA English DT Article DE GNE; distal myopathy with rimmed vacuoles; DMRV; hereditary inclusion body myopathy; HIBM; adult onset muscular dystrophy ID INCLUSION-BODY MYOPATHY; ACETYLGLUCOSAMINE 2-EPIMERASE/N-ACETYLMANNOSAMINE KINASE; GLCNAC 2-EPIMERASE/MANNAC KINASE; SIALIC-ACID BIOSYNTHESIS; N-ACETYLNEURAMINIC ACID; RIMMED VACUOLES DMRV; DISTAL MYOPATHY; BIFUNCTIONAL ENZYME; KEY ENZYME; HETEROZYGOUS MUTATIONS AB The GNE gene encodes the rate-limiting, bifunctional enzyme of sialic acid biosynthesis, uridine diphosphate-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). Biallelic GNE mutations underlie GNE myopathy, an adult-onset progressive myopathy. GNE myopathy-associated GNE mutations are predominantly missense, resulting in reduced, but not absent, GNE enzyme activities. The exact pathomechanism of GNE myopathy remains unknown, but likely involves aberrant (muscle) sialylation. Here, we summarize 154 reported and novel GNE variants associated with GNE myopathy, including 122 missense, 11 nonsense, 14 insertion/deletions, and seven intronic variants. All variants were deposited in the online GNE variation database (http://www.dmd.nl/nmdb2/home.php?select_db=GNE). We report the predicted effects on protein function of all variants well as the predicted effects on epimerase and/or kinase enzymatic activities of selected variants. By analyzing exome sequence databases, we identified three frequently occurring, unreported GNE missense variants/polymorphisms, important for future sequence interpretations. Based on allele frequencies, we estimate the world-wide prevalence of GNE myopathy to be similar to 4-21/1,000,000. This previously unrecognized high prevalence confirms suspicions that many patients may escape diagnosis. Awareness among physicians for GNE myopathy is essential for the identification of new patients, which is required for better understanding of the disorder's pathomechanism and for the success of ongoing treatment trials. Published 2014 Wiley Periodicals, Inc.** C1 [Celeste, Frank V.; McKew, John C.; Carrillo-Carrasco, Nuria] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Vilboux, Thierry; Ciccone, Carla; de Dios, John Karl; Malicdan, May Christine V.; Leoyklang, Petcharat; Gahl, William A.; Huizing, Marjan] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Gahl, William A.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Huizing, M (reprint author), NHGRI, NIH, 10 Ctr Dr,Bld 10,Rm 10C103, Bethesda, MD 20892 USA. EM huizing@mail.nih.gov RI Carrillo-Carrasco, Nuria/B-9034-2009 OI Carrillo-Carrasco, Nuria/0000-0003-0374-0808 FU Intramural Research Program of the National Human Genome Research Institute (NHGRI); Therapeutics for Rare and Neglected Diseases (TRND) Program of the National Center for Advancing Translational Sciences (NCATS); National Institutes of Health, Bethesda, Maryland, United States FX Contract grant sponsors: The Intramural Research Program of the National Human Genome Research Institute (NHGRI); The Therapeutics for Rare and Neglected Diseases (TRND) Program of the National Center for Advancing Translational Sciences (NCATS); National Institutes of Health, Bethesda, Maryland, United States. NR 101 TC 9 Z9 9 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD AUG PY 2014 VL 35 IS 8 BP 915 EP 926 DI 10.1002/humu.22583 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA AL9AL UT WOS:000339431600003 PM 24796702 ER PT J AU Park, JE Liang, TW AF Park, Jung E. Liang, Tsao-Wei TI Reversible cerebellar ataxia due to ovarian teratoma SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Ataxia; Nystagmus; Oscillopsia; Ovarian teratoma; Paraneoplastic ID ANTI-NMDAR ENCEPHALITIS AB Cerebellar dysfunction is a classic paraneoplastic syndrome associated with various types of cancer, including gynecological and breast tumors, small-cell lung cancer, thymoma, and Hodgkin's lymphoma. We present a 22-year-old woman with acute cerebellar ataxia that subsided upon removal of an ovarian teratoma. This patient may represent a new category of immune-mediated cerebellar ataxia that is reversible with removal of an underlying tumor. Published by Elsevier Ltd. C1 [Park, Jung E.] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Liang, Tsao-Wei] Thomas Jefferson Univ, Dept Neurol, Parkinsons Dis & Movement Disorders Program, Philadelphia, PA 19107 USA. RP Park, JE (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, 10 Ctr Dr Room 7D42, Bethesda, MD 20892 USA. EM junge.park@nih.gov FU Dystonia Medical Research Foundation FX Dr. Park is supported by the Dystonia Medical Research Foundation. NR 4 TC 1 Z9 2 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD AUG PY 2014 VL 21 IS 8 BP 1467 EP 1469 DI 10.1016/j.jocn.2013.12.019 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AM1JE UT WOS:000339601400046 PM 24726236 ER PT J AU Saligan, LN AF Saligan, Leorey N. TI The relationship between physical activity, functional performance and fatigue in sarcoidosis SO JOURNAL OF CLINICAL NURSING LA English DT Article DE depression; fatigue; functional performance; physical activity; sarcoidosis C1 NINR, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Saligan, LN (reprint author), NINR, Intramural Res Program, NIH, 10 Ctr Dr,Bldg 10,Room 2-1339, Bethesda, MD 20892 USA. EM saliganl@mail.nih.gov FU Intramural Research Program of the National Institute of Nursing Research, National Institutes of Health, Bethesda, Maryland, USA FX This study is fully supported by the Intramural Research Program of the National Institute of Nursing Research, National Institutes of Health, Bethesda, Maryland, USA. NR 5 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1067 EI 1365-2702 J9 J CLIN NURS JI J. Clin. Nurs. PD AUG PY 2014 VL 23 IS 15-16 BP 2376 EP 2379 DI 10.1111/jocn.12490 PG 4 WC Nursing SC Nursing GA AL9AN UT WOS:000339431800031 PM 24460760 ER PT J AU Katsounas, A Rasimas, JJ Schlaak, JF Lempicki, RA Rosenstein, DL Kottilil, S AF Katsounas, Antonios Rasimas, Joseph J. Schlaak, Joerg F. Lempicki, Richard A. Rosenstein, Donald L. Kottilil, Shyam TI Interferon Stimulated Exonuclease Gene 20 kDa Links Psychiatric Events to Distinct Hepatitis C Virus Responses in Human Immunodeficiency Virus Positive Patients SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE HIV/HCV co-infection; interferon-alpha; neuro-psychiatric toxicity; ISG20 ID CENTRAL-NERVOUS-SYSTEM; SPINAL MUSCULAR-ATROPHY; CAJAL COILED BODIES; EXPRESSION PROFILES; BIPOLAR DISORDER; POSTMORTEM BRAINS; HIV COINFECTION; ADVERSE EVENTS; HCV THERAPY; PROTEIN AB Hepatitis C Virus (HCV) infection occurs frequently in patients with preexisting mental illness. Treatment for chronic hepatitis C using interferon formulations often increases risk for neuro-psychiatric symptoms. Pegylated-Interferon-alpha (PegIFN-alpha) remains crucial for attaining sustained virologic response (SVR); however, PegIFN-alpha based treatment is associated with psychiatric adverse effects, which require dose reduction and/or interruption. This study's main objective was to identify genes induced by PegIFN-alpha and expressed in the central nervous system and immune system, which could mediate the development of psychiatric toxicity in association with antiviral outcome. Using peripheral blood mononuclear cells from Human Immunodeficiency Virus (HIV)/HCV co-infected donors (N = 28), DNA microarray analysis was performed and 21 differentially regulated genes were identified in patients with psychiatric toxicity versus those without. Using these 21 expression profiles a two-way-ANOVA was performed to select genes based on antiviral outcome and occurrence of neuropsychiatric adverse events. Microarray analysis demonstrated that Interferon-stimulated-exonuclease-gene 20 kDa (ISG20) and Interferon-alpha-inducible-protein 27 (IFI27) were the most regulated genes (P < 0.05) between three groups that were built by combining antiviral outcome and neuro-psychiatric toxicity. Validation by bDNA assay confirmed that ISG20 expression levels were significantly associated with these outcomes (P < 0.035). Baseline levels and induction of ISG20 correlated independently with no occurrence of psychiatric adverse events and non-response to therapy (P < 0.001). Among the 21 genes that were associated with psychiatric adverse events and 20 Interferon-inducible genes (IFIGs) used as controls, only ISG20 expression was able to link PegIFN-alpha related neuro-psychiatric toxicity to distinct HCV-responses in patients co-infected with HIV and HCV in vivo. (C) 2014 Wiley Periodicals, Inc. C1 [Katsounas, Antonios; Schlaak, Joerg F.] Univ Hosp Essen, Dept Gastroenterol & Hepatol, D-45147 Essen, Germany. [Rasimas, Joseph J.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Lempicki, Richard A.] NCI, Lab Immunopathogenesis & Bioinformat, SAIC Frederick Inc, Frederick, MD 21702 USA. [Rosenstein, Donald L.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. [Kottilil, Shyam] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Katsounas, A (reprint author), Univ Hosp Essen, Dept Gastroenterol & Hepatol, Hufelandstr 55, D-45147 Essen, Germany. EM antonios.katsounas@uk-essen.de FU NIH (National Institute of Allergy and Infectious Diseases) [HHSN261200800001E]; NIH (Clinical Research Center) [HHSN261200800001E] FX Grant sponsor: Intramural Research Program of the NIH (National Institute of Allergy and Infectious Diseases, and the Clinical Research Center; Grant number: HHSN261200800001E) NR 48 TC 0 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0146-6615 EI 1096-9071 J9 J MED VIROL JI J. Med. Virol. PD AUG PY 2014 VL 86 IS 8 BP 1323 EP 1331 DI 10.1002/jmv.23956 PG 9 WC Virology SC Virology GA AL9UB UT WOS:000339486200006 PM 24782267 ER PT J AU Li, Z Hu, Z Gu, Q AF Li, Z. Hu, Z. Gu, Q. TI Role of microRNAs in TBI and synaptic plasticity SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 12th Biennial Meeting of the Asian-Pacific-Society-for-Neurochemistry CY AUG 23-26, 2014 CL Kaohsiung, TAIWAN SP Asian Pacific Soc Neurochemistry C1 [Li, Z.; Hu, Z.; Gu, Q.] NIMH, Unit Synapse Dev & Plast, NIH, Bethesda, MD 20892 USA. RI Li, Zheng/I-8016-2014 OI Li, Zheng/0000-0002-2978-2531 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2014 VL 130 SU 1 SI SI MA S12-1 BP 24 EP 24 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AL9VZ UT WOS:000339492800049 ER PT J AU Ding, XH Zhang, C Frerich, JM Germanwala, A Yang, CZ Lonser, RR Mao, Y Zhuang, ZP Zhang, MG AF Ding, Xinghua Zhang, Chao Frerich, Jason M. Germanwala, Anand Yang, Chunzhang Lonser, Russell R. Mao, Ying Zhuang, Zhengping Zhang, Mingguang TI De novo VHL germline mutation detected in a patient with mild clinical phenotype of von Hippel-Lindau disease Case report SO JOURNAL OF NEUROSURGERY LA English DT Article DE hemangioblastoma; von Hippel-Lindau disease; de novo mutation; oncology ID GENE; FAMILY AB Von Hippel-Lindau (VHL) disease is an autosomal dominant multiorgan tumor syndrome caused by a germline mutation in the VHL gene. Characteristic tumors include CNS hemangioblastomas (HBs), endolymphatic sac tumors, renal cell carcinomas, pheochromocytomas, and pancreatic neuroendocrine tumors. Sporadic VHL disease with a de novo germline mutation is rare. The authors describe a case of multiple CNS HBs in a patient with a heterozygous de novo germline mutation at c.239G>T [p.S80I] of VHL. This is the first known case of a sporadic de novo germline mutation of VHL at c.239G>T. Clinicians should continue to consider VHL disease in patients presenting with sporadic CNS HBs, including those without a family history, to confirm or exclude additional VIAL-associated visceral lesions. C1 [Ding, Xinghua; Mao, Ying; Zhang, Mingguang] Fudan Univ, Huashan Hosp, Dept Neurosurg, Shanghai 200040, Peoples R China. [Zhang, Chao; Frerich, Jason M.; Germanwala, Anand; Yang, Chunzhang; Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Zhang, Chao] Third Mil Med Univ, Xinqiao Hosp, Dept Orthoped, Chongqing, Peoples R China. [Lonser, Russell R.] Ohio State Univ, Dept Neurol Surg, Columbus, OH 43210 USA. RP Zhang, MG (reprint author), Fudan Univ, Huashan Hosp, Dept Neurosurg, Shanghai 200040, Peoples R China. EM mgzhd300@163.com FU National Institute of Neurological Disorders and Stroke at the National Institutes of Health FX The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. This work was supported by the intramural program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. NR 13 TC 0 Z9 0 U1 1 U2 4 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD AUG PY 2014 VL 121 IS 2 BP 384 EP 386 DI 10.3171/2014.2.JNS131190 PG 3 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AL9PK UT WOS:000339473000021 PM 24678776 ER PT J AU Heiss, JD Oldfield, EH AF Heiss, John D. Oldfield, Edward H. TI Asymmetric patterns of CSF flow in the spinal subarachnoid cisterns in patients with syringomyelia: clinical implications RESPONSE SO JOURNAL OF NEUROSURGERY-SPINE LA English DT Letter ID CHIARI I MALFORMATION; PATHOPHYSIOLOGY C1 [Heiss, John D.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Oldfield, Edward H.] Univ Virginia, Charlottesville, VA USA. RP Heiss, JD (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA NS003050-07] NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1547-5654 EI 1547-5646 J9 J NEUROSURG-SPINE JI J. Neurosurg.-Spine PD AUG PY 2014 VL 21 IS 2 BP 315 EP 316 PG 2 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AL9PI UT WOS:000339472800032 PM 25221803 ER PT J AU Chukmaitov, A Bradley, CJ Dahman, B Siangphoe, U Bouhaidar, D Warren, JL AF Chukmaitov, Askar Bradley, Cathy J. Dahman, Bassam Siangphoe, Umaporn Bouhaidar, Doumit Warren, Joan L. TI Polypectomy Techniques, Endoscopist Characteristics, and Serious Gastrointestinal Adverse Events SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Article DE polypectomy techniques; endoscopist specialty; serious gastrointestinal adverse events ID COLORECTAL-CANCER; COLONOSCOPIC POLYPECTOMY; OUTPATIENT COLONOSCOPY; RISK-ADJUSTMENT; SPECIALIST CARE; GASTROENTEROLOGY; COMPLICATIONS; PERFORMANCE; GENERALISTS; GUIDELINES AB Background: A use of polypectomy techniques by endoscopist specialty (primary care, surgery, and gastroenterology) and experience (volume), and associations with serious gastrointestinal adverse events, were examined. Methods: A retrospective follow-up study with ambulatory surgery and hospital discharge datasets from Florida, 1999-2001, was used. Thirty-day hospitalizations due to colonic perforations and gastrointestinal bleeding were investigated for 323,585 patients. Results: Primary care endoscopists and surgeons used hot biopsy forceps/ablation, while gastroenterologists provided snare polypectomy or complex colonoscopy. Low-volume endoscopists were more likely to use simpler rather than complex procedures. For hot forceps/ablation and snare polypectomy, low-and medium-volume endoscopists reported higher odds of adverse events. For complex colonoscopy, higher odds of adverse events were reported for primary care endoscopists (1.74 [95% CI, 1.18-2.56]) relative to gastroenterologists. Conclusions: Endoscopists regardless of specialty and experience can safely use cold biopsy forceps. For hot biopsy and snare polypectomy, low volume, but not specialty, contributed to increased odds of adverse events. For complex colonoscopy, primary care specialty, but not low volume, added to the odds of adverse events. Comparable outcomes were reported for surgeons and gastroenterologists. Cross-training and continuing medical education of primary care endoscopists in high-volume endoscopy settings are recommended for complex colonoscopy procedures. (C) 2014 Wiley Periodicals, Inc. C1 [Chukmaitov, Askar; Bradley, Cathy J.; Dahman, Bassam; Siangphoe, Umaporn] Virginia Commonwealth Univ, Dept Healthcare Policy & Res, Sch Med, Richmond, VA 23298 USA. [Bouhaidar, Doumit] Virginia Commonwealth Univ, Div Gastroenterol, Sch Med, Richmond, VA 23298 USA. [Warren, Joan L.] NCI, Hlth Serv & Econ Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Chukmaitov, A (reprint author), Virginia Commonwealth Univ, Dept Healthcare Policy & Res, Sch Med, Med Coll Virginia Campus, Richmond, VA 23298 USA. EM achukmaitov@vcu.edu FU NCI NIH HHS [P30 CA016059] NR 28 TC 3 Z9 3 U1 3 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4790 EI 1096-9098 J9 J SURG ONCOL JI J. Surg. Oncol. PD AUG PY 2014 VL 110 IS 2 BP 207 EP 213 DI 10.1002/jso.23615 PG 7 WC Oncology; Surgery SC Oncology; Surgery GA AL9BP UT WOS:000339434800017 PM 24706376 ER PT J AU Churchill, S AF Churchill, Sheba TI Possible, but prudent? SO LAB ANIMAL LA English DT Editorial Material C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Churchill, S (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 3 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 EI 1548-4475 J9 LAB ANIMAL JI Lab Anim. PD AUG PY 2014 VL 43 IS 8 BP 266 EP 267 PG 2 WC Veterinary Sciences SC Veterinary Sciences GA AM1KP UT WOS:000339605100015 PM 25050723 ER PT J AU Brown, P Gipson, C AF Brown, Patricia Gipson, Chester TI A word from OLAW and USDA SO LAB ANIMAL LA English DT Editorial Material C1 [Brown, Patricia] NIH, OLAW, OER, OD,US DHHS, Bethesda, MD 20892 USA. [Gipson, Chester] APHIS, USDA, AC, Riverdale, MD 20737 USA. RP Brown, P (reprint author), NIH, OLAW, OER, OD,US DHHS, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 EI 1548-4475 J9 LAB ANIMAL JI Lab Anim. PD AUG PY 2014 VL 43 IS 8 BP 267 EP 267 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA AM1KP UT WOS:000339605100016 PM 25050725 ER PT J AU Van Boeckel, TP Gandra, S Ashok, A Caudron, Q Grenfell, BT Levin, SA Laxminarayan, R AF Van Boeckel, Thomas P. Gandra, Sumanth Ashok, Ashvin Caudron, Quentin Grenfell, Bryan T. Levin, Simon A. Laxminarayan, Ramanan TI Global antibiotic consumption 2000 to 2010: an analysis of Cross Mark 742 national pharmaceutical sales data SO LANCET INFECTIOUS DISEASES LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; ACUTE DIARRHEA; NEW-DELHI; ANTIMICROBIAL RESISTANCE; DEVELOPING-COUNTRIES; INCOME COUNTRIES; UNITED-STATES; SOUTH-INDIA; HEALTH; ENTEROBACTERIACEAE AB Background Antibiotic drug consumption is a major driver of antibiotic resistance. Variations in antibiotic resistance across countries are attributable, in part, to different volumes and patterns for antibiotic consumption. We aimed to assess variations in consumption to assist monitoring of the rise of resistance and development of rational-use policies and to provide a baseline for future assessment. Methods With use of sales data for retail and hospital pharmacies from the IMS Health MIDAS database, we reviewed trends for consumption of standard units of antibiotics between 2000 and 2010 for 71 countries. We used compound annual growth rates to assess temporal differences in consumption for each country and Fourier series and regression methods to assess seasonal differences in consumption in 63 of the countries. Findings Between 2000 and 2010, consumption of antibiotic drugs increased by 36% (from 54083 964 813 standard units to 73 620 748 816 standard units). Brazil, Russia, India, China, and South Africa accounted for 76% of this increase. In most countries, antibiotic consumption varied significantly with season. There was increased consumption of carbapenems (45%) and polymixins (13%), two last-resort classes of antibiotic drugs. Interpretation The rise of antibiotic consumption and the increase in use of last-resort antibiotic drugs raises serious concerns for public health. Appropriate use of antibiotics in developing countries should be encouraged. However, to prevent a striking rise in resistance in low-income and middle-income countries with large populations and to preserve antibiotic efficacy worldwide, programmes that promote rational use through coordinated efforts by the international community should be a priority. C1 [Van Boeckel, Thomas P.; Caudron, Quentin; Grenfell, Bryan T.; Levin, Simon A.] Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. [Gandra, Sumanth; Ashok, Ashvin; Laxminarayan, Ramanan] Ctr Dis Dynam Econ & Policy, Washington, DC USA. [Grenfell, Bryan T.; Levin, Simon A.; Laxminarayan, Ramanan] Princeton Environm Inst, Princeton, NJ 08544 USA. [Laxminarayan, Ramanan] Publ Hlth Fdn India, New Delhi, India. [Levin, Simon A.] Inst Ecol Econ, Stockholm, Sweden. [Grenfell, Bryan T.] Natl Inst Hlth, Fogarty Int Ctr, Bethesda, MD USA. RP Laxminarayan, R (reprint author), Princeton Environm Inst, Princeton, NJ 08544 USA. EM rlaxmina@princeton.edu OI CAUDRON, Quentin/0000-0002-0132-5005 FU US Department of Homeland Security; Bill & Melinda Gates Foundation; US National Institutes of Health; Princeton Grand Challenges Program FX Funding US Department of Homeland Security, Bill & Melinda Gates Foundation, US National Institutes of Health, Princeton Grand Challenges Program. NR 57 TC 158 Z9 162 U1 35 U2 146 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD AUG PY 2014 VL 14 IS 8 BP 742 EP 750 DI 10.1016/S1473-3099(14)70780-7 PG 9 WC Infectious Diseases SC Infectious Diseases GA AL9LD UT WOS:000339461700033 PM 25022435 ER PT J AU Levin, SW Baker, EH Zein, WM Zhang, ZJ Quezado, ZMN Miao, N Gropman, A Griffin, KJ Bianconi, S Chandra, G Khan, OI Caruso, RC Liu, AY Mukherjee, AB AF Levin, Sondra W. Baker, Eva H. Zein, Wadih M. Zhang, Zhongjian Quezado, Zenaide M. N. Miao, Ning Gropman, Andrea Griffin, Kurt J. Bianconi, Simona Chandra, Goutam Khan, Omar I. Caruso, Rafael C. Liu, Aiyi Mukherjee, Anil B. TI Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study SO LANCET NEUROLOGY LA English DT Article ID PALMITOYL-PROTEIN THIOESTERASE; MOUSE MODEL; NEURODEGENERATIVE DISEASES; THERAPEUTIC IMPLICATIONS; MOLECULAR-GENETICS; BATTEN-DISEASE; CHILDREN; BRAIN; NCL; NEUROINFLAMMATION AB Background Infantile neuronal ceroid lipofuscinosis is a devastating neurodegenerative lysosomal storage disease caused by mutations in the gene (CLN1 or PPT1) encoding palmitoyl-protein thioesterase-1 (PPT1). We have previously reported that phosphocysteamine and N-acetylcysteine mediate ceroid depletion in culured cells from patients with this disease. We aimed to assess whether combination of oral cysteamine bitartrate and N-acetylcysteine is beneficial for patients with neuronal ceroid lipofuscinosis. Methods Children between 6 months and 3 years of age with infantile neuronal ceroid lipofuscinosis with any two of the seven most lethal PPT1 mutations were eligible for inclusion in this pilot study. All patients were recruited from physician referrals. Patients received oral cysteamine bitartrate (60 mg/kg per day) and N-acetylcysteine (60 mg/kg per day) and were assessed every 6-12 months until they had an isoelectric electroencephalogram (EEG, attesting to a vegetative state) or were too ill to travel. Patients were also assessed by electroretinography, brain MRI and magnetic resonance spectroscopy (MRS), and electron microscopic analyses of leukocytes for granular osmiophilic deposits (GRODs). Children also underwent physical and neurodevelopmental assessments on the Denver scale. Outcomes were compared with the reported natural history of infantile neuronal ceroid lipofuscinosis and that of affected older siblings. Findings Between March 14, 2001, and June 30, 2012, we recruited ten children with infantile neuronal ceroid lipofuscinosis; one child was lost to follow-up after the first visit and nine patients (five girls and four boys) were followed up for 8 to 75 months. MRI showed abnormalities similar to those in previous reports; brain volume and N-acetyl aspartic acid (NAA) decreased steadily, but no published quantitative MRI or MRS studies were available for comparison. None of the children acquired new developmental skills, and their retinal function decreased progressively. Average time to isoelectric EEG (52 months, SD 13) was longer than reported previously (36 months). At the first follow-up visit, peripheral leukocytes in all nine patients showed virtually complete depletion of GRODs. Parents and physicians reported less irritability, improved alertness, or both in seven patients. No treatment-related adverse events occurred apart from mild gastrointestinal discomfort in two patients, which disappeared when liquid cysteamine bitartrate was replaced with capsules. Interpretation Our findings suggest that combination therapy with cysteamine bitartrate and N-acetylcysteine is associated with delay of isoelectric EEG, depletion of GRODs, and subjective benefits as reported by parents and physicians. Our systematic and quantitative report of the natural history of patients with infantile neuronal ceroid lipofuscinosis provides a guide for future assessment of experimental therapies. C1 [Levin, Sondra W.; Zhang, Zhongjian; Griffin, Kurt J.; Bianconi, Simona; Chandra, Goutam; Mukherjee, Anil B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, NIH, Bethesda, MD USA. [Baker, Eva H.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD USA. [Quezado, Zenaide M. N.; Miao, Ning] NIH, Dept Anesthesiol, Ctr Clin, Bethesda, MD USA. [Caruso, Rafael C.] NEI, NIH, Bethesda, MD 20892 USA. [Gropman, Andrea; Khan, Omar I.] NINDS, NIH, Bethesda, MD 20892 USA. [Levin, Sondra W.] Walter Reed Natl Mil Med Ctr, Dept Pediat, Bethesda, MD USA. [Quezado, Zenaide M. N.] Childrens Natl Med Ctr, Dept Anesthesiol, Washington, DC 20010 USA. [Gropman, Andrea] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Griffin, Kurt J.] Sanford Res Univ South, Dakota Med Ctr, Sioux Falls, SD USA. [Caruso, Rafael C.] Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. RP Mukherjee, AB (reprint author), NIH, Bldg 10,Room 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM mukherja@exchange.nih.gov RI Quezado, Zenaide/O-4860-2016; OI Quezado, Zenaide/0000-0001-9793-4368; Liu, Aiyi/0000-0002-6618-5082 FU National Institutes of Health FX National Institutes of Health. NR 49 TC 14 Z9 15 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD AUG PY 2014 VL 13 IS 8 BP 777 EP 787 DI 10.1016/S1474-4422(14)70142-5 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA AL9JB UT WOS:000339456300012 PM 24997880 ER PT J AU Sun, JY Shen, JY Thibodeaux, J Huang, G Wang, YG Gao, JM Low, PS Dimitrov, DS Sumer, BD AF Sun, Joel Y. Shen, Jiayin Thibodeaux, Joel Huang, Gang Wang, Yiguang Gao, Jinming Low, Philip S. Dimitrov, Dimiter S. Sumer, Baran D. TI In Vivo Optical Imaging of Folate Receptor-beta in Head and Neck Squamous Cell Carcinoma SO LARYNGOSCOPE LA English DT Article DE Head and neck; squamous cell carcinoma; folate receptor; optical imaging; fluorescence; tumor-associated macrophages ID TUMOR-ASSOCIATED MACROPHAGES; OVARIAN-CANCER; ALPHA; EXPRESSION; TARGET; LYMPHANGIOGENESIS; SURVIVAL; MARGINS; AGENTS AB Objectives/Hypothesis: Folate receptor (FR) expression, although known to be elevated in many types of cancer and inflammatory cells, has not been well characterized in head and neck squamous cell carcinoma (HNSCC). We hypothesized that tumor infiltrating inflammatory cells expressing FR-beta could allow fluorescent visualization of HNSCC tumors using folate conjugated dyes even when FR expression in cancer cells is low. Study Design: Retrospective review of clinical pathologic specimens and in vivo animal study. Methods: A tissue microarray with tumor and tumor-free tissue from 22 patients with HNSCC was stained with antibodies to FR-alpha and FR-beta. We characterized FR-beta 1 cells by examining CD45, CD68, CD206, and transforming growth factor (TGF)-beta expression. To investigate fluorescent imaging, mice with orthotopic tumor xenografts were imaged in vivo after intravenous injections of folate conjugated fluorescein isothiocyanate (folate-FITC) and were histologically evaluated ex vivo. Results: All tumor samples demonstrated significant FR-beta staining and negligible FR-alpha staining. FR-beta 1 cells found in tumors coexpressed CD68 and had increased expression of CD206 and TGF-beta characteristic of tumor-associated macrophages. In the xenograft models, tumors showed strong in vivo fluorescence after folate-FITC injection in contrast to surrounding normal tissues. Histologic examination of the xenograft tissue similarly showed folate-FITC uptake in areas of inflammatory cellular infiltrate. Conclusions: Although HNSCC tumor cells do not express FR, HNSCC tumors contain a significant population of FR-beta-expressing macrophages. Folate conjugated fluorescent dye is able to specifically target and label tumor xenografts to permit macroscopic fluorescence imaging due to FR-beta expression on the infiltrating inflammatory cells. C1 [Sun, Joel Y.; Sumer, Baran D.] Univ Texas SW Med Ctr Dallas, Dept Otolaryngol, Dallas, TX 75390 USA. [Thibodeaux, Joel] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Huang, Gang; Wang, Yiguang; Gao, Jinming] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Shen, Jiayin; Low, Philip S.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Dimitrov, Dimiter S.] NCI, NIH, Frederick, MD 21701 USA. RP Sumer, BD (reprint author), Univ Texas SW Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dept Otolaryngol Head & Neck Surg, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM baran.sumer@UTSouthwestern.edu RI Wang, Yiguang/H-7402-2014 OI Wang, Yiguang/0000-0002-1676-4211 FU Cancer Prevention and Research Institute of Texas [RP120094] FX This study was supported by the Cancer Prevention and Research Institute of Texas grant RP120094 to B.D.S. and J.G. NR 31 TC 8 Z9 8 U1 2 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD AUG PY 2014 VL 124 IS 8 BP E312 EP E319 DI 10.1002/lary.24606 PG 8 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA AL9ST UT WOS:000339482100003 PM 24448885 ER PT J AU Al Otaiba, S Wagner, RK Miller, B AF Al Otaiba, Stephanie Wagner, Richard K. Miller, Brett TI "Waiting to Fail" Redux: Understanding Inadequate Response to Intervention SO LEARNING DISABILITY QUARTERLY LA English DT Editorial Material DE reading; response to innovation; reading disabilities; identification ID MINORITY-STUDENTS AB This introduction to the special series provides an overview of the promise, and the ongoing challenges, related to Response to Intervention (RTI) as a means of both prevention and identification of reading disabilities. We conclude by describing the articles in this special series and considering their implications for future research. C1 [Al Otaiba, Stephanie] So Methodist Univ, Dallas, TX 75275 USA. [Wagner, Richard K.] Florida State Univ, Tallahassee, FL 32306 USA. [Miller, Brett] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. RP Al Otaiba, S (reprint author), So Methodist Univ, Dept Teaching & Learning, Annette Caldwell Simmons Sch Educ & Human Dev, POB 750455, Dallas, TX 75275 USA. EM salotaiba@smu.edu FU NICHD NIH HHS [P50 HD052120] NR 30 TC 1 Z9 1 U1 3 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0731-9487 EI 2168-376X J9 LEARN DISABILITY Q JI Learn. Disabil. Q. PD AUG PY 2014 VL 37 IS 3 BP 129 EP 133 DI 10.1177/0731948714525622 PG 5 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA AM1GF UT WOS:000339593700003 PM 25422530 ER PT J AU Cunningham, BA Bonham, VL Sellers, SL Yeh, HC Cooper, LA AF Cunningham, Brooke A. Bonham, Vence L. Sellers, Sherrill L. Yeh, Hsin-Chieh Cooper, Lisa A. TI Physicians' Anxiety Due to Uncertainty and Use of Race in Medical Decision Making SO MEDICAL CARE LA English DT Article DE medical decision making; race and ethnicity; uncertainty ID FORCE RECOMMENDATION STATEMENT; HEALTH-CARE DISPARITIES; STATISTICAL DISCRIMINATION; CLINICAL UNCERTAINTY; PATIENT; COMMUNICATION; ATTITUDES; RACE/ETHNICITY; PERCEPTIONS; DEPRESSION AB Background: The explicit use of race in medical decision making is contested. Researchers have hypothesized that physicians use race in care when they are uncertain. Objectives: The aim of this study was to investigate whether physician anxiety due to uncertainty (ADU) is associated with a higher propensity to use race in medical decision making. Research Design: This study included a national cross-sectional survey of general internists. Subjects: A national sample of 1738 clinically active general internists drawn from the SK&A physician database were included in the study. Measures: ADU is a 5-item measure of emotional reactions to clinical uncertainty. Bonham and Sellers Racial Attributes in Clinical Evaluation (RACE) scale includes 7 items that measure self-reported use of race in medical decision making. We used bi-variate regression to test for associations between physician characteristics, ADU, and RACE. Multivariate linear regression was performed to test for associations between ADU and RACE while adjusting for potential confounders. Results: The mean score on ADU was 19.9 (SD = 5.6). Mean score on RACE was 13.5 (SD = 5.6). After adjusting for physician demographics, physicians with higher levels of ADU scored higher on RACE (+beta = 0.08 in RACE, P = 0.04, for each 1-point increase in ADU), as did physicians who understood "race" to mean biological or genetic ancestral, rather than sociocultural, group. Physicians who graduated from a US medical school, completed fellowship, and had more white patients scored lower on RACE. Conclusions: This study demonstrates positive associations between physicians' ADU, meanings attributed to race, and self-reported use of race in medical decision making. Future research should examine the potential impact of these associations on patient outcomes and health care disparities. C1 [Cunningham, Brooke A.] Medica Res Inst, Minneapolis, MN 55440 USA. [Bonham, Vence L.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Sellers, Sherrill L.] Miami Univ, Dept Family Studies & Social Work, Oxford, OH 45056 USA. [Yeh, Hsin-Chieh; Cooper, Lisa A.] Johns Hopkins Sch Med, Div Gen Internal Med, Dept Med, Baltimore, MD USA. RP Cunningham, BA (reprint author), Medica Res Inst, MR CW105,POB 9310, Minneapolis, MN 55440 USA. EM brooke.cunningham@medica.com OI Cunningham, Brooke/0000-0002-3205-5538 FU National Human Genome Research Institute, National Institutes of Health [ZIA HG200324-08]; Greenwall Fellowship Program in Bioethics and Health Policy; Health Resources and Services Administration [T32HP10025]; National Heart, Lung, and Blood Institute [K24 HL083113] FX Supported, in part, by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, (V.L.B., ZIA HG200324-08). B.A.C. supported by the Greenwall Fellowship Program in Bioethics and Health Policy and Health Resources and Services Administration training grant (T32HP10025). L.A.C. supported by a grant from the National Heart, Lung, and Blood Institute (K24 HL083113). NR 49 TC 3 Z9 3 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD AUG PY 2014 VL 52 IS 8 BP 728 EP 733 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AL7RQ UT WOS:000339332900010 PM 25025871 ER PT J AU Risinger, JI Custer, M Feigenbaum, L Simpson, RM Hoover, SB Webster, JD Chandramouli, GVR Tessarollo, L Barrett, JC AF Risinger, John I. Custer, Mary Feigenbaum, Lionel Simpson, R. Mark Hoover, Shelley B. Webster, Joshua D. Chandramouli, Gadisetti V. R. Tessarollo, Lino Barrett, J. Carl TI Normal Viability of Kai1/Cd82 Deficient Mice SO MOLECULAR CARCINOGENESIS LA English DT Article DE metastasis suppressor; gene knockout; CD82 ID METASTASIS SUPPRESSOR PROTEIN; SQUAMOUS-CELL CARCINOMA; LEUKEMIA-VIRUS TYPE-1; PROSTATE-CANCER; GENE-EXPRESSION; TRANSMEMBRANE-4 SUPERFAMILY; TETRASPANIN SUPERFAMILY; SYNCYTIUM FORMATION; CD9-DEFICIENT MICE; DOWN-REGULATION AB The KAI1/CD82 tetraspanin is a widely expressed cell surface molecule thought to organize diverse cellular signaling processes. KAI1/CD82 suppresses metastasis but not tumorigenicity, establishing it as one of a class of metastasis suppressor genes. In order to further assess its functions, we have characterized the phenotypic properties of Kai1/Cd82 deleted mice, including viability, fertility, lymphocyte composition, blood chemistry and tissue histopathology, and of their wild-type and heterozygote littermates. Interestingly, Kai1/Cd82(-/-) showed no obvious genotype associated defects in any of these processes and displayed no genotype associated histopathologic abnormalities after 12 or 18 months of life. Expression profiles of non-immortal, wild-type and Kai1/Cd82(-/-) mouse embryo fibroblast (MEFs) indicated distinct sex-specific and genotype-specific profiles. These data identify 191 and 1,271 differentially expressed transcripts (by twofold at P < 0.01) based on Kai1/CD82 genotype status in female and male MEFs, respectively. Differentially expressed genes in male MEFs were surprisingly enriched for cell division related processes, suggesting that Kai1/Cd82 may functionally affect these processes. This suggests that Kai/Cd82 has an unappreciated role in the early establishment of proliferation and division when challenged with a new environment that might play a role in adaptability to new metastatic sites. (C) 2013 Wiley Periodicals, Inc. C1 [Risinger, John I.; Chandramouli, Gadisetti V. R.] Michigan State Univ, Coll Human Med, Dept Obstet Gynecol & Reprod Biol, Grand Rapids, MI 49503 USA. [Risinger, John I.; Custer, Mary; Feigenbaum, Lionel; Simpson, R. Mark; Hoover, Shelley B.; Webster, Joshua D.; Tessarollo, Lino; Barrett, J. Carl] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Barrett, J. Carl] AstraZeneca Pharmaceut LP, Translat Sci Oncol Innovat Med, Waltham, MA USA. RP Risinger, JI (reprint author), Michigan State Univ, Coll Human Med, Dept Obstectr Gynecol & Reprod Biol, Grand Rapids, MI 49503 USA. NR 50 TC 2 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD AUG PY 2014 VL 53 IS 8 BP 610 EP 624 DI 10.1002/mc.22009 PG 15 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA AM0UQ UT WOS:000339562800003 PM 23401136 ER PT J AU Wulfert, S Kratochwil, C Choyke, PL Afshar-Oromieh, A Mier, W Kauczor, HU Schenk, JP Haberkorn, U Giesel, FL AF Wulfert, Sarah Kratochwil, Clemens Choyke, Peter L. Afshar-Oromieh, Ali Mier, Walter Kauczor, Hans-Ulrich Schenk, Jens-Peter Haberkorn, Uwe Giesel, Frederik L. TI Multimodal Imaging for Early Functional Response Assessment of Y-90-/Lu-177-DOTATOC Peptide Receptor Targeted Radiotherapy with DW-MRI and Ga-68-DOTATOC-PET/CT SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE Peptide receptor-targeted radiotherapy; Multimodal imaging; Neuroendocrine cancer; Response monitoring; 68Ga-DOTATOC PET; DW-MRI ID GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS; APPARENT DIFFUSION-COEFFICIENT; LIVER-DIRECTED THERAPIES; HEPATIC METASTASES; RADIOPEPTIDE THERAPY; SELECTIVE ARTERIAL; CARCINOID-TUMORS; TRACT; PET; EPIDEMIOLOGY AB The purpose of this study is to investigate the utility of contrast-enhanced magnetic resonance imaging (CE-MRI), diffusion-weighted MRI (DW-MRI), and Ga-68-DOTATOC positron emission tomography/computer tomography (Ga-68-DOTATOC PET/CT) in the assessment of response to loco-regional peptide receptor radiotherapy (PRRT) with Y-90-/Lu-177-DOTATOC in patients with hepatic metastases from gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). CE-MRI, DW-MRI, and Ga-68-DOTATOC-PET/CT images were acquired before and 3 months after one to two cycles of intra-arterial Y-90-/Lu-177-DOTATOC therapy in 14 patients (nine female, five male; mean age, 54 +/- 9 years; range, 41-69 years) with hepatic metastases from GEP-NET. A total of 38 liver metastases were defined as target lesions for which the longest diameter, mean apparent diffusion coefficient (ADC(mean)) and maximum standardized uptake value (SUVmax) were assessed. Based on changes in size on follow-up imaging, target lesions were classified as responding (RL) or nonresponding (NRL). Relative changes in tumor size, ADC(mean), and SUVmax were compared between the two subgroups. A total of 27 responding and 11 nonresponding lesions were successfully evaluated. Mean ADC(mean) increased significantly in RL (p = 0.011) as well as NRL (p = 0.025). A significant correlation was found between baseline ADC(mean) and both the percent ADC(mean) change (p = 0.033) and decrease in lesion size after therapy (diameter p = 0.006; volume p = 0.002). SUVmax of RL declined significantly by 24.1 % (p = 0.014) and remained nearly unchanged in NRL. The change of SUVmax correlated significantly with the pretreatment SUVmax (p < 0.001) and the change in lesion diameter (p = 0.009). NRL with an ADC(mean) change > 0.31 x 10(-3) mm(2)/s on first follow-up imaging showed a decrease in size in the long-term course. These results suggest that both DW-MRI and DOTATOC-PET imaging provide potential biomarkers for early assessment of treatment and stratification of therapy response, but that DW-MRI should be interpreted only in combination with SSTR expression and morphologic changes. C1 [Wulfert, Sarah; Kratochwil, Clemens; Afshar-Oromieh, Ali; Mier, Walter; Haberkorn, Uwe; Giesel, Frederik L.] Univ Heidelberg Hosp, Dept Nucl Med, D-69120 Heidelberg, Germany. [Choyke, Peter L.] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Kauczor, Hans-Ulrich; Schenk, Jens-Peter] Univ Heidelberg Hosp, Dept Diagnost & Intervent Radiol, D-69120 Heidelberg, Germany. RP Giesel, FL (reprint author), Univ Heidelberg Hosp, Dept Nucl Med, INF 400, D-69120 Heidelberg, Germany. EM frederik@egiesel.com NR 36 TC 6 Z9 6 U1 2 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 EI 1860-2002 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD AUG PY 2014 VL 16 IS 4 BP 586 EP 594 DI 10.1007/s11307-014-0722-7 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AL8HC UT WOS:000339377900017 PM 24526358 ER PT J AU Lucantonio, F Takahashi, YK Hoffman, AF Chang, C Bali-Chaudhary, S Shaham, Y Lupica, CR Schoenbaum, G AF Lucantonio, Federica Takahashi, Yuji K. Hoffman, Alexander F. Chang, Chun Bali-Chaudhary, Sheena Shaham, Yavin Lupica, Carl R. Schoenbaum, Geoffrey TI Orbitofrontal activation restores insight lost after cocaine use SO NATURE NEUROSCIENCE LA English DT Article ID PREFRONTAL CORTEX; SYNAPTIC PLASTICITY; DRUG-ADDICTION; OUTCOMES; DEFICITS; OVEREXPECTATION; BEHAVIOR; NEURONS; RATS; REINSTATEMENT AB Addiction is characterized by a lack of insight into the likely outcomes of one's behavior. Insight, or the ability to imagine outcomes, is evident when outcomes have not been directly experienced. Using this concept, work in both rats and humans has recently identified neural correlates of insight in the medial and orbital prefrontal cortices. We found that these correlates were selectively abolished in rats by cocaine self-administration. Their abolition was associated with behavioral deficits and reduced synaptic efficacy in orbitofrontal cortex, the reversal of which by optogenetic activation restored normal behavior. These results provide a link between cocaine use and problems with insight. Deficits in these functions are likely to be particularly important for problems such as drug relapse, in which behavior fails to account for likely adverse outcomes. As such, our data provide a neural target for therapeutic approaches to address these defining long-term effects of drug use. C1 [Lucantonio, Federica; Takahashi, Yuji K.; Hoffman, Alexander F.; Chang, Chun; Bali-Chaudhary, Sheena; Shaham, Yavin; Lupica, Carl R.; Schoenbaum, Geoffrey] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Lucantonio, Federica; Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Schoenbaum, Geoffrey] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD USA. RP Lucantonio, F (reprint author), NIDA, Intramural Res Program, Baltimore, MD 21224 USA. EM federica.lucantonio@nih.gov; geoffrey.schoenbaum@nih.gov RI Hoffman, Alexander/H-3035-2012 OI Hoffman, Alexander/0000-0002-2676-0628 FU National Institute on Drug Abuse (NIDA) FX The authors would like to thank K. Deisseroth (Stanford University) and the Gene Therapy Center at the University of North Carolina at Chapel Hill core for providing viral reagents, and B. Harvey of the NIDA Optogenetic and Transgenic Core for technical advice on their use. This work was supported by funding from the National Institute on Drug Abuse (NIDA). The opinions expressed in this article are the authors' own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. NR 49 TC 15 Z9 15 U1 1 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD AUG PY 2014 VL 17 IS 8 BP 1092 EP 1099 DI 10.1038/nn.3763 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AM1XA UT WOS:000339641400015 PM 25042581 ER PT J AU Chaiworapongsa, T Chaemsaithong, P Yeo, L Romero, R AF Chaiworapongsa, Tinnakorn Chaemsaithong, Piya Yeo, Lami Romero, Roberto TI Pre-eclampsia part 1: current understanding of its pathophysiology SO NATURE REVIEWS NEPHROLOGY LA English DT Review ID GROWTH-FACTOR RECEPTOR-1; PREGNANCY-INDUCED HYPERTENSION; LATE-ONSET PREECLAMPSIA; CATECHOL-O-METHYLTRANSFERASE; CIRCULATING ANGIOGENIC FACTORS; TYROSINE KINASE-1 EXPRESSION; REDUCED UTERINE PERFUSION; ELEVATED LIVER-ENZYMES; LOW PLATELET COUNT; AGONISTIC AUTOANTIBODIES AB Pre-eclampsia is characterized by new-onset hypertension and proteinuria at 20 weeks of gestation. In the absence of proteinuria, hypertension together with evidence of systemic disease (such as thrombocytopenia or elevated levels of liver transaminases) is required for diagnosis. This multisystemic disorder targets Several organs, including the kidneys, liver and brain, and is a leading cause of maternal and perinatal morbidity and mortality. Glomeruloendotheliosis is considered to be a characteristic lesion of pre-eclampsia, but can also occur in healthy pregnant women. The placenta has an essential role in development of this disorder. Pathogenetic mechanisms implicated in pre-eclampsia include defective deep placentation, oxidative and endoplasmic reticulum stress, autoantibodies to type-1 angiotensin II receptor, platelet and thrombin activation, intravascular inflammation, endothelial dysfunction and the presence of an antiangiogenic state, among which an imbalance of angiogenesis has emerged as one of the most important factors. However, this imbalance is not specific to pre-eclampsia, as it also occurs in intrauterine growth restriction, fetal death, spontaneous preterm labour and maternal floor infarction (massive perivillous fibrin deposition). The severity and timing of the angiogenic imbalance, together with maternal susceptibility, might determine the clinical presentation of pre-eclampsia. This Review discusses the diagnosis, classification, clinical manifestations and putative pathogenetic mechanisms of pre-eclampsia. C1 [Chaiworapongsa, Tinnakorn; Chaemsaithong, Piya; Yeo, Lami; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD 20892 USA. RP Chaiworapongsa, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. EM tchaiwor@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriven National Institute of Child Health and Human Development, NIH, Department of Health and Human Services (NICHD/NIH/DHHS); NICHD; NIH [HHSN275201300006C] FX The authors' research is supported partly by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriven National Institute of Child Health and Human Development, NIH, Department of Health and Human Services (NICHD/NIH/DHHS) and partly with Federal funding from the NICHD and NIH under contract no. HHSN275201300006C. NR 201 TC 103 Z9 112 U1 8 U2 56 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5061 EI 1759-507X J9 NAT REV NEPHROL JI Nat. Rev. Nephrol. PD AUG PY 2014 VL 10 IS 8 BP 466 EP 480 DI 10.1038/nrneph.2014.102 PG 15 WC Urology & Nephrology SC Urology & Nephrology GA AM0JQ UT WOS:000339532300009 PM 25003615 ER PT J AU Seidel, J Bernardo, ML Wong, KJ Xu, BY Williams, MR Kuo, F Jagoda, EM Basuli, F Li, CH Griffiths, GL Green, MV Choyke, PL AF Seidel, Jurgen Bernardo, Marcelino L. Wong, Karen J. Xu, Biying Williams, Mark R. Kuo, Frank Jagoda, Elaine M. Basuli, Falguni Li, Changhui Griffiths, Gary L. Green, Michael V. Choyke, Peter L. TI Simultaneous ECG-gated PET imaging of multiple mice SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE Pre-clinical cardiac PET imaging; ECG-gated PET imaging; Blood pool imaging; [F-18] albumin ID TOMOGRAPHY; SCANNER AB Introduction: We describe and illustrate a method for creating ECG-gated PET images of the heart for each of several mice imaged at the same time. The method is intended to increase "throughput" in PET research studies of cardiac dynamics or to obtain information derived from such studies, e.g. tracer concentration in end-diastolic left ventricular blood. Methods: An imaging bed with provisions for warming, anesthetic delivery, etc., was fabricated by 3D printing to allow simultaneous PET imaging of two side-by-side mice. After electrode attachment, tracer injection and placement of the animals in the scanner field of view, ECG signals from each animal were continuously analyzed and independent trigger markers generated whenever an R-wave was detected in each signal. PET image data were acquired in "list" mode and these trigger markers were inserted into this list along with the image data. Since each mouse is in a different spatial location in the FOV, sorting of these data using trigger markers first from one animal and then the other yields two independent and correctly formed ECG-gated image sequences that reflect the dynamical properties of the heart during an "average" cardiac cycle. Results: The described method yields two independent ECG-gated image sequences that exhibit the expected properties in each animal, e.g. variation of the ventricular cavity volumes from maximum to minimum and back during the cardiac cycle in the processed animal with little or no variation in these volumes during the cardiac cycle in the unprocessed animal. Conclusion: ECG-gated image sequences for each of several animals can be created from a single list mode data collection using the described method. In principle, this method can be extended to more than two mice (or other animals) and to other forms of physiological gating, e.g. respiratory gating, when several subjects are imaged at the same time. (C) 2014 Elsevier Inc. All rights reserved. C1 [Seidel, Jurgen; Bernardo, Marcelino L.; Wong, Karen J.; Williams, Mark R.; Kuo, Frank; Jagoda, Elaine M.; Griffiths, Gary L.; Green, Michael V.; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Seidel, Jurgen; Bernardo, Marcelino L.; Williams, Mark R.; Green, Michael V.] Leidos Biomed Res Inc, Frederick, MD USA. [Xu, Biying; Basuli, Falguni; Li, Changhui] NHLBI, Imaging Probe Dev Ctr, NIH, Bethesda, MD 20892 USA. [Xu, Biying; Basuli, Falguni; Li, Changhui] Kelly Serv Inc, Troy, MI USA. [Kuo, Frank] NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Griffiths, Gary L.] Leidos Biomed Res Inc, Clin Res Directorate CMRP, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Seidel, J (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,Room B3B69,MSC1088, Bethesda, MD 20892 USA. EM jseidel1@mail.nih.gov FU CCR NIH HHS [HHSN261200800001C]; Intramural NIH HHS [ZIA BC010668-09]; NCI NIH HHS [HHSN261200800001E] NR 9 TC 0 Z9 0 U1 2 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 EI 1872-9614 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD AUG PY 2014 VL 41 IS 7 BP 582 EP 586 DI 10.1016/j.nucmedbio.2014.03.015 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AM1IL UT WOS:000339599500005 PM 24909865 ER PT J AU Tatu, U Neckers, L AF Tatu, Utpal Neckers, Len TI Chaperoning parasitism: the importance of molecular chaperones in pathogen virulence PREFACE SO PARASITOLOGY LA English DT Editorial Material ID SHOCK-PROTEIN 90; ATPASE CYCLE; HSP90; TRAP1; HEAT-SHOCK-PROTEIN-90; INHIBITORS; MACHINERY; THERAPY; COMPLEX; TARGET C1 [Tatu, Utpal] Indian Inst Sci, Dept Biochem, Bangalore 560012, Karnataka, India. [Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Tatu, U (reprint author), Indian Inst Sci, Dept Biochem, Bangalore 560012, Karnataka, India. EM tatu@biochem.iisc.ernet.in NR 32 TC 1 Z9 1 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0031-1820 EI 1469-8161 J9 PARASITOLOGY JI Parasitology PD AUG PY 2014 VL 141 IS 9 SI SI BP 1123 EP 1126 DI 10.1017/S0031182014000778 PG 4 WC Parasitology SC Parasitology GA AM1PL UT WOS:000339619600001 PM 25004925 ER PT J AU Hong, JH Park, S Shcheynikov, N Muallem, S AF Hong, Jeong Hee Park, Seonghee Shcheynikov, Nikolay Muallem, Shmuel TI Mechanism and synergism in epithelial fluid and electrolyte secretion SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Review DE Secretory glands; WNK/SPAK pathway; IRBIT/PP1 pathway; Coordination; Synergism ID TRANSMEMBRANE CONDUCTANCE REGULATOR; PANCREATIC ACINAR-CELLS; CYSTIC-FIBROSIS GENE; SODIUM-BICARBONATE COTRANSPORTER; CA2+-ACTIVATED K+ CHANNELS; RECEPTOR-BINDING PROTEIN; KELCH-LIKE 3; HCO3-SECRETION; WNK KINASES; IP3 RECEPTOR AB A central function of epithelia is the control of the volume and electrolyte composition of bodily fluids through vectorial transport of electrolytes and the obligatory H2O. In exocrine glands, fluid and electrolyte secretion is carried out by both acinar and duct cells, with the portion of fluid secreted by each cell type varying among glands. All acinar cells secrete isotonic, plasma-like fluid, while the duct determines the final electrolyte composition of the fluid by absorbing most of the Cl- and secreting HCO3 (-). The key transporters mediating acinar fluid and electrolyte secretion are the basolateral Na+/K+ /2Cl(-) cotransporter, the luminal Ca2+-activated Cl- channel ANO1 and basolateral and luminal Ca2+-activated K+ channels. Ductal fluid and HCO3 (-) secretion are mediated by the basolateral membrane Na+-HCO3 (-) cotransporter NBCe1-B and the luminal membrane Cl-/HCO3 (-) exchanger slc26a6 and the Cl- channel CFTR. The function of the transporters is regulated by multiple inputs, which in the duct include major regulation by the WNK/SPAK pathway that inhibit secretion and the IRBIT/PP1 pathway that antagonize the effects of the WNK/SPAK pathway to both stimulate and coordinate the secretion. The function of these regulatory pathways in secretory glands acinar cells is yet to be examined. An important concept in biology is synergism among signaling pathways to generate the final physiological response that ensures regulation with high fidelity and guards against cell toxicity. While synergism is observed in all epithelial functions, the molecular mechanism mediating the synergism is not known. Recent work reveals a central role for IRBIT as a third messenger that integrates and synergizes the function of the Ca2+ and cAMP signaling pathways in activation of epithelial fluid and electrolyte secretion. These concepts are discussed in this review using secretion by the pancreatic and salivary gland ducts as model systems. C1 [Hong, Jeong Hee; Shcheynikov, Nikolay; Muallem, Shmuel] Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Park, Seonghee] Ewha Womans Univ, Dept Physiol, Sch Med, Seoul 158710, South Korea. RP Muallem, S (reprint author), Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM Shmuel.muallem@nih.gov FU NIH, NIDCR [DE000735] FX The work in the authors' laboratory was funded by Intramural Research Program of the NIH, NIDCR grant DE000735. NR 158 TC 9 Z9 10 U1 0 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0031-6768 EI 1432-2013 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD AUG PY 2014 VL 466 IS 8 BP 1487 EP 1499 DI 10.1007/s00424-013-1390-1 PG 13 WC Physiology SC Physiology GA AL8KQ UT WOS:000339387900001 PM 24240699 ER PT J AU Colon-Saez, JO Yakel, JL AF Colon-Saez, Jose O. Yakel, Jerrel L. TI A mutation in the extracellular domain of the alpha 7 nAChR reduces calcium permeability SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article DE Alpha 7 nAChR; Calcium permeability; Extracellular domain; Mutagenesis ID NICOTINIC ACETYLCHOLINE-RECEPTOR; HIPPOCAMPAL SYNAPTIC PLASTICITY; CA2+ PERMEABILITY; CA1 INTERNEURONS; RAT HIPPOCAMPAL; CHANNEL DOMAIN; CELLS; ACTIVATION; NEURONS; DISEASE AB The alpha 7 neuronal nicotinic acetylcholine receptor (nAChR) displays the highest calcium permeability among the different subtypes of nAChRs expressed in the mammalian brain and can impact cellular events including neurotransmitter release, second messenger cascades, cell survival, and apoptosis. The selectivity for cations in nAChRs is thought to be achieved in part by anionic residues which are located on either side of the channel mouth and increase relative cationic concentration. Mutagenesis studies have improved our understanding of the role of the second transmembrane domain and the intracellular loop of the channel in ion selectivity. However, little is known about the influence that the extracellular domain (ECD) plays in ion permeation. In the alpha 7 nAChR, it has been found that the ECD contains a ring of ten aspartates (two per subunit) that is believed to face the lumen of the pore and could attract cations for permeation. Using mutagenesis and a combination of electrophysiology and imaging techniques, we tested the possible involvement of these aspartate residues in the calcium permeability of the rat alpha 7 nAChR. We found that one of these residues (the aspartate at position 44) appears to be essential since mutating it to alanine resulted in a decrease in amplitude for both whole cell and single-channel responses and in the complete disappearance of detectable calcium changes in most cells, which indicates that the ECD of the alpha 7 nAChR plays a key role in calcium permeation. C1 [Colon-Saez, Jose O.; Yakel, Jerrel L.] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM yakel@niehs.nih.gov FU Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS) FX This work was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS). The authors also thank Dr. Ezequiel Marron and Dr. Christian Erxleben for their helpful insights and suggestions in the manuscript preparation process and Pattie Lamb for preparing all of the constructs used in this study. NR 46 TC 4 Z9 4 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0031-6768 EI 1432-2013 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD AUG PY 2014 VL 466 IS 8 BP 1571 EP 1579 DI 10.1007/s00424-013-1385-y PG 9 WC Physiology SC Physiology GA AL8KQ UT WOS:000339387900008 PM 24177919 ER PT J AU McNeil, S AF McNeil, Scott TI A Matter of Size SO SCIENTIST LA English DT Editorial Material C1 [McNeil, Scott] Leidos Biomed Res Inc, NCL, Frederick, MD 21702 USA. [McNeil, Scott] Frederick Natl Lab Canc Res, Frederick, MD USA. [McNeil, Scott] NCL, Pune, Maharashtra, India. RP McNeil, S (reprint author), Leidos Biomed Res Inc, NCL, Frederick, MD 21702 USA. RI Nanotechnology Characterization Lab, NCL/K-8454-2012 NR 0 TC 0 Z9 0 U1 1 U2 5 PU LABX MEDIA GROUP PI MIDLAND PA PO BOX 216, 478 BAY ST, MIDLAND, ONTARIO L4R 1K9, CANADA SN 0890-3670 EI 1547-0806 J9 SCIENTIST JI Scientist PD AUG PY 2014 VL 28 IS 8 BP 24 EP 25 PG 2 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA AM0MY UT WOS:000339540900006 ER PT J AU Ford, JS Puleo, E Sprunck-Harrild, K deMoor, J Emmons, KM AF Ford, Jennifer S. Puleo, Elaine Sprunck-Harrild, Kim deMoor, Janet Emmons, Karen M. TI Perceptions of risk among childhood and young adult cancer survivors who smoke SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Childhood; Young adult; Cancer survivor; Risk perception ID LONG-TERM SURVIVORS; PEDIATRIC CANCER; HEALTH BEHAVIORS; ADOLESCENT SURVIVORS; MEDICAL-CARE; INTERVENTIONS; PREDICTORS; MAMMOGRAPHY; INTENTIONS; GUIDELINES AB Despite the fact that childhood and young adult cancer survivors are at increased risk for chronic health problems as a result of their cancer treatment, many use tobacco, thereby increasing their risks. Perceptions of risk related to tobacco use can be targeted for interventions aimed at improving health behaviors for childhood, adolescent, and young adult cancer survivors. Understanding the covariates of perceptions of health risks among young adult survivors who smoke will help to determine targets for intervention. Three hundred seventy-four participants who were diagnosed with cancer prior to age 35, currently between 18 and 55 years of age, and current smokers were recruited as part of a larger smoking cessation study, Partnership for Health-2 (PFH-2). Data were collected by telephone survey. Overall, women had the highest perception of risk for serious health problems, a second cancer, and heart problems. Additionally, those participants who were dependent on nicotine endorsed that they were at higher risk of serious health problems and second cancers, but not heart problems. Finally, Hodgkin lymphoma survivors reported that they were at increased risk for second cancers and heart problems compared to their "healthy" peers. Young adult cancer survivors who smoke correctly perceived some of their increased health risks. Additional motivation and education is needed for those young adult cancer survivors who perceive their increased health risks yet continue to smoke. Further education is needed for young survivors so they have a fully appropriate sense of risk, especially as it relates to their tobacco use. C1 [Ford, Jennifer S.] Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, New York, NY 10022 USA. [Puleo, Elaine] Univ Massachusetts, Boston, MA 02125 USA. [Sprunck-Harrild, Kim; Emmons, Karen M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sprunck-Harrild, Kim; Emmons, Karen M.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [deMoor, Janet] NCI, Bethesda, MD 20892 USA. RP Ford, JS (reprint author), Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, 641 Lexington Ave,7th Floor, New York, NY 10022 USA. EM fordj@mskcc.org NR 44 TC 5 Z9 5 U1 0 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD AUG PY 2014 VL 22 IS 8 BP 2207 EP 2217 DI 10.1007/s00520-014-2165-8 PG 11 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA AL7TT UT WOS:000339339300024 PM 24659242 ER PT J AU Waidyanatha, S Ryan, K AF Waidyanatha, Suramya Ryan, Kristen TI Disposition of fragrance ingredient [C-14]1-(1,2,3,4,5,6,7,8-octahydro-2,3,8,8-tetramethyl-2-naphthalenyl)et hanone in male Fisher rats following oral administration and dermal application SO XENOBIOTICA LA English DT Article DE 1-(1,2,3,4,5,6,7,8-Octahydro-2,3,8,8-tetramethyl-2-naphthalenyl)ethanone ; biliary excretion; dermal absorption; enterohepatic recirculation; fragrance ingredient; oral absorption ID SEWAGE-TREATMENT PLANTS; OTNE AB 1. Disposition of 1-(1,2,3,4,5,6,7,8-octahydro-2,3,8,8-tetramethyl-2-naphthalenyl)ethanone (beta-OTNE), a fragrance ingredient in variety of consumer products, was investigated following a single oral (20 mg/kg) or a dermal (55 or 550 mg/kg) dose of [C-14]beta-OTNE to male Fisher rats. 2. Following oral administration, 28% and 39% of the dose was recovered in urine and feces, respectively, 48 h following administration. About 73% of a 20 mg/kg dose was excreted in bile within 48 h post-administration supporting significant oral absorption of [C-14]beta-OTNE. 3. Following dermal application to a covered site, absorption of [C-14]beta-OTNE 96 h following application was low (ca. 14%) and dose-independent. When the dose site was uncovered, the absorption increased to ca. 33% (55 mg/kg) and ca. 72% (550 mg/kg). 4. [C-14]beta-OTNE was distributed to tissues following both routes of exposure with the highest radioactive equivalents found in bladder, liver, kidney, adipose and pancreas. 5. Elimination of [C-14]beta-OTNE equivalents in blood and tissues was slow following both oral and dermal application suggesting potential for accumulation following multiple exposure. C1 [Waidyanatha, Suramya; Ryan, Kristen] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Waidyanatha, S (reprint author), NIEHS, Div Natl Toxicol Program, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM waidyanathas@niehs.nih.gov FU National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, U.S. Department of Health and Human Services [N01-ES-25482] FX The authors are grateful to Drs. Matt Stout and Mike DeVito for their review of this manuscript. This work was performed by RTI International (RTP, NC) for the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, U.S. Department of Health and Human Services, under contract No. N01-ES-25482. NR 13 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0049-8254 EI 1366-5928 J9 XENOBIOTICA JI Xenobiotica PD AUG PY 2014 VL 44 IS 8 BP 749 EP 756 DI 10.3109/00498254.2014.888489 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA AM0VB UT WOS:000339564100009 PM 24533629 ER PT J AU Gigante, ED Santerre, JL Carter, JM Werner, DF AF Gigante, Eduardo D. Santerre, Jessica L. Carter, Jenna M. Werner, David F. TI Adolescent and adult rat cortical protein kinase A display divergent responses to acute ethanol exposure SO ALCOHOL LA English DT Article DE Protein kinase A; cAMP; Ethanol; Adolescence ID CAMP/PKA SIGNALING PATHWAY; MEDIATED GENE-EXPRESSION; NUCLEOSIDE TRANSPORTER; GABA RELEASE; SENSITIVITY; PKA; ACTIVATION; ADENOSINE; BEHAVIOR; CALCIUM AB Adolescent rats display reduced sensitivity to many dysphoria-related effects of alcohol (ethanol) including motor ataxia and sedative hypnosis, but the underlying neurobiological factors that contribute to these differences remain unknown. The cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) pathway, particularly the type II regulatory subunit (RII), has been implicated in ethanol-induced molecular and behavioral responses in adults. Therefore, the current study examined cerebral cortical PKA in adolescent and adult ethanol responses. With the exception of early adolescence, PKA RII alpha and RII beta subunit levels largely did not differ from adult levels in either whole cell lysate or P2 synaptosomal expression. However, following acute ethanol exposure, PKA RII beta P2 synaptosomal expression and activity were increased in adults, but not in adolescents. Behaviorally, intracerebroventricular administration of the PKA activator Sp-cAMP and inhibitor Rp-cAMP prior to ethanol administration increased adolescent sensitivity to the sedative-hypnotic effects of ethanol compared to controls. Sp-cAMP was ineffective in adults whereas Rp-cAMP suggestively reduced loss of righting reflex (LORR) with paralleled increases in blood ethanol concentrations. Overall, these data suggest that PKA activity modulates the sedative/hypnotic effects of ethanol and may potentially play a wider role in the differential ethanol responses observed between adolescents and adults. (C) 2014 Elsevier Inc. All rights reserved. C1 [Gigante, Eduardo D.; Santerre, Jessica L.; Carter, Jenna M.; Werner, David F.] SUNY Binghamton, Dept Psychol, Ctr Dev & Behav Neurosci, Binghamton, NY 13902 USA. [Gigante, Eduardo D.] Natl Inst Drug Abuse, Dept Hlth & Human Serv, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Werner, DF (reprint author), SUNY Binghamton, Dept Psychol, Ctr Dev & Behav Neurosci, 4400 Vestal Pkwy East, Binghamton, NY 13902 USA. EM dwerner@binghamton.edu OI Werner, David/0000-0002-2914-7706 FU National Institutes of Health [AA019367, AA017823]; Developmental Exposure Alcohol Research Center FX This work was supported by National Institutes of Health grants AA019367 (Linda P. Spear - faculty recruitment of David F. Werner) and AA017823 (DFW) and the Developmental Exposure Alcohol Research Center. We would also like to thank Dr. A. Leslie Morrow, Linda Spear, and Terrence Deak for thoughtful discussions during the drafting of this manuscript and Eric Truxell for editing. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. NR 54 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD AUG PY 2014 VL 48 IS 5 BP 463 EP 470 DI 10.1016/j.alcohol.2014.01.011 PG 8 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA AL8CJ UT WOS:000339365200007 PM 24874150 ER PT J AU Beane, JD Yang, JC White, D Steinberg, SM Rosenberg, SA Rudloff, U AF Beane, Joal D. Yang, James C. White, Donald Steinberg, Seth M. Rosenberg, Steven A. Rudloff, Udo TI Efficacy of Adjuvant Radiation Therapy in the Treatment of Soft Tissue Sarcoma of the Extremity: 20-year Follow-Up of a Randomized Prospective Trial SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID LIMB-SPARING SURGERY; COMBINED-MODALITY TREATMENT; LOCAL RECURRENCE; PROGNOSTIC-FACTORS; BREAST-CANCER; RADIOTHERAPY; CHEMOTHERAPY; BRACHYTHERAPY; SURVIVAL; TRUNK AB This update of a randomized, prospective study presents the effect of external beam radiation therapy (EBRT) on long-term overall survival, local control, and limb function following limb-sparing surgery (LSS) for the treatment extremity soft tissue sarcoma (STS). Following LSS, patients with extremity STS were randomized to receive EBRT or surgery alone. All patients with high-grade STS received adjuvant chemotherapy. Long-term follow-up was obtained through telephone interviews using a questionnaire based on validated methods. Overall survival (OS) was determined by Kaplan-Meier method. A total of 141 patients with extremity STS were randomized to receive adjuvant EBRT (n = 70) or LSS alone (n = 71). Median follow-up was 17.9 years. The 10- and 20-year survival was 77 % (95 % CI 66-85 %) and 64 % (95 % CI 52-75 %) for patients receiving LSS alone and 82 % (95 % CI 72-90 %) and 71 % (95 % CI 59-81 %) for patients receiving EBRT (p = 0.22). Of the 54 patients who completed telephone interviews, the incidence of local recurrence during the follow-up period was 4 % (1 of 24) in the LSS alone cohort compared with 0 % (0 of 30) in those who received EBRT (p = 0.44). Patients treated with EBRT tended to have more wound complications (17 vs. 12.5 %, p = 0.72), clinically significant edema (25 vs. 12 %, p = 0.31), and functional limb deficits (15 vs. 12 %, p = 0.84). Adjuvant EBRT following surgery for STS of the extremity provides excellent local control with acceptable treatment-related morbidity and no statistically significant improvement in overall survival. C1 [Beane, Joal D.; Yang, James C.; White, Donald; Rosenberg, Steven A.; Rudloff, Udo] NCI, Surg Branch, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. RP Beane, JD (reprint author), NCI, Surg Branch, Bldg 10, Bethesda, MD 20892 USA. EM rudloffu@mail.nih.gov NR 33 TC 22 Z9 23 U1 0 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD AUG PY 2014 VL 21 IS 8 BP 2484 EP 2489 DI 10.1245/s10434-014-3732-4 PG 6 WC Oncology; Surgery SC Oncology; Surgery GA AL4LZ UT WOS:000339105800006 PM 24756814 ER PT J AU Dyall, J Coleman, CM Hart, BJ Venkataraman, T Holbrook, MR Kindrachuk, J Johnson, RF Olinger, GG Jahrling, PB Laidlaw, M Johansen, LM Lear-Rooney, CM Glass, PJ Hensley, LE Frieman, MB AF Dyall, Julie Coleman, Christopher M. Hart, Brit J. Venkataraman, Thiagarajan Holbrook, Michael R. Kindrachuk, Jason Johnson, Reed F. Olinger, Gene G., Jr. Jahrling, Peter B. Laidlaw, Monique Johansen, Lisa M. Lear-Rooney, Calli M. Glass, Pamela J. Hensley, Lisa E. Frieman, Matthew B. TI Repurposing of Clinically Developed Drugs for Treatment of Middle East Respiratory Syndrome Coronavirus Infection SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; MERS-COV; SAUDI-ARABIA; BALB/C MICE; VIRUS; REPLICATION; CELLS; ENTRY; CHLORPROMAZINE; INHIBITORS AB Outbreaks of emerging infections present health professionals with the unique challenge of trying to select appropriate pharmacologic treatments in the clinic with little time available for drug testing and development. Typically, clinicians are left with general supportive care and often untested convalescent-phase plasma as available treatment options. Repurposing of approved pharmaceutical drugs for new indications presents an attractive alternative to clinicians, researchers, public health agencies, drug developers, and funding agencies. Given the development times and manufacturing requirements for new products, repurposing of existing drugs is likely the only solution for outbreaks due to emerging viruses. In the studies described here, a library of 290 compounds was screened for antiviral activity against Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV). Selection of compounds for inclusion in the library was dependent on current or previous FDA approval or advanced clinical development. Some drugs that had a well-defined cellular pathway as target were included. In total, 27 compounds with activity against both MERS-CoV and SARS-CoV were identified. The compounds belong to 13 different classes of pharmaceuticals, including inhibitors of estrogen receptors used for cancer treatment and inhibitors of dopamine receptor used as antipsychotics. The drugs identified in these screens provide new targets for in vivo studies as well as incorporation into ongoing clinical studies. C1 [Dyall, Julie; Hart, Brit J.; Holbrook, Michael R.; Kindrachuk, Jason; Olinger, Gene G., Jr.; Jahrling, Peter B.; Hensley, Lisa E.] NIAID, Integrated Res Facil, NIH, Frederick, MD 21702 USA. [Coleman, Christopher M.; Venkataraman, Thiagarajan; Frieman, Matthew B.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Johnson, Reed F.; Jahrling, Peter B.] NIAID, Emerging Viral Pathogens Sect, NIH, Frederick, MD USA. [Laidlaw, Monique; Johansen, Lisa M.] Zalicus Inc, Cambridge, MA USA. [Lear-Rooney, Calli M.; Glass, Pamela J.] US Army Med Res Inst Infect Dis, Frederick, MD USA. RP Frieman, MB (reprint author), NIAID, Integrated Res Facil, NIH, Frederick, MD 21702 USA. EM MFrieman@som.umaryland.edu RI Hart, Brit/G-6205-2015; OI Hart, Brit/0000-0002-9389-2786; Kindrachuk, Jason/0000-0002-3305-7084; Venkataraman, Thiagarajan/0000-0003-0921-6345 FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID); Integrated Research Facility (NIAID, Division of Clinical Research); Battelle Memorial Institute's prime contract with NIAID [HHSN2722007000161]; NIH [R01AI1095569]; U.S. Army Research Institute of Infectious Diseases (USAMRIID) [W81XWH-12-2-0064] FX This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID), the Integrated Research Facility (NIAID, Division of Clinical Research), the Battelle Memorial Institute's prime contract with NIAID (contract number HHSN2722007000161) and NIH grant R01AI1095569 (to M. B. F.), and a subcontract (W81XWH-12-2-0064) awarded to L.M.J. from the U.S. Army Research Institute of Infectious Diseases (USAMRIID). NR 46 TC 49 Z9 53 U1 1 U2 16 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2014 VL 58 IS 8 BP 4885 EP 4893 DI 10.1128/AAC.03036-14 PG 9 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA AL6RA UT WOS:000339259200074 PM 24841273 ER PT J AU Amaratunga, C Witkowski, B Dek, D Try, V Khim, N Miotto, O Menard, D Fairhurst, RM AF Amaratunga, Chanaki Witkowski, Benoit Dek, Dalin Try, Vorleak Khim, Nimol Miotto, Olivo Menard, Didier Fairhurst, Rick M. TI Plasmodium falciparum Founder Populations in Western Cambodia Have Reduced Artemisinin Sensitivity In Vitro SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID PARASITE CLEARANCE; RESISTANT MALARIA; RATES AB Reduced Plasmodium falciparum sensitivity to short-course artemisinin (ART) monotherapy manifests as a long parasite clearance half-life. We recently defined three parasite founder populations with long half-lives in Pursat, western Cambodia, where reduced ART sensitivity is prevalent. Using the ring-stage survival assay, we show that these founder populations have reduced ART sensitivity in vitro at the early ring stage of parasite development and that a genetically admixed population contains subsets of parasites with normal or reduced ART sensitivity. C1 [Amaratunga, Chanaki; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Witkowski, Benoit; Khim, Nimol; Menard, Didier] Inst Pasteur Cambodge, Malaria Mol Epidemiol Unit, Phnom Penh, Cambodia. [Dek, Dalin; Try, Vorleak] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia. [Miotto, Olivo] Univ Oxford, MRC, Ctr Genom & Global Hlth, Oxford, England. [Miotto, Olivo] Mahidol Univ, Mahidol Oxford Trop Med Res Unit, Bangkok 10700, Thailand. [Miotto, Olivo] Wellcome Trust Sanger Inst, Cambridge, England. RP Menard, D (reprint author), Inst Pasteur Cambodge, Malaria Mol Epidemiol Unit, Phnom Penh, Cambodia. EM dmenard@pasteur-kh.org; rfairhurst@niaid.nih.gov OI Miotto, Olivo/0000-0001-8060-6771 FU NIAID; NIH; Institut Pasteur du Cambodge (International Division, Institut Pasteur, and Banque Natixis); International Division, Institut Pasteur; French Ministry of Foreign Affairs FX This work was supported by the Intramural Research Program of the NIAID, NIH, and grants from the Institut Pasteur du Cambodge (International Division, Institut Pasteur, and Banque Natixis).; B.W. was supported by a postdoctoral fellowship from the International Division, Institut Pasteur, and D.M. was supported by the French Ministry of Foreign Affairs. NR 19 TC 13 Z9 14 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2014 VL 58 IS 8 BP 4935 EP 4937 DI 10.1128/AAC.03055-14 PG 3 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA AL6RA UT WOS:000339259200085 PM 24867977 ER PT J AU Amaratunga, C Neal, AT Fairhurst, RM AF Amaratunga, Chanaki Neal, Aaron T. Fairhurst, Rick M. TI Flow Cytometry-Based Analysis of Artemisinin-Resistant Plasmodium falciparum in the Ring-Stage Survival Assay SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID CAMBODIA; MALARIA AB The ring-stage survival assay (RSA) is a powerful tool for phenotyping artemisinin-resistant Plasmodium falciparum but requires experienced microscopists to count viable parasites among 10,000 erythrocytes in Giemsa-stained thin blood smears. Here we describe a rapid flow cytometric assay that accurately counts viable parasites among 250,000 erythrocytes in suspension. This method performs as well as light microscopy and can be used to standardize the collection of RSA data between research groups in laboratory and field settings. C1 [Amaratunga, Chanaki; Neal, Aaron T.; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Fairhurst, RM (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rfairhurst@niaid.nih.gov FU NIAID, NIH FX This work was funded by the Intramural Research Program of the NIAID, NIH. NR 14 TC 9 Z9 9 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2014 VL 58 IS 8 BP 4938 EP 4940 DI 10.1128/AAC.02902-14 PG 3 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA AL6RA UT WOS:000339259200086 PM 24867976 ER PT J AU Yeboah, J Delaney, JA Nance, R McClelland, RL Polak, JF Sibley, CT Bertoni, A Burke, GL Carr, JJ Herrington, DM AF Yeboah, Joseph Delaney, Joseph A. Nance, Robin McClelland, Robyn L. Polak, Joseph F. Sibley, Christopher T. Bertoni, Alain Burke, Gregory L. Carr, J. Jeffery Herrington, David M. TI Mediation of Cardiovascular Risk Factor Effects Through Subclinical Vascular Disease The Multi-Ethnic Study of Atherosclerosis SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE cardiovascular events; carotid intima-media thickness; coronary artery calcium score; flow-mediated dilation; risk factors ID CORONARY-HEART-DISEASE; YOUNG-ADULTS; PROGRESSION; THICKNESS; MARKERS; YOUTH; 21ST-CENTURY; INDIVIDUALS; CHOLESTEROL; MECHANISMS AB Objective-It is unclear to what extent subclinical cardiovascular disease (CVD) such as coronary artery calcium (CAC), carotid intima-media thickness (CIMT), and brachial flow-mediated dilation (FMD) are mediators of the known associations between traditional cardiovascular risk factors and incident CVD events. We assessed the portion of the effects of risk factors on incident CVD events that are mediated through CAC, CIMT, and FMD. Approach and Results-Six thousand three hundred fifty-five of 6814 Multi-Ethnic Study of Atherosclerosis participants were included. Nonlinear implementation of structural equation modeling (STATA mediation package) was used to assess whether CAC, CIMT, or FMD are mediators of the association between traditional risk factors and incident CVD event. Mean age was 62 years, with 47% men, 12% diabetics, and 13% current smokers. After a mean follow-up of 7.5 years, there were 539 CVD adjudicated events. CAC showed the highest mediation while FMD showed the least. Age had the highest percent of total effect mediated via CAC for CVD outcomes, whereas current cigarette smoking had the least percent of total effect mediated via CAC (percent [95% confidence interval]: 80.2 [58.8-126.7] versus 10.6 [6.1-38.5], respectively). Body mass index showed the highest percent of total effect mediated via CIMT (17.7 [11.6-38.9]); only a negligible amount of the association between traditional risk factors and CVD was mediated via FMD. Conclusions-Many of the risk factors for incident CVD (other than age, sex, and body mass index) showed a modest level of mediation via CAC, CIMT, and FMD, suggesting that current subclinical CVD markers may not be optimal intermediaries for gauging upstream risk factor modification. C1 [Yeboah, Joseph; Herrington, David M.] Wake Forest Univ, Bowman Gray Sch Med, Heart & Vasc Ctr Excellence, Winston Salem, NC 27157 USA. [Delaney, Joseph A.; Nance, Robin; McClelland, Robyn L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Polak, Joseph F.] Tufts Med Ctr, Dept Radiol, Boston, MA USA. [Sibley, Christopher T.] NIH, Bethesda, MD 20892 USA. [Bertoni, Alain; Burke, Gregory L.] Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Carr, J. Jeffery] Vanderbilt Univ, Sch Med, Dept Radiol, Nashville, TN 37212 USA. RP Yeboah, J (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Heart & Vasc Ctr Excellence, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jyeboah@wakehealth.edu RI Carr, John/A-1938-2012 OI Carr, John/0000-0002-4398-8237 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; National Center for Research Resources [UL1-TR-000040, UL1-RR-025005]; [R01HL098445]; [R01 HL 103729-01A1] FX This research was supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute and by grants UL1-TR-000040 and UL1-RR-025005 from National Center for Research Resources and a Diversity Supplement to R01HL098445 (Principal Investigator: J.J. Carr). Drs McClelland and Delaney and R. Nance were also supported by R01 HL 103729-01A1. NR 32 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD AUG PY 2014 VL 34 IS 8 BP 1778 EP + DI 10.1161/ATVBAHA.114.303753 PG 13 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AL6WM UT WOS:000339274200026 PM 24876350 ER PT J AU Madsen, DH Szabo, R Molinolo, AA Bugge, TH AF Madsen, Daniel H. Szabo, Roman Molinolo, Alfredo A. Bugge, Thomas H. TI TMPRSS13 deficiency impairs stratum corneum formation and epidermal barrier acquisition SO BIOCHEMICAL JOURNAL LA English DT Article DE mosaic serine protease large-form (MSPL); mouse gene targeting; skin development; transmembrane protease serine 13; type II transmembrane serine protease ID TRANSMEMBRANE SERINE PROTEASES; IRON-DEFICIENCY; MATRIPTASE; CELL; HOMEOSTASIS; EXPRESSION; ACTIVATOR; CHANNEL AB Membrane-anchored serine proteases serve as important regulators of multiple developmental and homoeostatic processes in mammals. TMPRSS13 (transmembrane protease, serine 13; also known as mosaic serine protease large-form, MSPL) is a membrane-anchored serine protease with unknown biological functions. In the present study, we used mice with the Tmprss13 gene disrupted by a p-galactosidase-neomycin fusion gene insertion to study the expression and function of the membrane-anchored serine protease. High levels of Tmprss13 expression were found in the epithelia of the oral cavity, upper digestive tract and skin. Compatible with this expression pattern, Tmprss13-deficient mice displayed abnormal skin development, leading to a compromised barrier function, as measured by the transepidermal fluid loss rate of newborn mice. The present study provides the first biological function for the transmembrane serine protease TMPRSS13. C1 [Madsen, Daniel H.; Szabo, Roman; Molinolo, Alfredo A.; Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Bugge, TH (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM thomas.bugge@nih.gov OI Madsen, Daniel Hargboel/0000-0002-3183-6201 FU National Institute of Dental and Craniofacial Research Intramural Research Program FX This work was supported by the National Institute of Dental and Craniofacial Research Intramural Research Program. NR 30 TC 3 Z9 3 U1 0 U2 1 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD AUG 1 PY 2014 VL 461 BP 487 EP 495 DI 10.1042/BJ20140337 PN 3 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AL4TB UT WOS:000339126600014 PM 24832573 ER PT J AU Gao, ZG Balasubramanian, R Kiselev, E Wei, Q Jacobson, KA AF Gao, Zhan-Guo Balasubramanian, Ramachandran Kiselev, Evgeny Wei, Qiang Jacobson, Kenneth A. TI Probing biased/partial agonism at the G protein-coupled A(2B) adenosine receptor SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE GPCR; Adenosine receptor; Purines; Cyclic AMP; Calcium; Arrestin ID TUMOR-GROWTH; CELL-LINE; DERIVATIVES; ACTIVATION; EFFICACY; AFFINITY; POTENT; MICE; DIFFERENTIATION; INFLAMMATION AB G protein-coupled A(2B) adenosine receptor (AR) regulates numerous important physiological functions, but its activation by diverse A(2B)AR agonists is poorly profiled. We probed potential partial and/or biased agonism in cell lines expressing variable levels of endogenous or recombinant A(2B)AR. In cAMP accumulation assays, both 5'-substituted NECA and C2-substituted MRS3997 are full agonists. However, only 5'-substituted adenosine analogs are full agonists in calcium mobilization, ERK1/2 phosphorylation and P-arrestin translocation. A(2B)AR overexpression in HEK293 cells markedly increased the agonist potency and maximum effect in cAMP accumulation, but less in calcium and ERK1/2. A(2B)AR siRNA silencing was more effective in reducing the maximum cAMP effect of non-nucleoside agonist BAY60-6583 than NECA's. A quantitative 'operational model' characterized C2-substituted MRS3997 as either balanced (cAMP accumulation, ERK1/2) or strongly biased agonist (against calcium, beta-arrestin). N-6-substitution biased against ERK1/2 (weakly) and calcium and beta-arrestin (strongly) pathways. BAY60-6583 is ERK1/2-biased, suggesting a mechanism distinct from adenosine derivatives. BAY60-6583, as A(2B)AR antagonist in MIN-6 mouse pancreatic beta cells expressing low A(2B)AR levels, induced insulin release. This is the first relatively systematic study of structure-efficacy relationships of this emerging drug target. Published by Elsevier Inc. C1 [Gao, Zhan-Guo; Balasubramanian, Ramachandran; Kiselev, Evgeny; Wei, Qiang; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Gao, ZG (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Blg 8A,Rm B1 A-17,NDDK 8 Ctr Dr, Bethesda, MD 20892 USA. EM zg21o@nih.gov; kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA FX Supported the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. The authors thank Ad IJzerman for providing BAY and LUF5833, Ray Olsson for providing MRS3534, Hayamitsu Adachi for MRS3997 and Dilip K. Tosh for CPCA. NR 56 TC 6 Z9 6 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 EI 1873-2968 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD AUG 1 PY 2014 VL 90 IS 3 BP 297 EP 306 DI 10.1016/j.bcp.2014.05.008 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AL6FV UT WOS:000339228900011 PM 24853985 ER PT J AU Tosh, DK Paoletta, S Chen, ZM Moss, SM Gao, ZG Salvemini, D Jacobson, KA AF Tosh, Dilip K. Paoletta, Silvia Chen, Zhoumou Moss, Steven M. Gao, Zhan-Guo Salvemini, Daniela Jacobson, Kenneth A. TI Extended N-6 substitution of rigid C2-arylethynyl nucleosides for exploring the role of extracellular loops in ligand recognition at the A(3) adenosine receptor SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE G protein-coupled receptor; Purines; Molecular modeling; Structure activity relationship; Radioligand binding; Adenylate cyclase ID ADENINE NUCLEOSIDES; NEUROPATHIC PAIN; RAT-BRAIN; AFFINITY; AGONISTS; POTENT; DRUGS AB 2-Arylethynyl-(N)-methanocarba adenosine 5'-methyluronamides containing rigid N-6-(trans-2-phenylcyclopropyl) and 2-phenylethynyl groups were synthesized as agonists for probing structural features of the A(3) adenosine receptor (AR). Radioligand binding confirmed A(3)AR selectivity and N-6-1S,2R stereoselectivity for one diastereomeric pair. The environment of receptor-bound, conformationally constrained N-6 groups was explored by docking to an A(3)AR homology model, indicating specific hydrophobic interactions with the second extracellular loop able to modulate the affinity profile. 2-Pyridylethynyl derivative 18 was administered orally in mice to reduce chronic neuropathic pain in the chronic constriction injury model. Published by Elsevier Ltd. C1 [Tosh, Dilip K.; Paoletta, Silvia; Moss, Steven M.; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Chen, Zhoumou; Salvemini, Daniela] St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, St Louis, MO 63104 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU National Institutes of Health (Intramural Research Program of the NIDDK) [R01HL077707] FX We thank Dr. John Lloyd and Dr. Noel Whittaker (NIDDK) for mass spectral determinations. This research was supported by the National Institutes of Health (Intramural Research Program of the NIDDK and R01HL077707). NR 25 TC 2 Z9 2 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD AUG 1 PY 2014 VL 24 IS 15 BP 3302 EP 3306 DI 10.1016/j.bmcl.2014.06.006 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA AL6FT UT WOS:000339228700016 PM 24969016 ER PT J AU Schinkel, JK Zahm, SH Jatoi, I McGlynn, KA Gallagher, C Schairer, C Shriver, CD Zhu, KM AF Schinkel, Jill K. Zahm, Shelia Hoar Jatoi, Ismail McGlynn, Katherine A. Gallagher, Christopher Schairer, Catherine Shriver, Craig D. Zhu, Kangmin TI Racial/ethnic differences in breast cancer survival by inflammatory status and hormonal receptor status: an analysis of the Surveillance, Epidemiology, and End Results data SO CANCER CAUSES & CONTROL LA English DT Article DE Breast cancer; Hormone receptor; Inflammatory; Race; SEER; Survival ID RACIAL DISPARITIES; ESTROGEN-RECEPTOR; ADJUVANT CHEMOTHERAPY; BLACK-WOMEN; OLDER WOMEN; RACE; STAGE; DIAGNOSIS; OUTCOMES; CARCINOMA AB Compared to non-inflammatory breast cancer (non-IBC), inflammatory breast cancer (IBC) has less favorable survival and is more likely to be estrogen receptor (ER) and progesterone receptor (PR) negative. ER-/PR- tumors, regardless of histology, have less favorable survival. While black women are more likely to have IBC and ER-/PR- tumors than white women, it is unclear whether the racial disparity in survival is explained by these factors. The objective of this study was to assess racial/ethnic differences in breast cancer survival by inflammatory status and hormone receptor status. This study examined breast cancer mortality among non-Hispanic white (NHW), Hispanic white, black, and Asian/Pacific Islander (API) women diagnosed between 1990 and 2004 using the National Cancer Institute's Surveillance, Epidemiology, and End Results data. Kaplan-Meier survival curves and Cox proportional hazard ratios (HRs) assessed the relationship between race/ethnicity and survival. Black women had significantly poorer survival than NHW women regardless of inflammatory status and hormone receptor status. Compared to NHWs, the HRs for black women were 1.32 (95 % confidence interval (CI) 1.21-1.44), 1.43 (95 % CI 1.20-1.69), and 1.30 (95 % CI 1.16-1.47) for IBC, IBC with ER+/PR+, and with ER-/PR-, respectively. Similar HRs were found for non-IBC, non-IBC with ER+/PR-, and non-IBC with ER-/PR-. API women had significantly better survival than NHW women regardless of inflammatory status and hormone receptor status. Compared to NHW women, black women had poorer survival regardless of inflammatory status and hormone receptor status and API women had better survival. These results suggest that factors other than inflammatory status and hormone receptor status may play a role in racial/ethnic disparities in breast cancer survival. C1 [Schinkel, Jill K.; Gallagher, Christopher; Shriver, Craig D.; Zhu, Kangmin] Walter Reed Natl Mil Med Ctr, John P Murtha Canc Ctr, Bethesda, MD USA. [Zahm, Shelia Hoar; McGlynn, Katherine A.; Schairer, Catherine] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Jatoi, Ismail] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Shriver, Craig D.] Walter Reed Natl Mil Med Ctr, Gen Surg Serv, Bethesda, MD USA. [Shriver, Craig D.; Zhu, Kangmin] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Zhu, Kangmin] Walter Reed Natl Mil Med Ctr, John P Murtha Canc Ctr, Rockville, MD 20852 USA. RP Zhu, KM (reprint author), Walter Reed Natl Mil Med Ctr, John P Murtha Canc Ctr, 11300 Rockville Pike,Suite 1215, Rockville, MD 20852 USA. EM jschinkel@hjfresearch.org; zahms@mail.nih.gov; jatoi@uthscsa.edu; mcglynnk@mail.nih.gov; Christopher.M.Gallagher.mil@health.mil; schairec@mail.nih.gov; Craig.D.Shriver.mil@health.mil; kzhu@hjfresearch.org RI Zahm, Shelia/B-5025-2015 FU John P. Murtha Cancer Center; Walter Reed National Military Medical Center via the Uniformed Services University of the Health Sciences under Henry M. Jackson Foundation for the Advancement of Military Medicine FX This project was supported by John P. Murtha Cancer Center, Walter Reed National Military Medical Center via the Uniformed Services University of the Health Sciences under the auspices of the Henry M. Jackson Foundation for the Advancement of Military Medicine. The authors thank Dr. Lindsey Enewold at the National Cancer Institute for her comments on the manuscript. NR 57 TC 2 Z9 2 U1 1 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD AUG PY 2014 VL 25 IS 8 BP 959 EP 968 DI 10.1007/s10552-014-0395-1 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AL4MW UT WOS:000339108100004 PM 24839049 ER PT J AU Marini, JC Reich, A Smith, SM AF Marini, Joan C. Reich, Adi Smith, Simone M. TI Osteogenesis imperfecta due to mutations in non-collagenous genes: lessons in the biology of bone formation SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE bone dysplasia; collagen; OI; osteogenesis imperfecta; recessive osteogenesis imperfecta ID EPITHELIUM-DERIVED FACTOR; PROLYL 3-HYDROXYLATION COMPLEX; ENDOPLASMIC-RETICULUM; BRUCK SYNDROME; I COLLAGEN; HYPERPLASTIC CALLUS; IFITM5 MUTATION; WNT1 MUTATIONS; BINDING-SITES; VI AB Purpose of review Osteogenesis imperfecta or 'brittle bone disease' has mainly been considered a bone disorder caused by collagen mutations. Within the last decade, however, a surge of genetic discoveries has created a new paradigm for osteogenesis imperfecta as a collagen-related disorder, where most cases are due to autosomal dominant type I collagen defects, while rare, mostly recessive, forms are due to defects in genes whose protein products interact with collagen protein. This review is both timely and relevant in outlining the genesis, development, and future of this paradigm shift in the understanding of osteogenesis imperfecta. Recent findings Bone-restricted interferon induced transmembrane (IFITM)-like protein (BRIL) and pigment epithelium-derived factor (PEDF) defects cause types V and VI osteogenesis imperfecta via defective bone mineralization, while defects in cartilage-associated protein (CRTAP), prolyl 3-hydroxylase 1 (P3H1), and cyclophilin B (CyPB) cause types VII-IX osteogenesis imperfecta via defective collagen post-translational modification. Heat shock protein 47 (HSP47) and FK506-binding protein-65 (FKBP65) defects cause types X and XI osteogenesis imperfecta via aberrant collagen crosslinking, folding, and chaperoning, while defects in SP7 transcription factor, wingless type MMTV integration site family member 1 (WNT1), trimeric intracellular cation channel type b (TRIC-B), and old astrocyte specifically induced substance (OASIS) disrupt osteoblast development. Finally, absence of the type I collagen C-propeptidase bone morphogenetic protein 1 (BMP1) causes type XII osteogenesis imperfecta due to altered collagen maturation/processing. Summary Identification of these multiple causative defects has provided crucial information for accurate genetic counseling, inspired a recently proposed functional grouping of osteogenesis imperfecta types by shared mechanism to simplify current nosology, and has prodded investigations into common pathways in osteogenesis imperfecta. Such investigations could yield critical information on cellular and bone tissue mechanisms and translate to new mechanistic insight into clinical therapies for patients. C1 [Marini, Joan C.; Reich, Adi; Smith, Simone M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD USA. RP Marini, JC (reprint author), NICHHD, Bone & Extracellular Matrix Branch, NIH, Bldg 10 Rm 10D39,9000 Rockville Pike, Bethesda, MD 20892 USA. EM oidoc@helix.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by intramural funding (to J.C.M.) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 58 TC 31 Z9 31 U1 4 U2 43 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8703 EI 1531-698X J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD AUG PY 2014 VL 26 IS 4 BP 500 EP 507 DI 10.1097/MOP.0000000000000117 PG 8 WC Pediatrics SC Pediatrics GA AL5FI UT WOS:000339158500017 PM 25007323 ER PT J AU Thompson, RG Shmulewitz, D Meyers, JL Stohl, M Aharonovich, E Spivak, B Weizman, A Frisch, A Grant, BF Hasin, DS AF Thompson, Ronald G., Jr. Shmulewitz, Dvora Meyers, Jacquelyn L. Stohl, Malki Aharonovich, Efrat Spivak, Baruch Weizman, Abraham Frisch, Amos Grant, Bridget F. Hasin, Deborah S. TI Parental psychopathology moderates the influence of parental divorce on lifetime alcohol use disorders among Israeli adults SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Alcohol use disorders; Parental divorce; Parental psychopathology; Israel ID INTERVIEW SCHEDULE AUDADIS; RECENT RUSSIAN IMMIGRANTS; SUBSTANCE USE DISORDERS; DSM-IV ALCOHOL; NATIONAL EPIDEMIOLOGIC SURVEY; GENERAL-POPULATION SAMPLE; FAMILY-HISTORY; DRUG MODULES; CHILDHOOD EXPERIENCES; MAJOR DEPRESSION AB Background: Parental divorce and psychopathology are well-documented risk factors for alcohol use disorders (AUD) in the United States and other countries where divorce is common and per capita total alcohol consumption is moderate to high. However, little is known about these relationships in countries where divorce and alcohol problems are less common, such as Israel. Methods: Israeli adult household residents (N=797) age 21-45 were interviewed in person between 2007 and 2009. Logistic regression models were used to examine main and additive interaction effects of parental divorce and psychopathology on lifetime DSM-IV AUD, adjusting for age, gender, and ethnicity. Results: Parental divorce (OR=2.18, p <= 0.001) and parental psychopathology (OR=1.61, p <= 0.01) were independently associated with lifetime AUD and, when considered together, showed significant interaction (p=0.026). Specifically, the effect of divorce on AUD was only significant among those who also reported parental psychopathology. Conclusions: This is the first study showing the influence of parental divorce and psychopathology on risk for AUD among Israeli adults, where both divorce and AUD are less common than in the United States. Alcohol prevention and treatment professionals should recognize that children who experience parental divorce and/or psychopathology could be more vulnerable to later developing AUD than those whose parents remain together and without psychopathology. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Thompson, Ronald G., Jr.; Shmulewitz, Dvora; Aharonovich, Efrat; Hasin, Deborah S.] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. [Shmulewitz, Dvora; Stohl, Malki; Aharonovich, Efrat; Hasin, Deborah S.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Meyers, Jacquelyn L.; Hasin, Deborah S.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Spivak, Baruch; Weizman, Abraham; Frisch, Amos] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Weizman, Abraham; Frisch, Amos] Felsenstein Med Res Ctr, IL-49100 Petah Tiqwa, Israel. [Weizman, Abraham] Geha Mental Hlth Ctr, Res Unit, IL-49100 Petah Tiqwa, Israel. [Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Bethesda, MD 20892 USA. RP Hasin, DS (reprint author), Columbia Univ Coll Phys & Surg, Dept Psychiat, 1051 Riverside Dr 123, New York, NY 10032 USA. EM dsh2@columbia.edu FU National Institutes of Health [K23DA032323, T32MH13043, R01AA013654, K05AA014223, U01AA018111] FX This research was supported in part by grants from the National Institutes of Health, K23DA032323 (Thompson), T32MH13043 (Meyers), and R01AA013654, K05AA014223, U01AA018111New York State Psychiatric Institute (Hasin). NR 71 TC 0 Z9 0 U1 2 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD AUG 1 PY 2014 VL 141 BP 85 EP 91 DI 10.1016/j.drugalcdep.2014.05.009 PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA AL5BU UT WOS:000339149300014 PM 24939440 ER PT J AU Conway, KP Vullo, GC Kennedy, AP Finger, MS Agrawal, A Bjork, JM Farrer, LA Hancock, DB Hussong, A Wakim, P Huggins, W Hendershot, T Nettles, DS Pratt, J Maiese, D Junkins, HA Ramos, EM Strader, LC Hamilton, CM Sher, KJ AF Conway, Kevin P. Vullo, Genevieve C. Kennedy, Ashley P. Finger, Matthew S. Agrawal, Arpana Bjork, James M. Farrer, Lindsay A. Hancock, Dana B. Hussong, Andrea Wakim, Paul Huggins, Wayne Hendershot, Tabitha Nettles, Destiney S. Pratt, Joseph Maiese, Deborah Junkins, Heather A. Ramos, Erin M. Strader, Lisa C. Hamilton, Carol M. Sher, Kenneth J. TI Data compatibility in the addiction sciences: An examination of measure commonality SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Measure commonality; Data harmonization; Standard measures; Gene-environment interactions; Substance use, abuse, and addiction ID GENOME-WIDE ASSOCIATION; GENE; DEPENDENCE; RISK AB The need for comprehensive analysis to compare and combine data across multiple studies in order to validate and extend results is widely recognized. This paper aims to assess the extent of data compatibility in the substance abuse and addiction (SAA) sciences through an examination of measure commonality, defined as the use of similar measures, across grants funded by the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Data were extracted from applications of funded, active grants involving human-subjects research in four scientific areas (epidemiology, prevention, services, and treatment) and six frequently assessed scientific domains. A total of 548 distinct measures were cited across 141 randomly sampled applications. Commonality, as assessed by density (range of 0-1) of shared measurement, was examined. Results showed that commonality was low and varied by domain/area. Commonality was most prominent for (1) diagnostic interviews (structured and semi-structured) for substance use disorders and psychopathology (density of 0.88), followed by (2) scales to assess dimensions of substance use problems and disorders (0.70), (3) scales to assess dimensions of affect and psychopathology (0.69), (4) measures of substance use quantity and frequency (0.62), (5) measures of personality traits (0.40), and (6) assessments of cognitive/neurologic ability (0.22). The areas of prevention (density of 0.41) and treatment (0.42) had greater commonality than epidemiology (0.36) and services (0.32). To address the lack of measure commonality, NIDA and its scientific partners recommend and provide common measures for SAA researchers within the PhenX Toolkit. Published by Elsevier Ireland Ltd. C1 [Conway, Kevin P.; Vullo, Genevieve C.; Finger, Matthew S.] NIDA, Div Epidemiol Serv & Prevent Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Vullo, Genevieve C.] Kelly Govt Solut, Bethesda, MD USA. [Kennedy, Ashley P.] NIDA, Intramural Res Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Agrawal, Arpana] Washington Univ, St Louis, MO USA. [Bjork, James M.] NIDA, Div Clin Neurosci & Behav Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Farrer, Lindsay A.] Boston Univ, Boston, MA 02215 USA. [Hancock, Dana B.; Huggins, Wayne; Hendershot, Tabitha; Nettles, Destiney S.; Pratt, Joseph; Maiese, Deborah; Strader, Lisa C.; Hamilton, Carol M.] RTI Int, Res Triangle Pk, NC USA. [Hussong, Andrea] Univ N Carolina, Chapel Hill, NC USA. [Wakim, Paul] NIDA, Ctr Clin Trials Network, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Junkins, Heather A.; Ramos, Erin M.] NHGRI, Bethesda, MD 20892 USA. [Sher, Kenneth J.] Univ Missouri, Columbia, MO USA. RP Conway, KP (reprint author), NIDA, Div Epidemiol Serv & Prevent Res, 6001 Execut Blvd,Suite 5185, Bethesda, MD 20892 USA. EM kconway@nida.nih.gov OI Farrer, Lindsay/0000-0001-5533-4225; Conway, Kevin/0000-0002-7638-339X; Bjork, James/0000-0003-0593-3291; Hancock, Dana/0000-0003-2240-3604 FU National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH) [U01-HG004597]; National Institute on Drug Abuse (NIDA) FX Funding for the PhenX Toolkit was primarily provided by the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH) Cooperative Agreement U01-HG004597 with supplements from the Office of Behavioral and Social Sciences Research (OBSSR) and the National Institute on Drug Abuse (NIDA). The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of NIDA, NHGRI, NIAAA, or any of the sponsoring organizations, agencies, or the U.S. Government. NR 20 TC 7 Z9 7 U1 1 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD AUG 1 PY 2014 VL 141 BP 153 EP 158 DI 10.1016/j.drugalcdep.2014.04.029 PG 6 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA AL5BU UT WOS:000339149300024 PM 24954640 ER PT J AU Thompson, RG Eaton, NR Hu, MC Grant, BF Hasin, DS AF Thompson, Ronald G., Jr. Eaton, Nicholas R. Hu, Mei-Chen Grant, Bridget F. Hasin, Deborah S. TI Regularly drinking alcohol before sex in the United States: Effects of relationship status and alcohol use disorders SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Drinking alcohol before sex; Sexual risk behaviors; Alcohol use disorders; Relationship status; NESARC ID NATIONAL EPIDEMIOLOGIC SURVEY; INTERVIEW SCHEDULE AUDADIS; GENERAL-POPULATION SAMPLE; SUBSTANCE-ABUSE TREATMENT; PSYCHIATRIC DIAGNOSTIC MODULES; DSM-IV ALCOHOL; SENSATION SEEKING; DRUG MODULES; RISK BEHAVIORS; YOUNG-ADULTS AB Background: Drinking alcohol before sex increases the likelihood of engaging in sexual risk behaviors and risk for HIV infection. Relationship status (single versus partnered) and alcohol use disorders (AUD) are associated with each other and sexual risk behaviors, yet have not been examined as predictors of drinking alcohol before sex, using national data. This study examined whether relationship status and AUD increased the likelihood of regularly drinking alcohol before sex in a nationally representative sample. Methods: The main and additive interaction effects of relationship status and AUD on regularly drinking alcohol before sex were analyzed among sexually active drinkers (N = 17,491) from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Regularly drinking alcohol before sex was defined as drinking alcohol most or all of the time before sex. Results: After adjustment for controls, relationship status (AOR = 3.51; CI = 2.59-4.75) and AUD (AOR = 6.24; CI = 5.16-7.53) increased the likelihood of regularly drinking alcohol before sex and interacted to differentially increase this risk, with the effect of being single on the likelihood of regularly drinking alcohol before sex increased among participants with AUD (p < .001). Conclusions: This study reinforces the importance of relationship status and AUD to the risk for regularly drinking alcohol before sex. Public health efforts should target alcohol and HIV prevention messages to single adults, particularly those with AUD, highlighting their risk for regularly drinking alcohol before sex. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Thompson, Ronald G., Jr.; Hu, Mei-Chen; Hasin, Deborah S.] Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York, NY 10032 USA. [Eaton, Nicholas R.] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Bethesda, MD 20892 USA. [Hasin, Deborah S.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Hasin, Deborah S.] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY 10032 USA. RP Thompson, RG (reprint author), Columbia Univ, Dept Psychiat, Coll Phys & Surg, 1051 Riverside Dr 123, New York, NY 10032 USA. EM rgt2101@columbia.edu FU National Institutes of Health [K23DA032323, U01AA018111, K05AA014223]; New York State Psychiatric Institute FX Support is acknowledged from the National Institutes of Health, K23DA032323 (Thompson), U01AA018111 and K05AA014223 (Hasin), and the New York State Psychiatric Institute (Hasin). No authors have any relevant financial interests. NR 40 TC 4 Z9 4 U1 3 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD AUG 1 PY 2014 VL 141 BP 167 EP 170 DI 10.1016/j.drugalcdep.2014.05.021 PG 4 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA AL5BU UT WOS:000339149300027 PM 24950638 ER PT J AU Jamal, L Sapp, JC Lewis, K Yanes, T Facio, FM Biesecker, LG Biesecker, BB AF Jamal, Leila Sapp, Julie C. Lewis, Katie Yanes, Tatiane Facio, Flavia M. Biesecker, Leslie G. Biesecker, Barbara B. TI Research participants' attitudes towards the confidentiality of genomic sequence information SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE genomics; privacy; confidentiality ID CLINICAL GENOMICS; INFORMED-CONSENT; PRIVACY; PROTECTION AB Respecting the confidentiality of personal data contributed to genomic studies is an important issue for researchers using genomic sequencing in humans. Although most studies adhere to rules of confidentiality, there are different conceptions of confidentiality and why it is important. The resulting ambiguity obscures what is at stake when making tradeoffs between data protection and other goals in research, such as transparency, reciprocity, and public benefit. Few studies have examined why participants in genomic research care about how their information is used. To explore this topic, we conducted semi-structured phone interviews with 30 participants in two National Institutes of Health research protocols using genomic sequencing. Our results show that research participants value confidentiality as a form of control over information about themselves. To the individuals we interviewed, control was valued as a safeguard against discrimination in a climate of uncertainty about future uses of individual genome data. Attitudes towards data sharing were related to the goals of research and details of participants' personal lives. Expectations of confidentiality, trust in researchers, and a desire to advance science were common reasons for willingness to share identifiable data with investigators. Nearly, all participants were comfortable sharing personal data that had been de-identified. These findings suggest that views about confidentiality and data sharing are highly nuanced and are related to the perceived benefits of joining a research study. C1 [Jamal, Leila] Kennedy Krieger Inst, Dept Neurogenet, Baltimore, MD 21205 USA. [Jamal, Leila] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. [Sapp, Julie C.; Lewis, Katie; Facio, Flavia M.; Biesecker, Leslie G.; Biesecker, Barbara B.] NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. [Yanes, Tatiane] Griffith Univ, Sch Biomol & Phys Sci, Brisbane, Qld 4111, Australia. [Biesecker, Barbara B.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. RP Jamal, L (reprint author), Kennedy Krieger Inst, Dept Neurogenet, 707 N Broadway, Baltimore, MD 21205 USA. EM jamal@kennedykrieger.org OI Yanes, Tatiane/0000-0002-3905-3025 FU Intramural Research Program of the National Human Genome Research Institute FX We thank the participants in this study, Lauren Ivey and Toby Emanuel for coordinating the interviews, and Nancy Kass for reviewing an earlier version of this manuscript. The Intramural Research Program of the National Human Genome Research Institute funded this research. NR 26 TC 7 Z9 7 U1 0 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD AUG PY 2014 VL 22 IS 8 DI 10.1038/ejhg.2013.276 PG 5 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AL7PX UT WOS:000339328100006 PM 24281371 ER PT J AU Fujikawa, T Petralia, RS Fitzgerald, TS Wang, YX Millis, B Morgado-Diaz, JA Kitamura, K Kachar, B AF Fujikawa, Taro Petralia, Ronald S. Fitzgerald, Tracy S. Wang, Ya-Xian Millis, Bryan Morgado-Diaz, Jose Andres Kitamura, Ken Kachar, Bechara TI Localization of kainate receptors in inner and outer hair cell synapses SO HEARING RESEARCH LA English DT Article ID GUINEA-PIG COCHLEA; II AFFERENT-FIBERS; SPIRAL GANGLION; GLUTAMATE RECEPTORS; IMMUNOCYTOCHEMICAL LOCALIZATION; SYNAPTIC-TRANSMISSION; MAMMALIAN COCHLEA; RIBBON SYNAPSES; FUNCTIONAL-ROLE; AMPA RECEPTORS AB Glutamate plays a role in hair cell afferent transmission, but the receptors that mediate neurotransmission between outer hair cells (OHCs) and type H ganglion neurons are not well defined. A previous study using in situ hybridization showed that several kainate-type glutamate receptor (KAR) subunits are expressed in cochlear ganglion neurons. To determine whether KARs are expressed in hair cell synapses, we performed X-gal staining on mice expressing lacZ driven by the GluK5 promoter, and immunolabeling of glutamate receptors in whole-mount mammalian cochleae. X-gal staining revealed GluK5 expression in both type I and type II ganglion neurons and OHCs in adults. OHCs showed X-gal reactivity throughout maturation from postnatal day 4 (P4) to 1.5 months. Immunoreactivity for GluK5 in IHC afferent synapses appeared to be postsynaptic, similar to GluA2 (GluR2; AMPA-type glutamate receptor (AMPAR) subunit), while GluK2 may be on both sides of the synapses. In OHC afferent synapses, immunoreactivity for GluK2 and GluK5 was found, although GluK2 was only in those synapses bearing ribbons. GluA2 was not detected in adult OHC afferent synapses. Interestingly, GluK1, GluK2 and GluK5 were also detected in OHC efferent synapses, forming several active zones in each synaptic area. At P8, GluA2 and all KAR subunits except GluK4 were detected in OHC afferent synapses in the apical turn, and GluA2, GluK1, GluK3 decreased dramatically in the basal turn. These results indicate that AMPARs and KARs (GluK2/ GluK5) are localized to IHC afferent synapses, while only KARs (GluK2/GluK5) are localized to OHC afferent synapses in adults. Glutamate spillover near OHCs may act on KARs in OHC efferent terminals to modulate transmission of acoustic information and OHC electromotility. Published by Elsevier B.V. C1 [Fujikawa, Taro; Millis, Bryan; Kachar, Bechara] NIDCD, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20892 USA. [Fujikawa, Taro; Kitamura, Ken] Tokyo Med & Dent Univ, Dept Otolaryngol, Bunkyo Ku, Tokyo 1138519, Japan. [Petralia, Ronald S.; Wang, Ya-Xian] NIDCD, Adv Imaging Core, NIH, Bethesda, MD 20892 USA. [Fitzgerald, Tracy S.] NIDCD, Mouse Auditory Testing Core Facil, NIH, Bethesda, MD 20892 USA. [Morgado-Diaz, Jose Andres] Natl Canc Inst, Cellular Biol Div, BR-20230050 Rio De Janeiro, Brazil. RP Petralia, RS (reprint author), NIDCD, NIH, 35A Convent Dr,35A-1E614, Bethesda, MD 20892 USA. EM petralia@nidcd.nih.gov FU Intramural Research Program of the NIDCD at the National Institutes of Health FX This work was supported by the Intramural Research Program of the NIDCD at the National Institutes of Health. We also thank Dr. Stephan Brenowitz for reviewing the manuscript, and Dr. Kai Chang for advice related to the GluK5 mutant mouse. NR 71 TC 8 Z9 8 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 EI 1878-5891 J9 HEARING RES JI Hear. Res. PD AUG PY 2014 VL 314 BP 20 EP 32 DI 10.1016/j.heares.2014.05.001 PG 13 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA AL5CF UT WOS:000339150400003 PM 24858010 ER PT J AU Torjesen, AA Wang, N Larson, MG Hamburg, NM Vita, JA Levy, D Benjamin, EJ Vasan, RS Mitchell, GF AF Torjesen, Alyssa A. Wang, Na Larson, Martin G. Hamburg, Naomi M. Vita, Joseph A. Levy, Daniel Benjamin, Emelia J. Vasan, Ramachandran S. Mitchell, Gary F. TI Forward and Backward Wave Morphology and Central Pressure Augmentation in Men and Women in the Framingham Heart Study SO HYPERTENSION LA English DT Article DE blood pressure; pulse wave analysis; vascular stiffness ID AORTIC INPUT IMPEDANCE; PULSE PRESSURE; SYSTOLIC HYPERTENSION; NONINVASIVE DETERMINATION; GENDER-DIFFERENCES; BLOOD-PRESSURE; STIFFNESS; REFLECTION; FAILURE; AGE AB Central pressure augmentation is associated with greater backward wave amplitude and shorter transit time and is higher in women for reasons only partially elucidated. Augmentation also is affected by left ventricular function and shapes of the forward and backward waves. The goal of this study was to examine the relative contributions of forward and backward wave morphology to central pressure augmentation in men and women. From noninvasive measurements of central pressure and flow in 7437 participants (4036 women) aged from 19 to 90 years (mean age, 51 years), we calculated several variables: augmentation index, backward wave arrival time, reflection factor, forward wave amplitude, forward wave peak width, and slope of the backward wave upstroke. Linear regression models for augmentation index, adjusted for height and heart rate, demonstrated nonlinear relations with age (age: B=4.6 +/- 0.1%; P<0.001; age(2): B=-4.2 +/- 0.1%; P<0.001) and higher augmentation in women (B=4.5 +/- 0.4%; P<0.001; model R-2=0.35). Addition of reflection factor and backward wave arrival time improved model fit (R-2=0.62) and reduced the age coefficients: age (B= 2.3 +/- 0.1%; P<0.001) and age(2) (B=-2.2 +/- 0.1%; P<0.001). Addition of width of forward wave peak, slope of backward wave upstroke, and forward wave amplitude further improved model fit (R-2=0.75) and attenuated the sex coefficient (B= 1.9 +/- 0.2%; P<0.001). Thus, shape and amplitude of the forward wave may be important correlates of augmentation index, and part of the sex difference in augmentation index may be explained by forward and backward wave morphology. C1 [Torjesen, Alyssa A.; Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA 02062 USA. [Wang, Na] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Larson, Martin G.; Levy, Daniel; Benjamin, Emelia J.; Vasan, Ramachandran S.] NHLBI, Framingham Study, Boston, MA USA. [Hamburg, Naomi M.; Vita, Joseph A.; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02215 USA. [Hamburg, Naomi M.; Vita, Joseph A.; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02215 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02215 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02215 USA. [Levy, Daniel] NHLBI, Populat Sci Branch, Div Intramural Res, Bethesda, MD 20892 USA. RP Mitchell, GF (reprint author), Cardiovasc Engn Inc, 1 Edgewater Dr,Suite 201, Norwood, MA 02062 USA. EM GaryFMitchell@mindspring.com OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung, and Blood Institute (NHLBI); NHLBI/National Institutes of Health [N01-HC-25195]; Boston University School of Medicine; [HL076784]; [G028321]; [HL070100]; [HL060040]; [HL080124]; [HL071039]; [HL077447]; [HL107385]; [2-K24-HL04334] FX This work was supported by the National Heart, Lung, and Blood Institute (NHLBI), Framingham Heart Study (NHLBI/National Institutes of Health contract No. N01-HC-25195), and the Boston University School of Medicine and by grants HL076784, G028321, HL070100, HL060040, HL080124, HL071039, HL077447, HL107385, and 2-K24-HL04334. NR 28 TC 23 Z9 23 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD AUG PY 2014 VL 64 IS 2 BP 259 EP + DI 10.1161/HYPERTENSIONAHA.114.03371 PG 17 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AL4RQ UT WOS:000339120700015 PM 24866142 ER PT J AU Bayry, J Beaussart, A Dufrene, YF Sharma, M Bansal, K Kniemeyer, O Aimanianda, V Brakhage, AA Kaveri, SV Kwon-Chung, KJ Latge, JP Beauvais, A AF Bayry, Jagadeesh Beaussart, Audrey Dufrene, Yves F. Sharma, Meenu Bansal, Kushagra Kniemeyer, Olaf Aimanianda, Vishukumar Brakhage, Axel A. Kaveri, Srini V. Kwon-Chung, Kyung J. Latge, Jean-Paul Beauvais, Anne TI Surface Structure Characterization of Aspergillus fumigatus Conidia Mutated in the Melanin Synthesis Pathway and Their Human Cellular Immune Response SO INFECTION AND IMMUNITY LA English DT Article ID CHEMICAL FORCE MICROSCOPY; HOST ENDOCYTOSIS PATHWAY; DENDRITIC CELLS; PIGMENT BIOSYNTHESIS; FUNGAL MELANIN; GENE-CLUSTER; PHAGOCYTOSIS; MACROPHAGES; VIRULENCE; RECOGNITION AB In Aspergillus fumigatus, the conidial surface contains dihydroxynaphthalene (DHN)-melanin. Six-clustered gene products have been identified that mediate sequential catalysis of DHN-melanin biosynthesis. Melanin thus produced is known to be a virulence factor, protecting the fungus from the host defense mechanisms. In the present study, individual deletion of the genes involved in the initial three steps of melanin biosynthesis resulted in an altered conidial surface with masked surface rodlet layer, leaky cell wall allowing the deposition of proteins on the cell surface and exposing the otherwise-masked cell wall polysaccharides at the surface. Melanin as such was immunologically inert; however, deletion mutant conidia with modified surfaces could activate human dendritic cells and the subsequent cytokine production in contrast to the wild-type conidia. Cell surface defects were rectified in the conidia mutated in downstream melanin biosynthetic pathway, and maximum immune inertness was observed upon synthesis of vermelone onward. These observations suggest that although melanin as such is an immunologically inert material, it confers virulence by facilitating proper formation of the A. fumigatus conidial surface. C1 [Bayry, Jagadeesh; Sharma, Meenu; Bansal, Kushagra; Kaveri, Srini V.] Inst Natl Sant & Rech Med, Unite 1138, Paris, France. [Bayry, Jagadeesh; Sharma, Meenu; Bansal, Kushagra; Kaveri, Srini V.] Univ Paris 06, Ctr Rech Cordeliers, Paris, France. [Beaussart, Audrey; Dufrene, Yves F.] Catholic Univ Louvain, Inst Life Sci, Louvain, Belgium. [Kniemeyer, Olaf; Brakhage, Axel A.] Univ Jena, Leibniz Inst Nat Product Res & Infect Biol, Jena, Germany. [Kniemeyer, Olaf] Univ Hosp, Ctr Sepsis Control & Care Jena, Integrated Res & Treatment Ctr, Jena, Germany. [Aimanianda, Vishukumar; Latge, Jean-Paul; Beauvais, Anne] Inst Pasteur, Unit Aspergillus, Paris, France. [Kwon-Chung, Kyung J.] NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Latge, JP (reprint author), Inst Pasteur, Unit Aspergillus, Paris, France. EM jean-paul.latge@pasteur.fr; anne.beauvais@pasteur.fr RI Kniemeyer, Olaf/K-1253-2013; Bayry, Jagadeesh/A-6589-2011; Beauvais, Anne/A-6358-2012; Aimanianda, Vishukumar/E-9204-2011; Beaussart, Audrey/N-5645-2016; OI Kniemeyer, Olaf/0000-0002-9493-6402; Aimanianda, Vishukumar/0000-0001-5813-7497; Beaussart, Audrey/0000-0002-4602-3019; Dufrene, Yves/0000-0002-7289-4248 FU Aviesan [BA-P1-09 Aspergillus]; European Community [260338 ALLFUN, ANR-10-BLAN-1309 HYDROPHOBIN]; National Fund for Scientific Research; Universite Catholique de Louvain (Fonds Speciaux de Recherche); Federal Office for Scientific, Technical, and Cultural Affairs (Interuniversity Poles of Attraction Programme); Research Department of the Communaute Francaise de Belgique (Concerted Research Action) FX This study was partly supported by Aviesan grant BA-P1-09 Aspergillus. Research in the Unite des Aspergillus, Institut Pasteur, and the Institut National de la Sante et de la Recherche Medicale Unite 1138 was supported by European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement 260338 ALLFUN and ANR-10-BLAN-1309 HYDROPHOBIN. Work at the Universite Catholique de Louvain was supported by the National Fund for Scientific Research, the Universite Catholique de Louvain (Fonds Speciaux de Recherche), the Federal Office for Scientific, Technical, and Cultural Affairs (Interuniversity Poles of Attraction Programme), and the Research Department of the Communaute Francaise de Belgique (Concerted Research Action). NR 51 TC 12 Z9 16 U1 7 U2 30 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 2014 VL 82 IS 8 BP 3141 EP 3153 DI 10.1128/IAI.01726-14 PG 13 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AL5GK UT WOS:000339161400005 PM 24818666 ER PT J AU Berube, BJ Sampedro, GR Otto, M Wardenburg, JB AF Berube, Bryan J. Sampedro, Georgia R. Otto, Michael Wardenburg, Juliane Bubeck TI The psm alpha Locus Regulates Production of Staphylococcus aureus Alpha-Toxin during Infection SO INFECTION AND IMMUNITY LA English DT Article ID VIRULENCE DETERMINANTS; ENDOTHELIAL-CELLS; MONOCLONAL-ANTIBODIES; ECONOMIC BURDEN; SKIN INFECTION; PROTEIN-A; IN-VITRO; AGR; HEMOLYSIN; GENE AB Staphylococcus aureus is a leading cause of human bacterial infection, causing a wide spectrum of disease ranging from skin and soft tissue infections to life-threatening pneumonia and sepsis. S. aureus toxins play an essential role in disease pathogenesis, contributing to both immunomodulation and host tissue injury. Prominent among these toxins are the membrane-active pore-forming cytolysin alpha-toxin (Hla) and the amphipathic alpha-helical phenol-soluble modulin (PSM) peptides. As deletion of either the hla or psm locus leads to a phenotypically similar virulence defect in skin and soft tissue infection, we sought to determine the relative contribution of each locus to disease pathogenesis. Here we show that production of Hla can be modulated by PSM expression. An S. aureus mutant lacking PSM expression exhibits a transcriptional delay in hla mRNA production and therefore fails to secrete normal levels of Hla at early phases of growth. This leads to attenuation of virulence in vitro and in murine skin and lung models of infection, correlating with reduced recovery of Hla from host tissues. Production of Hla and restoration of staphylococcal virulence can be achieved in the psm mutant by plasmid-driven overexpression of hla. Our study suggests the coordinated action of Hla and PSMs in host tissue during early pathogenesis, confirming a major role for Hla in epithelial injury during S. aureus infection. These findings highlight the possibility that therapeutics targeting PSM production may simultaneously prevent Hla-mediated tissue injury. C1 [Berube, Bryan J.; Sampedro, Georgia R.; Wardenburg, Juliane Bubeck] Univ Chicago, Dept Microbiol, Chicago, IL 60637 USA. [Otto, Michael] NIAID, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. [Wardenburg, Juliane Bubeck] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. RP Wardenburg, JB (reprint author), Univ Chicago, Dept Microbiol, Chicago, IL 60637 USA. EM jbubeckw@peds.bsd.uchicago.edu FU NIH [AI097434-01, T32 GM007183]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), NIH; Burroughs Wellcome Foundation Investigators in the Pathogenesis of Infectious Disease fellowship; Region V Great Lakes RCE (NIH) [2-U54-AI-057153] FX This work was supported by NIH award AI097434-01 to J.B.W., the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), NIH, to M.O., and a Burroughs Wellcome Foundation Investigators in the Pathogenesis of Infectious Disease fellowship to J.B.W. We acknowledge membership in and support from the Region V Great Lakes RCE (NIH award 2-U54-AI-057153). B.J.B. was partially supported by NIH grant T32 GM007183. NR 70 TC 13 Z9 13 U1 1 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 2014 VL 82 IS 8 BP 3350 EP 3358 DI 10.1128/IAI.00089-14 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AL5GK UT WOS:000339161400024 PM 24866799 ER PT J AU Jelacic, TM Chabot, DJ Bozue, JA Tobery, SA West, MW Moody, K Yang, D Oppenheim, JJ Friedlander, AM AF Jelacic, Tanya M. Chabot, Donald J. Bozue, Joel A. Tobery, Steven A. West, Michael W. Moody, Krishna Yang, De Oppenheim, Joost J. Friedlander, Arthur M. TI Exposure to Bacillus anthracis Capsule Results in Suppression of Human Monocyte-Derived Dendritic Cells SO INFECTION AND IMMUNITY LA English DT Article ID D-GLUTAMIC ACID; CHEMOKINE RECEPTOR; CHEMICAL BASIS; HOST-DEFENSE; GUINEA-PIGS; VIVO FATE; IN-VIVO; PEPTIDOGLYCAN; VIRULENCE; ANTIGEN AB The antiphagocytic capsule of Bacillus anthracis is a major virulence factor. We hypothesized that it may also mediate virulence through inhibition of the host's immune responses. During an infection, the capsule exists attached to the bacterial surface but also free in the host tissues. We sought to examine the impact of free capsule by assessing its effects on human monocytes and immature dendritic cells (iDCs). Human monocytes were differentiated into iDCs by interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GM-CSF) over 7 days in the presence of capsule derived from wild-type encapsulated B. anthracis Ames (WT) or a control preparation from an isogenic B. anthracis Ames strain that produces only 2% of the capsule of the WT (capA mutant). WT capsule consistently induced release of IL-8 and IL-6 while the capA mutant control preparation elicited either no response or only a minimal release of IL-8. iDCs that were differentiated in the presence of WT capsule had increased side scatter (SSC), a measure of cellular complexity, when assessed by flow cytometry. iDCs differentiated in the presence of WT capsule also matured less well in response to subsequent B. anthracis peptidoglycan (Ba PGN) exposure, with reduced upregulation of the chemokine receptor CCR7, reduced CCR7-dependent chemotaxis, and reduced release of certain cytokines. Exposure of naive differentiated control iDCs to WT capsule did not alter cell surface marker expression but did elicit IL-8. These results indicate that free capsule may contribute to the pathogenesis of anthrax by suppressing the responses of immune cells and interfering with the maturation of iDCs. C1 [Jelacic, Tanya M.; Chabot, Donald J.; Bozue, Joel A.; Tobery, Steven A.; West, Michael W.; Friedlander, Arthur M.] US Army Med Res Inst Infect Dis, Frederick, MD 21702 USA. [Yang, De; Oppenheim, Joost J.] Frederick Natl Lab Canc Res, Mol Immunoregulat Lab, Frederick, MD USA. [Moody, Krishna] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. RP Jelacic, TM (reprint author), US Army Med Res Inst Infect Dis, Frederick, MD 21702 USA. EM tanya.obreiter@us.army.mil; arthur.friedlander@us.army.mil FU Defense Threat Reduction Agency [CBM.VAXBT.03.10.RD.015] FX The work was supported by the Defense Threat Reduction Agency grant CBM.VAXBT.03.10.RD.015. NR 47 TC 4 Z9 4 U1 4 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 2014 VL 82 IS 8 BP 3405 EP 3416 DI 10.1128/IAI.01857-14 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AL5GK UT WOS:000339161400029 PM 24891109 ER PT J AU Rosenbaum, AJ Gage, JC Alfaro, KM Ditzian, LR Maza, M Scarinci, IC Felix, JC Castle, PE Villalta, S Miranda, E Cremer, ML AF Rosenbaum, Alan J. Gage, Julia C. Alfaro, Karla M. Ditzian, Lauren R. Maza, Mauricio Scarinci, Isabel C. Felix, Juan C. Castle, Philip E. Villalta, Sofia Miranda, Esmeralda Cremer, Miriam L. TI Acceptability of self-collected versus provider-collected sampling for HPV DNA testing among women in rural El Salvador SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Article DE Acceptability; Cervical cancer; HPV; Latin America; Self-sampling ID CLINICAL ACCURACY; LATIN-AMERICA; POPULATION; SPECIMENS; BARRIERS AB Objective: To determine the acceptability of self-collected versus provider-collected sampling among women participating in public sector HPV-based cervical cancer screening in El Salvador. Methods: Two thousand women aged 30-49 years underwent self-collected and provider-collected sampling with careHPV between October 2012 and March 2013 (Qiagen, Gaithersburg, MD, USA). After sample collection, a random sample of women (n = 518) were asked about their experience. Participants were questioned regarding sampling method preference, previous cervical cancer screening, HPV and cervical cancer knowledge, HPV risk factors, and demographic information. Results: All 518 women approached to participate in this questionnaire study agreed and were enrolled, 27.8% (142 of 511 responding) of whom had not received cervical cancer screening within the past 3 years and were considered under-screened. Overall, 38.8% (n = 201) preferred self-collection and 31.9% (n = 165) preferred provider collection. Self-collection preference was associated with prior tubal ligation, HPV knowledge, future self-sampling preference, and future home-screening preference (P < 0.05). Reasons for self-collection preference included privacy/embarrassment ease, and less pain; reasons cited for provider-collection preference were result accuracy and provider knowledge/experience. Conclusion: Self-sampling was found to be acceptable, therefore screening programs could consider offering this option either in the clinic or at home. Self-sampling at home may increase coverage in low-resource countries and reduce the burden that screening places upon clinical infrastructure. (C) 2014 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Rosenbaum, Alan J.; Cremer, Miriam L.] Univ Pittsburgh, Sch Med, Dept Obstet & Gynecol, Pittsburgh, PA USA. [Rosenbaum, Alan J.] US Dept State, Fulbright US Student Program, Washington, DC USA. [Gage, Julia C.] NCI, Dept Canc Epidemiol & Genet, Rockville, MD USA. [Alfaro, Karla M.; Ditzian, Lauren R.; Maza, Mauricio; Cremer, Miriam L.] Basic Hlth Int, San Salvador, El Salvador. [Scarinci, Isabel C.] Univ AL Birmingham, Birmingham, AL USA. [Felix, Juan C.] Univ Southern CA, Dept Pathol, Los Angeles, CA USA. [Castle, Philip E.] Global Canc Inst, Chestertown, MD USA. [Villalta, Sofia; Miranda, Esmeralda] Minist Hlth El Salvador, San Salvador, El Salvador. RP Cremer, ML (reprint author), 300 Halket St, Pittsburgh, PA 15213 USA. EM cremerm@mail.magee.edu FU Einhorn Family Charitable Trust; Fulbright US Student Program FX The Einhorn Family Charitable Trust and the Fulbright US Student Program provided financial support. NR 22 TC 12 Z9 12 U1 1 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 EI 1879-3479 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD AUG PY 2014 VL 126 IS 2 BP 156 EP 160 DI 10.1016/j.ijgo.2014.02.026 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AL4YA UT WOS:000339139500013 PM 24880188 ER PT J AU Jacobson, JM Wang, HY Bordi, R Zheng, L Gross, BH Landay, AL Spritzler, J Routy, JP Benson, C Aberg, J Tebas, P Haas, DW Tiu, J Coughlin, K Purdue, L Sekaly, RP AF Jacobson, Jeffrey M. Wang, Hongying Bordi, Rebeka Zheng, Lu Gross, Barry H. Landay, Alan L. Spritzler, John Routy, Jean-Pierre Benson, Constance Aberg, Judith Tebas, Pablo Haas, David W. Tiu, Jennifer Coughlin, Kristine Purdue, Lynette Sekaly, Rafick-Pierre CA AIDS Clinical Trials Grp ACTG TI A Randomized Controlled Trial of Palifermin (Recombinant Human Keratinocyte Growth Factor) for the Treatment of Inadequate CD4(+) T-Lymphocyte Recovery in Patients with HIV-1 Infection on Antiretroviral Therapy SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE keratinocyte growth factor; palifermin; HIV; thymus; CD4 T lymphocytes ID THYMIC FUNCTION; PROGNOSTIC IMPORTANCE; CELL TRANSPLANTATION; ORAL MUCOSITIS; RNA LEVELS; RECONSTITUTION; MORTALITY; COUNTS; INJURY; CHEMOTHERAPY AB Background: Poor CD4 lymphocyte recovery on antiretroviral therapy (ART) is associated with reduced function of the thymus. Palifermin (keratinocyte growth factor), by providing support to the thymic epithelium, promotes lymphopoiesis in animal models of bone marrow transplantation and graft-versus-host disease. Methods: In AIDS Clinical Trials Group A5212, a randomized, double-blind, placebo-controlled study, 99 HIV-infected patients on ART with plasma HIV-1 RNA levels <= 200 copies per milliliter for >= 6 months and CD4 lymphocyte counts <200 cells per cubic milliliter were randomized 1: 1: 1: 1 to receive once daily intravenous administration of placebo or 20, 40, or 60 mu g/kg of palifermin on 3 consecutive days. Results: The median change in the CD4(+) T-cell count from baseline to week 12 was not significantly different between the placebo arm [15 (-16, 23) cells/mm(3)] and the 20-mu g/kg dose [11 (2, 32) cells/mm(3)], the 40-mu g/kg dose [12 (-2, 25) cells/mm(3)], or the 60-mu g/kg dose arm [8 (-13, 35) cells/mm(3)] of palifermin. No significant changes were observed in thymus size or in the number of naive T cells or recent thymic emigrants. Conclusions: Palifermin in the doses studied was not effective in improving thymic function and did not raise CD4 lymphocyte counts in HIV-infected patients with low CD4 cell counts despite virologically effective ART. C1 [Jacobson, Jeffrey M.] Drexel Univ, Coll Med, Div Infect Dis & HIV Med, Philadelphia, PA 19102 USA. [Wang, Hongying; Zheng, Lu; Spritzler, John] Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, AIDS Clin Trials Grp, Boston, MA 02115 USA. [Bordi, Rebeka; Sekaly, Rafick-Pierre] Vaccine & Gene Therapy Inst, Port St Lucie, FL USA. [Gross, Barry H.] Univ Michigan, Sch Med, Dept Radiol, Ann Arbor, MI USA. [Landay, Alan L.] Rush Univ, Sch Med, Dept Immunol Microbiol, Chicago, IL 60612 USA. [Routy, Jean-Pierre] McGill Univ, Ctr Hlth, Div Hematol, Montreal, PQ, Canada. [Routy, Jean-Pierre] McGill Univ, Ctr Hlth, Chron Viral Illness Serv, Montreal, PQ, Canada. [Benson, Constance] Univ Calif San Diego, Sch Med, Dept Med, Div Infect Dis, San Diego, CA 92103 USA. [Aberg, Judith] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [Tebas, Pablo] Univ Penn, Dept Med, Div Infect Dis, Philadelphia, PA 19104 USA. [Haas, David W.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Tiu, Jennifer] Social & Sci Syst Inc, Silver Spring, MD USA. [Coughlin, Kristine] Frontier Sci, Buffalo, NY USA. [Purdue, Lynette] NIAID, Div Aids, Bethesda, MD 20892 USA. RP Jacobson, JM (reprint author), Drexel Univ, Coll Med, Div Infect Dis & HIV Med, 245 N 15th St,MS461, Philadelphia, PA 19102 USA. EM jeffrey.jacobson@drexelmed.edu FU ACTG CTU [AI69432]; New York University/NYC HHC at Bellevue Hospital Center ACTG CTU [UM1AI069532]; Vanderbilt University ACTG CTU [AI-069439]; Hospital of the University of Pennsylvania CRS ACTG CTU [1U01AI69467]; Center for AIDS Research (CFAR) [P30 AI 045008]; University of Southern California CRS ACTG CTU [AI069428]; Institute of Human Virology Baltimore Treatment CRS ACTG CTU [U01A1069447]; Harbor-UCLA ACTG CTU [A1 069424]; CTSI [UL1TR000124]; UCLA CARE ACTG CTU [UM1 AI069424]; AIDS Care, CRS ACTG CTU [U01AI069511-02]; CRC [UL1 RR024160]; Duke University Medical Center CRS ACTG CTU [5UM1-AI069484-07]; Case CRS ACTG CTU [AI69501]; Boston Medical Center ACTG CRS ACTG CTU [5UO1A1069472]; University of Rochester CRS ACTG CTU [U01AI069511-02]; Washington University CRS ACTG CTU [AI069495]; UNC AIDS Clinical Trials Unit ACTG CTU [5-U01 AI069423-03]; UNC Clinical Trials Research Center of the Clinical and Translational Science Award [RR 025747]; UNC Center for AIDS Research Grant [AI050410]; Emory University HIV/AIDS Clinical Trials Unit ACTG CTU [1U01Al069418-01]; Emory Center for AIDS Research (CFAR) [P30Al050409]; National Center for Advancing Translational Sciences for the National Institutes of Health [(ACTSI)-UL1TR000454]; Ohio State University Medical Center ACTG CTU [U01 AI069474]; Columbia University HPT CRS ACTG CTU [5UM1AI069470-07]; CTSA [UL1 TR000040]; University of Miami AIDS CRS ACTG CTU [5 UM1 AI069477]; University of Washington AIDS CRS ACTG CTU [AI069434]; MetroHealth Medical Center ACTG CTU [AI69501]; [5P30AI073961] FX Julie Hoffman, RN, and Susan Cahill, RN, University of California, San Diego AVRC CRS (Site 701); ACTG CTU Grant AI69432.; Karen Cavanagh, RN, and Judith A. Aberg, MD, New York University/NYC HHC at Bellevue Hospital Center (Site 401) ACTG CTU Grant UM1AI069532.; Vicki Bailey, RN, and Rebecca Basham, Vanderbilt University (Site 3652) ACTG CTU Grant AI-069439.; Pablo Tebas, MD, and Wayne Wagner, RN, Hospital of the University of Pennsylvania CRS (Site 6201) ACTG CTU Grant 1U01AI69467; Penn Center for AIDS Research (CFAR) Grant P30 AI 045008.; Connie A. Funk, RN, MPH, and Luis M. Mendez, University of Southern California CRS (Site 1201) ACTG CTU Grant AI069428.; Charles E. Davis, Jr, MD, and William A. Blattner, MD, Institute of Human Virology Baltimore Treatment CRS (Site 4651) ACTG CTU Grant U01A1069447.; Gunter Rieg, MD, and Angela Grbic, RN, Harbor-UCLA (Site 603) ACTG CTU Grant A1 069424; CTSI Grant UL1TR000124.; Dr Ronald Mitsuyasu and Maricela Gonzalez, UCLA CARE (Site 601) ACTG CTU Grant UM1 AI069424; CTSI Grant UL1TR000124.; Roberto Corales, DO, and Christine Hurley, RN, AIDS Care, CRS (Site 1108) ACTG CTU U01AI069511-02 (as of 2/12/08); CRC Grant UL1 RR024160.; Nathan M. Thielman, MD, and Joan Riddle, RN, Duke University Medical Center CRS (Site 1601) ACTG CTU Grant 5UM1-AI069484-07.; Benigno Rodriguez, MD, and Patricia Walton, RN, Case CRS (Site 2501) ACTG CTU Grant AI69501.; Paul Skolnik, MD, and Ioana Bica, MD, Boston Medical Center ACTG CRS (Site 104) ACTG CTU Grant 5UO1A1069472.; Amneris Luque, MD, and Mary Adams, RN, University of Rochester CRS (Site 1101) ACTG CTU U01AI069511-02 (as of 2/12/08); CRC Grant UL1 RR024160.; Michael Royal, RpH, and Ge-Youl Kim, RN, BS, Washington University CRS (Site 2101) ACTG CTU Grant AI069495.; Susan Richard, ANC, and Susan Pedersen, BS, BSN, UNC AIDS Clinical Trials Unit (Site 3201) ACTG CTU Grant 5-U01 AI069423-03; UNC Clinical Trials Research Center of the Clinical and Translational Science Award RR 025747; UNC Center for AIDS Research Grant AI050410.; Melody Pratt-Palmore, MD, and Karen Chan, RN, BSN, Emory University HIV/AIDS Clinical Trials Unit (Site 5802) ACTG CTU Grant 1U01Al069418-01; Emory Center for AIDS Research (CFAR) P30Al050409; National Center for Advancing Translational Sciences for the National Institutes of Health (ACTSI)-UL1TR000454.; Michael F. Para, MD, and Laura Laughlin, RN, The Ohio State University Medical Center (Site 2301) ACTG CTU Grant U01 AI069474.; Michael Yin, MD, and Jolene Noel-Connor, RN, Columbia University HPT CRS (Site 30329) ACTG CTU Grant 5UM1AI069470-07; CTSA grant UL1 TR000040.; Margaret A. Fischl, MD, and Hector Bolivar, MD, University of Miami AIDS CRS (Site 901) ACTG CTU Grant 5 UM1 AI069477; 5P30AI073961.; Shelia Dunaway, MD, and Sheryl Storey, PA-C, University of Washington AIDS CRS (Site 1401) ACTG CTU Grant AI069434.; Robert Kalayjian, MD, Ann Marie Anderson, RN, MetroHealth Medical Center (Site 2503) ACTG CTU Grant AI69501. NR 34 TC 3 Z9 3 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 1 PY 2014 VL 66 IS 4 BP 399 EP 406 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AL3FQ UT WOS:000339012300014 PM 24815851 ER PT J AU King, KA Gordon-Salant, S Pawlowski, KS Taylor, AM Griffith, AJ Houser, A Kurima, K Wassif, CA Wright, CG Porter, FD Repa, JJ Brewer, CC AF King, Kelly A. Gordon-Salant, Sandra Pawlowski, Karen S. Taylor, Anna M. Griffith, Andrew J. Houser, Ari Kurima, Kiyoto Wassif, Christopher A. Wright, Charles G. Porter, Forbes D. Repa, Joyce J. Brewer, Carmen C. TI Hearing Loss is an Early Consequence of Npc1 Gene Deletion in the Mouse Model of Niemann-Pick Disease, Type C SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE NPC; hearing; auditory maturation; auditory brainstem response (ABR) ID PRODUCT OTOACOUSTIC EMISSIONS; CHOLESTEROL; MICE; NEURODEGENERATION; FIBROBLASTS; THRESHOLD; COCHLEA; MOTOR AB Niemann-Pick disease, type C1 (NPC1) is a rare lysosomal lipidosis that is most often the result of biallelic mutations in NPC1, and is characterized by a fatal neurological degeneration. The pathophysiology is complex, and the natural history of the disease is poorly understood. Recent findings from patients with NPC1 and hearing loss suggest that multiple steps along the auditory pathway are affected. The current study was undertaken to determine the auditory phenotype in the Npc1 (nih) mutant mouse model, to extend analyses to histologic evaluation of the inner ear, and to compare our findings to those reported from human patients. Auditory testing revealed a progressive high-frequency hearing loss in Npc1 (-/-) mice that is present as early as postnatal day 20 (P20), well before the onset of overt neurological symptoms, with evidence of abnormalities involving the cochlea, auditory nerve, and brainstem auditory centers. Distortion product otoacoustic emission amplitude and auditory brainstem response latency data provided evidence for a disruption in maturational development of the auditory system in Npc1 (-/-) mice. Anatomical study demonstrated accumulation of lysosomes in neurons, hair cells, and supporting cells of the inner ear in P30 Npc1 (-/-) mice, as well as increased numbers of inclusion bodies, myelin figures, and swollen nerve endings in older (P50-P70) mutant animals. These findings add unique perspective to the pathophysiology of NPC disease and suggest that hearing loss is an early and sensitive marker of disease progression. C1 [King, Kelly A.; Griffith, Andrew J.; Kurima, Kiyoto; Brewer, Carmen C.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. [Gordon-Salant, Sandra] Univ Maryland, Dept Hearing & Speech Sci, College Pk, MD 20742 USA. [Houser, Ari] Univ Maryland, Dept Human Dev & Quantitat Methodol, College Pk, MD 20742 USA. [Wassif, Christopher A.; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Pawlowski, Karen S.; Wright, Charles G.] UT Southwestern Med Ctr, Dept Otolaryngol, Dallas, TX 75390 USA. [Taylor, Anna M.; Repa, Joyce J.] UT Southwestern Med Ctr, Dept Physiol, Dallas, TX 75390 USA. [Repa, Joyce J.] UT Southwestern Med Ctr, Dept Internal Med, Dallas, TX 75390 USA. RP Brewer, CC (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. EM brewerc@nidcd.nih.gov OI Wassif, Christopher/0000-0002-2524-1420 FU National Institute on Deafness and Other Communication Disorders [Z01 DC 000060, Z01 DC 000064, T32DC000046]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Ara Parseghian Medical Research Foundation; National Institute of General Medical Sciences of the National Institutes of Health [T32GM007062]; NCI Cancer Center Support Grant [1P30 CA142543-01] FX This work was supported by intramural research funds Z01 DC 000060 and Z01 DC 000064 of the National Institute on Deafness and Other Communication Disorders and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (to AJG, FDP, CCB) and the Ara Parseghian Medical Research Foundation (to JJR). Further support came from training grants from the National Institute on Deafness and Other Communication Disorders (T32DC000046 supporting KAK), and the National Institute of General Medical Sciences (T32GM007062 supporting AMT) of the National Institutes of Health. The authors would like to acknowledge the assistance of Katherine Luby-Phelps (Director) and the UT Southwestern Live Cell Imaging Facility, a Shared Resource of the Harold C. Simmons Cancer Center, supported in part by an NCI Cancer Center Support Grant, 1P30 CA142543-01. The authors are grateful to Robert Dooling, Tracy Fitzgerald, Arthur Popper, and Thomas Friedman for their insightful feedback on methodology and careful review of the manuscript. Thanks to Suzanne Lenhard and Elena Koulich for technical assistance and to the veterinary staff at NIDCD who provided exceptional support, most notably Pat Diers, Donny Catts, and James McGehee. NR 35 TC 3 Z9 3 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 EI 1438-7573 J9 JARO-J ASSOC RES OTO JI JARO PD AUG PY 2014 VL 15 IS 4 BP 529 EP 541 DI 10.1007/s10162-014-0459-7 PG 13 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA AL0QT UT WOS:000338832500003 PM 24839095 ER PT J AU Liu, Q Manis, PB Davis, RL AF Liu, Qing Manis, Paul B. Davis, Robin L. TI I (h) and HCN Channels in Murine Spiral Ganglion Neurons: Tonotopic Variation, Local Heterogeneity, and Kinetic Model SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE I-h; HCN; spiral ganglion neuron; tonotopic; heterogeneity ID MAMMALIAN COCHLEAR NUCLEUS; PRIMARY AUDITORY NEURONS; RABBIT SINOATRIAL NODE; CATION CURRENT I(H); PACEMAKER CHANNELS; OCTOPUS CELLS; BRAIN-STEM; VOLTAGE; MODULATION; CURRENTS AB One of the major contributors to the response profile of neurons in the auditory pathways is the I (h) current. Its properties such as magnitude, activation, and kinetics not only vary among different types of neurons (Banks et al., J Neurophysiol 70:1420-1432, 1993; Fu et al., J Neurophysiol 78:2235-2245, 1997; Bal and Oertel, J Neurophysiol 84:806-817, 2000; Cao and Oertel, J Neurophysiol 94:821-832, 2005; Rodrigues and Oertel, J Neurophysiol 95:76-87, 2006; Yi et al., J Neurophysiol 103:2532-2543, 2010), but they also display notable diversity in a single population of spiral ganglion neurons (Mo and Davis, J Neurophysiol 78:3019-3027, 1997), the first neural element in the auditory periphery. In this study, we found from somatic recordings that part of the heterogeneity can be attributed to variation along the tonotopic axis because I (h) in the apical neurons have more positive half-activation voltage levels than basal neurons. Even within a single cochlear region, however, I (h) current properties are not uniform. To account for this heterogeneity, we provide immunocytochemical evidence for variance in the intracellular density of the hyperpolarization-activated cyclic nucleotide-gated channel alpha-subunit 1 (HCN1), which mediates I (h) current. We also observed different combinations of HCN1 and HCN4 alpha-subunits from cell to cell. Lastly, based on the physiological data, we performed kinetic analysis for the I (h) current and generated a mathematical model to better understand varied I (h) on spiral ganglion function. Regardless of whether I (h) currents are recorded at the nerve terminals (Yi et al., J Neurophysiol 103:2532-2543, 2010) or at the somata of spiral ganglion neurons, they have comparable mean half-activation voltage and induce similar resting membrane potential changes, and thus our model may also provide insights into the impact of I (h) on synaptic physiology. C1 [Liu, Qing] NIMH, Unit Neural Circuits & Adapt Behav Genes, Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Manis, Paul B.] Univ N Carolina, Dept Otolaryngol Head & Neck Surg, Chapel Hill, NC 27599 USA. [Manis, Paul B.] Univ N Carolina, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA. [Davis, Robin L.] Rutgers State Univ, Dept Cell Biol & Neurosci, Nelson Labs, Piscataway, NJ 08854 USA. RP Davis, RL (reprint author), Rutgers State Univ, Dept Cell Biol & Neurosci, Nelson Labs, 604 Allison Rd, Piscataway, NJ 08854 USA. EM rldavis@rci.rutgers.edu OI /0000-0003-0131-8961 FU NIH NIDCD [RO1-DC01856, R01-DC004551] FX We thank Drs. Robert Crozier and Mark R. Plummer for reading previous versions of the manuscript and Hui Zhong Xue for expert technical support. This study is funded by NIH NIDCD RO1-DC01856 (RLD) and R01-DC004551 (PBM). NR 40 TC 9 Z9 9 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 EI 1438-7573 J9 JARO-J ASSOC RES OTO JI JARO PD AUG PY 2014 VL 15 IS 4 BP 585 EP 599 DI 10.1007/s10162-014-0446-z PG 15 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA AL0QT UT WOS:000338832500007 PM 24558054 ER PT J AU Pomerantsev, AP Chang, Z Rappole, C Leppla, SH AF Pomerantsev, Andrei P. Chang, Zanetta Rappole, Catherine Leppla, Stephen H. TI Identification of Three Noncontiguous Regions on Bacillus anthracis Plasmid pXO1 That Are Important for Its Maintenance SO JOURNAL OF BACTERIOLOGY LA English DT Article ID THURINGIENSIS SUBSP ISRAELENSIS; TOXIN-ANTITOXIN SYSTEMS; TUBULIN HOMOLOG TUBZ; DNA-BINDING; BACTERIA; PARTITION; PROTEIN; SUBTILIS; SEQUENCE; ORGANIZATION AB Bacillus anthracis pXO1 minireplicon (MR) plasmid consisting of open reading frames (ORFs) GBAA_pXO1_0020 to GBAA_pXO1_0023 is not stably maintained in B. anthracis, whereas the full-size parent pXO1 plasmid (having 181,677 bp and 217 ORFs) is extremely stable under the same growth conditions. Two genetic tools developed for DNA manipulation in B. anthracis (Cre-loxP and Flp-FRT systems) were used to identify pXO1 regions important for plasmid stability. We localized a large segment of pXO1 that enables stable plasmid maintenance during vegetative growth. Further genetic analysis identified three genes that are necessary for pXO1 maintenance: amsP (GBAA_pXO1_0069), minP (GBAA_pXO1_0082), and sojP (GBAA_pXO1_0084). Analysis of conserved domains in the corresponding proteins indicated that only AmsP (activator of maintenance system of pXO1) is predicted to bind DNA, due to its strong helix-turn-helix domain. Two conserved domains were found in the MinP protein (Min protein from pXO1): an N-terminal domain having some similarity to the B. anthracis septum site-determining protein MinD and a C-terminal domain that resembles a baculovirus single-stranded-DNA-binding protein. The SojP protein (Soj from pXO1) contains putative Walker box motifs and belongs to the ParA family of ATPases. No sequences encoding other components of type I plasmid partition systems, namely, cis-acting centromere parS and its binding ParB protein, were identified within the pXO1 genome. A model describing the role of the MinP protein in pXO1 distribution between daughter cells is proposed. C1 [Pomerantsev, Andrei P.; Chang, Zanetta; Rappole, Catherine; Leppla, Stephen H.] NIAID, NIH, Bethesda, MD 20892 USA. RP Leppla, SH (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov FU NIH National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the NIH National Institute of Allergy and Infectious Diseases. NR 36 TC 3 Z9 3 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD AUG PY 2014 VL 196 IS 16 BP 2921 EP 2933 DI 10.1128/JB.01747-14 PG 13 WC Microbiology SC Microbiology GA AL6XL UT WOS:000339276900003 PM 24914182 ER PT J AU Bao, XF Gylfe, A Sturdevant, GL Gong, Z Xu, S Caldwell, HD Elofsson, M Fan, HZ AF Bao, Xiaofeng Gylfe, Asa Sturdevant, Gail L. Gong, Zheng Xu, Shuang Caldwell, Harlan D. Elofsson, Mikael Fan, Huizhou TI Benzylidene Acylhydrazides Inhibit Chlamydial Growth in a Type III Secretion- and Iron Chelation-Independent Manner SO JOURNAL OF BACTERIOLOGY LA English DT Article ID OUTER-MEMBRANE PROTEIN; OBLIGATE INTRACELLULAR PATHOGEN; SMALL-MOLECULE INHIBITORS; GENITAL-TRACT; PEPTIDE DEFORMYLASE; DEVELOPMENTAL CYCLE; GENOME SEQUENCE; TRACHOMATIS; VIRULENCE; PNEUMONIAE AB Chlamydiae are widespread Gram-negative pathogens of humans and animals. Salicylidene acylhydrazides, developed as inhibitors of type III secretion system (T3SS) in Yersinia spp., have an inhibitory effect on chlamydial infection. However, these inhibitors also have the capacity to chelate iron, and it is possible that their antichlamydial effects are caused by iron starvation. Therefore, we have explored the modification of salicylidene acylhydrazides with the goal to uncouple the antichlamydial effect from iron starvation. We discovered that benzylidene acylhydrazides, which cannot chelate iron, inhibit chlamydial growth. Biochemical and genetic analyses suggest that the derivative compounds inhibit chlamydiae through a T3SS-independent mechanism. Four single nucleotide polymorphisms were identified in a Chlamydia muridarum variant resistant to benzylidene acylhydrazides, but it may be necessary to segregate the mutations to differentiate their roles in the resistance phenotype. Benzylidene acylhydrazides are well tolerated by host cells and probiotic vaginal Lactobacillus species and are therefore of potential therapeutic value. C1 [Bao, Xiaofeng; Gong, Zheng; Xu, Shuang; Fan, Huizhou] Rutgers State Univ, Robert Wood Johnson Med Sch, Dept Pharmacol, Piscataway, NJ 08854 USA. [Bao, Xiaofeng] Nantong Univ, Dept Pharmacol, Sch Pharm, Nantong, Peoples R China. [Gylfe, Asa] Umea Univ, Dept Clin Microbiol, Umea, Sweden. [Sturdevant, Gail L.; Caldwell, Harlan D.] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Elofsson, Mikael] Umea Univ, Dept Chem, Umea, Sweden. RP Fan, HZ (reprint author), Rutgers State Univ, Robert Wood Johnson Med Sch, Dept Pharmacol, Piscataway, NJ 08854 USA. EM huizhou.fan@rutgers.edu FU extramural National Institutes of Health grant [AI071954]; New Jersey Health Foundation grant [PC7-13]; Swedish Research Council; intramural NIH grant; Astrazeneca Sweden grant; National Natural Science Foundation of China grant [31370209] FX This work was supported by an extramural National Institutes of Health grant (AI071954) and a New Jersey Health Foundation grant (PC7-13) to H. F., a Swedish Research Council grant to M. E., an intramural NIH grant to H. D. C., an Astrazeneca Sweden grant to. G., and a National Natural Science Foundation of China grant (no. 31370209) to X. B. We also thank the Ume Centre for Microbial Research and Molecular Infection Medicine Sweden for support. NR 69 TC 3 Z9 3 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD AUG PY 2014 VL 196 IS 16 BP 2989 EP 3001 DI 10.1128/JB.01677-14 PG 13 WC Microbiology SC Microbiology GA AL6XL UT WOS:000339276900009 PM 24914180 ER PT J AU Horenstein, RB Madabushi, R Zineh, I Yerges-Armstrong, LM Peer, CJ Schuck, RN Figg, WD Shuldiner, AR Pacanowski, MA AF Horenstein, Richard B. Madabushi, Rajnikanth Zineh, Issam Yerges-Armstrong, Laura M. Peer, Cody J. Schuck, Robert N. Figg, William Douglas Shuldiner, Alan R. Pacanowski, Michael A. TI Effectiveness of Clopidogrel Dose Escalation to Normalize Active Metabolite Exposure and Antiplatelet Effects in CYP2C19 Poor Metabolizers SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE pharmacogenomics; clopidogrel; CYP2C19; pharmacokinetics ID PERCUTANEOUS CORONARY INTERVENTION; PLATELET REACTIVITY; TREATED PATIENTS; PRASUGREL; GENOTYPE; THERAPY; METAANALYSIS; RISK; PHARMACOGENETICS; POLYMORPHISMS AB Carriers of two copies of the loss-of-function CYP2C19*2 variant convert less clopidogrel into its active metabolite, resulting in diminished antiplatelet responses and higher cardiovascular event rates. To evaluate whether increasing the daily clopidogrel dose in poor metabolizers (PM) overcomes the effect of the CYP2C19*2 variant, we enrolled 18 healthy participants in a genotype-stratified, multi-dose, three-period, fixed-sequence crossover study. Six participants with the *1/*1 extensive (EM), *1/*2 intermediate (IM), and *2/*2 poor metabolizer genotypes each received 75 mg, 150 mg, and 300 mg each for 8 days. In each period, maximal platelet aggregation 4 hours post-dose (MPA4) and active metabolite area under the curve (AUC) differed among genotype groups (P<.05 for all). At day 8, PMs needed 300 mg daily and IMs needed 150 mg daily to attain a similar MPA4 as EMs on the 75 mg dose (32.6%, 33.2%, 31.3%, respectively). Similarly, PMs needed 300 mg daily to achieve active metabolite concentrations that were similar to EMs on 75 mg (AUC 37.7 and 33.5 ng h/mL, respectively). These results suggest that quadrupling the usual clopidogrel dose might be necessary to overcome the effect of poor CYP2C19 metabolism. C1 [Horenstein, Richard B.; Yerges-Armstrong, Laura M.; Shuldiner, Alan R.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Madabushi, Rajnikanth; Zineh, Issam; Schuck, Robert N.; Pacanowski, Michael A.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Peer, Cody J.; Figg, William Douglas] NCI, Clin Pharmacol Program, Bethesda, MD 20892 USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. RP Pacanowski, MA (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,White Oak Bldg 51, Silver Spring, MD 20993 USA. EM michael.pacanowski@fda.hhs.gov RI Figg Sr, William/M-2411-2016 FU National Institutes of Health [128475, U01GM074518, U01HL105198] FX This study was funded by the Bench to Bedside Program of the National Institutes of Health (128475) and the National Institutes of Health (U01GM074518 and U01HL105198). NR 32 TC 10 Z9 10 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD AUG PY 2014 VL 54 IS 8 BP 865 EP 873 DI 10.1002/jcph.293 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AL5HB UT WOS:000339163200005 PM 24710841 ER PT J AU Wang, L Foster, BL Kram, V Nociti, FH Zerfas, PM Tran, AB Young, MF Somerman, MJ AF Wang, L. Foster, B. L. Kram, V. Nociti, F. H., Jr. Zerfas, P. M. Tran, A. B. Young, M. F. Somerman, M. J. TI Fibromodulin and Biglycan Modulate Periodontium through TGF beta/BMP Signaling SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE extracellular matrix; periodontal ligament; proteoglycan; tooth root; mineralization; signal transduction ID LEUCINE-RICH PROTEOGLYCANS; ABNORMAL COLLAGEN FIBRILS; DEFICIENT MICE; EXTRACELLULAR-MATRIX; IMMUNOHISTOCHEMICAL LOCALIZATION; CANCELLOUS BONE; LIGAMENT CELLS; NULL MICE; CEMENTUM; DECORIN AB A full understanding of the key regulators controlling periodontal development and homeostasis is necessary for the design of improved periodontal regenerative therapies. Small leucine-rich proteoglycans (SLRPs) are extracellular matrix molecules suggested to regulate collagen organization and cell signaling. Mice with double-deficiency of 2 SLRPs, fibromodulin and biglycan (dKO), acquire skeletal abnormalities, but their roles in regulating the periodontium remain undefined and were the focus of our studies. Transmission electron microscopy studies showed abnormal collagen fibrils in the periodontal ligament (PDL) and altered remodeling of alveolar bone in dKO mice. Immunohistochemistry (IHC) revealed increased staining of SLRPs (asporin, lumican, and decorin) and dentin matrix protein-1 (DMP1, a mechanosensory/osteocyte marker), while osteoblast markers, bone sialoprotein and osteopontin, remained unchanged. Disruption of homeostasis was further evidenced by increased expression of receptor-activator of nuclear factor-kappa B ligand (RANKL) and elevated numbers of osteoclasts, especially noted around the alveolar bone of molars (buccal side) and incisors. Polymerase chain reaction (PCR) array revealed hyperactive transforming growth factors beta/bone morphogenetic protein (TGF beta/BMP) signaling in dKO PDL tissues, which was further confirmed by elevated expression of phosphorylated Smad5 (p-Smad5) by IHC in dKO PDL. These studies highlight the importance of SLRPs in maintaining periodontal homeostasis through regulation of TGF beta/BMP signaling, matrix turnover, and collagen organization. C1 [Wang, L.; Foster, B. L.; Nociti, F. H., Jr.; Tran, A. B.; Somerman, M. J.] Natl Inst Arthrit & Musculoskeletal & Skin Dis N, NIH, Bethesda, MD 20892 USA. [Kram, V.; Young, M. F.] NIDCR, NIH, Bethesda, MD USA. [Nociti, F. H., Jr.] Univ Estadual Campinas, Piracicaba Dent Sch, Dept Prosthodont & Periodont, Piracicaba, Brazil. [Zerfas, P. M.] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. RP Wang, L (reprint author), Natl Inst Arthrit & Musculoskeletal & Skin Dis N, NIH, Bethesda, MD 20892 USA. EM le.wang@nih.gov RI Nociti, Francisco/G-4907-2015; Foster, Brian/H-8375-2015 OI Foster, Brian/0000-0003-3444-0576 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Institute of Dental and Craniofacial Research (NIDCR) (Bethesda, MD, USA) FX This research was supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (MJS) and the National Institute of Dental and Craniofacial Research (NIDCR) (MFY) (Bethesda, MD, USA). The authors thank Drs. Min Ao, Brendan Lopez, and Kanako Nagatomo for their contributions to this research. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 35 TC 3 Z9 3 U1 1 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD AUG PY 2014 VL 93 IS 8 BP 780 EP 787 DI 10.1177/0022034514541126 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AL7OX UT WOS:000339325200009 PM 24966230 ER PT J AU Naugle, MM Nguyen, LT Merceron, TK Filardo, E Janssen, WGM Morrison, JH Rapp, PR Gore, AC AF Naugle, Michelle M. Nguyen, Long T. Merceron, Tyler K. Filardo, Edward Janssen, William G. M. Morrison, John H. Rapp, Peter R. Gore, Andrea C. TI G-Protein Coupled Estrogen Receptor, Estrogen Receptor alpha, and Progesterone Receptor Immunohistochemistry in the Hypothalamus of Aging Female Rhesus Macaques Given Long-Term Estradiol Treatment SO JOURNAL OF EXPERIMENTAL ZOOLOGY PART A-ECOLOGICAL GENETICS AND PHYSIOLOGY LA English DT Article ID MESSENGER-RNA EXPRESSION; CENTRAL-NERVOUS-SYSTEM; GROWTH-FACTOR RECEPTOR; AGE-RELATED-CHANGES; POSTMENOPAUSAL WOMEN; NEGATIVE FEEDBACK; HORMONE NEURONS; RAT-BRAIN; GONADOTROPIN-SECRETION; LUTEINIZING-HORMONE AB Steroid hormone receptors are widely and heterogeneously expressed in the brain, and are regulated by age and gonadal hormones. Our goal was to quantify effects of aging, long-term estradiol (E-2) treatment, and their interactions, on expression of G protein-coupled estrogen receptor (GPER), estrogen receptor a (ER alpha) and progesterone receptor (PR) immunoreactivity in two hypothalamic regions, the arcuate (ARC) and the periventricular area (PERI) of rhesus monkeys as a model of menopause and hormone replacement. Ovariectomized (OVX) rhesus macaques were young (similar to 11 years) or aged (similar to 25 years), given oil (vehicle) or E-2 every 3 weeks for 2 years. Immunohistochemistry and stereologic analysis of ER alpha, PR, and GPER was performed. More effects were detected for GPER than the other two receptors. Specifically, GPER cell density in the ARC and PERI, and the percent of GPER-immunoreactive cells in the PERI, were greater in aged than in young monkeys. In addition, we mapped the qualitative distribution of GPER in the monkey hypothalamus and nearby regions. For ER alpha, E-2 treated monkeys tended to have higher cell density than vehicle monkeys in the ARC. The percent of PR density in the PERI tended to be higher in E-2 than vehicle monkeys of both ages. This study shows that the aged hypothalamus maintains expression of hormone receptors with age, and that long-term cyclic E-2 treatment has few effects on their expression, although GPER was affected more than ER alpha or PR. This result is surprising in light of evidence for E-2 regulation of the receptors studied here, and differences may be due to the selected regions, long-term nature of E-2 treatment, among other possibilities. J. Exp. Zool. 321A: 399-414, 2014. (C) 2014 Wiley Periodicals, Inc. C1 [Naugle, Michelle M.; Gore, Andrea C.] Univ Texas Austin, Inst Neurosci, Austin, TX 78712 USA. [Nguyen, Long T.; Merceron, Tyler K.; Gore, Andrea C.] Univ Texas Austin, Coll Pharm, Austin, TX 78712 USA. [Filardo, Edward] Brown Univ, Dept Med, Providence, RI 02912 USA. [Janssen, William G. M.; Morrison, John H.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. [Janssen, William G. M.; Morrison, John H.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Rapp, Peter R.] NIA, Bethesda, MD 20892 USA. [Gore, Andrea C.] Univ Texas Austin, Inst Cellular & Mol Biol, Austin, TX 78712 USA. RP Gore, AC (reprint author), Univ Texas Austin, 107 West Dean Keeton,C0875, Austin, TX 78712 USA. EM andrea.gore@austin.utexas.edu FU NIH [PO1 AG16765] FX Grant sponsor: NIH; grant number: PO1 AG16765. NR 115 TC 10 Z9 10 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-5223 EI 1932-5231 J9 J EXP ZOOL PART A JI J. Exp. Zool. Part A PD AUG PY 2014 VL 321 IS 7 BP 399 EP 414 DI 10.1002/jez.1871 PG 16 WC Zoology SC Zoology GA AL4KI UT WOS:000339101400005 PM 24862737 ER PT J AU Hooker, GW Ormond, KE Sweet, K Biesecker, BB AF Hooker, Gillian W. Ormond, Kelly E. Sweet, Kevin Biesecker, Barbara B. TI Teaching Genomic Counseling: Preparing the Genetic Counseling Workforce for the Genomic Era SO JOURNAL OF GENETIC COUNSELING LA English DT Article DE Genomics; Next generation sequencing; Genetic counseling training; Continuing education ID INCIDENTAL FINDINGS; INFORMATION; INDIVIDUALS; UNCERTAINTY; MECHANISMS; MUTATIONS; RESPONSES; OUTCOMES; DISEASE; CARE AB Genetic counselors have a long-standing history of working on the clinical forefront of implementing new genetic technology. Genomic sequencing is no exception. The rapid advancement of genomic sequencing technologies, including but not limited to next generation sequencing approaches, across all subspecialties of genetic counseling mandates attention to genetic counselor training at both the graduate and continuing education levels. The current era provides a tremendous opportunity for counselors to become actively involved in making genomics more accessible, engaging the population in decisions to undergo sequencing and effectively translating genomic information to promote health and well-being. In this commentary, we explore reasons why genomic sequencing warrants particular consideration and put forward strategies for training program curricula and continuing education programs to meet this need. C1 [Hooker, Gillian W.; Biesecker, Barbara B.] NHGRI, Social & Behav Res Branch, Genet Counseling Training Program, Johns Hopkins Sch Publ Hlth,NIH, Bethesda, MD 20892 USA. [Ormond, Kelly E.] Stanford Univ, Dept Genet, MS Human Genet & Genet Counseling Program, Stanford, CA 94305 USA. [Ormond, Kelly E.] Stanford Univ, Stanford Ctr Biomed Eth, Stanford, CA 94305 USA. [Sweet, Kevin] Ohio State Univ, Div Human Genet, Wexner Med Ctr, Columbus, OH 43210 USA. [Hooker, Gillian W.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. RP Hooker, GW (reprint author), NHGRI, Social & Behav Res Branch, 31 Ctr Dr,Room B1B36K,MSC 2073, Bethesda, MD 20892 USA. EM gillian.hooker@gmail.com RI Sweet, Kevin/E-4172-2011 FU Intramural NIH HHS [Z99 HG999999] NR 44 TC 14 Z9 14 U1 1 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1059-7700 EI 1573-3599 J9 J GENET COUNS JI J. Genet. Couns. PD AUG PY 2014 VL 23 IS 4 BP 445 EP 451 DI 10.1007/s10897-014-9689-4 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA AL8FV UT WOS:000339374400002 PM 24504939 ER PT J AU Abe, T Shin, J Hosur, K Udey, MC Chavakis, T Hajishengallis, G AF Abe, Toshiharu Shin, Jieun Hosur, Kavita Udey, Mark C. Chavakis, Triantafyllos Hajishengallis, George TI Regulation of Osteoclast Homeostasis and Inflammatory Bone Loss by MFG-E8 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PORPHYROMONAS-GINGIVALIS; SIGNALING MECHANISMS; NEGATIVE REGULATION; HOST RESPONSE; PERIODONTITIS; LACTADHERIN; CELLS; MICE; INTERVENTION; ANGIOGENESIS AB The glycoprotein milk fat globule epidermal growth factor factor 8 (MFG-E8) is expressed in several tissues and mediates diverse homeostatic functions. However, whether it plays a role in bone homeostasis has not been established. In this study, we show for the first time, to our knowledge, that osteoclasts express and are regulated by MFG-E8. Bone marrow derived osteoclast precursors from MFG-E8-deficient (Mfge8(-/-)) mice underwent increased receptor activator of NF-kappa B ligand-induced osteoclastogenesis, leading to enhanced resorption pit formation compared with wild-type controls. Consistently, exogenously added MFG-E8 inhibited receptor activator of NF-kappa B ligand-induced osteoclastogenesis from mouse or human osteoclast precursors. Upon induction of experimental periodontitis, an oral inflammatory disease characterized by loss of bone support of the dentition, Mfge8(-/-) mice exhibited higher numbers of osteoclasts and more bone loss than did wild-type controls. Accordingly, local microinjection of anti MFG-E8 mAb exacerbated periodontal bone loss in wild-type mice. Conversely, microinjection of MFG-E8 inhibited bone loss in experimental mouse periodontitis. In comparison with wild-type controls, Mfge8(-/-) mice also experienced >60% more naturally occurring chronic periodontal bone loss. In conclusion, MFG-E8 is a novel homeostatic regulator of osteoclasts that could be exploited therapeutically to treat periodontitis and perhaps other immunological disorders associated with inflammatory bone loss. C1 [Abe, Toshiharu; Shin, Jieun; Hosur, Kavita; Hajishengallis, George] Univ Penn, Sch Dent Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Udey, Mark C.] NCI, Ctr Canc Res, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Chavakis, Triantafyllos] Tech Univ Dresden, Inst Clin Chem & Lab Med, Dept Med, D-01307 Dresden, Germany. [Chavakis, Triantafyllos] Tech Univ Dresden, Inst Clin Chem & Lab Med, Dept Clin Pathobiochem, D-01307 Dresden, Germany. RP Hajishengallis, G (reprint author), Univ Penn, Sch Dent Med, 240 South 40th St, Philadelphia, PA 19104 USA. EM geoh@upenn.edu FU National Institutes of Health [DE015254, DE017138, DE021685]; Deutsche Forschungsgemeinschaft [CH279/5-1]; European Research Council; National Institutes of Health Intramural Research Program FX This work was supported by the National Institutes of Health (Grants DE015254, DE017138, and DE021685 to G.H.), the Deutsche Forschungsgemeinschaft (Grant CH279/5-1 to T.C.), the European Research Council (to T.C.), and the National Institutes of Health Intramural Research Program (to M.C.U.). NR 36 TC 13 Z9 13 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2014 VL 193 IS 3 BP 1383 EP 1391 DI 10.4049/jimmunol.1400970 PG 9 WC Immunology SC Immunology GA AL8XB UT WOS:000339422000043 PM 24958900 ER PT J AU Lu, MF Kho, T Munford, RS AF Lu, Mingfang Kho, Terry Munford, Robert S. TI Prolonged Triglyceride Storage in Macrophages: pH(o) Trumps pO(2) and TLR4 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHAIN FATTY-ACIDS; MAMMALIAN CELLS; TRIACYLGLYCEROL HYDROLYSIS; ATHEROSCLEROTIC PLAQUES; ACTIVATED MACROPHAGES; NLRP3 INFLAMMASOME; LIPID-METABOLISM; KETONE-BODIES; PH; HYPOXIA AB Lipid-laden macrophages contribute to pathologies as diverse as atherosclerosis and tuberculosis. Three common stimuli are known to promote macrophage lipid storage: low tissue oxygen tension (pO(2)), low extracellular pH (pH(o)), and exposure to agonists such as bacterial LPS. Noting that cells responding to low pO(2) or agonistic bacterial molecules often decrease pH(o) by secreting lactic and other carboxylic acids, we studied how pH(o) influences the stimulation of triacylglycerol (TAG) storage by low pO(2) and LPS. We found that TAG retention after incubation for 48-72 h was inversely related to pH(o) when primary macrophages were cultured in 21% oxygen, 4% oxygen, or with LPS at either oxygen concentration. Maintaining pH(o) at similar to 7.4 was sufficient to prevent the increase in prolonged TAG storage induced by either low pO(2) or LPS. The strong influence of pH(o) on TAG retention may explain why lipid-laden macrophages are found in some tissue environments and not in others. It is also possible that other long-term cellular changes currently attributed to low pO(2) or bacterial agonists may be promoted, at least in part, by the decrease in pH(o) that these stimuli induce. C1 [Lu, Mingfang; Kho, Terry; Munford, Robert S.] NIAID, Antibacterial Host Def Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Munford, RS (reprint author), 9000 Rockville Pike, Bethesda, MD 20892 USA. EM munfordrs@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 46 TC 2 Z9 2 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2014 VL 193 IS 3 BP 1392 EP 1397 DI 10.4049/jimmunol.1400886 PG 6 WC Immunology SC Immunology GA AL8XB UT WOS:000339422000044 PM 24973452 ER PT J AU Sindberg, GM Lindborg, BA Wang, Q Clarkson, C Graham, M Donahue, R Hering, BJ Verfaillie, CM Bansal-Pakala, P O'Brien, TD AF Sindberg, Gregory M. Lindborg, Beth A. Wang, Qi Clarkson, Christina Graham, Melanie Donahue, Robert Hering, Bernhard J. Verfaillie, Catherine M. Bansal-Pakala, Pratima O'Brien, Timothy D. TI Comparisons of phenotype and immunomodulatory capacity among rhesus bone-marrow-derived mesenchymal stem/stromal cells, multipotent adult progenitor cells, and dermal fibroblasts SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article DE cellular therapy; immunophenotype; T-cell suppression ID STEM-CELLS; STROMAL CELLS; INTERFERON-GAMMA; IMMUNOSUPPRESSION; DIFFERENTIATION; ACTIVATION; STRATEGY; DISEASE; CULTURE; CD4(+) AB Background Potent immunomodulatory effects have been reported for mesenchymal stem/stromal cells (MSCs), multipotent adult progenitor cells (MAPCs), and fibroblasts. However, side-by-side comparisons of these cells specifically regarding immunophenotype, gene expression, and suppression of proliferation of CD4(+) and CD8(+) lymphocyte populations have not been reported. Methods We developed MAPC and MSC lines from rhesus macaque bone marrow and fibroblast cell lines from rhesus dermis and assessed phenotypes based upon differentiation potential, flow cytometric analysis of immunophenotype, and quantitative RT-PCR analysis of gene expression. Using allogeneic lymphocyte proliferation assays, we compared the in vitro immunomodulatory potency of each cell type. Results and Conclusions Extensive phenotypic similarities exist among each cell type, although immunosuppressive potencies are distinct. MAPCs are most potent, and fibroblasts are the least potent cell type. All three cell types demonstrated immunomodulatory capacity such that each may have potential therapeutic applications such as in organ transplantation, where reduced local immune response is desirable. C1 [Sindberg, Gregory M.; Graham, Melanie; Hering, Bernhard J.; Bansal-Pakala, Pratima] Univ Minnesota, Dept Surg, St Paul, MN 55108 USA. [Sindberg, Gregory M.; Graham, Melanie; Hering, Bernhard J.; Bansal-Pakala, Pratima] Univ Minnesota, Schulze Diabet Inst, St Paul, MN 55108 USA. [Lindborg, Beth A.; O'Brien, Timothy D.] Univ Minnesota, Vet Populat Med Dept, St Paul, MN 55108 USA. [Lindborg, Beth A.; Clarkson, Christina; O'Brien, Timothy D.] Univ Minnesota, Stem Cell Inst, St Paul, MN 55108 USA. [Wang, Qi] Univ Minnesota, Biostat Design & Anal Ctr, Clin & Translat Sci Inst, St Paul, MN 55108 USA. [Clarkson, Christina] Univ Minnesota, Vet & Biomed Sci Dept, St Paul, MN 55108 USA. [Donahue, Robert] NHLBI, Hematol Branch, Rockville, MD USA. [Verfaillie, Catherine M.] Univ Leuven, Stem Cell Inst, Leuven, Belgium. RP O'Brien, TD (reprint author), Univ Minnesota, Vet Diagnost Lab, 1333 Gortner Ave, St Paul, MN 55108 USA. EM obrie004@umn.edu OI Sindberg, Greg/0000-0002-4773-0305 FU Primate Center base operating Grant [OD011107] FX The authors wish to thank Dr. Alice Tarantal (Primate Center base operating Grant No. OD011107) for providing bone marrow for these studies. The authors also wish to acknowledge Dan Kaufman (University of Minnesota, KG1a and hMSC control cell lines), Ross Kopher (University of Minnesota, expertise in hMSC culture), and James Dutton (University of Minnesota, expertise in fibroblast derivation and culture) for their contributions to this work. NR 31 TC 3 Z9 5 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD AUG PY 2014 VL 43 IS 4 BP 231 EP 241 DI 10.1111/jmp.12122 PG 11 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA AL6YE UT WOS:000339278900003 PM 24825538 ER PT J AU Sakamuri, RM Capek, P Dickerson, TJ Barry, CE Mukundan, H Swanson, BI AF Sakamuri, Rama Murthy Capek, Petr Dickerson, Tobin J. Barry, Clifton E., III Mukundan, Harshini Swanson, Basil I. TI Detection of stealthy small amphiphilic biomarkers SO JOURNAL OF MICROBIOLOGICAL METHODS LA English DT Article DE Amphiphiles; Biomarkers; Phenolic glycolipid; Mycobactin; Lipid bilayer; Membrane insertion assay ID PHENOLIC GLYCOLIPID-I; HIGH-DENSITY-LIPOPROTEIN; MYCOBACTERIUM-TUBERCULOSIS; PATHOGEN DETECTION; IRON ACQUISITION; LEPROSY; LIPOARABINOMANNAN; LEPRAE; RECEPTORS; BIOSENSOR AB Pathogen-specific biomarkers are secreted in the host during infection. Many important biomarkers are not proteins but rather small molecules that cannot be directly detected by conventional methods. However, these small molecule biomarkers, such as phenolic glycolipid-I (PGL-I) of Mycobacterium leprae and Mycobactin T (MbT) of Mycobacterium tuberculosis, are critical to the pathophysiology of infection, and may be important in the development of diagnostics, vaccines, and novel therapeutic strategies. Methods for the direct detection of these biomarkers may be of significance both for the diagnosis of infectious disease, and also for the laboratory study of such molecules. Herein, we present, for the first time, a transduction approach for the direct and rapid (30 min) detection of small amphiphilic biomarkers in complex samples (e.g. serum) using a single affinity reagent. To our knowledge, this is the first demonstration of an assay for the direct detection of PGL-I, and the first single-reporter assay for the detection of MbT. The assay format exploits the amphiphilic chemistry of the small molecule biomarkers, and is universally applicable to all amphiphiles. The assay is only the first step towards developing a robust system for the detection of amphiphilic biomarkers that are critical to infectious disease pathophysiology. Published by Elsevier B.V. C1 [Sakamuri, Rama Murthy; Mukundan, Harshini; Swanson, Basil I.] Los Alamos Natl Lab, Div Chem, Los Alamos, NM 87544 USA. [Capek, Petr; Dickerson, Tobin J.] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. [Barry, Clifton E., III] NIAID, TB Res Sect, Bethesda, MD USA. RP Mukundan, H (reprint author), Los Alamos Natl Lab, Div Chem, MS J567, Los Alamos, NM 87544 USA. EM harshini@lanl.gov; basil@lanl.gov RI Capek, Petr/G-1303-2012; Barry, III, Clifton/H-3839-2012; Sakamuri, Rama Murthy/D-8919-2012 OI Sakamuri, Rama Murthy/0000-0002-1640-0709 FU LANL LDRD Directed Research Award; LDRD Exploratory Research Award; Bill and Melinda Gates Foundation through the Tuberculosis Drug Accelerator Program FX The authors thank Dr. L. Via at the TB Research Section of the NIAID, for technical discussions and suggestions. We thank K.W. Grace, A.S. Anderson, and Felicia Archuleta for technical help and helpful consultation. This work was supported by a LANL LDRD Directed Research Award to Drs. B.I. Swanson and B.T. Korber, LDRD Exploratory Research Award to Dr. H. Mukundan, and the Bill and Melinda Gates Foundation through the Tuberculosis Drug Accelerator Program (C.E.B. and T.J.D.). The authors thank BEI Resources (Colorado State Materials Consortium) for the antigens and antibodies used for the PGL-1 assay. NR 34 TC 4 Z9 4 U1 2 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7012 EI 1872-8359 J9 J MICROBIOL METH JI J. Microbiol. Methods PD AUG PY 2014 VL 103 BP 112 EP 117 DI 10.1016/j.mimet.2014.05.012 PG 6 WC Biochemical Research Methods; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA AL5CE UT WOS:000339150300019 PM 24880131 ER PT J AU Absinta, M Nair, G Filippi, M Ray-Chaudhury, A Reyes-Mantilla, MI Pardo, CA Reich, DS AF Absinta, Martina Nair, Govind Filippi, Massimo Ray-Chaudhury, Abhik Reyes-Mantilla, Maria I. Pardo, Carlos A. Reich, Daniel S. TI Postmortem Magnetic Resonance Imaging to Guide the Pathologic Cut: Individualized, 3-Dimensionally Printed Cutting Boxes for Fixed Brains SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE Cutting box; High resolution; MRI-Pathology correlations; Postmortem MRI ID MULTIPLE-SCLEROSIS BRAIN; CORTICAL-LESIONS; FORMALDEHYDE FIXATION; FORMALIN FIXATION; HISTOPATHOLOGY; NEUROPATHOLOGY; MATTER; MRI AB Interfacing magnetic resonance imaging (MRI) with pathology is critically important for understanding the pathologic basis of MRI signal changes in vivo and for clinicopathologic correlations. Postmortem MRI is an intermediate step in this process; unfortunately, however, relating the data to standard pathologic sections, which are relatively thick and often nonparallel, is both time-consuming and insufficiently accurate. The aim of this project was to develop technology to integrate postmortem, high-resolution, whole-brain MRI into the planning and execution of pathologic analysis through precise localization of the target and coordinates of cut. Compared with standard pathologic sectioning, the use of an individualized, 3-dimensionally printed cutting box-designed based on postmortem MRI of formalin-fixed whole brains-improved the speed, quality, and accuracy of radiologic-pathologic correlations and, specifically, the histopathologic localization of imaging findings. The technology described herein is easily implemented, applicable to any brain disorder, and potentially extendable to other organs. From the point of view of the pathologist, this technique can improve localization of small or subtle abnormalities, whereas from the point of view of the radiologist, it has the potential to improve understanding of MRI signal changes observed in diseases. C1 [Absinta, Martina; Nair, Govind; Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, NIH, Bethesda, MD 20892 USA. [Ray-Chaudhury, Abhik] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Reyes-Mantilla, Maria I.; Pardo, Carlos A.; Reich, Daniel S.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Absinta, Martina; Filippi, Massimo] Univ Vita Salute San Raffaele, San Raffaele Sci Inst, Inst Expt Neurol, Neuroimaging Res Unit,Div Neurosci, Milan, Italy. RP Reich, DS (reprint author), NINDS, Translat Neuroradiol Unit, NIH, 10 Ctr Dr MSC 1400,Bldg 10 Room 5C103, Bethesda, MD 20892 USA. EM daniel.reich@nih.gov RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke; Bart McLean Fund for Neuroimmunology Research-Project Restore at Johns Hopkins University School of Medicine FX The Intramural Research Program of the National Institute of Neurological Disorders and Stroke supported this study. Carlos A. Pardo and Maria I. Reyes-Mantilla were supported by the Bart McLean Fund for Neuroimmunology Research-Project Restore at Johns Hopkins University School of Medicine. NR 28 TC 7 Z9 7 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 EI 1554-6578 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD AUG PY 2014 VL 73 IS 8 BP 780 EP 788 PG 9 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA AL8KF UT WOS:000339386600005 PM 25007244 ER PT J AU Brunetto, GS Massoud, R Leibovitch, EC Caruso, B Johnson, K Ohayon, J Fenton, K Cortese, I Jacobson, S AF Brunetto, Giovanna S. Massoud, Raya Leibovitch, Emily C. Caruso, Breanna Johnson, Kory Ohayon, Joan Fenton, Kaylan Cortese, Irene Jacobson, Steven TI Digital droplet PCR (ddPCR) for the precise quantification of human T-lymphotropic virus 1 proviral loads in peripheral blood and cerebrospinal fluid of HAM/TSP patients and identification of viral mutations SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE Human T-lymphotropic virus; Digital droplet PCR; Proviral load; HAM/TSP; Viral quantification ID MYELOPATHY/TROPICAL SPASTIC PARAPARESIS; DNA COPY NUMBER; REAL-TIME PCR; HTLV-I; ASYMPTOMATIC CARRIERS; TYPE-1 HTLV-1; CD8(+) CELLS; DISEASE; QUANTITATION; EXPANSION AB An elevated human T cell lymphotropic virus 1 (HTLV)-1 proviral load (PVL) is the main risk factor for developing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in HTLV-1 infected subjects, and a high cerebrospinal fluid (CSF) to peripheral blood mononuclear cell (PBMC) PVL ratio may be diagnostic of the condition. However, the standard method for quantification of HTLV-1 PVL-real-time PCR-has multiple limitations, including increased inter-assay variability in compartments with low cell numbers, such as CSF. Therefore, in this study, we evaluated a novel technique for HTVL-1 PVL quantification, digital droplet PCR (ddPCR). In ddPCR, PCR samples are partitioned into thousands of nanoliter-sized droplets, amplified on a thermocycler, and queried for fluorescent signal. Due to the high number of independent events (droplets), Poisson algorithms are used to determine absolute copy numbers independently of a standard curve, which enables highly precise quantitation. This assay has low intra-assay variability allowing for reliable PVL measurement in PBMC and CSF compartments of both asymptomatic carriers (AC) and HAM/TSP patients. It is also useful for HTLV-1-related clinical applications, such as longitudinal monitoring of PVL and identification of viral mutations within the region targeted by the primers and probe. C1 [Brunetto, Giovanna S.; Massoud, Raya; Leibovitch, Emily C.; Caruso, Breanna; Ohayon, Joan; Fenton, Kaylan; Cortese, Irene; Jacobson, Steven] NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Leibovitch, Emily C.] George Washington Univ, Sch Med & Hlth Sci, Inst Biomed Sci, Washington, DC 20037 USA. [Johnson, Kory] NINDS, Bioinformat Sect, Informat Technol & Bioinformat Program, NIH, Bethesda, MD 20892 USA. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 5C-103, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov NR 23 TC 21 Z9 23 U1 0 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD AUG PY 2014 VL 20 IS 4 BP 341 EP 351 DI 10.1007/s13365-014-0249-3 PG 11 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA AL7RF UT WOS:000339331700003 PM 24781526 ER PT J AU Martelle, SE Nader, SH Czoty, PW John, WS Duke, AN Garg, PK Garg, S Newman, AH Nader, MA AF Martelle, Susan E. Nader, Susan H. Czoty, Paul W. John, William S. Duke, Angela N. Garg, Pradeep K. Garg, Sudha Newman, Amy H. Nader, Michael A. TI Further Characterization of Quinpirole-Elicited Yawning as a Model of Dopamine D-3 Receptor Activation in Male and Female Monkeys SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; HUMAN COCAINE FATALITIES; SUBSTANCE USE DISORDERS; SEX-DIFFERENCES; RHESUS-MONKEYS; DRUG-ABUSE; NUCLEUS-ACCUMBENS; D2 RECEPTORS; IN-VIVO; RATS AB The dopamine (DA) D-3 receptor (D3R) has been associated with impulsivity, pathologic gambling, and drug addiction, making it a potential target for pharmacotherapy development. Positron emission tomography studies using the D3R-preferring radio-ligand [C-11]PHNO ([C-11](+)-propyl-hexahydro-naphtho-oxazin) have shown higher binding potentials in drug abusers compared with control subjects. Preclinical studies have examined D3R receptor activation using the DA agonist quinpirole and the unconditioned behavior of yawning. However, the relationship between quinpirole-elicited yawning and D3R receptor availability has not been determined. In Experiment 1, eight drug-naive male rhesus monkeys were scanned with [C-11]PHNO, and the ability of quinpirole (0.01-0.3 mg/kg i.m.) to elicit yawning was examined. Significant positive (globus pallidus) and negative (caudate nucleus, putamen, ventral pallidum, and hippocampus) relationships between D3R receptor availability and quinpirole-induced yawns were noted. Experiment 2 replicated earlier findings that a history of cocaine self-administration (n = 11) did not affect quinpirole-induced yawning and extended this to examine monkeys (n = 3) with a history of methamphetamine (MA) self-administration and found that monkeys with experience self-administering MA showed greater potency and significantly higher quinpirole-elicited yawning compared with controls. Finally, quinpirole-elicited yawning was studied in drug-naive female monkeys (n = 6) and compared with drug-naive male monkeys (n = 8). Sex differences were noted, with quinpirole being more potent and eliciting significantly more yawns in males compared with females. Taken together these findings support the use of quinpirole-elicited yawning as a behavioral tool for examining D3R activation in monkeys and that both drug history and sex may influence individual sensitivity to the behavioral effects of D3R compounds. C1 [Martelle, Susan E.; Nader, Susan H.; Czoty, Paul W.; John, William S.; Duke, Angela N.; Nader, Michael A.] Wake Forest Univ, Bowman Gray Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC 27157 USA. [Garg, Pradeep K.; Garg, Sudha; Nader, Michael A.] Wake Forest Univ, Bowman Gray Sch Med, Dept Radiol, Winston Salem, NC 27157 USA. [Newman, Amy H.] NIDA, Intramural Res Program, Baltimore, MD USA. RP Nader, MA (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Physiol & Pharmacol, 546 NRC,Med Ctr Blvd, Winston Salem, NC 27157 USA. EM mnader@wakehealth.edu FU National Institutes of Health National Institute on Drug Abuse [DA012460, DA021658]; National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [AA021099]; National Institutes of Health [National Institute on Drug Abuse] FX The research described in this manuscript was supported by grants from the National Institutes of Health National Institute on Drug Abuse [Grants DA012460 and DA021658]; the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grant AA021099]; and the Intramural Research Program of the National Institutes of Health [National Institute on Drug Abuse]. NR 65 TC 4 Z9 4 U1 0 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG PY 2014 VL 350 IS 2 BP 205 EP 211 DI 10.1124/jpet.114.214833 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AL6VJ UT WOS:000339270800003 PM 24876234 ER PT J AU Schountz, T Quackenbush, S Rovnak, J Haddock, E Black, WC Feldmann, H Prescott, J AF Schountz, Tony Quackenbush, Sandra Rovnak, Joel Haddock, Elaine Black, William C. Feldmann, Heinz Prescott, Joseph TI Differential Lymphocyte and Antibody Responses in Deer Mice Infected with Sin Nombre Hantavirus or Andes Hantavirus SO JOURNAL OF VIROLOGY LA English DT Article ID MOUSE PEROMYSCUS-MANICULATUS; REGULATORY T-CELLS; PULMONARY SYNDROME; HEMORRHAGIC-FEVER; GENETIC DIVERSITY; VIRUS-INFECTION; MESSENGER-RNA; NORTH-AMERICA; SEOUL-VIRUS; LONG-TERM AB Hantavirus cardiopulmonary syndrome (HCPS) is a rodent-borne disease with a high case-fatality rate that is caused by several New World hantaviruses. Each pathogenic hantavirus is naturally hosted by a principal rodent species without conspicuous disease and infection is persistent, perhaps for life. Deer mice (Peromyscus maniculatus) are the natural reservoirs of Sin Nombre virus (SNV), the etiologic agent of most HCPS cases in North America. Deer mice remain infected despite a helper T cell response that leads to high-titer neutralizing antibodies. Deer mice are also susceptible to Andes hantavirus (ANDV), which causes most HCPS cases in South America; however, deer mice clear ANDV. We infected deer mice with SNV or ANDV to identify differences in host responses that might account for this differential outcome. SNV RNA levels were higher in the lungs but not different in the heart, spleen, or kidneys. Most ANDV-infected deer mice had seroconverted 14 days after inoculation, but none of the SNV-infected deer mice had. Examination of lymph node cell antigen recall responses identified elevated immune gene expression in deer mice infected with ANDV and suggested maturation toward a Th2 or T follicular helper phenotype in some ANDV-infected deer mice, including activation of the interleukin 4 (IL-4) pathway in T cells and B cells. These data suggest that the rate of maturation of the immune response is substantially higher and of greater magnitude during ANDV infection, and these differences may account for clearance of ANDV and persistence of SNV. IMPORTANCE Hantaviruses persistently infect their reservoir rodent hosts without pathology. It is unknown how these viruses evade sterilizing immune responses in the reservoirs. We have determined that infection of the deer mouse with its homologous hantavirus, Sin Nombre virus, results in low levels of immune gene expression in antigen-stimulated lymph node cells and a poor antibody response. However, infection of deer mice with a heterologous hantavirus, Andes virus, results in a robust lymph node cell response, signatures of T and B cell maturation, and production of antibodies. These findings suggest that an early and aggressive immune response to hantaviruses may lead to clearance in a reservoir host and suggest that a modest immune response may be a component of hantavirus ecology. C1 [Schountz, Tony; Black, William C.] Colorado State Univ, Coll Vet Med & Biomed Sci, Arthropod Borne & Infect Dis Lab, Ft Collins, CO 80523 USA. [Schountz, Tony; Quackenbush, Sandra; Rovnak, Joel; Black, William C.] Colorado State Univ, Coll Vet Med & Biomed Sci, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Haddock, Elaine; Feldmann, Heinz; Prescott, Joseph] NIAID, Rocky Mt Lab, Virol Lab, Div Intramural Res,NIH, Hamilton, MT 59840 USA. RP Schountz, T (reprint author), Colorado State Univ, Coll Vet Med & Biomed Sci, Arthropod Borne & Infect Dis Lab, Ft Collins, CO 80523 USA. EM tony.schountz@colostate.edu FU NIH grant [AI054461]; Department of Microbiology, Immunology and Pathology, CSU; Intramural Program of NIAID, NIH FX This work was supported by NIH grant AI054461 and startup funds from the Department of Microbiology, Immunology and Pathology, CSU (to T.S.), and the Intramural Program of NIAID, NIH (H.F. and J.P.). NR 66 TC 6 Z9 6 U1 2 U2 20 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG PY 2014 VL 88 IS 15 BP 8319 EP 8331 DI 10.1128/JVI.00004-14 PG 13 WC Virology SC Virology GA AL1ZB UT WOS:000338924400011 PM 24829335 ER PT J AU Paldurai, A Kim, SH Nayak, B Xiao, S Shive, H Collins, PL Samal, SK AF Paldurai, Anandan Kim, Shin-Hee Nayak, Baibaswata Xiao, Sa Shive, Heather Collins, Peter L. Samal, Siba K. TI Evaluation of the Contributions of Individual Viral Genes to Newcastle Disease Virus Virulence and Pathogenesis SO JOURNAL OF VIROLOGY LA English DT Article ID HEMAGGLUTININ-NEURAMINIDASE PROTEIN; FUSION PROTEIN; CLEAVAGE-SITE; PARAMYXOVIRUS TYPE-1; NUCLEOTIDE-SEQUENCE; GENOME SEQUENCE; PATHOGENICITY; REPLICATION; STRAIN; TROPISM AB Naturally occurring Newcastle disease virus (NDV) strains vary greatly in virulence. The presence of multibasic residues at the proteolytic cleavage site of the fusion (F) protein has been shown to be a primary determinant differentiating virulent versus avirulent strains. However, there is wide variation in virulence among virulent strains. There also are examples of incongruity between cleavage site sequence and virulence. These observations suggest that additional viral factors contribute to virulence. In this study, we evaluated the contribution of each viral gene to virulence individually and in different combinations by exchanging genes between velogenic (highly virulent) strain GB Texas (GBT) and mesogenic (moderately virulent) strain Beaudette C (BC). These two strains are phylogenetically closely related, and their F proteins contain identical cleavage site sequences, (112)RRQKR down arrow F-117. A total of 20 chimeric viruses were constructed and evaluated in vitro, in 1-day-old chicks, and in 2-week-old chickens. The results showed that both the envelope-associated and polymerase-associated proteins contribute to the difference in virulence between rBC and rGBT, with the envelope-associated proteins playing the greater role. The F protein was the major individual contributor and was sometimes augmented by the homologous M and HN proteins. The dramatic effect of F was independent of its cleavage site sequence since that was identical in the two strains. The polymerase L protein was the next major individual contributor and was sometimes augmented by the homologous N and P proteins. The leader and trailer regions did not appear to contribute to the difference in virulence between BC and GBT. IMPORTANCE This study is the first comprehensive and systematic study of NDV virulence and pathogenesis. Genetic exchanges between a mesogenic and a velogenic strain revealed that the fusion glycoprotein is the major virulence determinant regardless of the identical virulence protease cleavage site sequence present in both strains. The contribution of the large polymerase protein to NDV virulence is second only to that of the fusion glycoprotein. The identification of virulence determinants is of considerable importance, because of the potential to generate better live attenuated NDV vaccines. It may also be possible to apply these findings to other paramyxoviruses. C1 [Paldurai, Anandan; Kim, Shin-Hee; Nayak, Baibaswata; Xiao, Sa; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Shive, Heather] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu RI Nayak, Baibaswata/L-6156-2016 FU NIAID [N01A060009]; NIAID, NIH Intramural Research Program FX This research was supported by NIAID contract N01A060009 (85% support) and the NIAID, NIH Intramural Research Program (15% support). NR 31 TC 8 Z9 9 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG PY 2014 VL 88 IS 15 BP 8579 EP 8596 DI 10.1128/JVI.00666-14 PG 18 WC Virology SC Virology GA AL1ZB UT WOS:000338924400034 PM 24850737 ER PT J AU Gabriel, KP Sidney, S Jacobs, DR Quesenberry, CP Reis, JP Jiang, SF Sternfeld, B AF Gabriel, Kelley Pettee Sidney, Stephen Jacobs, David R., Jr. Quesenberry, Charles P., Jr. Reis, Jared P. Jiang, Sheng-Fang Sternfeld, Barbara TI Convergent Validity of a Brief Self-reported Physical Activity Questionnaire SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE SELF-REPORT; CONVERGENT VALIDITY; PHYSICAL ACTIVITY ASSESSMENT; COMPONENTS OF PHYSICAL ACTIVITY BEHAVIOR ID ARTERY RISK DEVELOPMENT; YOUNG-ADULTS; FOLLOW-UP; CARDIA; ACCURACY AB Purpose: The objective of this study is to determine whether summary estimates of a self - report physical activity questionnaire that does not specifically assess frequency or duration (the Coronary Artery Risk Development in Young Adults (CARDIA) physical activity history (PAH)) differs from the summary estimates of one that does (CARDIA Supplemental Questionnaire). Methods: After the year 25 examination (2010 - 2011), 203 CARDIA black and white men and women (age 50.3 +/- 3.6 yr) at the Oakland, CA, site participated in this comparison study. The between - questionnaire association and agreement were determined for continuous and categorical estimates on the basis of 1) quartiles and 2) meeting 2008 physical activity guidelines. Differences in participant characteristics by concordance/discordance status were also examined. Finally, receiver operating characteristic curves were computed to determine the accuracy of the PAH compared with the supplemental questionnaire. Results: Reported physical activity levels were high and varied significantly by race and sex (all P G 0.01). Between - questionnaire estimates were significantly correlated (rho = 0.75 to 0.90, all P < 0.001) and had high agreement (kappa = 0.51 to 0.80) across all race/sex groups. A higher proportion of women than men were classified as concordant by quartile of vigorous intensity (P - 0.001), but no other participant characteristics were associated with concordant/discordant quartile ranking. Participants classified as concordant on the basis of physical activity guidelines had lower body mass index than those classified as discordant (both P < 0.05). The area under the curve was 0.95, suggesting that the PAH has high accuracy for classifying individuals as meeting physical activity guidelines. Conclusions: Although it is inconvenient that the PAH is not expressed in more standard units, these findings support the practice of not directly assessing frequency and duration, which are frequent sources of reporting error. C1 [Gabriel, Kelley Pettee] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol Human Genet & Environm Sci, Austin, TX 78701 USA. [Sidney, Stephen; Quesenberry, Charles P., Jr.; Jiang, Sheng-Fang; Sternfeld, Barbara] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Jacobs, David R., Jr.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Reis, Jared P.] NHLBI, Div Cardiovasc Sci, Program Prevent & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Gabriel, KP (reprint author), Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Div Epidemiol Human Genet & Environm Sci, Austin Reg Campus,1616 Guadalupe St,Suite 6-300, Austin, TX 78701 USA. EM Kelley.P.Gabriel@uth.tmc.edu FU National Heart, Lung, and Blood Institute [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C, AG0005]; National Institute on Aging; NIA [AG0005] FX The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the National Heart, Lung, and Blood Institute, the Intramural Research Program of the National Institute on Aging, and an intraagency agreement between NIA and National Heart, Lung, and Blood Institute (AG0005). No authors report any conflict of interest. NR 16 TC 7 Z9 7 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD AUG PY 2014 VL 46 IS 8 BP 1570 EP 1577 DI 10.1249/MSS.0000000000000278 PG 8 WC Sport Sciences SC Sport Sciences GA AL6RF UT WOS:000339259700012 PM 24496119 ER PT J AU Ghazaryan, S Sy, C Hu, TH An, XL Mohandas, N Fu, HQ Aladjem, MI Chang, VT Opavsky, R Wu, LZ AF Ghazaryan, Seda Sy, Chandler Hu, Tinghui An, Xiuli Mohandas, Narla Fu, Haiqing Aladjem, Mirit I. Chang, Victor T. Opavsky, Rene Wu, Lizhao TI Inactivation of Rb and E2f8 Synergizes To Trigger Stressed DNA Replication during Erythroid Terminal Differentiation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RETINOBLASTOMA TUMOR-SUPPRESSOR; HEMATOPOIETIC STEM-CELLS; EMBRYONIC-DEVELOPMENT; ERYTHROPOIESIS; MICE; GENE; DEFICIENT; CANCER; CYCLE; PRB AB Rb is critical for promoting cell cycle exit in cells undergoing terminal differentiation. Here we show that during erythroid terminal differentiation, Rb plays a previously unappreciated and unorthodox role in promoting DNA replication and cell cycle progression. Specifically, inactivation of Rb in erythroid cells led to stressed DNA replication, increased DNA damage, and impaired cell cycle progression, culminating in defective terminal differentiation and anemia. Importantly, all of these defects associated with Rb loss were exacerbated by the concomitant inactivation of E2f8. Gene expression profiling and chromatin immunoprecipitation (ChIP) revealed that Rb and E2F8 cosuppressed a large array of E2F target genes that are critical for DNA replication and cell cycle progression. Remarkably, inactivation of E2f2 rescued the erythropoietic defects resulting from Rb and E2f8 deficiencies. Interestingly, real-time quantitative PCR (qPCR) on E2F2 ChIPs indicated that inactivation of Rb and E2f8 synergizes to increase E2F2 binding to its target gene promoters. Taken together, we propose that Rb and E2F8 collaborate to promote DNA replication and erythroid terminal differentiation by preventing E2F2-mediated aberrant transcriptional activation through the ability of Rb to bind and sequester E2F2 and the ability of E2F8 to compete with E2F2 for E2f-binding sites on target gene promoters. C1 [Ghazaryan, Seda; Sy, Chandler; Hu, Tinghui; Wu, Lizhao] Rutgers New Jersey Med Sch, Ctr Canc, Dept Microbiol & Mol Genet, Newark, NJ 07103 USA. [An, Xiuli] New York Blood Ctr, Membrane Biol Lab, New York, NY 10021 USA. [Mohandas, Narla] New York Blood Ctr, Red Cell Physiol Lab, New York, NY 10021 USA. [Fu, Haiqing; Aladjem, Mirit I.] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Chang, Victor T.] VA New Jersey Hlth Care Syst, Hematol Oncol Sect, E Orange, NJ USA. [Opavsky, Rene] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE USA. RP Wu, LZ (reprint author), Rutgers New Jersey Med Sch, Ctr Canc, Dept Microbiol & Mol Genet, Newark, NJ 07103 USA. EM wuli@njms.rutgers.edu RI Hu, Tinghui/F-3213-2015; Aladjem, Mirit/G-2169-2010; OI Aladjem, Mirit/0000-0002-1875-3110; Sy, Chandler/0000-0002-8739-561X FU Leukemia Research Foundation; New York Community Trust; Foundation of the University of Medicine and Dentistry of New Jersey FX This study was supported by grants from the Leukemia Research Foundation, the New York Community Trust, and the Foundation of the University of Medicine and Dentistry of New Jersey. NR 51 TC 2 Z9 2 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2014 VL 34 IS 15 BP 2833 EP 2847 DI 10.1128/MCB.01651-13 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AL1GV UT WOS:000338874700006 PM 24865965 ER PT J AU Xie, LW Xue, X Taylor, M Ramakrishnan, SK Nagaoka, K Hao, C Gonzalez, FJ Shah, YM AF Xie, Liwei Xue, Xiang Taylor, Matthew Ramakrishnan, Sadeesh K. Nagaoka, Kenjiro Hao, Cathy Gonzalez, Frank J. Shah, Yatrik M. TI Hypoxia-Inducible Factor/MAZ-Dependent Induction of Caveolin-1 Regulates Colon Permeability through Suppression of Occludin, Leading to Hypoxia-Induced Inflammation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID FACTOR-I; INTESTINAL EPITHELIA; EXPERIMENTAL COLITIS; CANCER PROGRESSION; CELL-PROLIFERATION; BARRIER FUNCTION; UP-REGULATION; EXPRESSION; TUMORIGENESIS; GENE AB Caveolae are specialized microdomains on membranes that are critical for signal transduction, cholesterol transport, and endocytosis. Caveolin-1 (CAV1) is a multifunctional protein and a major component of caveolae. Cav1 is directly activated by hypoxia- inducible factor (HIF). HIFs are heterodimers of an oxygen-sensitive alpha subunit, HIF1 alpha or HIF2 alpha, and a constitutively expressed beta subunit, aryl hydrocarbon receptor nuclear translocator (ARNT). Whole-genome expression analysis demonstrated that Cav1 is highly induced in mouse models of constitutively activated HIF signaling in the intestine. Interestingly, Cav1 was increased only in the colon and not in the small intestine. Currently, the mechanism and role of HIF induction of CAV1 in the colon are unclear. In mouse models, mice that overexpressed HIF1 alpha or HIF2 alpha specifically in intestinal epithelial cells demonstrated an increase in Cav1 gene expression in the colon but not in the duodenum, jejunum, or ileum. HIF2 alpha activated the Cav1 promoter in a HIF response element-independent manner. myc-associated zinc finger (MAZ) protein was essential for HIF2 alpha activation of the Cav1 promoter. Hypoxic induction of CAV1 in the colon was essential for intestinal barrier integrity by regulating occludin expression. This may provide an additional mechanism by which chronic hypoxia can activate intestinal inflammation. C1 [Xie, Liwei; Xue, Xiang; Taylor, Matthew; Ramakrishnan, Sadeesh K.; Nagaoka, Kenjiro; Hao, Cathy; Shah, Yatrik M.] Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Shah, Yatrik M.] Univ Michigan, Sch Med, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI USA. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Shah, YM (reprint author), Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. EM shahy@umich.edu RI Xue, Xiang/P-9071-2014 OI Xue, Xiang/0000-0003-4704-1814 FU NIH [CA148828, DK095201]; University of Michigan Gastrointestinal Peptide Center; University of Michigan GI Spore [CA130810]; Crohn's Colitis Foundation of America [276556]; National Cancer Institute Intramural Research Program FX This work was supported by NIH grants (CA148828 and DK095201 to Y.M.S.), the University of Michigan Gastrointestinal Peptide Center (Y.M.S.), a pilot grant from the University of Michigan GI Spore (CA130810 to Y.M.S.), the Crohn's Colitis Foundation of America (grant number 276556 to X.X.), and the National Cancer Institute Intramural Research Program (F.J.G.). NR 58 TC 11 Z9 12 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2014 VL 34 IS 16 BP 3013 EP 3023 DI 10.1128/MCB.00324-14 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AL8IE UT WOS:000339381000005 PM 24891620 ER PT J AU Panda, AC Abdelmohsen, K Yoon, JH Martindale, JL Yang, XL Curtis, J Mercken, EM Chenette, DM Zhang, YQ Schneider, RJ Becker, KG de Cabo, R Gorospe, M AF Panda, Amaresh C. Abdelmohsen, Kotb Yoon, Je-Hyun Martindale, Jennifer L. Yang, Xiaoling Curtis, Jessica Mercken, Evi M. Chenette, Devon M. Zhang, Yongqing Schneider, Robert J. Becker, Kevin G. de Cabo, Rafael Gorospe, Myriam TI RNA-Binding Protein AUF1 Promotes Myogenesis by Regulating MEF2C Expression Levels SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID POSTTRANSCRIPTIONAL GENE-REGULATION; SKELETAL-MUSCLE DEVELOPMENT; BOX TRANSCRIPTION FACTORS; HELIX-LOOP-HELIX; HNRNP-D; HEART DEVELOPMENT; MESSENGER-RNAS; RICH ELEMENT; FIBER-TYPE; PAR-CLIP AB The mammalian RNA-binding protein AUF1 (AU-binding factor 1, also known as heterogeneous nuclear ribonucleoprotein D [hnRNP D]) binds to numerous mRNAs and influences their posttranscriptional fate. Given that many AUF1 target mRNAs encode muscle-specific factors, we investigated the function of AUF1 in skeletal muscle differentiation. In mouse C2C12 myocytes, where AUF1 levels rise at the onset of myogenesis and remain elevated throughout myocyte differentiation into myotubes, RNP immunoprecipitation (RIP) analysis indicated that AUF1 binds prominently to Mef2c (myocyte enhancer factor 2c) mRNA, which encodes the key myogenic transcription factor MEF2C. By performing mRNA half-life measurements and polysome distribution analysis, we found that AUF1 associated with the 3' untranslated region (UTR) of Mef2c mRNA and promoted MEF2C translation without affecting Mef2c mRNA stability. In addition, AUF1 promoted Mef2c gene transcription via a lesser-known role of AUF1 in transcriptional regulation. Importantly, lowering AUF1 delayed myogenesis, while ectopically restoring MEF2C expression levels partially rescued the impairment of myogenesis seen after reducing AUF1 levels. We propose that MEF2C is a key effector of the myogenesis program promoted by AUF1. C1 [Panda, Amaresh C.; Abdelmohsen, Kotb; Yoon, Je-Hyun; Martindale, Jennifer L.; Yang, Xiaoling; Zhang, Yongqing; Becker, Kevin G.; Gorospe, Myriam] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Curtis, Jessica; Mercken, Evi M.; de Cabo, Rafael] NIA, Translat Gerontol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Chenette, Devon M.; Schneider, Robert J.] NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. RP Gorospe, M (reprint author), NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; PANDA, AMARESH/0000-0003-3189-8995; , rafael/0000-0003-2830-5693; Schneider, Robert/0000-0001-5807-5564 FU NIA-IRP, NIH; NIH [GM085693, T32 GM13-A0-S1-090476] FX This work was supported by the NIA-IRP, NIH, and by NIH grants GM085693 (R.J.S.) and T32 GM13-A0-S1-090476 (D.M.C.). NR 62 TC 6 Z9 6 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2014 VL 34 IS 16 BP 3106 EP 3119 DI 10.1128/MCB.00423-14 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AL8IE UT WOS:000339381000013 PM 24891619 ER PT J AU Makia, NL Surapureddi, S Monostory, K Prough, RA Goldstein, JA AF Makia, Ngome L. Surapureddi, Sailesh Monostory, Katalin Prough, Russell A. Goldstein, Joyce A. TI Regulation of Human CYP2C9 Expression by Electrophilic Stress Involves Activator Protein 1 Activation and DNA Looping SO MOLECULAR PHARMACOLOGY LA English DT Article ID CONSTITUTIVE ANDROSTANE RECEPTOR; PREGNANE X RECEPTOR; CHROMOSOME CONFORMATION CAPTURE; HUMAN HEPATOCYTES; OXIDATIVE STRESS; TRANSCRIPTIONAL REGULATION; DRUG-METABOLISM; PROMOTER; GENE; INDUCTION AB Cytochrome P450 (CYP) 2C9 and CYP2C19 are important human enzymes that metabolize therapeutic drugs, environmental chemicals, and physiologically important endogenous compounds. Initial studies using primary human hepatocytes showed induction of both the CYP2C9 and CYP2C19 genes by tertbutylhydroquinone (tBHQ). As a pro-oxidant, tBHQ regulates the expression of cytoprotective genes by activation of redox-sensing transcription factors, such as the nuclear factor E2-related factor 2 (Nrf2) and members of the activator protein 1 (AP-1) family of proteins. The promoter region of CYP2C9 contains two putative AP-1 sites (TGAGTCA) at positions -2201 and -1930, which are also highly conserved in CYP2C19. The CYP2C9 promoter is activated by ectopic expression of cFos and JunD, whereas Nrf2 had no effect. Using specific kinase inhibitors formitogen-activated protein kinase, we showed that extracellular signal-regulated kinase and Jun N-terminal kinase are essential for tBHQ-induced expression of CYP2C9. Electrophoretic mobility shift assays demonstrate that cFos distinctly interacts with the distal AP-1 site and JunD with the proximal site. Because cFos regulates target genes as heterodimers with Jun proteins, we hypothesized that DNA looping might be required to bring the distal and proximal AP-1 sites together to activate the CYP2C9 promoter. Chromosome conformation capture analyses confirmed the formation of a DNA loop in the CYP2C9 promoter, possibly allowing interaction between cFos at the distal site and JunD at the proximal site to activate CYP2C9 transcription in response to electrophiles. These results indicate that oxidative stress generated by exposure to electrophilic xenobiotics and metabolites induces the expression of CYP2C9 and CYP2C19 in human hepatocytes. C1 [Makia, Ngome L.; Surapureddi, Sailesh; Goldstein, Joyce A.] NIEHS, Human Metab Grp, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. [Prough, Russell A.] Univ Louisville, Sch Med, Dept Biochem & Mol Biol, Louisville, KY 40292 USA. [Monostory, Katalin] Hungarian Acad Sci, Res Ctr Nat Sci, Budapest, Hungary. RP Goldstein, JA (reprint author), NIEHS, Lab Toxicol & Pharmacol, 111 TW Alexander Dr,Bldg 101,POB 12233, Res Triangle Pk, NC 27709 USA. EM goldste1@niehs.nih.gov RI Monostory, Katalin/N-1064-2016 FU Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences [ES021024]; National Institutes of Health National Institute of Environmental Health Sciences [ES11860]; National Development Agency [GOP-1.3.1-11/B-2011-0042]; Hungarian Scientific Research Fund [OTKA K104459] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences [Project ES021024]; National Institutes of Health National Institute of Environmental Health Sciences [Grant ES11860]; National Development Agency [GOP-1.3.1-11/B-2011-0042]; and Hungarian Scientific Research Fund [OTKA K104459]. NR 50 TC 1 Z9 1 U1 1 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD AUG PY 2014 VL 86 IS 2 BP 125 EP 137 DI 10.1124/mol.114.092585 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AL6UD UT WOS:000339267500001 PM 24830941 ER PT J AU Khiati, S Seol, Y Agama, K Dalla Rosa, I Agrawal, S Fesen, K Zhang, HL Neuman, KC Pommier, Y AF Khiati, Salim Seol, Yeonee Agama, Keli Dalla Rosa, Ilaria Agrawal, Surbhi Fesen, Katherine Zhang, Hongliang Neuman, Keir C. Pommier, Yves TI Poisoning of Mitochondrial Topoisomerase I by Lamellarin D SO MOLECULAR PHARMACOLOGY LA English DT Article ID BREAST-CANCER; TARGETING DRUGS; ANTITUMOR DRUGS; DNA-DAMAGE; CAMPTOTHECIN; ANTICANCER; INHIBITOR; COMPLEXES; TRANSCRIPTION; REPLICATION AB Lamellarin D (Lam-D) is a hexacyclic pyrole alkaloid isolated from marine invertebrates, whose biologic properties have been attributed to mitochondrial targeting. Mitochondria contain their own DNA (mtDNA), and the only specific mitochondrial topoisomerase in vertebrates is mitochondrial topoisomerase I (Top1mt). Here, we show that Top1mt is a direct mitochondrial target of Lam-D. In vitro Lam-D traps Top1mt and induces Top1mt cleavage complexes (Top1mtcc). Using single-molecule analyses, we also show that Lam-D slows down supercoil relaxation of Top1mt and strongly inhibits Top1mt religation in contrast to the inefficacy of camptothecin on Top1mt. In living cells, we show that Lam-D accumulates rapidly inside mitochondria, induces cellular Top1mtcc, and leads to mtDNA damage. This study provides evidence that Top1mt is a direct mitochondrial target of Lam-D and suggests that developing Top1mt inhibitors represents a novel strategy for targeting mitochondrial DNA. C1 [Khiati, Salim; Agama, Keli; Dalla Rosa, Ilaria; Agrawal, Surbhi; Fesen, Katherine; Zhang, Hongliang; Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20814 USA. [Khiati, Salim; Agama, Keli; Dalla Rosa, Ilaria; Agrawal, Surbhi; Fesen, Katherine; Zhang, Hongliang; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20814 USA. [Seol, Yeonee; Neuman, Keir C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bldg 37,Rm 5068,37 Convent Dr,MSC 4255, Bethesda, MD 20814 USA. EM pommier@nih.gov RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU Intramural Research Program of the National Institutes of Health National Cancer Institute, Center of Cancer Research [Z01 BC006161]; National Heart, Lung, and Blood Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health National Cancer Institute, Center of Cancer Research [Z01 BC006161] and the National Heart, Lung, and Blood Institute. NR 52 TC 11 Z9 11 U1 2 U2 20 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD AUG PY 2014 VL 86 IS 2 BP 193 EP 199 DI 10.1124/mol.114.092833 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AL6UD UT WOS:000339267500007 PM 24890608 ER PT J AU Bachovchin, DA Koblan, LW Wu, WG Liu, YX Li, YH Zhao, P Woznica, I Shu, Y Lai, JH Poplawski, SE Kiritsy, CP Healey, SE DiMare, M Sanford, DG Munford, RS Bachovchin, WW Golub, TR AF Bachovchin, Daniel A. Koblan, Luke W. Wu, Wengen Liu, Yuxin Li, Youhua Zhao, Peng Woznica, Iwona Shu, Ying Lai, Jack H. Poplawski, Sarah E. Kiritsy, Christopher P. Healey, Sarah E. DiMare, Matthew Sanford, David G. Munford, Robert S. Bachovchin, William W. Golub, Todd R. TI A high-throughput, multiplexed assay for superfamily-wide profiling of enzyme activity SO NATURE CHEMICAL BIOLOGY LA English DT Article ID RETINOBLASTOMA-BINDING PROTEIN; KINASE INHIBITOR SELECTIVITY; DIPEPTIDYL PEPTIDASE-IV; A-LIKE ENZYME; SERINE HYDROLASES; IN-VIVO; PANCREATIC ELASTASE; COVALENT INHIBITORS; PROTEASOME; PROLYLCARBOXYPEPTIDASE AB The selectivity of an enzyme inhibitor is a key determinant of its usefulness as a tool compound or its safety as a drug. Yet selectivity is never assessed comprehensively in the early stages of the drug discovery process, and only rarely in the later stages, because technical limitations prohibit doing otherwise. Here, we report EnPlex, an efficient, high-throughput method for simultaneously assessing inhibitor potency and specificity, and pilot its application to 96 serine hydrolases. EnPlex analysis of widely used serine hydrolase inhibitors revealed numerous previously unrecognized off-target interactions, some of which may help to explain previously confounding adverse effects. In addition, EnPlex screening of a hydrolase-directed library of boronic acid-and nitrile-containing compounds provided structure-activity relationships in both potency and selectivity dimensions from which lead candidates could be more effectively prioritized. Follow-up of a series of dipeptidyl peptidase 4 inhibitors showed that EnPlex indeed predicted efficacy and safety in animal models. These results demonstrate the feasibility and value of high-throughput, superfamily-wide selectivity profiling and suggest that such profiling can be incorporated into the earliest stages of drug discovery. C1 [Bachovchin, Daniel A.; Koblan, Luke W.; Golub, Todd R.] Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. [Wu, Wengen; Liu, Yuxin; Li, Youhua; Zhao, Peng; Woznica, Iwona; Shu, Ying; Lai, Jack H.; Poplawski, Sarah E.; Healey, Sarah E.; DiMare, Matthew; Sanford, David G.; Bachovchin, William W.] Tufts Univ, Dept Biochem, Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA. [Kiritsy, Christopher P.; Bachovchin, William W.] Arisaph Pharmaceut, Boston, MA USA. [Munford, Robert S.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Golub, Todd R.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Golub, Todd R.] Harvard Univ, Sch Med, Boston, MA USA. [Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Golub, TR (reprint author), Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. EM golub@broadinstitute.org FU National Cancer Institute [U54CA112962]; Howard Hughes Medical Institute; US National Institutes of Health (NIH) [R01 CA163930]; Arisaph Pharmaceuticals; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH FX We thank B. Cravatt (The Scripps Research Institute) for the FP serine hydrolase probe; B. Martin (University of Michigan), J. Long (Dana-Farber Cancer Institute), A. Lone and A. Saghatelian (both at Harvard University) for constructs; J. Davis and D. Peck (both at The Broad Institute) for technical assistance; and D. Gray and C. Yu (both at The Broad Institute) for helpful discussions. This work was supported by the National Cancer Institute (grant no. U54CA112962 to T. R. G.), Howard Hughes Medical Institute (T. R. G.), the US National Institutes of Health (NIH; grant R01 CA163930 to W. W. B.), Arisaph Pharmaceuticals (W. W. B.) and in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH (R. S. M.). NR 53 TC 14 Z9 14 U1 2 U2 31 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD AUG PY 2014 VL 10 IS 8 BP 656 EP U203 DI 10.1038/NCHEMBIO.1578 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AL8HW UT WOS:000339380100012 PM 24997602 ER PT J AU Vahedi, G Richard, AC O'Shea, JJ AF Vahedi, Golnaz Richard, Arianne C. O'Shea, John J. TI Enhancing the understanding of asthma SO NATURE IMMUNOLOGY LA English DT Editorial Material ID CHROMATIN; CELLS AB The chromatin signature of genomic enhancers in CD4(+) T cells distinguishes asthmatic patients from healthy subjects. C1 [Vahedi, Golnaz; Richard, Arianne C.; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Vahedi, G (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM osheajo@mail.nih.gov FU Intramural NIH HHS [ZIA AR041159-06] NR 13 TC 1 Z9 1 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD AUG PY 2014 VL 15 IS 8 BP 701 EP 703 DI 10.1038/ni.2946 PG 4 WC Immunology SC Immunology GA AL7OF UT WOS:000339323000004 PM 25045871 ER PT J AU Sampaio-Baptista, C Scholz, J Jenkinson, M Thomas, AG Filippini, N Smit, G Douaud, G Johansen-Berg, H AF Sampaio-Baptista, Cassandra Scholz, Jan Jenkinson, Mark Thomas, Adam G. Filippini, Nicola Smit, Gabrielle Douaud, Gwenaelle Johansen-Berg, Heidi TI Gray matter volume is associated with rate of subsequent skill learning after a long term training intervention SO NEUROIMAGE LA English DT Article DE Structural plasticity; Skill learning; MRI ID BRAIN STRUCTURE CHANGES; INDIVIDUAL-DIFFERENCES; WHITE-MATTER; MOTOR CORTEX; SYNAPTOGENESIS; PLASTICITY; MEMORY; REORGANIZATION; SCHIZOPHRENIA; NEUROGENESIS AB The ability to predict learning performance from brain imaging data has implications for selecting individuals for training or rehabilitation interventions. Here, we used structural MRI to test whether baseline variations in gray matter (GM) volume correlated with subsequent performance after a long-term training of a complex whole-body task. 44 naive participants were scanned before undertaking daily juggling practice for 6 weeks, following either a high intensity or a low intensity training regime. To assess performance across the training period participants' practice sessions were filmed. Greater GM volume in medial occipito-parietal areas at baseline correlated with steeper learning slopes. We also tested whether practice time or performance outcomes modulated the degree of structural brain change detected between the baseline scan and additional scans performed immediately after training and following a further 4 weeks without training. Participants with better performance had higher increases in GM volume during the period following training (i.e., between scans 2 and 3) in dorsal parietal cortex and M1. When contrasting brain changes between the practice intensity groups, we did not find any straightforward effects of practice time though practice modulated the relationship between performance and GM volume change in dorsolateral prefrontal cortex. These results suggest that practice time and performance modulate the degree of structural brain change evoked by long-term training regimes. (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/). C1 [Sampaio-Baptista, Cassandra; Scholz, Jan; Jenkinson, Mark; Thomas, Adam G.; Filippini, Nicola; Smit, Gabrielle; Douaud, Gwenaelle; Johansen-Berg, Heidi] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Oxford Ctr Funct MRI Brain FMRIB, Oxford OX3 9DU, England. [Scholz, Jan] Hosp Sick Children, Mouse Imaging Ctr, Toronto, ON M5T 3H7, Canada. [Filippini, Nicola] Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford OX3 7JX, England. [Thomas, Adam G.] NIMH, NIH, Bethesda, MD 20892 USA. RP Johansen-Berg, H (reprint author), John Radcliffe Hosp, FMRIB, Oxford OX3 9DU, England. EM heidi.johansen-berg@ndcn.ox.ac.uk OI , /0000-0002-7893-0289; Jenkinson, Mark/0000-0001-6043-0166; Thomas, Adam/0000-0002-2850-1419 FU Wellcome Trust [WT090955AIA]; FCT [SFRH/BD/43862/2008]; MRC Career Development Fellowship [MR/K006673/1]; Marie Curie Actions (Adaptive Brain Computations network) [PITN-GA-2008-290011]; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust; University of Oxford FX This work was supported by the Wellcome Trust (WT090955AIA to HJ-B) and FCT (SFRH/BD/43862/2008 to CS-B). GD is supported by an MRC Career Development Fellowship (MR/K006673/1). The research was further supported by Marie Curie Actions (Adaptive Brain Computations network PITN-GA-2008-290011) and by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and University of Oxford. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. NR 52 TC 13 Z9 14 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2014 VL 96 BP 158 EP 166 DI 10.1016/j.neuroimage.2014.03.056 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AL0HY UT WOS:000338809200016 PM 24680712 ER PT J AU Jenkins, A Apud, JA Zhang, FY Decot, H Weinberger, DR Law, AJ AF Jenkins, Aaron Apud, Jose A. Zhang, Fengyu Decot, Heather Weinberger, Daniel R. Law, Amanda J. TI Identification of Candidate Single-Nucleotide Polymorphisms in NRXN1 Related to Antipsychotic Treatment Response in Patients with Schizophrenia SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID COPY NUMBER VARIATIONS; CLOZAPINE RESPONSE; GENETIC-VARIATION; NICOTINE DEPENDENCE; ALPHA-NEUREXINS; ASSOCIATION; DELETIONS; DISORDERS; PHARMACOGENETICS; RECEPTORS AB Neurexins are presynaptic neuronal adhesion molecules that interact with postsynaptic neuroligins to form an inter-synaptic complex required for synaptic specification and efficient neurotransmission. Deletions and point mutations in the neurexin 1 (NRXN1) gene are associated with a broad spectrum of neuropsychiatric and neurodevelopmental disorders, including autism, intellectual disability, epilepsy, developmental delay, and schizophrenia. Recently, small nucleotide polymorphisms in NRXN1 have been associated with antipsychotic drug response in patients with schizophrenia. Based on previous suggestive evidence of an impact on clozapine response in patients with schizophrenia, we conducted an association study of NRXN1 polymorphisms (rs12467557 and rs10490162) with antipsychotic treatment response in 54 patients with schizophrenia in a double blind, placebo-controlled NIMH inpatient crossover trial and examined for association with risk for schizophrenia in independent case-control and family-based clinical cohorts. Pharmacogenetic analysis in the placebo controlled trial revealed significant association of rs12467557and rs10490162 with drug response, whereby individuals homozygous for the A allele, at either SNP, showed significant improvement in positive symptoms, general psychopathology, thought disturbance, and negative symptoms, whereas patients carrying the G allele showed no overall response. Although we did not find evidence of the same NRXN1 SNPs being associated with results of the NIMH sponsored CATIE trial, other SNPs showed weakly positive signals. The family and case-control analyses for schizophrenia risk were negative. Our results provide confirmatory evidence of genetically determined differences in drug response in patients with schizophrenia related to NRXN1 variation. Furthermore, these findings potentially implicate NRXN1 in the therapeutic actions of antipsychotic drugs. C1 [Jenkins, Aaron; Apud, Jose A.; Decot, Heather] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Jenkins, Aaron] Univ Kentucky, Coll Med, Lexington, KY USA. [Zhang, Fengyu; Weinberger, Daniel R.] Johns Hopkins Univ, Lieber Inst Brain Dev, Baltimore, MD USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Law, Amanda J.] Univ Colorado, Dept Psychiat, Sch Med, Aurora, CO 80045 USA. [Weinberger, Daniel R.; Law, Amanda J.] Univ Colorado, Dept Cell & Dev Biol, Sch Med, Aurora, CO 80045 USA. RP Law, AJ (reprint author), Univ Colorado, Dept Psychiat, Sch Med, Mailstop 8344,RC1 North,RM 8101, Aurora, CO 80045 USA. EM amanda.law@ucdenver.edu OI Law, Amanda/0000-0002-2574-1564 FU Intramural Research Program of the National Institutes of Mental Health, National Institutes of Health FX This work was supported by funds from the Intramural Research Program of the National Institutes of Mental Health, National Institutes of Health. We thank Bhaskar Kolachana for genotyping of the NIMH samples. NR 52 TC 10 Z9 10 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2014 VL 39 IS 9 BP 2170 EP 2178 DI 10.1038/npp.2014.65 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AL5ML UT WOS:000339177800014 PM 24633560 ER PT J AU Lindsey, JC Hughes, MD Violari, A Eshleman, SH Abrams, EJ Bwakura-Dangarembizi, M Barlow-Mosha, L Kamthunzi, P Sambo, PM Cotton, MF Moultrie, H Khadse, S Schimana, W Bobat, R Zimmer, B Petzold, E Mofenson, LM Jean-Philippe, P Palumbo, P AF Lindsey, Jane C. Hughes, Michael D. Violari, Avy Eshleman, Susan H. Abrams, Elaine J. Bwakura-Dangarembizi, Mutsa Barlow-Mosha, Linda Kamthunzi, Portia Sambo, Pauline M. Cotton, Mark F. Moultrie, Harry Khadse, Sandhya Schimana, Werner Bobat, Raziya Zimmer, Bonnie Petzold, Elizabeth Mofenson, Lynne M. Jean-Philippe, Patrick Palumbo, Paul CA P1060 Study Team TI Predictors of Virologic and Clinical Response to Nevirapine versus Lopinavir/Ritonavir-based Antiretroviral Therapy in Young Children With and Without Prior Nevirapine Exposure for the Prevention of Mother-to-child HIV Transmission SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE pediatrics; antiretroviral therapy; clinical trials; Africa; prevention of mother-to-child transmission ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-1-INFECTED CHILDREN; INFECTED CHILDREN; ZIDOVUDINE; TRIAL; HIVNET-012; REGIMENS; INFANTS; DISEASE; COUNT AB Background: In a randomized trial comparing nevirapine (NVP)-based versus lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART) in HIV-infected children [primary endpoint discontinuation of study treatment for any reason or virologic failure by week 24] aged 2 months to 3 years, we assessed whether clinical, virologic, immunologic and safety outcomes varied by prior single-dose NVP exposure (PrNVP) for prevention of mother-to-child HIV transmission and other covariates. Methods: Efficacy was assessed by time to ART discontinuation or virologic failure, virologic failure/death and death; safety by time to ART discontinuation because of a protocol-defined toxicity and first >= grade 3 adverse event; immunology and growth by changes in CD4%, weight/height World Health Organization z-scores from entry to week 48. Cox proportional hazards and linear regression models were used to test whether treatment differences depended on PrNVP exposure and other covariates. Results: Over a median follow up of 48 (PrNVP) and 72 (no PrNVP) weeks, there was no evidence of differential treatment effects by PrNVP exposure or any other covariates. LPV/r-based ART was superior to NVP-based ART for efficacy and safety outcomes; however, those on NVP had larger improvements in CD4%, weight and height z-scores. Lower pretreatment CD4% and higher HIV-1 RNA levels were associated with reduced efficacy, lower pretreatment CD4% with shorter time to ART discontinuation because of a protocol-defined toxicity, and no PrNVP with shorter time to first grade >= 3 adverse event. Conclusions: Differences between LPV/r and NVP ART in efficacy, safety, immunologic and growth outcomes did not depend on PrNVP exposure, prior breast-feeding, sex, HIV-1 subtype, age, pretreatment CD4%, HIV-1 RNA or World Health Organization disease stage. This finding should be considered when selecting an ART regimen for young children. C1 [Lindsey, Jane C.; Hughes, Michael D.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Violari, Avy] Univ Witwatersrand, Perinatal HIV Res Unit, Chris Hani Baragwanath Hosp, Johannesburg, South Africa. [Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Abrams, Elaine J.] Columbia Univ, Dept Epidemiol, ICAP, Mailman Sch Publ Hlth, New York, NY USA. [Abrams, Elaine J.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Bwakura-Dangarembizi, Mutsa] Univ Zimbabwe, Coll Hlth Sci, Dept Paediat & Child Hlth, Harare, Zimbabwe. [Barlow-Mosha, Linda] Makerere Univ Johns Hopkins Univ Res Collaborat, Kampala, Uganda. [Kamthunzi, Portia] Univ North Carolina Project, Lilongwe, Malawi. [Sambo, Pauline M.] Univ Teaching Hosp, Lusaka, Zambia. [Cotton, Mark F.] Univ Stellenbosch, Tygerberg Childrens Hosp, Div Paediat & Infect Dis, ZA-7505 Tygerberg, South Africa. [Moultrie, Harry] Univ Witwatersrand, Reprod Hlth & HIV Inst, Fac Hlth Sci, Johannesburg, South Africa. [Khadse, Sandhya] BJ Med Coll, Dept Pediat, Pune, Maharashtra, India. [Khadse, Sandhya] Sassoon Gen Hosp, Pune, Maharashtra, India. [Schimana, Werner] Duke Univ Kilimanjaro Christian Med Ctr Collabora, Moshi, Tanzania. [Bobat, Raziya] Univ KwaZulu Natal, Dept Paediat & Child Hlth, Nelson R Mandela Sch Med, Durban, South Africa. [Zimmer, Bonnie] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Petzold, Elizabeth] Social & Sci Syst, Durham, NC USA. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, Rockville, MD USA. [Jean-Philippe, Patrick] HJF DAIDS, Bethesda, MD USA. [Palumbo, Paul] Geisel Sch Med Dartmouth, Div Infect Dis & Int Hlth, Lebanon, NH USA. RP Lindsey, JC (reprint author), Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, 651 Huntington Ave, Boston, MA 02115 USA. EM lindsey@sdac.harvard.edu FU National Institute of Allergies and Infectious Diseases; National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200800014C]; Statistical and Data Analysis Center at Harvard School of Public Health, under the NIAID [5 U01 AI41110]; Pediatric AIDS Clinical Trials Group; IMPAACT Group [1 U01 AI068616]; Abbott Diagnostics FX Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID; U01 AI068632) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health. This project was funded in part with Federal funds from the National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272200800014C. This work was supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the NIAID cooperative agreement #5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group and #1 U01 AI068616 with the IMPAACT Group.; Boehringer Ingelheim, Abbott and GlaxoSmithKline provided the antiretroviral agents used in the study. M. D. H. reports having been a paid member of clinical trial data monitoring committees for Boehringer Ingelheim, Medicines Development, Pfizer and Tibotec. S. H. E. received an honorarium from Abbott Laboratories (distributor of the ViroSeq Genotyping System) in 2009 for an invited presentation at a symposium sponsored by Abbott Diagnostics and collaborates with investigators from Abbott Diagnostics on research studies. H. M. has conducted clinical trials for GlaxoSmithKline, ViiV Healthcare and Tibotec in the last 3 years. However, these were unrelated to the current publication. A Violari received an honorarium for a lecture at Abbott in 2009. NR 17 TC 4 Z9 4 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD AUG PY 2014 VL 33 IS 8 BP 846 EP 854 DI 10.1097/INF.0000000000000337 PG 9 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA AL6WY UT WOS:000339275500019 PM 25222305 ER PT J AU Siberry, GK Patel, K Pinto, JA Puga, A Mirza, A Miller, TL Van Dyke, RB AF Siberry, George K. Patel, Kunjal Pinto, Jorge A. Puga, Ana Mirza, Ayesha Miller, Tracie L. Van Dyke, Russell B. CA Pediat HIV AIDS Cohort Study TI Elevated Aspartate Aminotransferase-to-Platelet Ratio Index in Perinatally HIV-Infected Children in the United States SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE HIV; liver; APRI ID LIVER FIBROSIS; HEPATITIS-C; RISK-FACTORS; PREVALENCE; PERFORMANCE; PREDICTORS; DISEASE; MARKER AB Elevated aspartate aminotransferase-to-platelet ratio index may signal liver fibrosis. Among 397 US children with perinatal HIV infection, at baseline was >1.5 in 0.8% [95% confidence interval (CI), 0.2-2.2%) and >0.5 in 6.5% (95% CI, 4.3-9.4%); incidence on study was 0.5 (95% CI, 0.2-1.2) and 6.4 (95% CI, 4.8-8.3) per 100 person-years, respectively. Long-term liver outcomes after perinatal HIV infection warrant further study. C1 [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, Bethesda, MD 20892 USA. [Patel, Kunjal] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Patel, Kunjal] Harvard Univ, Sch Publ Hlth, CBAR, Boston, MA 02115 USA. [Pinto, Jorge A.] Univ Fed Minas Gerais, Dept Pediat, Belo Horizonte, MG, Brazil. [Puga, Ana] Childrens Diagnost & Treatment Ctr Inc, Ft Lauderdale, FL USA. [Mirza, Ayesha] Univ Florida, Dept Pediat, Jacksonville, FL USA. [Miller, Tracie L.] Univ Miami, Miller Sch Med, Dept Pediat, Div Pediat Clin Res, Miami, FL 33136 USA. [Van Dyke, Russell B.] Tulane Univ, Dept Pediat, Hlth Sci Ctr, New Orleans, LA 70118 USA. RP Siberry, GK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, 6100 Execut Blvd,Room 4B11H, Bethesda, MD 20892 USA. EM siberryg@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; Office of AIDS Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders; National Heart Lung and Blood Institute; National Institute of Dental and Craniofacial Research; National Institute on Alcohol Abuse and Alcoholism; Harvard University School of Public Health [HD052102, 3 U01 HD052102-05S1, 3 U01 HD052102-06S3]; Tulane University School of Medicine [HD052104, 3U01HD052104-06S1] FX The Pediatric HIV/AIDS Cohort Study (PHACS) was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and Craniofacial Research and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard University School of Public Health (HD052102, 3 U01 HD052102-05S1, 3 U01 HD052102-06S3; Principal Investigator: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104, 3U01HD052104-06S1; Principal Investigator: Russell Van Dyke; Co-Principal Investigator: Kenneth Rich; Project Director: Patrick Davis). NR 13 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD AUG PY 2014 VL 33 IS 8 BP 855 EP 857 DI 10.1097/INF.0000000000000348 PG 3 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA AL6WY UT WOS:000339275500020 PM 25222306 ER PT J AU Langaee, TY Zhu, HJ Wang, XW El Rouby, N Markowitz, JS Goldstein, JA Johnson, JA AF Langaee, Taimour Y. Zhu, Hao-Jie Wang, Xinwen El Rouby, Nihal Markowitz, John S. Goldstein, Joyce A. Johnson, Julie A. TI The influence of the CYP2C19*10 allele on clopidogrel activation and CYP2C19(star)2 genotyping SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE clopidogrel; CYP2C19*10; genotyping; pharmacogenetic; pharmacokinetic ID IDENTIFICATION; INHIBITION; RESIDUES; CYP2C9; 2C19 AB Background/objectives The polymorphic hepatic enzyme CYP2C19 catalyzes the metabolism of clinically important drugs such as clopidogrel, proton-pump inhibitors, and others and clinical pharmacogenetic testing for clopidogrel is increasingly common. The CYP2C19(star)10 single-nucleotide polymorphism (SNP) is located 1 bp upstream the CYP2C19*2 SNP. Despite the low frequency of the CYP2C19(star)10 allele, its impact onmetabolism of CYP2C19 substrates and CYP2C19*2 genotyping makes it an important SNP to consider for pharmacogenetic testing of CYP2C19. However, the effect of the CYP2C19(star)10 allele on clopidogrel metabolism has not been explored to date. Methods We measured the enzymatic activity of the CYP2C19.10 protein against clopidogrel. DNA samples from two clinical studies were genotyped for CYP2C19*2 and (star)10 by pyrosequencing genotyping method. Results The catalytic activity of CYP2C19.10 in the biotransformation of clopidogrel and 2-oxo-clopidogrel was significantly decreased relative to the wild-type CYP2C19.1B. We also reported that the CYP2C19*10 SNP interferes with the CYP2C19*2 TaqMan genotyping assay, resulting in miscalling of CYP2C19(star)10/*2 as CYP2C19*2/*2. Conclusions Our data provide evidence that CYP2C19.10 variant partially metabolizes clopidogrel and 2-oxoclopidogrel, and the presence of CYP2C19*10 allele affects the CY2C19*2 TaqMan genotyping assay and results in misclassification of CYP2C19(star)10/*2 as CYP2C19*2/*2. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Langaee, Taimour Y.; Zhu, Hao-Jie; Wang, Xinwen; El Rouby, Nihal; Markowitz, John S.; Johnson, Julie A.] Univ Florida, Ctr Pharmacogen, Dept Pharmacotherapy & Translat Res, Coll Pharm, Gainesville, FL 32610 USA. [Zhu, Hao-Jie; Wang, Xinwen] Univ Michigan, Coll Pharm, Dept Clin Social & Adm Sci, Ann Arbor, MI 48109 USA. [Wang, Xinwen] China Pharmaceut Univ, Key Lab Drug Metab & Pharmacokinet, Nanjing, Jiangsu, Peoples R China. [Goldstein, Joyce A.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Johnson, JA (reprint author), Univ Florida, Ctr Pharmacogen, Dept Pharmacotherapy & Translat Res, POB 100486, Gainesville, FL 32610 USA. EM johnson@cop.ufl.edu FU Intramural Research Program of the National Institute of Environmental Health Sciences [ES021024-32]; [NIAID 1R21AI096345]; [UL1RR029890-03S3 (UL1TR000064)]; [U01 GM074492] FX This work was partially supported by the Intramural Research Program of the National Institute of Environmental Health Sciences (Project ES021024-32) (J.A.G.) and partially by grants NIAID 1R21AI096345 (J.S.M. and H.-J.Z.), UL1RR029890-03S3 (UL1TR000064) (J. A. J.), U01 GM074492 (J. A. J. and T.Y.L.), and U01 GM074492 (J. A. J. and T.Y.L.). NR 16 TC 3 Z9 3 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1744-6872 EI 1744-6880 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD AUG PY 2014 VL 24 IS 8 BP 381 EP 386 DI 10.1097/FPC.0000000000000068 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA AL5II UT WOS:000339166700001 PM 24945780 ER PT J AU Akpudo, H Aleksic, B Alkelai, A Burton, C Roa, TC Chen, DTW Cheng, MC Cocchi, E Davis, LK Giori, IG Hubbard, LM Merikangas, A Moily, NS Okewoleu, A Olfson, E Pappa, I Reitt, M Singh, AB Steinberg, J Strohmaier, J Ting, TT van Hulzen, KJE O'Shea, A DeLisi, LE AF Akpudo, Hilary Aleksic, Branko Alkelai, Anna Burton, Christie Roa, Tania Carillo Chen, David T. W. Cheng, Min-Chih Cocchi, Enrico Davis, Lea K. Giori, Isabele G. Hubbard, Leon M. Merikangas, Alison Moily, Nagaraj S. Okewoleu, Adeniran Olfson, Emily Pappa, Irene Reitt, Markus Singh, Ajeet B. Steinberg, Julia Strohmaier, Jana Ting, Te-Tien van Hulzen, Kimm J. E. O'Shea, Anne DeLisi, Lynn E. TI Summaries of oral sessions at the XXI World Congress of Psychiatric Genetics, Boston, Massachusetts, 17-21 October 2013: state of the field SO PSYCHIATRIC GENETICS LA English DT Article DE commercial DNA testing; DNA; International Society of Psychiatric Genetics; post-traumatic stress disorder; schizophrenia; sequencing; substance abuse; World Congress of Psychiatric Genetics ID GENOME-WIDE ASSOCIATION; POSTTRAUMATIC-STRESS-DISORDER; DEFICIT HYPERACTIVITY DISORDER; RICH-CLUB ORGANIZATION; NICOTINE DEPENDENCE; BIPOLAR-DISORDER; INCIDENTAL FINDINGS; ALCOHOL DEPENDENCE; ALZHEIMER-DISEASE; RECEPTOR GENE AB The XXI World Congress of Psychiatric Genetics (WCPG), sponsored by the International Society of Psychiatric Genetics (ISPG), took place in Boston, Massachusetts, on 17-21 October 2013. Approximately 900 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by student travel awardees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Akpudo, Hilary] Meharry Med Coll, Nashville, TN 37208 USA. [Chen, David T. W.] NIMH, Human Genet Branch, NIH, Bethesda, MD 20892 USA. [Davis, Lea K.] Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA. [Olfson, Emily] Washington Univ, Med Ctr, Sch Med, St Louis, MO USA. [O'Shea, Anne; DeLisi, Lynn E.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Brockton, MA 02301 USA. [Burton, Christie] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Aleksic, Branko] Nagoya Univ, Grad Sch Med, Dept Psychiat, Nagoya, Aichi 4648601, Japan. [Alkelai, Anna] Weizmann Inst Sci, IL-76100 Rehovot, Israel. [Roa, Tania Carillo] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Reitt, Markus] Univ Gottingen, Univ Med Ctr, Sect Psychiat Genet, D-37073 Gottingen, Germany. [Strohmaier, Jana] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Heidelberg, Germany. [Cheng, Min-Chih] Taipei Vet Gen Hosp, Yuli Branch, Yuli Mental Hlth Res Ctr, Dept Psychiat, Yuli, Taiwan. [Ting, Te-Tien] Natl Taiwan Univ, Coll Publ Hlth, Inst Epidemiol & Prevent Med, Taipei 10764, Taiwan. [Cocchi, Enrico] Univ Bologna, Dept Biomed & Neuromotor Sci DIBINEM, Inst Psychiat, Bologna, Italy. [Giori, Isabele G.] Univ Fed Fluminense, Dept Gen Biol, Rio De Janeiro, Brazil. [Hubbard, Leon M.] Cardiff Univ, Inst Psychol Med & Clin Neurosci, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales. [Steinberg, Julia] Univ Oxford, Dept Physiol Anat & Genet, Med Res Council Funct Genom Unit, Oxford, England. [Steinberg, Julia] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Merikangas, Alison] St James Hosp, Trinity Ctr Hlth Sci, Trinity Coll Dublin, Dept Psychiat, Dublin 8, Ireland. [Merikangas, Alison] St James Hosp, Trinity Ctr Hlth Sci, Trinity Coll Dublin, Neuropsychiat Genet Res Grp, Dublin 8, Ireland. [Moily, Nagaraj S.] Natl Inst Mental Hlth & Neurosci, Neurobiol Res Ctr, Mol Genet Lab, Abeokuta, Nigeria. [Okewoleu, Adeniran] Neuropsychiat Hosp, Abeokuta, Nigeria. [Pappa, Irene] Erasmus Univ, Sch Pedag & Educ Sci, Rotterdam, Netherlands. [Pappa, Irene] Erasmus Univ, Med Ctr, Generat Study Grp R, Rotterdam, Netherlands. [Pappa, Irene] Erasmus Univ, Med Ctr, Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands. [van Hulzen, Kimm J. E.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Singh, Ajeet B.] Deakin Univ, Sch Med, Geelong, Vic 3217, Australia. RP DeLisi, LE (reprint author), Harvard Univ, Sch Med, Brockton VA Boston Healthcare Syst, 940 Belmont St, Brockton, MA 02301 USA. EM delisi76@aol.com RI Aleksic, Branko/G-1540-2011; OI Pappa, Irene/0000-0003-4936-5791; Aleksic, Branko/0000-0001-8982-4580; Steinberg, Julia/0000-0002-0585-2312; Cocchi, Enrico/0000-0002-7532-956X FU NIMH; NIDA [R13MH060596, R13DA022792] FX This report was made possible by grants from NIMH and NIDA: R13MH060596 and R13DA022792. Each summary is the subjective understanding of the rapporteur for each session. The data reported are as heard during the presentation and where possible; all statements have been checked with the speaker for accuracy. However, the speakers are not responsible for any of the information contained in this report. NR 81 TC 4 Z9 4 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8829 EI 1473-5873 J9 PSYCHIAT GENET JI Psychiatr. Genet. PD AUG PY 2014 VL 24 IS 4 BP 125 EP 150 DI 10.1097/YPG.0000000000000043 PG 26 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA AL2BM UT WOS:000338930800001 PM 24912047 ER PT J AU Tucker, CA Cieza, A Riley, AW Stucki, G Lai, JS Ustun, TB Kostanjsek, N Riley, W Cella, D Forrest, CB AF Tucker, Carole A. Cieza, Alarcos Riley, Anne W. Stucki, Gerold Lai, Jin Shei Ustun, T. Bedirhan Kostanjsek, Nenad Riley, William Cella, David Forrest, Christopher B. TI Concept Analysis of the Patient Reported Outcomes Measurement Information System (PROMISA (R)) and the International Classification of Functioning, Disability and Health (ICF) SO QUALITY OF LIFE RESEARCH LA English DT Article DE Health; PROMIS; ICF; Self-report; Outcomes; Functioning ID QUALITY-OF-LIFE; DEFINITIONS AB The Patient Reported Outcomes Measurement Information System (PROMIS (A (R)) ) is a US National Institutes of Health initiative that has produced self-report outcome measures, using a framework of physical, mental, and social health defined by the World Health Organization in 1948 (WHO, in Preamble to the Constitution of the World Health Organization as adopted by the International Health Conference, New York, 1948). The World Health Organization's International Classification of Functioning, Disability and Health (ICF) is a comprehensive classification system of health and health-related domains that was put forward in 2001. The purpose of this report is to compare and contrast PROMIS and ICF conceptual frameworks to support mapping of PROMIS instruments to the ICF classification system . We assessed the objectives and the classification schema of the PROMIS and ICF frameworks, followed by content analysis to determine whether PROMIS domain and sub-domain level health concepts can be linked to the ICF classification. Both PROMIS and ICF are relevant to all individuals, irrespective of the presence of health conditions, person characteristics, or environmental factors in which persons live. PROMIS measures are intended to assess a person's experiences of his or her health, functional status, and well-being in multiple domains across physical, mental, and social dimensions. The ICF comprehensively describes human functioning from a biological, individual, and social perspective. The ICF supports classification of health and health-related states such as functioning, but is not a specific measure or assessment of health, per se. PROMIS domains and sub-domain concepts can be meaningfully mapped to ICF concepts. Theoretical and conceptual similarities support the use of PROMIS instruments to operationalize self-reported measurement for many body function, activity and participation ICF concepts, as well as several environmental factor concepts. Differences observed in PROMIS and ICF conceptual frameworks provide a stimulus for future research and development. C1 [Tucker, Carole A.] Temple Univ, Coll Hlth Profess & Social Work, Philadelphia, PA 19140 USA. [Cieza, Alarcos] Univ Southampton, Dept Psychol, Southampton SO9 5NH, Hants, England. [Cieza, Alarcos; Stucki, Gerold] WHO Collaborating Ctr Family Int Classificat Germ, ICF Res Branch, Nottwil, Switzerland. [Riley, Anne W.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Populat & Family Hlth Sci, Baltimore, MD USA. [Stucki, Gerold] Swiss Parapleg Res, Nottwil, Switzerland. [Lai, Jin Shei; Cella, David] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Ustun, T. Bedirhan; Kostanjsek, Nenad] WHO, CTS Team, CH-1211 Geneva, Switzerland. [Riley, William] NCI, NIH, Bethesda, MD 20892 USA. [Forrest, Christopher B.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Forrest, Christopher B.] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Forrest, Christopher B.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. RP Tucker, CA (reprint author), Temple Univ, Coll Hlth Profess & Social Work, 3307 North Broad St, Philadelphia, PA 19140 USA. EM tuckerc@temple.edu NR 16 TC 10 Z9 10 U1 0 U2 17 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD AUG PY 2014 VL 23 IS 6 BP 1677 EP 1686 DI 10.1007/s11136-014-0622-y PG 10 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AL6YU UT WOS:000339280700002 PM 24500657 ER PT J AU Himes, SK LaGasse, LL Derauf, C Newman, E Smith, LM Arria, AM Della Grotta, SA Dansereau, LM Abar, B Neal, CR Lester, BM Huestis, MA AF Himes, Sarah K. LaGasse, Linda L. Derauf, Chris Newman, Elana Smith, Lynne M. Arria, Amelia M. Della Grotta, Sheri A. Dansereau, Lynne M. Abar, Beau Neal, Charles R. Lester, Barry M. Huestis, Marilyn A. TI Risk of Neurobehavioral Disinhibition in Prenatal Methamphetamine-Exposed Young Children With Positive Hair Toxicology Results SO THERAPEUTIC DRUG MONITORING LA English DT Article DE methamphetamine; hair; children; prenatal drug exposure; toxicology ID SUBSTANCE USE DISORDER; LIFE-STYLE IDEAL; INFANT DEVELOPMENT; PREGNANT-WOMEN; SIMULTANEOUS QUANTIFICATION; BEHAVIOR PROBLEMS; EARLY ADVERSITY; DRUG EXPOSURE; CHILDHOOD; AGE AB Background: The objective was to evaluate the effects of prenatal methamphetamine exposure (PME) and postnatal drug exposures identified by child hair analysis on neurobehavioral disinhibition at 6.5 years of age. Methods: Mother-infant pairs were enrolled in the Infant Development, Environment, and Lifestyle (IDEAL) Study in Los Angeles, Honolulu, Tulsa, and Des Moines. PME was determined by maternal self-report and/or positive meconium results. At the 6.5-year follow-up visit, hair was collected and analyzed for methamphetamine, tobacco, cocaine, and cannabinoid markers. Child behavioral and executive function test scores were aggregated to evaluate child neurobehavioral disinhibition. Hierarchical linear regression models assessed the impact of PME, postnatal substances, and combined PME with postnatal drug exposures on the child's neurobehavioral disinhibition aggregate score. Past year caregiver substance use was compared with child hair results. Results: A total of 264 children were evaluated. Significantly more PME children (n = 133) had hair positive for methamphetamine/amphetamine (27.1% versus 8.4%) and nicotine/cotinine (38.3% versus 25.2%) than children without PME (n = 131). Overall, no significant differences in analyte hair concentrations were noted between groups. Significant differences in behavioral and executive function were observed between children with and without PME. No independent effects of postnatal methamphetamine or tobacco exposure, identified by positive hair test, were noted and no additional neurobehavioral disinhibition was observed in PME children with postnatal drug exposures, as compared with PME children without postnatal exposure. Conclusions: Child hair testing offered a noninvasive means to evaluate postnatal environmental drug exposure, although no effects from postnatal drug exposure alone were seen. PME, alone and in combination with postnatal drug exposures, was associated with behavioral and executive function deficits at 6.5 years. C1 [Himes, Sarah K.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [LaGasse, Linda L.; Della Grotta, Sheri A.; Dansereau, Lynne M.; Lester, Barry M.] Brown Univ, Warren Alpert Med Sch, Women & Infants Hosp Rhode Isl, Brown Ctr Study Children Risk,Dept Pediat, Providence, RI 02912 USA. [Derauf, Chris] Mayo Clin, Div Community Pediat & Adolescent Med, Rochester, MN USA. [Newman, Elana] Univ Tulsa, Dept Psychol, Tulsa, OK 74104 USA. [Smith, Lynne M.] Univ Calif Los Angeles, David Geffen Sch Med, Harbor UCLA Med Ctr, Dept Pediat,LABioMed Inst, Torrance, CA USA. [Arria, Amelia M.] Univ Maryland, Dept Family Sci, Ctr Young Adult Hlth & Dev, Sch Publ Hlth, College Pk, MD 20742 USA. [Abar, Beau] Univ Rochester, Med Ctr, Dept Emergency Med & Psychiat, Rochester, NY 14642 USA. [Neal, Charles R.] Univ Hawaii, John A Burns Sch Med, Dept Pediat, Honolulu, HI 96822 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov OI Arria, Amelia/0000-0002-6360-9265 FU National Institute on Drug Abuse (NIDA) [R01DA014948]; National Center for Research Resources [UL1TR000124, 5P20RR11091]; NIDA Intramural Research Program, National Institutes of Health FX Supported by National Institute on Drug Abuse (NIDA) grant R01DA014948, also in part by National Center for Research Resources Grants UL1TR000124 and 5P20RR11091, and by the NIDA Intramural Research Program, National Institutes of Health. NR 45 TC 2 Z9 2 U1 5 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 EI 1536-3694 J9 THER DRUG MONIT JI Ther. Drug Monit. PD AUG PY 2014 VL 36 IS 4 BP 535 EP 543 PG 9 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA AL6OI UT WOS:000339251800017 PM 24518561 ER PT J AU Demberg, T Mohanram, V Venzon, D Robert-Guroff, M AF Demberg, Thorsten Mohanram, Venkatramanan Venzon, David Robert-Guroff, Marjorie TI Phenotypes and distribution of mucosal memory B-cell populations in the SIV/SHIV rhesus macaque model SO CLINICAL IMMUNOLOGY LA English DT Article DE SIV/SHIV rhesus macaque model; Mucosal memory B cell phenotypes and distribution; Homing markers; Plasmablasts/plasma cells ID IMMUNODEFICIENCY VIRUS-INFECTION; IGA-SECRETING CELLS; HUMAN PLASMA-CELLS; GASTROINTESTINAL-TRACT; PERIPHERAL-BLOOD; CHEMOKINE RECEPTORS; IMMUNE-RESPONSES; DENDRITIC CELLS; SIV INFECTION; ANIMAL-MODELS AB As vaccine-elicited antibodies have now been associated with HIV protective efficacy, a thorough understanding of mucosal and systemic B-cell development and maturation is needed. We phenotyped mucosal memory B-cells, investigated isotype expression and homing patterns, and defined plasmablasts and plasma cells at three mucosal sites (duodenum, jejunum and rectum) in rhesus macaques, the commonly used animal model for pre-clinical vaccine studies. Unlike humans, macaque mucosal memory B-cells lacked CD27 expression; only two sub-populations were present: naive (CD21(+)CD27(-)) and tissue-like (CD21(-)CD27(-)) memory. Similar to humans, IgA was the dominant isotype expressed. The homing markers CXCR4; CCR6, CCR9 and alpha 4 beta 7 were differentially expressed between nave and tissue-like memory B-cells. Mucosal plasmablasts were identified as CD19(+)CD20(+/-)HLA-DR(+)Ki-67(+)IRF4(+)CD138(+/-) and mucosal plasma cells as CD19(+)CD20(-)FILA-DR(-)Ki-67(-)IRF4(+)CD138(+). Both populations were CD39(+/-)CD27(-). Plasma cell phenotype was confirmed by spontaneous IgA secretion by ELISpot of positively-selected cells and J-chain expression by real-time PCR. Duodenal, jejunal and rectal samples were similar in B-cell memory phenotype, isotype expression, homing receptors and plasmablast/plasma cell distribution among the three tissues. Thus rectal biopsies adequately monitor B-cell dynamics in the gut mucosa, and provide a critical view of mucosal B-cell events associated with development of vaccine-elicited protective immune responses and SIV/SHIV pathogenesis and disease control. Published by Elsevier Inc. C1 [Demberg, Thorsten; Mohanram, Venkatramanan; Robert-Guroff, Marjorie] NCI, Vaccine Branch, Sect Immune Biol Retroviral Infect, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. RP Robert-Guroff, M (reprint author), NCI, NIH, Bldg 41,Room D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute FX We thank Deborah Weiss and James Treece (ABL) and Jeremy Smedley and Mercy Gathuka (NIH Animal Facility) for the animal care and technical procedures; Nancy Miller (DAIDS, NIAID) and Ranajit Pal (ABL) for the provision of animal samples, and Kathy McKinnon (NCI Vaccine Branch FACS Core) for the flow cytometry support. The following reagents were obtained through the NIH Nonhuman Primate Reagent Resource Program: alpha 4 beta 7 antibody. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 62 TC 11 Z9 11 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 EI 1521-7035 J9 CLIN IMMUNOL JI Clin. Immunol. PD AUG PY 2014 VL 153 IS 2 BP 264 EP 276 DI 10.1016/j.clim.2014.04.017 PG 13 WC Immunology SC Immunology GA AL0MQ UT WOS:000338821400003 PM 24814239 ER PT J AU Vargas-Inchaustegui, DA Tuero, I Mohanram, V Musich, T Pegu, P Valentin, A Sui, Y Rosati, M Bear, J Venzon, DJ Kulkarni, V Alicea, C Pilkington, GR Liyanage, NPM Demberg, T Gordon, SN Wang, YC Hogg, AE Frey, B Patterson, LJ DiPasquale, J Montefiori, DC Sardesai, NY Reed, SG Berzofsky, JA Franchini, G Felber, BK Pavlakis, GN Robert-Guroff, M AF Vargas-Inchaustegui, Diego A. Tuero, Iskra Mohanram, Venkatramanan Musich, Thomas Pegu, Poonam Valentin, Antonio Sui, Yongjun Rosati, Margherita Bear, Jenifer Venzon, David J. Kulkarni, Viraj Alicea, Candido Pilkington, Guy R. Liyanage, Namal P. M. Demberg, Thorsten Gordon, Shari N. Wang, Yichuan Hogg, Alison E. Frey, Blake Patterson, L. Jean DiPasquale, Janet Montefiori, David C. Sardesai, Niranjan Y. Reed, Steven G. Berzofsky, Jay A. Franchini, Genoveffa Felber, Barbara K. Pavlakis, George N. Robert-Guroff, Marjorie TI Humoral immunity induced by mucosal and/or systemic SIV-specific vaccine platforms suggests novel combinatorial approaches for enhancing responses SO CLINICAL IMMUNOLOGY LA English DT Article DE Simian Immunodeficiency Virus; Poxvitus-, adenovirus-, and DNA-based vaccines; Mucosal and systemic humoral immunity; Memory B cells; Functional antibody activities ID SIMIAN IMMUNODEFICIENCY VIRUS; T-CELL RESPONSES; RHESUS MACAQUES; ENVELOPE PROTEIN; HIV-1 VACCINE; NEUTRALIZING ANTIBODIES; SIVMAC251 CHALLENGE; DNA VACCINATION; IGA SYNTHESIS; HIGH-AVIDITY AB Combinatorial HIV/SIV vaccine approaches targeting multiple arms of the immune system might improve protective efficacy. We compared SIV-specific humoral immunity induced in rhesus macaques by five vaccine regimens. Systemic regimens included ALVAC-SIVenv priming and Env boosting (ALVAC/Env); DNA immunization; and DNA plus Env co-immunization (DNA&Env). RepAd/Env combined rnucosal replication-competent Ad-env priming with systemic Env boosting. A Peptide/Env regimen, given solely intrarectally, included HIV/SIV peptides followed by MVA-env and Env boosts. Serum antibodies mediating neutralizing, phagocytic and ADCC activities were induced by ALVAC/Env, RepAd/Env and DNA&Env vaccines. Memory B cells and plasma cells were maintained in the bone marrow. RepAd/Env vaccination induced early SIV-specific IgA in rectal secretions before Env boosting, although mucosal IgA and IgG responses were readily detected at necropsy in ALVAC/Env, RepAd/Env, DNA&Env and DNA vaccinated animals. Our results suggest that combined Rep Ad priming with ALVAC/Env or DNA&Env regimen boosting might induce potent, functional, long-lasting systemic and mucosal Sly-specific antibodies. Published by Elsevier Inc. C1 [Vargas-Inchaustegui, Diego A.; Tuero, Iskra; Mohanram, Venkatramanan; Musich, Thomas; Demberg, Thorsten; Patterson, L. Jean; DiPasquale, Janet; Robert-Guroff, Marjorie] NCI, Immune Biol Retroviral Infect Sect, Vaccine Branch, CCR,NIH, Bethesda, MD 20892 USA. [Pegu, Poonam; Liyanage, Namal P. M.; Gordon, Shari N.; Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccine Sect, Vaccine Branch, CCR,NIH, Bethesda, MD 20892 USA. [Valentin, Antonio; Rosati, Margherita; Pavlakis, George N.] NCI, Human Retrovirus Sect, Vaccine Branch, CCR,NIH, Frederick, MD 21702 USA. [Sui, Yongjun; Wang, Yichuan; Hogg, Alison E.; Frey, Blake; Berzofsky, Jay A.] NCI, Mol Immunogenet & Vaccine Res Sect, Vaccine Branch, CCR,NIH, Bethesda, MD 20892 USA. [Bear, Jenifer; Kulkarni, Viraj; Alicea, Candido; Pilkington, Guy R.; Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, CCR,NIH, Frederick, MD 21702 USA. [Venzon, David J.] NCI, Biostat & Data Management Sect, CCR, NIH, Rockville, MD 20850 USA. [Montefiori, David C.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC 27710 USA. [Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Sardesai, Niranjan Y.] Inovio Pharmaceut Inc, Blue Bell, PA 19422 USA. [Reed, Steven G.] Infect Dis Res Inst, Seattle, WA 98102 USA. RP Robert-Guroff, M (reprint author), NCI, Vaccine Branch, CCR, NIH, 41 Medlars Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov RI Mohanram, Venkatramanan/I-3652-2016 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH); National Institute of Allergy and Infectious Diseases NIH [HHSN27201100016C] FX This work was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH) (B.K.F., G.N.P., J.A.B., G.F., M.R.G.), and National Institute of Allergy and Infectious Diseases NIH contract HHSN27201100016C (D.C.M.). G.N.P. and B.K.F. are inventors on US Government-owned patents and patent applications related to DNA vaccines and gene expression optimization. G.F. is an inventor on a US Government patent filed jointly with Sanofi Pasteur on the use of the ALVAC vector as a platform for an HIV vaccine. N.Y.S. is a full time employee of Inovio Pharmaceuticals and as such receives compensation in the form of salary and stock options. S.G.R. is a full time employee of Infectious Diseases Research Institute and as such receives compensation in the form of salary and stock options. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 6 Z9 6 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 EI 1521-7035 J9 CLIN IMMUNOL JI Clin. Immunol. PD AUG PY 2014 VL 153 IS 2 BP 308 EP 322 DI 10.1016/j.clim.2014.05.008 PG 15 WC Immunology SC Immunology GA AL0MQ UT WOS:000338821400008 PM 24907411 ER PT J AU Cui, C Yin, M Sims, J Childress, V Michel, M Piao, Y Schlessinger, D AF Cui, C. Yin, M. Sims, J. Childress, V. Michel, M. Piao, Y. Schlessinger, D. TI Cascade regulation of sweat gland development by Wnt, Eda and Shh pathways SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 07-10, 2014 CL Albuquerque, NM SP Soc Invest Dermatol C1 [Cui, C.; Yin, M.; Sims, J.; Childress, V.; Michel, M.; Piao, Y.; Schlessinger, D.] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2014 VL 134 IS 8 MA LB803 BP S2 EP S2 PG 1 WC Dermatology SC Dermatology GA AL4SW UT WOS:000339126100049 ER PT J AU Smith, SH Peredo, CE Takeda, Y Richter, K Bui, T Neil, J Aloor, H Millerman, B Therrien, J Nicodeme, E Brusq, J Viviani, F Hofland, H Jetten, A Cote-Sierra, J AF Smith, S. H. Peredo, C. E. Takeda, Y. Richter, K. Bui, T. Neil, J. Aloor, H. Millerman, B. Therrien, J. Nicodeme, E. Brusq, J. Viviani, F. Hofland, H. Jetten, A. Cote-Sierra, J. TI Topical delivery of a potent and selective ROR gamma inhibitor abrogates Th17 cytokines from human skin resident immune cells SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 07-10, 2014 CL Albuquerque, NM SP Soc Invest Dermatol C1 [Smith, S. H.; Peredo, C. E.; Richter, K.; Bui, T.; Neil, J.; Aloor, H.; Millerman, B.; Therrien, J.; Hofland, H.; Cote-Sierra, J.] GSK, Stiefel, Res Triangle Pk, NC USA. [Takeda, Y.; Jetten, A.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Nicodeme, E.; Brusq, J.; Viviani, F.] GSK, FDU, Les Ulis, France. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2014 VL 134 IS 8 MA LB805 BP S3 EP S3 PG 1 WC Dermatology SC Dermatology GA AL4SW UT WOS:000339126100053 ER PT J AU Zhou, XD Wang, JC Zou, HJ Ward, MM Weisman, MH Espitia, MG Xiao, XJ Petersdorf, E Mignot, E Martin, J Gensler, LS Scheet, P Reveille, JD AF Zhou, Xiaodong Wang, Jiucun Zou, Hejian Ward, Michael M. Weisman, Michael H. Espitia, Maribel G. Xiao, Xiangjun Petersdorf, Effie Mignot, Emmanuel Martin, Javier Gensler, Lianne S. Scheet, Paul Reveille, John D. TI MICA, a gene contributing strong susceptibility to ankylosing spondylitis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID TRIPLET REPEAT POLYMORPHISM; INFLAMMATORY-BOWEL-DISEASE; RHEUMATOID-ARTHRITIS; TRANSMEMBRANE REGION; PSORIATIC-ARTHRITIS; A MICA; ASSOCIATION; HLA-B27; PREVALENCE; ALLELE AB Objective The human major histocompatibility complex class I chain-related gene A (MICA) controls the immune process by balancing activities of natural killer cells, gamma delta T cells and alpha beta CD8 T cells, and immunosuppressive CD4 T cells. MICA is located near HLA-B on chromosome 6. Recent genomewide association studies indicate that genes most strongly linked to ankylosing spondylitis (AS) susceptibility come from the region containing HLA-B and MICA. While HLA-B27 is a well-known risk genetic marker for AS, the potential effect of linkage disequilibrium (LD) shields any associations of genes around HLA-B with AS. The aim of this study was to investigate a novel independent genetic association of MICA to AS. Methods We examined 1543 AS patients and 1539 controls from two ethnic populations by sequencing MICA and genotyping HLA-B alleles. Initially, 1070 AS patients and 1003 controls of European ancestry were used as a discovery cohort, followed by a confirmation cohort of 473 Han Chinese AS patients and 536 controls. We performed a stratified analysis based on HLA-B27 carrier status. We also conducted logistic regression with a formal interaction term. Results Sequencing of MICA identified that MICA*007:01 is a significant risk allele for AS in both Caucasian and Han Chinese populations, and that MICA*019 is a major risk allele in Chinese AS patients. Conditional analysis of MICA alleles on HLA-B27 that unshielded LD effect confirmed associations of the MICA alleles with AS. Conclusions Parallel with HLA-B27, MICA confers strong susceptibility to AS in US white and Han Chinese populations. C1 [Zhou, Xiaodong; Espitia, Maribel G.; Reveille, John D.] Univ Texas Med Sch Houston, Dept Internal Med, Div Rheumatol, Houston, TX 77030 USA. [Wang, Jiucun] Fudan Univ, Sch Life Sci, Minist Educ, Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China. [Zou, Hejian] Fudan Univ, Huashan Hosp, Dept Rheumatol, Shanghai 200433, Peoples R China. [Ward, Michael M.] NIAMS, Bethesda, MD USA. [Weisman, Michael H.] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA. [Xiao, Xiangjun; Scheet, Paul] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Petersdorf, Effie] Univ Washington, Fred Hutchinson Canc Res Ctr, Dept Med, Div Clin Res, Seattle, WA 98195 USA. [Petersdorf, Effie] Univ Washington, Div Oncol, Seattle, WA 98195 USA. [Mignot, Emmanuel] Stanford Univ, Sch Med, Dept Psychiat, Stanford, CA 94305 USA. [Martin, Javier] CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain. [Gensler, Lianne S.] Univ Calif San Francisco, Div Rheumatol, San Francisco, CA USA. RP Zhou, XD (reprint author), Univ Texas Med Sch Houston, Dept Internal Med, Div Rheumatol, 6431 Fannin St,MSB5270, Houston, TX 77030 USA. EM Xiaodong.zhou@uth.tmc.edu RI Martin, Javier/B-8141-2008 FU NIH NIAID FX NIH NIAID. NR 31 TC 5 Z9 5 U1 0 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD AUG PY 2014 VL 73 IS 8 BP 1552 EP 1557 DI 10.1136/annrheumdis-2013-203352 PG 6 WC Rheumatology SC Rheumatology GA AK8RX UT WOS:000338696800025 PM 23727634 ER PT J AU Ciccia, F Accardo-Palumbo, A Rizzo, A Guggino, G Raimondo, S Giardina, A Cannizzaro, A Colbert, RA Alessandro, R Triolo, G AF Ciccia, Francesco Accardo-Palumbo, Antonina Rizzo, Aroldo Guggino, Giuliana Raimondo, Stefania Giardina, AnnaRita Cannizzaro, Alessandra Colbert, Robert A. Alessandro, Riccardo Triolo, Giovanni TI Evidence that autophagy, but not the unfolded protein response, regulates the expression of IL-23 in the gut of patients with ankylosing spondylitis and subclinical gut inflammation SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID ENDOPLASMIC-RETICULUM; PANETH CELLS; INTESTINAL INFLAMMATION; DENDRITIC CELLS; TRANSGENIC RATS; HEAVY-CHAINS; ER STRESS; ACTIVATION; INTERLEUKIN-23; DISEASE AB Objectives Interleukin (IL)-23 has been implicated in the pathogenesis of ankylosing spondylitis (AS). The aim of the study was to clarify the mechanisms underlying the increased IL-23 expression in the gut of AS patients. Methods Consecutive gut biopsies from 30 HLA-B27(+) AS patients, 15 Crohn's disease (CD) patients and 10 normal subjects were obtained. Evidence for HLA-B27 misfolding was studied. Unfolded protein response (UPR) and autophagy were assessed by RT-PCR and immunohistochemistry. The contribution of UPR and autophagy in the regulation of IL-23 expression was evaluated in in vitro experiments on isolated lamina propria mononuclear cells (LPMCs). Results Intracellular colocalisation of SYVN1 and FHCs but not a significant overexpression of UPR genes was observed in the gut of AS patients. Conversely, upregulation of the genes involved in the autophagy pathway was observed in the gut of AS and CD patients. Immunohistochemistry showed an increased expression of LC3II, ATG5 and ATG12 but not of SQSTM1 in the ileum of AS and CD patients. LC3II was expressed among infiltrating mononuclear cells and epithelial cells resembling Paneth cells (PC) and colocalised with ATG5 in AS and CD. Autophagy but not UPR was required to modulate the expression of IL-23 in isolated LPMCs of AS patients with chronic gut inflammation, CD patients and controls. Conclusions Our data suggest that HLA-B27 misfolding occurs in the gut of AS patients and is accompanied by activation of autophagy rather than a UPR. Autophagy appears to be associated with intestinal modulation of IL-23 in AS. C1 [Ciccia, Francesco; Guggino, Giuliana; Giardina, AnnaRita; Triolo, Giovanni] Univ Palermo, Dipartimento Biomed Med Interna & Specialist, Sez Reumatol, I-90127 Palermo, Italy. [Accardo-Palumbo, Antonina; Rizzo, Aroldo; Cannizzaro, Alessandra] Osped Riuniti Villa Sofia Cervello, Palermo, Italy. [Raimondo, Stefania; Alessandro, Riccardo] Univ Palermo, Dipartimento Biopatol & Biotecnol Med & Forensi, I-90127 Palermo, Italy. [Colbert, Robert A.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Triolo, G (reprint author), Univ Palermo, Div Rheumatol, Dept Internal Med, Piazza Clin 2, I-90127 Palermo, Italy. EM giovanni.triolo@unipa.it OI Ciccia, Francesco/0000-0002-9352-1264; Giardina, Annarita/0000-0001-8414-9643; TRIOLO, GIOVANI/0000-0002-7067-6896; GUGGINO, Giuliana/0000-0003-2479-6958 FU Ministero della Universita e della Ricerca Scientifica of Italy FX This study was supported in part by a grant from Ministero della Universita e della Ricerca Scientifica of Italy. NR 42 TC 42 Z9 46 U1 3 U2 9 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD AUG PY 2014 VL 73 IS 8 BP 1566 EP 1574 DI 10.1136/annrheumdis-2012-202925 PG 9 WC Rheumatology SC Rheumatology GA AK8RX UT WOS:000338696800027 PM 23740229 ER PT J AU Laudisio, A Bandinelli, S Gemma, A Ferrucci, L Incalzi, RA AF Laudisio, Alice Bandinelli, Stefania Gemma, Antonella Ferrucci, Luigi Incalzi, Raffaele Antonelli TI Metabolic syndrome and functional ability in older age: The InCHIANTI study SO CLINICAL NUTRITION LA English DT Article DE Metabolic syndrome; Disability; Elderly; Epidemiology ID CARDIOVASCULAR RISK-FACTORS; BODY-MASS INDEX; HEART-FAILURE; REVERSE EPIDEMIOLOGY; ASSOCIATION; PREVALENCE; DISABILITY; MORTALITY; DEPRESSION; DECLINE AB Background & aims: Metabolic syndrome (MetS) is associated with incident disability in middle-aged subjects. We evaluated the association of MetS with functional ability in an older population. Methods: We enrolled 1155 participants aged 65+, derived from the InCHIANTI study, and followed for 3 years. MetS was diagnosed according to the National Cholesterol Education Program's ATP-III criteria. Functional ability was estimated using the Katz's activities of daily living (ADLs), and the Lawton and Brody for the instrumental activities of daily living (IADLs) scales. The association between disability and MetS at baseline and after follow-up was assessed by logistic regression. Results: At baseline, MetS was associated with reduced probability of ADLs disability among participants aged 74+ (OR = .33, 95% CI = .14.77; p = .010), but not in younger (5.08, 95% CI = .88-29.24; p = .069). Also, MetS was associated with reduced probability of incident ADLs disability (OR = .61, 95% CI .41-.91; p = .016), but neither with prevalent, nor incident IADLs disability. Conclusions: In older persons, MetS is associated with reduced probability of prevalent and incident ADLs disability. Whether older persons with MetS should receive treatment and whether the current diagnostic criteria for MetS apply to older individuals need further investigation. (C) 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved. C1 [Laudisio, Alice; Incalzi, Raffaele Antonelli] Campus Biomed Univ, Area Geriatria, I-00128 Rome, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. [Gemma, Antonella] Azienda Sanit Locale Roma E, UOS Accesso & Presa Car Assistenziale, Rome, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. RP Laudisio, A (reprint author), Campus Biomed Univ, Area Geriatria, Via Alvaro del Portillo 200, I-00128 Rome, Italy. EM lavoralice@gmail.com OI Antonelli Incalzi, Raffaele/0000-0003-2100-2075 FU Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336]; InCHIANTI - U.S. National Institute on Aging [N.1-AG-1-1, N.1-AG-1-2111] FX Support: The InCHIANTI study baseline (1998-2000) was supported as a targeted project (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts 263 MD 9164 and 263 MD 821336); the InCHIANTI Follow-Up 1 (2001-2003) was funded by the U.S. National Institute on Aging (Contracts N.1-AG-1-1 and N.1-AG-1-2111). NR 30 TC 5 Z9 5 U1 1 U2 4 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0261-5614 EI 1532-1983 J9 CLIN NUTR JI Clin. Nutr. PD AUG PY 2014 VL 33 IS 4 BP 626 EP 633 DI 10.1016/j.clnu.2013.08.005 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AL0IJ UT WOS:000338810300009 PM 24035348 ER PT J AU Khraiwesh, H Lopez-Dominguez, JA del Rio, LF Gutierrez-Casado, E Lopez-Lluch, G Navas, P de Cabo, R Ramsey, JJ Buron, MI Villalba, JM Gonzalez-Reyes, JA AF Khraiwesh, Husam Lopez-Dominguez, Jose A. Fernandez del Rio, Lucia Gutierrez-Casado, Elena Lopez-Lluch, Guillermo Navas, Placido de Cabo, Rafael Ramsey, Jon J. Buron, Maria I. Villalba, Jose M. Gonzalez-Reyes, Jose A. TI Mitochondrial ultrastructure and markers of dynamics in hepatocytes from aged, calorie restricted mice fed with different dietary fats SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE Calorie restriction; Dietary fat; Hepatocyte; Mitochondria; Mature/old-aged mice ID PEROXIDE PRODUCTION; LIVER-MITOCHONDRIA; LIPID COMPOSITION; OXIDATIVE STRESS; SKELETAL-MUSCLE; RHESUS-MONKEYS; FINE-STRUCTURE; PROTON LEAK; LIFE-SPAN; HEALTH AB In this paper we analyzed changes in hepatocyte mitochondrial mass and ultrastructure as well as in mitochondrial markers of fission/fusion and biogenesis in mice subjected to 40% calorie restriction (CR) for 18 months versus ad libitum-fed controls. Animals subjected to CR were separated into three groups with different dietary fats: soybean oil (also in controls), fish oil and lard. Therefore, the effect of the dietary fat under CR was studied as well. Our results show that CR induced changes in hepatocyte and mitochondrial size, in the volume fraction occupied by mitochondria, and in the number of mitochondria per hepatocyte. Also, mean number of mitochondrial cristae and lengths were significantly higher in all CR groups compared with controls. Finally, CR had no remarkable effects on the expression levels of fission and fusion protein markers. However, considerable differences in many of these parameters were found when comparing the CR groups, supporting the idea that dietary fat plays a relevant role in the modulation of CR effects in aged mice. (C) 2014 Elsevier Inc All rights reserved. C1 [Khraiwesh, Husam; Lopez-Dominguez, Jose A.; Fernandez del Rio, Lucia; Gutierrez-Casado, Elena; Buron, Maria I.; Villalba, Jose M.; Gonzalez-Reyes, Jose A.] Univ Cordoba, CeiA3, Dept Biol Celular Fisiol & Inmunol, Cordoba, Spain. [Lopez-Dominguez, Jose A.; Ramsey, Jon J.] Univ Calif Davis, VM Mol Biosci, Davis, CA 95616 USA. [Lopez-Lluch, Guillermo; Navas, Placido] Univ Pablo Olavide, CSIC, Inst Salud Carlos III, Ctr Andaluz Biol Desarrollo, Seville, Spain. [de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. RP Villalba, JM (reprint author), Univ Cordoba, CeiA3, Dept Biol Celular Fisiol & Inmunol, Campus Excelencia Intemadonal Agroalimentario, Cordoba, Spain. EM bc1gorej@uco.es RI Gonzalez-Reyes, Jose A/K-1367-2014; Lopez-Lluch, Guillermo/N-4742-2014; de Cabo, Rafael/J-5230-2016; OI Gonzalez-Reyes, Jose A/0000-0003-1918-5490; Lopez-Lluch, Guillermo/0000-0001-9830-8502; de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU NIH [1R01AG028125-01A1]; Ministerio de Economia y Competitividad; European FEDER [BFU2011-23578]; Junta de Andalucia Proyectos de Excelencia grant [P09-CVI-4887]; Junta de Andalucia Proyectos Internacionales; Junta de Andalucia [BIO-276]; University of Cordoba [BIO-276]; Spanish Ministerio de Educacion; Agencia Espanola de Cooperacion Internacional al Desarrollo FX Supported by NIH grant 1R01AG028125-01A1 (to JJR, PN and JMV), Ministerio de Economia y Competitividad and European FEDER BFU2011-23578 (to JMV), Junta de Andalucia Proyectos de Excelencia grant P09-CVI-4887 (to JMV), Junta de Andalucia Proyectos Internacionales (to JMV), and BIO-276 (Junta de Andalucia and the University of Cordoba, to JMV and EGC). JALD and LFdR were funded by predoctoral fellowships of the Spanish Ministerio de Educacion and by BIO-276. HK was funded by a predoctoral fellowship of the Agencia Espanola de Cooperacion Internacional al Desarrollo and by BIO-276. NR 49 TC 8 Z9 9 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 EI 1873-6815 J9 EXP GERONTOL JI Exp. Gerontol. PD AUG PY 2014 VL 56 SI SI BP 77 EP 88 DI 10.1016/j.exger.2014.03.023 PG 12 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA AK7KL UT WOS:000338607100010 PM 24704714 ER PT J AU Morse, RS Rojahn, J Smith, ACM AF Morse, Rebecca S. Rojahn, Johannes Smith, Ann C. M. TI Effects of Behavior Problems, Family Functioning, and Family Coping on Parent Stress in Families with a Child with Smith-Magenis Syndrome SO JOURNAL OF DEVELOPMENTAL AND PHYSICAL DISABILITIES LA English DT Article DE Smith-Magenis syndrome; Maladaptive behavior; Parent stress; Family functioning ID SYNDROME DEL 17P11.2; ASSESSMENT DEVICE; DISABILITIES; RELIABILITY; PREDICTORS AB Smith Magenis Syndrome (SMS) is a rare genetic syndrome most commonly caused by a microdeletion on chromosome 17 p11.2. It is associated with a pattern of physical, developmental, and behavioral characteristics including intellectual disability, sleep disturbance, and a variety of behavior problems. The purpose was to examine the relationship between maladaptive behaviors in children with SMS and parent stress, and to determine whether family functioning and effective parent coping strategies may alleviate the impact of child maladaptive behaviors on parent stress. Data were collected on 25 individuals with SMS ages 1.4 to 19.4 years old. Parents were interviewed using the Vineland Adaptive Behavior Scale (VABS; Sparrow et al. 1984), the Achenbach Child Behavior Checklist (CBCL; Achenbach 1991), the Family Assessment Device-General Functioning Scale (Epstein et al. 1983), the Family Crisis Oriented Personal Evaluation Scales (McCubin et al. 1991), the Parental Stress Index-3rd edition (Abidin 1995), and the Stress Index for Parents of Adolescents (Abidin 1995). Using multiple hierarchical regression analyses we found that maladaptive behaviors (CBCL internalizing and externalizing behaviors) affected parent stress; however, we also saw that parent stress was alleviated in well-functioning families. Maladaptive behaviors did not have a significant negative impact on life stress. C1 [Morse, Rebecca S.; Rojahn, Johannes] George Mason Univ, Fairfax, VA 22030 USA. [Smith, Ann C. M.] NHGRI, NIH, Bethesda, MD 20892 USA. [Morse, Rebecca S.] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. RP Morse, RS (reprint author), George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. EM rebecca@nullpointer.net NR 28 TC 2 Z9 2 U1 7 U2 21 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1056-263X EI 1573-3580 J9 J DEV PHYS DISABIL JI J. Dev. Phys. Disabil. PD AUG PY 2014 VL 26 IS 4 BP 391 EP 401 DI 10.1007/s10882-014-9367-3 PG 11 WC Rehabilitation SC Rehabilitation GA AK9XZ UT WOS:000338783200002 ER PT J AU Smirnov, MS Cabral, KA Geller, HM Urbach, JS AF Smirnov, Michael S. Cabral, Katelyn A. Geller, Herbert M. Urbach, Jeffrey S. TI The effects of confinement on neuronal growth cone morphology and velocity SO BIOMATERIALS LA English DT Article DE Neural cell; Polyvinylalcohol; Nerve regeneration; Laminin; Laser ablation ID CENTRAL-NERVOUS-SYSTEM; NEURITE OUTGROWTH; SOFT LITHOGRAPHY; LAMININ; DYNAMICS; SURFACES; ADHESION; GUIDANCE; PATHWAY; EXTENSION AB Optimizing growth cone guidance through the use of patterned substrates is important for designing regenerative substrates to aid in recovery from neuronal injury. Using laser ablation, we designed micron-scale patterns capable of confining dissociated mouse cerebellar granule neuron growth cones to channels of different widths ranging from 1.5 to 12 mu m. Growth cone dynamics in these channels were observed using time-lapse microscopy. Growth cone area was decreased in channels between 1.5 and 6 pm as compared to that in 12 mu m and unpatterned substrates. Growth cone aspect ratio was also affected as narrower channels forced growth cones into a narrow, elongated shape. There was no difference in the overall rate of growth cone advance in uniform channels between 1.5 and 12 mu m as compared to growth on unpattemed substrates. The percentage of time growth cones advanced, paused, and retracted was also similar. However, growth cones did respond to changes in confinement: growth cones in narrow lanes rapidly sped up when encountering a wide region and then slowed down as they entered another narrow region. Our results suggest that the rate of neurite extension is not affected by the degree of confinement, but does respond to changes in confinement. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Smirnov, Michael S.] Georgetown Univ, Interdisciplinary Program Neurosci, Washington, DC 20057 USA. [Smirnov, Michael S.; Urbach, Jeffrey S.] Georgetown Univ, Dept Phys, Washington, DC 20057 USA. [Smirnov, Michael S.; Urbach, Jeffrey S.] Georgetown Univ, Inst Soft Matter Synth & Metrol, Washington, DC 20057 USA. [Cabral, Katelyn A.; Geller, Herbert M.] NHLBI, Dev Neurobiol Sect, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Urbach, JS (reprint author), Georgetown Univ, Dept Phys, 320 Regents Hall, Washington, DC 20057 USA. EM urbach@physics.georgetown.edu OI Geller, Herbert/0000-0002-7048-6144; Urbach, Jeffrey/0000-0002-1593-520X; Smirnov, Michael/0000-0003-2248-8863 FU National Institutes of Health (NIH) [1R01N5064250]; NHLBI Intramural Research Program [1 ZIA HL006021] FX Special thanks to Dr. Andrew Doyle as well as the NHLBI Light Microscopy Core for their help with the photoablation process and to the NHLBI EM Core for their help in collecting SEM images. Funding was provided by National Institutes of Health (NIH) grant 1R01N5064250 to J.S.U. and the NHLBI Intramural Research Program (H.M.G) (1 ZIA HL006021) NR 40 TC 1 Z9 1 U1 1 U2 14 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD AUG PY 2014 VL 35 IS 25 BP 6750 EP 6757 DI 10.1016/j.biomaterials.2014.04.097 PG 8 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA AK4IB UT WOS:000338386800009 PM 24840617 ER PT J AU Shi, ZZ Ren, WZ Gong, A Zhao, XM Zou, YH Brown, EMB Chen, XY Wu, AG AF Shi, Zhenzhi Ren, Wenzhi Gong, An Zhao, Xinmei Zou, Yuehong Brown, Eric Michael Bratsolias Chen, Xiaoyuan Wu, Aiguo TI Stability enhanced polyelectrolyte-coated gold nanorod-photosensitizer complexes for high/low power density photodynamic therapy SO BIOMATERIALS LA English DT Article DE High/low power density; AlPcS4 photosensitizer; Gold nanorods; Photodynamic therapy (PDT); Near-infrared; Synergistic therapy ID CANCER; NANOPARTICLES; RELEASE; GROWTH AB Photodynamic therapy (PDT) is a promising treatment modality for cancer and other malignant diseases, however safety and efficacy improvements are required before it reaches its full potential and wider clinical use. Herein, we investigated a highly efficient and safe photodynamic therapy procedure by developing a high/low power density photodynamic therapy mode (high/low PDT mode) using methoxypoly(ethylene glycol) thiol (mPEG-SH) modified gold nanorod (GNR)-AlPcS4 photosensitizer complexes. mPEG-SH conjugated to the surface of simple polyelectrolyte-coated GNRs was verified using Fourier transform infrared spectroscopy; this improved stability, reduced cytotoxicity, and increased the encapsulation and loading efficiency of the nanoparticle dispersions. The GNR-photosensitizer complexes were exposed to the high/low PDT mode (high light dose = 80 mW/cm(2) for 0.5 min; low light dose = 25 mW/cm(2) for 1.5 min), and a high PDT efficacy leads to approximately 90% tumor cell killing. Due to synergistic plasmonic photothermal properties of the complexes, the high/low PDT mode demonstrated improved efficacy over using single wavelength continuous laser irradiation. Additionally, no significant loss in viability was observed in cells exposed to free AlPcS4 photosensitizer under the same irradiation conditions. Consequently, free AlPcS4 released from GNRs prior to cellular entry did not contribute to cytotoxicity of normal cells or impose limitations on the use of the high power density laser. This high/low PDT mode may effectively lead to a safer and more efficient photodynamic therapy for superficial tumors. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Shi, Zhenzhi; Ren, Wenzhi; Gong, An; Zhao, Xinmei; Zou, Yuehong; Wu, Aiguo] Chinese Acad Sci, Ningbo Inst Mat Technol & Engn, Key Lab Magnet Mat & Devices, Ningbo 315201, Zhejiang, Peoples R China. [Shi, Zhenzhi; Ren, Wenzhi; Gong, An; Zhao, Xinmei; Zou, Yuehong; Wu, Aiguo] Chinese Acad Sci, Ningbo Inst Mat Technol & Engn, Div Funct Mat & Nanodevices, Ningbo 315201, Zhejiang, Peoples R China. [Brown, Eric Michael Bratsolias] Univ Wisconsin, Dept Biol Sci, Whitewater, WI 53190 USA. [Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Wu, AG (reprint author), Room A510,1219 Zhongguan West Rd, Ningbo 315201, Zhejiang, Peoples R China. EM aiguo@nimte.ac.cn RI Wu, Aiguo/C-1837-2015; Wu, Aiguo/A-5414-2008 OI Wu, Aiguo/0000-0001-7200-8923; FU China Postdoctoral Science Foundation [2013M541805]; Hundred Talents Program of Chinese Academy of Science [2010-735]; Natural Science Foundation of China [21305148, 31128007, 31170964]; aided program for Science and Technology Innovative Research Team of Ningbo Municipality [2009821005] FX This work was supported by China Postdoctoral Science Foundation funded project (Grant No. 2013M541805), Hundred Talents Program of Chinese Academy of Science (Grant No. 2010-735), Natural Science Foundation of China (Grant No. 21305148, 31128007 and 31170964), and the aided program for Science and Technology Innovative Research Team of Ningbo Municipality (Grant No. 2009821005). The authors also thank Dr. Keqiang Li from Ningbo No.2 Hospital for providing MCF-7 cells. NR 34 TC 19 Z9 20 U1 6 U2 150 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD AUG PY 2014 VL 35 IS 25 BP 7058 EP 7067 DI 10.1016/j.biomaterials.2014.04.105 PG 10 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA AK4IB UT WOS:000338386800037 PM 24855961 ER PT J AU Andersen, BL Croyle, RT Dekker, J Diefenbach, MA Prins, JB Stanton, AL AF Andersen, Barbara L. Croyle, Robert T. Dekker, Joost Diefenbach, Michael A. Prins, Judith B. Stanton, Annette L. TI DESIGNING AND PROMOTING INTERVENTIONS IN PSYCHOSOCIAL CANCER CARE SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract CT INTERNATIONAL CONGRESS OF BEHAVIORAL MEDICINE (ICBM 2014) CY AUG 14-17, 2014 CL Brainerd, MN C1 [Andersen, Barbara L.] Ohio State Univ, Psychol, Columbus, OH 43210 USA. [Andersen, Barbara L.] Ohio State Univ, Livestrong Survivorship Ctr Excellence, Columbus, OH 43210 USA. [Croyle, Robert T.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Dekker, Joost] Vrije Univ Amsterdam, Med Ctr, Allied Hlth Care, Dept Psychiat, Amsterdam, Netherlands. [Dekker, Joost] Vrije Univ Amsterdam, Med Ctr, Dept Rehabil Med, Amsterdam, Netherlands. [Diefenbach, Michael A.] Icahn Sch Med Mt Sinai, Dept Urol, Res, New York, NY 10029 USA. [Prins, Judith B.] Radboud 190 UniversityMed Ctr, Dept Med Psychol, Nijmegen, Netherlands. [Stanton, Annette L.] Univ Calif Los Angeles, Psychol & Psychiat Biobehav Sci, Los Angeles, CA 90024 USA. [Stanton, Annette L.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr 192, Los Angeles, CA 90024 USA. [Stanton, Annette L.] Univ Calif Los Angeles, Cousins Ctr Psychoneuroimmunol 193, Los Angeles, CA 90024 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD AUG PY 2014 VL 21 SU 1 MA 5 BP S2 EP S2 PG 1 WC Psychology, Clinical SC Psychology GA V45KS UT WOS:000209816100006 ER PT J AU Kaufmann, PG Powell, LH Freedland, KE AF Kaufmann, Peter G. Powell, Lvnda H. Freedland, Kenneth E. TI DESIGN AND CONDUCT OF RANDOMIZED BEHAVIORAL SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract CT INTERNATIONAL CONGRESS OF BEHAVIORAL MEDICINE (ICBM 2014) CY AUG 14-17, 2014 CL Brainerd, MN C1 [Kaufmann, Peter G.] NHLBI, Bethesda, MD 20892 USA. [Powell, Lvnda H.] Rush Univ, Chicago, IL 60612 USA. [Freedland, Kenneth E.] Washington Univ, St Louis, MO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD AUG PY 2014 VL 21 SU 1 MA 1 BP S1 EP S1 PG 1 WC Psychology, Clinical SC Psychology GA V45KS UT WOS:000209816100002 ER PT J AU Kaufmann, PG Powell, LH Freedland, KE AF Kaufmann, Peter G. Powell, Lynda H. Freedland, Kenneth E. TI DESIGN AND CONDUCT OF RANDOMIZED BEHAVIORAL SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract CT INTERNATIONAL CONGRESS OF BEHAVIORAL MEDICINE (ICBM 2014) CY AUG 14-17, 2014 CL Brainerd, MN C1 [Kaufmann, Peter G.] NHLBI, Bethesda, MD 20892 USA. [Powell, Lynda H.] Rush Univ, Chicago, IL 60612 USA. [Freedland, Kenneth E.] Washington Univ, St Louis, MO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD AUG PY 2014 VL 21 SU 1 MA 6 BP S3 EP S3 PG 1 WC Psychology, Clinical SC Psychology GA V45KS UT WOS:000209816100008 ER PT J AU Schneiderman, N Llabre, M Cowie, C Barnhart, J Carnethon, M Gallo, L Giachello, A Heiss, G Kaplan, R LaVange, L Teng, Y Villa-Caballero, L Aviles-Santa, L AF Schneiderman, N. Llabre, M. Cowie, C. Barnhart, J. Carnethon, M. Gallo, L. Giachello, A. Heiss, G. Kaplan, R. LaVange, L. Teng, Y. Villa-Caballero, L. Aviles-Santa, L. TI DIABETES DISPARITIES AMONG US LATINOS/HISPANICS FROM DIVERSE BACKGROUNDS SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract CT INTERNATIONAL CONGRESS OF BEHAVIORAL MEDICINE (ICBM 2014) CY AUG 14-17, 2014 CL Brainerd, MN C1 [Schneiderman, N.; Llabre, M.] Univ Miami, Coral Gables, FL 33124 USA. [Cowie, C.] Natl Inst Diabet, Bethesda, MD USA. [Barnhart, J.; Kaplan, R.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Carnethon, M.; Giachello, A.] Northwestern, Chicago, IL USA. [Gallo, L.; Villa-Caballero, L.] San Diego State Univ, San Diego, CA 92182 USA. [Heiss, G.; Teng, Y.] Univ N Carolina, Chapel Hill, NC USA. [LaVange, L.] US FDA, US Dept HHS, Silver Spring, MD USA. [Aviles-Santa, L.] NHLBI, NIH, Bethesda, MD 20892 USA. EM nschneid@miami.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD AUG PY 2014 VL 21 SU 1 MA S440 BP S132 EP S132 PG 1 WC Psychology, Clinical SC Psychology GA V45KS UT WOS:000209816100456 ER PT J AU Guest, HJ Horowitz, TS Thornton, IM AF Guest, H. J. Horowitz, T. S. Thornton, I. M. TI Does action disrupt the ability to track multiple objects? SO PERCEPTION LA English DT Meeting Abstract C1 [Guest, H. J.] Univ Malta, Dept Psychol, Msida, Malta. [Horowitz, T. S.] NCI, NIH, Bethesda, MD 20892 USA. [Thornton, I. M.] Univ Malta, Dept Cognit Sci, Msida, Malta. EM ian.thornton@um.edu.mt NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0301-0066 EI 1468-4233 J9 PERCEPTION JI Perception PD AUG PY 2014 VL 43 IS 1 SU 1 MA 36 BP 26 EP 26 PG 1 WC Ophthalmology; Psychology; Psychology, Experimental SC Ophthalmology; Psychology GA EM0SU UT WOS:000395028800078 ER PT J AU Horowitz, TS AF Horowitz, T. S. TI From tools to tumors? A meta-analysis of the prevalence effect in visual search experiments and medical image perception SO PERCEPTION LA English DT Meeting Abstract C1 [Horowitz, T. S.] NCI, NIH, Bethesda, MD 20892 USA. EM todd.horowitz@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0301-0066 EI 1468-4233 J9 PERCEPTION JI Perception PD AUG PY 2014 VL 43 IS 1 SU 1 BP 63 EP 63 PG 1 WC Ophthalmology; Psychology; Psychology, Experimental SC Ophthalmology; Psychology GA EM0SU UT WOS:000395028800188 ER PT J AU Pitcher, DD Duchaine, B Walsh, V AF Pitcher, D. D. Duchaine, B. Walsh, V. TI Combined TMS/fMRI reveals dissociable cortical pathways for dynamic and static faces SO PERCEPTION LA English DT Meeting Abstract C1 [Pitcher, D. D.] NIMH, Lab Brain & Cognit, Bethesda, MD USA. [Duchaine, B.] Dartmouth Coll, Psychol, Hanover, NH USA. [Walsh, V.] UCL, Psychol, London WC1E 6BT, England. EM david.pitcher@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0301-0066 EI 1468-4233 J9 PERCEPTION JI Perception PD AUG PY 2014 VL 43 IS 1 SU 1 BP 122 EP 122 PG 1 WC Ophthalmology; Psychology; Psychology, Experimental SC Ophthalmology; Psychology GA EM0SU UT WOS:000395028800366 ER PT J AU Crawley, SA Caporino, NE Birmaher, B Ginsburg, G Piacentini, J Albano, AM Sherrill, J Sakolsky, D Compton, SN Rynn, M McCracken, J Gosch, E Keeton, C March, J Walkup, JT Kendall, PC AF Crawley, Sarah A. Caporino, Nicole E. Birmaher, Boris Ginsburg, Golda Piacentini, John Albano, Anne Marie Sherrill, Joel Sakolsky, Dara Compton, Scott N. Rynn, Moira McCracken, James Gosch, Elizabeth Keeton, Courtney March, John Walkup, John T. Kendall, Philip C. TI Somatic Complaints in Anxious Youth SO CHILD PSYCHIATRY & HUMAN DEVELOPMENT LA English DT Article DE Children; Adolescents; Anxiety; Treatment ID COGNITIVE-BEHAVIORAL THERAPY; CHILDHOOD ANXIETY DISORDERS; GLOBAL ASSESSMENT SCALE; CLINICAL CHARACTERISTICS; FOLLOW-UP; CHILDREN; ADOLESCENTS; SYMPTOMS; PREDICTION; INTERVIEW AB This study examined (a) demographic and clinical characteristics associated with physical symptoms in anxiety-disordered youth and (b) the impact of cognitive-behavioral therapy (Coping Cat), medication (sertraline), their combination, and pill placebo on physical symptoms. Youth (N = 488, ages 7-17 years) with a principal diagnosis of generalized anxiety disorder, separation anxiety disorder, or social phobia participated as part of a multi-site, randomized controlled trial and received treatment delivered over 12 weeks. Diagnostic status, symptom severity, and impairment were assessed at baseline and week 12. The total number and severity of physical symptoms was associated with age, principal diagnosis, anxiety severity, impairment, and the presence of comorbid internalizing disorders. Common somatic complaints were headaches, stomachaches, head cold or sniffles, sleeplessness, and feeling drowsy or too sleepy. Physical symptoms decreased over the course of treatment, and were unrelated to treatment condition. Clinical implications and directions for future research are discussed (ClinicalTrials.gov number, NCT00052078). C1 [Crawley, Sarah A.; Caporino, Nicole E.; Kendall, Philip C.] Temple Univ, Dept Psychol, Philadelphia, PA 19122 USA. [Birmaher, Boris; Sakolsky, Dara] Univ Pittsburgh, Western Psychiat Inst & Clin, Med Ctr, Pittsburgh, PA 15213 USA. [Ginsburg, Golda; Keeton, Courtney] Johns Hopkins Univ, Sch Med, Div Child & Adolescent Psychiat, Baltimore, MD USA. [Piacentini, John; McCracken, James] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [Albano, Anne Marie; Rynn, Moira] Columbia Univ, Med Ctr, Dept Psychiat, New York, NY USA. [Sherrill, Joel] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Compton, Scott N.; March, John] Duke Univ, Med Ctr, Dept Psychiat & Behav Serv, Durham, NC USA. [Gosch, Elizabeth] Philadelphia Coll Osteopath Med, Dept Psychol, Philadelphia, PA USA. [Walkup, John T.] Weill Cornell Med Coll, Div Child & Adolescent Psychiat, New York, NY USA. RP Kendall, PC (reprint author), Temple Univ, Dept Psychol, Weiss Hall,1701 North 13th St, Philadelphia, PA 19122 USA. EM pkendall@temple.edu FU NIMH NIH HHS [U01 MH64107, U01 MH064088, R01 MH064003, U01 MH64092, U01 MH063747, U01 MH63747, U01 MH64088, U01 MH064092, U01 MH64003, U01 MH064003, U01 MH064107, U01 MH064089] NR 39 TC 5 Z9 5 U1 2 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-398X EI 1573-3327 J9 CHILD PSYCHIAT HUM D JI Child Psychiat. Hum. Dev. PD AUG PY 2014 VL 45 IS 4 BP 398 EP 407 DI 10.1007/s10578-013-0410-x PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA AK3KU UT WOS:000338323400003 PM 24129543 ER PT J AU Montoya, JG Perl, TM AF Montoya, Jose G. Perl, Trish M. TI Editorial introductions SO CURRENT OPINION IN INFECTIOUS DISEASES LA English DT Editorial Material C1 [Montoya, Jose G.] Palo Alto Med Fdn, Lab Diag & Management Toxoplasmosis US, Palo Alto, CA USA. [Montoya, Jose G.] Stanford Univ, Med Ctr, Immunocompromised Host Serv Infect Dis, Stanford, CA 94305 USA. [Montoya, Jose G.] Amer Coll Phys FACP, Recognit Commitment Internal Med Community, Philadelphia, PA USA. [Montoya, Jose G.] Infect Dis Soc Amer FIDSA, Murray, MD USA. [Perl, Trish M.] Johns Hopkins Univ, Sch Med, Dept Med Infect Dis, Baltimore, MD USA. [Perl, Trish M.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Perl, Trish M.] Johns Hopkins Bloomberg Sch Publ Health, Dept Epidemiol, Baltimore, MD USA. [Perl, Trish M.] Johns Hopkins Med Baltimore, Baltimore, MD USA. [Perl, Trish M.] Johns Hopkins Med Baltimore, Baltimore, FL USA. [Perl, Trish M.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Perl, Trish M.] Ctr Dis Control, Atlanta, GA 30333 USA. [Perl, Trish M.] WHO, Geneva, Switzerland. [Perl, Trish M.] NIH, Bethesda, MD USA. RP Montoya, JG (reprint author), Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7375 EI 1473-6527 J9 CURR OPIN INFECT DIS JI Curr. Opin. Infect. Dis. PD AUG PY 2014 VL 27 IS 4 PG 2 WC Infectious Diseases SC Infectious Diseases GA AK0SS UT WOS:000338126200001 ER PT J AU Kim, SW Fowler, JS Skolnick, P Muench, L Kang, Y Shea, C Logan, J Kim, D Carter, P King, P Alexoff, D Volkow, ND AF Kim, Sung Won Fowler, Joanna S. Skolnick, Phil Muench, Lisa Kang, Yeona Shea, Colleen Logan, Jean Kim, Dohyun Carter, Pauline King, Payton Alexoff, David Volkow, Nora D. TI Therapeutic doses of buspirone block D3 receptors in the living primate brain SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Addiction; buspirone; dopamine receptors; 6'-hydroxybuspirone ID POSITRON-EMISSION-TOMOGRAPHY; DOPAMINE D-3 RECEPTOR; COCAINE-SEEKING BEHAVIOR; HIGH-AFFINITY STATE; FREELY MOVING RATS; IN-VIVO; ACTIVE METABOLITE; DRUG-ADDICTION; RHESUS-MONKEYS; BINDING AB Dopamine D-3 receptor (D3R) antagonists may be effective medications for multiple substance use disorders (SUDs). However, no selective D3R antagonists are currently available for clinical testing. Buspirone, originally characterized as a 5-HT1A partial agonist and used as an anxiolytic, also binds to D3R and D4R with high affinity, with lower affinity to D2R, and interferes with cocaine reward. Here we used PET with [C-11]PHNO (D3R-preferring radioligand), [C-11]raclopride (D2R/D3R radioligand) and [C-11]NNC-112 (D1R radioligand) to measure occupancy of oral and parenteral buspirone in the primate brain. Intramuscular buspirone (0.19 and 0.5 mg/kg) blocked both [C-11]PHNO and [C-11] raclopride binding to striatum, exhibiting high occupancy (50-85%) at 15 min and rapid wash-out over 2-6 h. In contrast, oral buspirone (3 mg/kg) significantly blocked [C-11]PHNO binding in D-3-rich regions (globus pallidum and midbrain) at 3 h, but had minimal effects on [C-11]raclopride binding (28-37% at 1 h and 10% at 3 h). Buspirone did not block [C-11]NNC-112. Our findings provide evidence that i.m. buspirone blocks D3R and D2R, whereas oral buspirone is more selective towards D3R blockade in vivo, consistent with extensive first pass metabolism and supporting the hypothesis that its metabolites (5- and 6'-hydroxybuspirone) merit evaluation for treating SUDs. They also indicate that for oral buspirone to achieve greater than 80% sustained D3R occupancy, as might be needed to treat addiction, higher doses (at least three-fold) than those used to treat anxiety (maximal 60 mg) will be required. Nonetheless, based on previous clinical studies, these doses would be safe and well tolerated. C1 [Kim, Sung Won; Muench, Lisa; Volkow, Nora D.] NIAAA, Lab Neuroimaging, Upton, NY USA. [Fowler, Joanna S.; Kang, Yeona; Shea, Colleen; Logan, Jean; Kim, Dohyun; Carter, Pauline; King, Payton; Alexoff, David] Brookhaven Natl Lab, Dept Biosci, Upton, NY 11973 USA. [Skolnick, Phil; Volkow, Nora D.] NIDA, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), NIDA, NIH, 6001 Execut Blvd Suite 5274,Mail Stop Code 9581, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov OI Logan, Jean/0000-0002-6993-9994 FU NIH Intramural Program of the National Institute National Institute on Alcohol Abuse and Alcoholism (NIAAA); Office Biological and Environmental Research of the U. S. Department of Energy [DE-AC02-98CH10886] FX The NIH Intramural Program of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) supported this research. All experiments were performed at Brookhaven National Laboratory (BNL) with PET infrastructure supported from Office of Biological and Environmental Research of the U. S. Department of Energy (DE-AC02-98CH10886). We would like to thank Chunyang Jin and Kenneth Rehder (RTI International) for providing the PHNO precursor, and Dah Ren Hwang and Alan Wilson for helpful discussions on the [11C]PHNO synthesis. We also thank the BNL staff: Wenchao Qu, Michael Schueller, Donald Warner, Youwen Xu, Mingwei Wei, and Barbara Hubbard for cyclotron operations, radiotracer synthesis and PET operations and we thank Ruben Baler for editorial assistance. NR 66 TC 10 Z9 11 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD AUG PY 2014 VL 17 IS 8 BP 1257 EP 1267 DI 10.1017/S1461145714000194 PG 11 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AK0JK UT WOS:000338098500013 PM 24679922 ER PT J AU Dougherty, LR Smith, VC Bufferd, SJ Carlson, GA Stringaris, A Leibenluft, E Klein, DN AF Dougherty, L. R. Smith, V. C. Bufferd, S. J. Carlson, G. A. Stringaris, A. Leibenluft, E. Klein, D. N. TI DSM-5 disruptive mood dysregulation disorder: correlates and predictors in young children SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Disruptive mood dysregulation disorder; early childhood; predictors ID PSYCHIATRIC-DISORDERS; DIAGNOSTIC INTERVIEW; ADULT OUTCOMES; MENTAL-HEALTH; SUBSTANCE USE; BEHAVIOR; TEMPERAMENT; YOUTH; PSYCHOPATHOLOGY; EMOTIONALITY AB Background. Despite the inclusion of disruptive mood dysregulation disorder (DMDD) in DSM-5, little empirical data exist on the disorder. We estimated rates, co-morbidity, correlates and early childhood predictors of DMDD in a community sample of 6-year-olds. Method. DMDD was assessed in 6-year-old children (n=462) using a parent-reported structured clinical interview. Age 6 years correlates and age 3 years predictors were drawn from six domains: demographics; child psychopathology, functioning, and temperament; parental psychopathology; and the psychosocial environment. Results. The 3-month prevalence rate for DMDD was 8.2% (n=38). DMDD occurred with an emotional or behavioral disorder in 60.5% of these children. At age 6 years, concurrent bivariate analyses revealed associations between DMDD and depression, oppositional defiant disorder, the Child Behavior Checklist - Dysregulation Profile, functional impairment, poorer peer functioning, child temperament (higher surgency and negative emotional intensity and lower effortful control), and lower parental support and marital satisfaction. The age 3 years predictors of DMDD at age 6 years included child attention deficit hyperactivity disorder, oppositional defiant disorder, the Child Behavior Checklist - Dysregulation Profile, poorer peer functioning, child temperament (higher child surgency and negative emotional intensity and lower effortful control), parental lifetime substance use disorder and higher parental hostility. Conclusions. A number of children met DSM-5 criteria for DMDD, and the diagnosis was associated with numerous concurrent and predictive indicators of emotional and behavioral dysregulation and poor functioning. C1 [Dougherty, L. R.; Smith, V. C.] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. [Bufferd, S. J.] Calif State Univ San Marcos, Dept Psychol, San Marcos, CA USA. [Carlson, G. A.; Klein, D. N.] Stony Brook Sch Med, Dept Psychiat, Stony Brook, NY USA. [Stringaris, A.] Kings Coll London, Inst Psychiat, London WC2R 2LS, England. [Leibenluft, E.] NIMH, Bipolar Spectrum Disorders Emot & Dev Branch, Bethesda, MD 20892 USA. [Klein, D. N.] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. RP Dougherty, LR (reprint author), Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. EM ldougher@umd.edu FU National Institute of Mental Health [R01 MH069942]; General Clinical Research Center (Stony Brook University, National Center for Research Resources) [M01 RR10710] FX The present study was supported by National Institute of Mental Health (to D.N.K., grant number R01 MH069942) and the General Clinical Research Center (Stony Brook University, National Center for Research Resources, grant number M01 RR10710). NR 38 TC 15 Z9 15 U1 6 U2 39 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD AUG PY 2014 VL 44 IS 11 BP 2339 EP 2350 DI 10.1017/S0033291713003115 PG 12 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA AK1TL UT WOS:000338199200009 PM 24443797 ER PT J AU Burstein, M Beesdo-Baum, K He, JP Merikangas, KR AF Burstein, M. Beesdo-Baum, K. He, J. -P. Merikangas, K. R. TI Threshold and subthreshold generalized anxiety disorder among US adolescents: prevalence, sociodemographic, and clinical characteristics SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Adolescents; children; epidemiology; generalized anxiety disorder; subthreshold ID COMORBIDITY SURVEY REPLICATION; SUPPLEMENT NCS-A; DSM-IV DISORDERS; DURATION REQUIREMENT; LIFETIME PREVALENCE; MENTAL-DISORDERS; CHILDREN; YOUTH; WORRY; IMPAIRMENT AB Background. Threshold and subthreshold forms of generalized anxiety disorder (GAD) are highly prevalent and impairing conditions among adults. However, there are few general population studies that have examined these conditions during the early life course. The primary objectives of this study were to: (1) examine the prevalence, and sociodemographic and clinical characteristics of threshold and subthreshold forms of GAD in a nationally representative sample of US youth; and (2) test differences in sociodemographic and clinical characteristics between threshold and subthreshold forms of the disorder. Method. The National Comorbidity Survey-Adolescent Supplement is a nationally representative face-to-face survey of 10 123 adolescents 13 to 18 years of age in the continental USA. Results. Approximately 3% of adolescents met criteria for threshold GAD. Reducing the required duration from 6 months to 3 months resulted in a 65.7% increase in prevalence (5.0%); further relaxing the uncontrollability criterion led to an additional 20.7% increase in prevalence (6.1%). Adolescents with all forms of GAD displayed a recurrent clinical course marked by substantial impairment and co-morbidity with other psychiatric disorders. There were few significant differences in sociodemographic and clinical characteristics between threshold and subthreshold cases of GAD. Results also revealed age-related differences in the associated symptoms and clinical course of GAD. Conclusions. Findings demonstrate the clinical significance of subthreshold forms of GAD among adolescent youth, highlighting the continuous nature of the GAD construct. Age-related differences in the associated symptoms and clinical course of GAD provide further support for criteria that capture variation in clinical features across development. C1 [Burstein, M.; He, J. -P.; Merikangas, K. R.] NIMH, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. [Beesdo-Baum, K.] Tech Univ Dresden, Inst Clin Psychol & Psychotherapy, D-01062 Dresden, Germany. RP Merikangas, KR (reprint author), NIMH, Genet Epidemiol Res Branch, Bldg 35,Room 1A201,35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. EM kathleen.merikangas@nih.gov FU National Institute of Mental Health [ZIA MH002808-11, U01-MH60220]; National Institute of Drug Abuse [R01-DA016558]; Intramural Research Program of the National Institute of Mental Health FX The NCS-A was funded by the National Institute of Mental Health (no. ZIA MH002808-11 and no. U01-MH60220), and the National Institute of Drug Abuse (no. R01-DA016558). This work was supported by the Intramural Research Program of the National Institute of Mental Health. NR 43 TC 4 Z9 4 U1 3 U2 28 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD AUG PY 2014 VL 44 IS 11 BP 2351 EP 2362 DI 10.1017/S0033291713002997 PG 12 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA AK1TL UT WOS:000338199200010 PM 24384401 ER PT J AU de Sousa, RT Zanetti, MV Busatto, GF Mouro, MG Zarate, CA Gattaz, WF Higa, EM Machado-Vieira, R AF de Sousa, Rafael T. Zanetti, Marcus V. Busatto, Geraldo F. Mouro, Margaret G. Zarate, Carlos A., Jr. Gattaz, Wagner F. Higa, Elisa M. Machado-Vieira, Rodrigo TI Lithium increases nitric oxide levels in subjects with bipolar disorder during depressive episodes SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Bipolar disorder; Nitric oxide; Lithium; Treatment; Depression; Plasticity ID PLASMA NITRATE LEVELS; MAJOR DEPRESSION; SUPEROXIDE-DISMUTASE; MULTIPLE-SCLEROSIS; BETA-CATENIN; SYNTHASE; EXPRESSION; SERUM; RAT; NEURONS AB Background: Altered nitric oxide (NO) signaling has been associated with the pathophysiology of Bipolar Disorder (BD), directly affecting neurotransmitter release and synaptic plasticity cascades. Lithium has shown to regulate NO levels in preclinical models. However, no study has addressed peripheral NO levels in unmedicated BD. Also, lithium's effects on NO levels have not been studied in humans. Methods: Plasma NO was evaluated in subjects with BD I and II during a depressive episode (n = 26). Subjects had a score of >= 18 in the 21-item Hamilton Depression Rating Scale and were followed-up during a 6-week trial with lithium. Plasma NO levels were also compared to matched healthy controls (n = 28). NO was determined by chemiluminescence method. Results: Lithium treatment significantly increased plasma NO levels after 6 weeks of treatment in comparison to baseline levels in bipolar depression (p = 0.016). Baseline NO levels during depressive episodes showed no difference when matching up to healthy controls (p = 0.66). Conclusion: The present findings suggest that lithium upregulates NO signaling in unmedicated BD with short illness duration. Further studies with larger samples are needed to confirm the effects of lithium on NO pathway and its association with synaptic plasticity and therapeutics of BD. Published by Elsevier Ltd. C1 [de Sousa, Rafael T.; Zanetti, Marcus V.; Gattaz, Wagner F.; Machado-Vieira, Rodrigo] Univ Sao Paulo, Dept & Inst Psychiat, Lab Neurosci, LIM 27, BR-05508 Sao Paulo, Brazil. [Zanetti, Marcus V.; Busatto, Geraldo F.; Gattaz, Wagner F.; Machado-Vieira, Rodrigo] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, BR-05508 Sao Paulo, Brazil. [Zanetti, Marcus V.; Busatto, Geraldo F.] Univ Sao Paulo, Dept & Inst Psychiat, Lab Psychiat Neuroimaging, LIM 21, BR-05508 Sao Paulo, Brazil. [Zarate, Carlos A., Jr.; Higa, Elisa M.; Machado-Vieira, Rodrigo] NIMH, ETPB, NIH, Bethesda, MD 20892 USA. [Mouro, Margaret G.] UNIFESP Escola Paulista Med, Div Nephrol, Dept Med, Sao Paulo, Brazil. RP Machado-Vieira, R (reprint author), Univ Sao Paulo, Dept & Inst Psychiat, Lab Neurosci, LIM 27, BR-05508 Sao Paulo, Brazil. EM machadovieirar@gmail.com RI Gattaz, Wagner/C-4456-2012; Busatto, Geraldo/D-4431-2009; Higa, Elisa/I-3672-2013; MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU Sao Paulo Research Foundation (Fapesp, Brazil) [2009/14891-9]; Associacao Beneficente Alzira Denise Hertzog da Silva (ABADHS) FX This study was sponsored by Sao Paulo Research Foundation (Fapesp, Brazil 2009/14891-9). The Laboratory of Neuroscience is supported by the Associacao Beneficente Alzira Denise Hertzog da Silva (ABADHS). NR 46 TC 5 Z9 5 U1 0 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD AUG PY 2014 VL 55 BP 96 EP 100 DI 10.1016/j.jpsychires.2014.03.023 PG 5 WC Psychiatry SC Psychiatry GA AJ7KW UT WOS:000337876600013 PM 24768108 ER PT J AU Savolainen, MH Richie, CT Harvey, BK Mannisto, PT Maguire-Zeiss, KA Myohanen, TT AF Savolainen, Mari H. Richie, Christopher T. Harvey, Brandon K. Mannisto, Pekka T. Maguire-Zeiss, Kathleen A. Myohanen, Timo T. TI The beneficial effect of a prolyl oligopeptidase inhibitor, KYP-2047, on alpha-synuclein clearance and autophagy in A30P transgenic mouse SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Synucleins; Protein misfolding; Serine protease; Parkinson's disease; Dementia with Lewy bodies; Synucleinopathies; Autophagy ID FAMILIAL PARKINSONS-DISEASE; ISOLATED RAT HEPATOCYTES; LEWY BODY DEMENTIA; ENDOPEPTIDASE INHIBITOR; SPATIAL MEMORY; IN-VIVO; PROTEIN-DEGRADATION; THERAPEUTIC TARGET; ALZHEIMERS-DISEASE; ANIMAL-MODELS AB The misfolding and aggregation of alpha-synuclein (aSyn) eventually lead to an accumulation of toxic forms that disturb normal neuronal function and result in cell death. aSyn rich inclusions are seen in Parkinson's disease, dementia with Lewy bodies and other synucleinopathies. Prolyl oligopeptidase (PREP) can accelerate the aggregation process of aSyn and the inhibition of PREP leads to a decreased amount of aggregated aSyn in cell models and in aSyn transgenic mice. In this study, we investigated the effect of 5- and 28-day PREP inhibitor (KYP-2047) treatments on a mouse strain carrying a point mutation in the aSyn coding gene. Following PREP inhibition, we found a decrease in high molecular-weight oligomeric aSyn and a concomitant increase in the amount of the autophagosome marker, LC3BII, suggesting enhanced macroautophagy (autophagy) and aSyn clearance by KYP-2047. Moreover, 28-day treatment with KYP-2047 caused significant increases in striatal dopamine levels. In cell culture, overexpression of PREP reduced the autophagy. Furthermore, the inhibition of PREP normalized the changes on autophagy markers (LC3BII and p62) caused by an autophagy inhibition or aSyn overexpression, and induced the expression of beclin 1, a positive regulator of autophagy. Taken together, our results suggest that PREP inhibition accelerates the clearance of protein aggregates via increased autophagy and thus normalizes the cell functions in vivo and in vitro. Therefore, PREP inhibition may have future potential in the treatment of synucleinopathies. (C) 2014 Elsevier Inc. All rights reserved. C1 [Savolainen, Mari H.; Mannisto, Pekka T.; Myohanen, Timo T.] Univ Helsinki, Div Pharmacol & Pharmacotherapy, FI-00014 Helsinki, Finland. [Savolainen, Mari H.; Richie, Christopher T.; Harvey, Brandon K.] NIDA, Optogenet & Transgen Technol Core, Baltimore, MD USA. [Maguire-Zeiss, Kathleen A.; Myohanen, Timo T.] Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20007 USA. RP Myohanen, TT (reprint author), Univ Helsinki, Fac Pharm, Div Pharmacol & Pharmacotherapy, Viikinkaari 5E POB 56, FI-00014 Helsinki, Finland. EM timo.myohanen@helsinki.fi RI Myohanen, Timo/N-8438-2014; OI Myohanen, Timo/0000-0002-9277-6687 FU Academy of Finland [138127, 267788]; Jane and Aatos Erkko Foundation; Sigrid Juselius Foundation; Finnish Pharmaceutical Society; Finnish Parkinson's Disease Foundation; Georgetown University; Intramural Research Program at the National Institute on Drug Abuse, NIH, USA FX These studies were supported by the grants from The Academy of Finland (nos. 138127 and 267788), Jane and Aatos Erkko Foundation, Sigrid Juselius Foundation, and Finnish Parkinson's Disease Foundation for Timo T Myohanen, grants from the Finnish Pharmaceutical Society and Finnish Parkinson's Disease Foundation for Mari Savolainen, and a grant from the Sigrid Juselius Foundation for Pekka T. Mannisto and Georgetown University for Kathleen Maguire-Zeiss. Brandon K. Harvey and Christopher T. Richie were supported by the Intramural Research Program at the National Institute on Drug Abuse, NIH, USA. NR 83 TC 14 Z9 15 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD AUG PY 2014 VL 68 BP 1 EP 15 DI 10.1016/j.nbd.2014.04.003 PG 15 WC Neurosciences SC Neurosciences & Neurology GA AJ8XV UT WOS:000337992300001 PM 24746855 ER PT J AU Ermanoska, B Motley, WW Leitao-Goncalves, R Asselbergh, B Lee, LH De Rijk, P Sleegers, K Ooms, T Godenschwege, TA Timmerman, V Fischbeck, KH Jordanova, A AF Ermanoska, Biljana Motley, William W. Leitao-Goncalves, Ricardo Asselbergh, Bob Lee, LaTasha H. De Rijk, Peter Sleegers, Kristel Ooms, Tinne Godenschwege, Tanja A. Timmerman, Vincent Fischbeck, Kenneth H. Jordanova, Albena TI CMT-associated mutations in glycyl- and tyrosyl-tRNA synthetases exhibit similar pattern of toxicity and share common genetic modifiers in Drosophila SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Drosophila; Aminoacyl-tRNA synthetase; Charcot-Marie-Tooth disease ID MARIE-TOOTH-DISEASE; SUBCELLULAR-LOCALIZATION; PERIPHERAL NEUROPATHY; EUKARYOTIC PROTEINS; PREDICTION SERVER; GIANT-FIBER; DCTN1 GENE; AMINOACYLATION; MELANOGASTER; PHENOTYPES AB Aminoacyl-tRNA synthetases are ubiquitously expressed proteins that charge tRNAs with their cognate amino acids. By ensuring the fidelity of protein synthesis, these enzymes are essential for the viability of every cell. Yet, mutations in six tRNA synthetases specifically affect the peripheral nerves and cause Charcot-Marie-Tooth (CMT) disease. The CMT-causing mutations in tyrosyl- and glycyl-tRNA synthetases (YARS and GARS, respectively) alter the activity of the proteins in a range of ways (some mutations do not impact charging function, while others abrogate it), making a loss of function in tRNA charging unlikely to be the cause of disease pathology. It is currently unknown which cellular mechanisms are triggered by the mutant enzymes and how this leads to neurodegeneration. Here, by expressing two pathogenic mutations (G240R, P234KY) in Drosophila, we generated a model for GARS-associated neuropathy. We observed compromised viability, and behavioral, electrophysiological and morphological impairment in flies expressing the cytoplasmic isoform of mutant GARS. Their features recapitulated several hallmarks of CMT pathophysiology and were similar to the phenotypes identified in our previously described Drosophila model of YARS-associated neuropathy. Furthermore, CG8316 and CG15599 - genes identified in a retinal degeneration screen to modify mutant YAKS, also modified the mutant GARS phenotypes. Our study presents genetic evidence for common mutant-specific interactions between two CMT-associated aminoacyl-tRNA synthetases, lending support for a shared mechanism responsible for the synthetase-induced peripheral neuropathies. (C) 2014 Elsevier Inc. All rights reserved. C1 [Ermanoska, Biljana; Leitao-Goncalves, Ricardo; Ooms, Tinne; Jordanova, Albena] Univ Antwerp VIB, Dept Mol Genet, Mol Neurogen Grp, B-2610 Antwerp, Belgium. [Ermanoska, Biljana; Leitao-Goncalves, Ricardo; Asselbergh, Bob; Sleegers, Kristel; Ooms, Tinne; Timmerman, Vincent; Jordanova, Albena] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, B-2610 Antwerp, Belgium. [Motley, William W.; Fischbeck, Kenneth H.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Motley, William W.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Asselbergh, Bob] Univ Antwerp VIB, Dept Mol Genet, Centralized Serv Facil, B-2610 Antwerp, Belgium. [Lee, LaTasha H.; Godenschwege, Tanja A.] Florida Atlantic Univ, Dept Biol Sci, Jupiter, FL 33458 USA. [De Rijk, Peter] Univ Antwerp VIB, Dept Mol Genet, Appl Mol Genom Unit, B-2610 Antwerp, Belgium. [Sleegers, Kristel] Univ Antwerp VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, B-2610 Antwerp, Belgium. [Leitao-Goncalves, Ricardo; Timmerman, Vincent] Univ Antwerp VIB, Dept Mol Genet, Peripheral Neuropathy Grp, B-2610 Antwerp, Belgium. RP Jordanova, A (reprint author), Univ Antwerp VIB, Dept Mol Genet, Mol Neurogen Grp, Univ Pl 1, B-2610 Antwerp, Belgium. EM albena.jordanova@molgen.vib-ua.be RI Jordanova, Albena/H-8323-2015; OI Jordanova, Albena/0000-0002-3833-3754; De Rijk, Peter/0000-0001-8558-9288; Goncalves, Ricardo/0000-0001-8792-2478; Godenschwege, Tanja/0000-0003-3322-4134 FU University of Antwerp Research Fund [TOP BOF UA 29069]; Research Foundation Flanders, FWO [G078414N, G043411N]; Research Excellence Center Neuro by University of Antwerp Research Fund (OEC); Association Beige contre les Maladies Neuromusculaire, ABMM; US Muscular Dystrophy Association [MDA175816]; Association Francaise contre les Myopaties, AFM [AFM16197]; NINDS, NIH [ZIA-NS003038]; National Institute of Child Health and Human Development [R01HD050725]; Research Foundation Flanders; Boehringer Ingelheim Funds FX We thank Jana Boerner, Monica Mejia, and Julie Freund for their help with GF electrophysiological experiments and dye filling. We are grateful to Lieve Svensson, Isabel Pintelon and Jean-Pierre Timmermans from the University of Antwerp Core Facility for Biomedical Microscopic Imaging for use of the scanning electron microscope. We acknowledge Mainak Guha Roy (VIB Department of Structural Biology, Brussels) for consulting our protein prediction analyses. This work was supported in part by the University of Antwerp Research Fund (TOP BOF UA 29069 to AJ); the Research Foundation Flanders, FWO (G078414N to AJ and G043411N to VT); the Research Excellence Center Neuro by University of Antwerp Research Fund (OEC); the Association Beige contre les Maladies Neuromusculaire, ABMM (to AJ, VT); the US Muscular Dystrophy Association (MDA175816 to AJ, VT); the Association Francaise contre les Myopaties, AFM (AFM16197 to AJ); intramural research funds from NINDS, NIH (ZIA-NS003038 to VVWM and KF); R01HD050725 grant from the National Institute of Child Health and Human Development (to TAG). BE is supported by a PhD fellowship from the Research Foundation Flanders and by travel grant from Boehringer Ingelheim Funds. NR 62 TC 8 Z9 9 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD AUG PY 2014 VL 68 BP 180 EP 189 DI 10.1016/j.nbd.2014.04.020 PG 10 WC Neurosciences SC Neurosciences & Neurology GA AJ8XV UT WOS:000337992300017 PM 24807208 ER PT J AU Wang, DS Patel, A Sim, HM Zhang, YK Wang, YJ Kathawala, RJ Zhang, H Talele, TT Ambudkar, SV Xu, RH Chen, ZS AF Wang, De-Shen Patel, Atish Sim, Hong-May Zhang, Yun-Kai Wang, Yi-Jun Kathawala, Rishil J. Zhang, Hui Talele, Tanaji T. Ambudkar, Suresh V. Xu, Rui-Hua Chen, Zhe-Sheng TI ARRY-334543 Reverses Multidrug Resistance by Antagonizing the Activity of ATP-Binding Cassette Subfamily G Member 2 SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE ARRY-334543; ABCG2; MULTIDRUG RESISTANCE; TYROSINE KINASE INHIBITOR; LUNG CANCER ID CELL LUNG-CANCER; TYROSINE KINASE INHIBITORS; FACTOR RECEPTOR EGFR; DRUG-RESISTANCE; SIGNALING PATHWAY; PROTEIN ABCG2; STEM-CELLS; B MEMBER-1; IN-VIVO; TRANSPORTER AB ARRY-334543 is a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases. We conducted this study to determine whether ARRY-334543 can enhance the efficacy of conventional anticancer drugs through interaction with ABC transporters. Lung cancer cell line NCI-H460 and its ABCG2-overexpressing NCI-H460/MX20, as well as the ABCG2-, ABCB1-, and ABCC10-overexpressing transfected cell lines were used for the reversal study. Our results demonstrated that ARRY-334543 (1.0 mu M) significantly reversed ABCG2-mediated multidrug resistance (MDR) by directly inhibiting the drug efflux function of ABCG2, resulting in the elevated intracellular accumulation of chemotherapeutic drugs in the ABCG2-overexpressing cell lines. In addition, in isolated membranes, ARRY-334543 stimulated ATPase activity and inhibited photolabeling of ABCG2 with [I-125]-iodoarylazidoprazosin in a concentration-dependent manner indicating that this drug directly interacts at the drug-binding pocket of this transporter. ARRY-334543 (1.0 mu M) only slightly reversed ABCB1- and partially reversed ABCC10-mediated MDR suggesting that it exhibits high affinity toward ABCG2. Moreover, homology modeling predicted the binding conformation of ARRY-334543 at Arg482 centroid-based grid of ABCG2. However, ARRY-334543 at reversal concentrations did not affect the expression level of ABCG2, AKT and ERK1/2 and regulate the re-localization of ABCG2. We conclude that ARRY-334543 significantly reverses drug resistance mediated by ABCG2. (C) 2014 Wiley Periodicals, Inc. C1 [Wang, De-Shen; Xu, Rui-Hua] Sun Yat Sen Univ, Dept Med Oncol, Ctr Canc, State Key Lab Oncol South China,Collaborat Innova, Guangzhou 510060, Guangdong, Peoples R China. [Wang, De-Shen; Patel, Atish; Zhang, Yun-Kai; Wang, Yi-Jun; Kathawala, Rishil J.; Zhang, Hui; Talele, Tanaji T.; Chen, Zhe-Sheng] St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Queens, NY USA. [Sim, Hong-May; Ambudkar, Suresh V.] NCI, Lab Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Chen, ZS (reprint author), St Johns Univ, Dept Pharmaceut Sci, Coll Pharm & Hlth Sci, Jamaica, NY 11439 USA. EM xurh@sysucc.org.cn; chenz@stjohns.edu RI Wang, Yi-Jun/K-3218-2016; Patel, Atish/J-4699-2014 OI Patel, Atish/0000-0002-5549-9166 FU National Institutes of Health [1R15CA143701]; St. John's University [579-1110-7002]; National Institutes of Health, National Cancer Institute, Center for Cancer Research; Ministry of Education [84000-3191003]; International Program of 985 Project, Sun Yat-sen University for overseas study at St. John's University FX Grant sponsor: National Institutes of Health; Grant number: 1R15CA143701; Grant sponsor: St. John's University Research Seed Grant; Grant number: 579-1110-7002; Grant sponsor: Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Grant sponsor: Scholarship Award for Excellent Doctoral Student granted by Ministry of Education; Grant number: 84000-3191003; Grant sponsor: International Program of 985 Project, Sun Yat-sen University for overseas study at St. John's University. NR 48 TC 6 Z9 6 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0730-2312 EI 1097-4644 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD AUG PY 2014 VL 115 IS 8 BP 1381 EP 1391 DI 10.1002/jcb.24787 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AJ5SG UT WOS:000337747300005 PM 24939447 ER PT J AU de Andrade, GB Long, SS Fleming, H Li, W Fuerst, PG AF de Andrade, Gabriel Belem Long, Samuel S. Fleming, Harrison Li, Wei Fuerst, Peter G. TI DSCAM Localization and Function at the Mouse Cone Synapse SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE synapse; development; adhesion; pedicle; spherule; rod; cone; horizontal cell; connectome; mosaic; differential adhesion hypothesis ID BAX-DEFICIENT MICE; BIPOLAR CELLS; MAMMALIAN RETINA; DROSOPHILA DSCAM; PRIMATE RETINA; HOMOTYPIC INTERACTIONS; NETRIN RECEPTOR; SELF-AVOIDANCE; AMACRINE CELLS; NULL ALLELE AB The Down syndrome cell adhesion molecule (DSCAM) is required for regulation of cell number, soma spacing, and cell type-specific dendrite avoidance in many types of retinal ganglion and amacrine cells. In this study we assay the organization of cells making up the outer plexiform layer of the retina in the absence of Dscam. Some types of OFF bipolar cells, type 3b and type 4 bipolar cells, had defects in dendrite arborization in the Dscam mutant retina, whereas other cell types appeared similar to wild type. The cone synapses that these cells project their dendrites to were intact, as visualized by electron microscopy, and had a distribution and density that was not significantly different from that of wild type. The spacing of type 3b bipolar cell dendrites was further analyzed by Voronoi domain analysis, density recovery profiling (DRP) analysis, and nearest neighbor analysis. Spacing was found to be significantly different when wild-type and mutant type 3b bipolar cell dendrites were compared. Defects in arborization of these bipolar cells could not be attributed to the disorganization of inner plexiform layer cells that occurs in the Dscam mutant retina or an increase in cell number, as they arborized when Dscam was targeted in retinal ganglion cells only or in the bax null retina. Localization of DSCAM was assayed and the protein was localized near to cone synapses in mouse, macaque, and ground squirrel retinas. DSCAM protein was detected in several types of bipolar cells, including type 3b and type 4 bipolar cells. (C) 2014 Wiley Periodicals, Inc. C1 [de Andrade, Gabriel Belem; Fuerst, Peter G.] Univ Idaho, Dept Biol Sci, Moscow, ID 83844 USA. [de Andrade, Gabriel Belem] CAPES Fdn, Minist Educ Brazil, BR-70040020 Brasilia, DF, Brazil. [Long, Samuel S.] Washington State Univ, Dept Elect Engn & Comp Sci, Pullman, WA 99164 USA. [Fleming, Harrison] Brigham Young Univ Idaho, Dept Biol, Rexburg, ID 83460 USA. [Li, Wei] NEI, Unit Retinal Neurophysiol, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Fuerst, Peter G.] Univ Washington, Sch Med, WWAMI Med Educ Program, Moscow, ID 83844 USA. RP Fuerst, PG (reprint author), Univ Idaho, Univ Washington WWAMI Med Educ Program, Dept Biol Sci, Moscow, ID 83844 USA. EM fuerst@uidaho.edu FU National Eye Institute [EY020857]; National Institutes of Health [P20 RR016454, P30 GM103324-01, P20 GM103408] FX Grant sponsor: the National Eye Institute; Grant number: EY020857; Grant sponsor: National Institutes of Health (for imaging support); Grant number: P20 RR016454, P30 GM103324-01, and P20 GM103408. NR 57 TC 10 Z9 10 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 EI 1096-9861 J9 J COMP NEUROL JI J. Comp. Neurol. PD AUG 1 PY 2014 VL 522 IS 11 BP 2609 EP 2633 DI 10.1002/cne.23552 PG 25 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA AJ4XW UT WOS:000337684300009 PM 24477985 ER PT J AU Wells, EM Navas-Acien, A Apelberg, BJ Herbstman, JB Jarrett, JM Lin, YH Verdon, CP Ward, C Caldwell, KL Hibbeln, JR Halden, RU Witter, FR Goldman, LR AF Wells, E. M. Navas-Acien, A. Apelberg, B. J. Herbstman, J. B. Jarrett, J. M. Lin, Y. H. Verdon, C. P. Ward, C. Caldwell, K. L. Hibbeln, J. R. Halden, R. U. Witter, F. R. Goldman, L. R. TI Association of selenium and copper with lipids in umbilical cord blood SO JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE LA English DT Article DE copper; infant; newborn; selenium; total cholesterol; triglyceride ID CARDIOVASCULAR RISK-FACTORS; SERUM SELENIUM; GLUTATHIONE-PEROXIDASE; RANDOMIZED-TRIAL; TRACE-ELEMENTS; HEART-DISEASE; YOUNG FINNS; ADULTS; ZINC; SUPPLEMENTATION AB Altered levels of selenium and copper have been linked with altered cardiovascular disease risk factors including changes in blood triglyceride and cholesterol levels. However, it is unclear whether this can be observed prenatally. This cross-sectional study includes 274 singleton births from 2004 to 2005 in Baltimore, Maryland. We measured umbilical cord serum selenium and copper using inductively coupled plasma mass spectrometry. We evaluated exposure levels vis-a-vis umbilical cord serum triglyceride and total cholesterol concentrations in multivariable regression models adjusted for gestational age, birth weight, maternal age, race, parity, smoking, prepregnancy body mass index, n-3 fatty acids and methyl mercury. The percent difference in triglycerides comparing those in the highest v. lowest quartile of selenium was 22.3% (95% confidence interval (CI): 7.1, 39.7). For copper this was 43.8% (95% CI: 25.9, 64.3). In multivariable models including both copper and selenium as covariates, copper, but not selenium, maintained a statistically significant association with increased triglycerides (percent difference: 40.7%, 95% CI: 22.1, 62.1). There was limited evidence of a relationship of increasing selenium with increasing total cholesterol. Our findings provide evidence that higher serum copper levels are associated with higher serum triglycerides in newborns, but should be confirmed in larger studies. C1 [Wells, E. M.] Purdue Univ, Sch Hlth Sci, W Lafayette, IN 47907 USA. [Navas-Acien, A.; Halden, R. U.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. [Navas-Acien, A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Apelberg, B. J.] US FDA, Off Policy, Ctr Tobacco Prod, Rockville, MD 20857 USA. [Herbstman, J. B.] Columbia Univ, Mailman Sch Publ Hlth, Columbia Ctr Childrens Environm Hlth, New York, NY USA. [Jarrett, J. M.; Verdon, C. P.; Ward, C.; Caldwell, K. L.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Div Sci Lab, Atlanta, GA USA. [Lin, Y. H.; Hibbeln, J. R.] NIAAA, NIH, Rockville, MD 20852 USA. [Halden, R. U.] Arizona State Univ, Biodesign Inst, Ctr Environm Secur, Tempe, AZ USA. [Witter, F. R.] Johns Hopkins Univ, Sch Med, Dept Obstet & Gynecol, Baltimore, MD 21205 USA. [Goldman, L. R.] George Washington Univ, Sch Publ Hlth & Hlth Serv, Washington, DC USA. RP Wells, EM (reprint author), Purdue Univ, Sch Hlth Sci, 550 Stadium Mall Dr,HAMP 1269, W Lafayette, IN 47907 USA. EM wells54@purdue.edu RI Halden, Rolf/F-9562-2010; OI Halden, Rolf/0000-0001-5232-7361; Jarrett, Jeffery/0000-0001-5755-3552; Wells, Ellen/0000-0002-7293-1395 FU Maryland Cigarette Restitution Program Research Grant; United States National Institute for Environmental Health Sciences [1R01ES015445]; United States STAR Fellowship Program FX This study received funding from the Maryland Cigarette Restitution Program Research Grant, the United States National Institute for Environmental Health Sciences (R.U.H., grant #: 1R01ES015445), and the United States STAR Fellowship Program (E.M.W.). NR 46 TC 2 Z9 2 U1 2 U2 10 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2040-1744 EI 2040-1752 J9 J DEV ORIG HLTH DIS JI J. Dev. Orig. Health Dis. PD AUG PY 2014 VL 5 IS 4 BP 281 EP 287 DI 10.1017/S2040174414000233 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AJ5VN UT WOS:000337758200002 PM 24965134 ER PT J AU Murphy, E Kohr, M Menazza, S Nguyen, T Evangelista, A Sun, J Steenbergen, C AF Murphy, Elizabeth Kohr, Mark Menazza, Sara Nguyen, Tiffany Evangelista, Alicia Sun, Junhui Steenbergen, Charles TI Signaling by S-nitrosylation in the heart SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Review DE Nitric oxide; Oxidation; Cardioportection ID NITRIC-OXIDE SYNTHASE; PARKINSONS-DISEASE; PRESSURE-OVERLOAD; CONSTITUTIVE-NOS; ACTIVE-SITE; CELL-DEATH; PROTEIN; TETRAHYDROBIOPTERIN; GLUTATHIONYLATION; CYSTEINE AB Nitric oxide is a gaseous signaling molecule that is well-known for the Nobel prize-winning research that defined nitric oxide as a physiological regulator of blood pressure in the cardiovascular system. Nitric oxide can signal via the classical pathway involving activation of guanylyl cyclase or by a post-translational modification, referred to as S-nitrosylation (SNO) that can occur on cysteine residues of proteins. As proteins with cysteine residues are common, this allows for amplification of the nitric oxide signaling. This review will focus on the possible mechanisms through which SNO can alter protein function in cardiac cells, and the role of SNO occupancy in these mechanisms. The specific mechanisms that regulate protein SNO, including redox-dependent processes, will also be discussed. This article is part of a Special Issue entitled "Redox Signalling in the Cardiovascular System". Published by Elsevier Ltd. C1 [Murphy, Elizabeth; Kohr, Mark; Menazza, Sara; Nguyen, Tiffany; Evangelista, Alicia; Sun, Junhui] NHLBI, Cardiac Physiol Lab, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Kohr, Mark; Steenbergen, Charles] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. RP Murphy, E (reprint author), NHLBI, Cardiac Physiol Lab, Syst Biol Ctr, NIH, MSC 1770,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM murphy1@mail.nih.gov OI Kohr, Mark/0000-0002-6034-5962 FU Intramural NIH HHS [ZIA HL006059-05, ZIA HL002066-07]; NHLBI NIH HHS [K99 HL114721, R00 HL114721, R01 HL039752] NR 71 TC 23 Z9 23 U1 1 U2 12 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD AUG PY 2014 VL 73 BP 18 EP 25 DI 10.1016/j.yjmcc.2014.01.003 PG 8 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA AJ3FD UT WOS:000337551000004 PM 24440455 ER PT J AU Xu, JL AF Xu, Jian-Lun TI An identity on order statistics of a set of random variables SO JOURNAL OF MULTIVARIATE ANALYSIS LA English DT Article DE Expectation; Order statistics; Sign-invariant distribution AB When an n x 1 random vector X = (X-1, ..., X-n)(T) has a sign-invariant distribution, Strait (1974) proved that the expectations of max(0, X-1, X-1 + X-2..... X-1 + X-n) and max(0, X-1, ...,X-n) are equal. In this note we assume a weaker condition that (X1, X2,, Xn) and (-X-1, X-2, ... X-n) are equal in distribution and prove a more general result that the expectations of L, (0, X-1, X-1 + X-2, ... , X-1 + Xi) and L, (0, X-1,..., X-n) are equal, where L,(0, X-1, ... X-5) is the rth order statistic of 0, X-1, ... Xn(,) for r = 1, ... , n+1. Published by Elsevier Inc. C1 NCI, Biometry Res Grp, Bethesda, MD 20892 USA. RP Xu, JL (reprint author), NCI, Biometry Res Grp, 9609 Med Ctr Dr,Room 5E124, Bethesda, MD 20892 USA. EM xujia@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 4 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0047-259X J9 J MULTIVARIATE ANAL JI J. Multivar. Anal. PD AUG PY 2014 VL 129 BP 243 EP 244 DI 10.1016/j.jmva.2014.04.016 PG 2 WC Statistics & Probability SC Mathematics GA AJ4LN UT WOS:000337647900020 PM 25258468 ER PT J AU Zro, K Azelmat, S Bendouro, Y Kuhn, JH El Fahime, E Ennaji, MM AF Zro, K. Azelmat, S. Bendouro, Y. Kuhn, J. H. El Fahime, E. Ennaji, M. M. TI PCR-based assay to detect sheeppox virus in ocular, nasal, and rectal swabs from infected Moroccan sheep SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE Capripoxvirus; Poxviridae; Poxvirus; Sheeppox virus; PCR ID POXVIRUS IDENTIFICATION; BIOPSY SAMPLES; GOAT POX; CAPRIPOXVIRUS; CULTURE; DISEASE; GENOMES; ELISA AB Sheeppox is now enzootic in Morocco. The development of a reliable method for rapid diagnosis of the disease is a central part of any control strategy. The aim of this study is to determine the diagnostic value of a variety of clinical samples such as ovine nasal, ocular or rectal swabs for the detection of sheeppox virus (SPPV) by qualitative conventional polymerase chain reaction (PCR), using a single pair of primers targeting the inverted terminal repeats of the SPPV InS-1 strain, a virulent field isolate. Swab and blood samples were collected from forty animals naturally infected with SPPV who had clinical signs of sheeppox. All animals tested PCR-positive for SPPV. Positive results were obtained infrequently with blood samples, whereas swab samples from at least two sites (nasal, ocular, rectal) were positive per evaluated animal. These results indicate that swab samples are suitable for quantitative molecular SPPV diagnosis. PCR product sequences obtained from all types of sheep samples proved to be identical to the corresponding regions of sheeppox virus strain Romania 65. (C) 2014 Published by Elsevier B.V. C1 [Zro, K.; Ennaji, M. M.] Hassan II Univ Mohammedia Casablanca, Fac Sci & Technol Mohammedia, Lab Virol Microbiol & Qual Ecotoxicol & Biodivers, Mohammadia 20650, Morocco. [Zro, K.; Bendouro, Y.] Reg Lab Anal & Res Oujda, Natl Off Safety Food Prod, Oujda 60000, Morocco. [Azelmat, S.] Mil Hosp Instruct Mohammed V, Rabat 14000, Morocco. [Kuhn, J. H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. [El Fahime, E.] Natl Ctr Sci & Tech Res, Funct Genom Platform Sci Res Tech Support Unit Bi, Rabat 14000, Morocco. RP Ennaji, MM (reprint author), Hassan II Univ Mohammedia Casablanca, Fac Sci & Technol Mohammedia, Lab Virol Microbiol & Qual Ecotoxicol & Biodivers, BP 146, Mohammadia 20650, Morocco. EM m.ennaji@yahoo.fr RI Kuhn, Jens H./B-7615-2011 OI Kuhn, Jens H./0000-0002-7800-6045 FU Ministry of Higher Education [UATRS-CNRST 2010]; Ministry of Agriculture and Sea Fisheries of Morocco [MAPE-ONSSA-LRARO-2010]; NIAID [HHSN272200700016I] FX We extend our thanks to Dr. D. Halout and Dr. O. Jelti (Veterinary Service of Oujda) for their support in carrying out this field work. We also thank the staff of the functional genomics platform at Scientific Research Technical Support Unit - Biology - National Center of Scientific and Technical Research for their technical and scientific support. Thanks are also due to Mr. Najib Cheddadi and Laura Bollinger for careful editing of this paper. The project was funded by the Ministry of Higher Education (UATRS-CNRST 2010) and the Ministry of Agriculture and Sea Fisheries of Morocco (MAPE-ONSSA-LRARO-2010). The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services or of the institutions and companies affiliated with the authors. JHK performed this work as an employee of Tunnell Consulting, Inc. under Battelle's prime contract with NIAID, under Contract No. HHSN272200700016I. NR 21 TC 4 Z9 4 U1 1 U2 29 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 EI 1879-0984 J9 J VIROL METHODS JI J. Virol. Methods PD AUG PY 2014 VL 204 BP 38 EP 43 DI 10.1016/j.jviromet.2014.03.019 PG 6 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA AJ4LY UT WOS:000337649100007 PM 24698762 ER PT J AU Kang, MH Reynolds, CP Maris, JM Gorlick, R Kolb, EA Lock, R Carol, H Keir, ST Wu, JR Lyalin, D Kurmasheva, RT Houghton, PJ Smith, MA AF Kang, Min H. Reynolds, C. Patrick Maris, John M. Gorlick, Richard Kolb, E. Anders Lock, Richard Carol, Hernan Keir, Stephen T. Wu, Jianrong Lyalin, Dmitry Kurmasheva, Raushan T. Houghton, Peter J. Smith, Malcolm A. TI Initial testing (stage 1) of the investigational mTOR kinase inhibitor MLN0128 by the pediatric preclinical testing program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; mTOR inhibitor; preclinical testing ID ACUTE LYMPHOBLASTIC-LEUKEMIA; MODELS; RAPAMYCIN AB MLN0128 is an investigational small molecule ATP-competitive inhibitor of the serine/threonine kinase mTOR. MLN0128 was tested against the in vitro panel at concentrations ranging from 0.1nM to 1M and against the PPTP in vivo panels at a dose of 1mg/kg administered orally dailyx28. In vitro the median relative IC50 concentration was 19nM. In vivo MLN0128 induced significant differences in EFS in 24/31 (77%) solid tumor models, but 0/7 ALL xenografts. The modest activity observed for MLN0128 against the PPTP preclinical models is similar to that previously reported for another TOR kinase inhibitor. Pediatr Blood Cancer 2014; 61:1486-1489. (c) 2014 Wiley Periodicals, Inc. C1 [Kang, Min H.; Reynolds, C. Patrick] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Maris, John M.] Univ Penn, Sch Med, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Lock, Richard; Carol, Hernan] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Wu, Jianrong] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Lyalin, Dmitry; Kurmasheva, Raushan T.; Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Kang, MH (reprint author), Texas Tech Univ, Hlth Sci Ctr, Ctr Canc, 3601 4th St STOP 9445, Lubbock, TX 79430 USA. EM min.kang@ttuhsc.edu RI Lock, Richard/G-4253-2013 OI Reynolds, C. Patrick/0000-0002-2827-8536; FU National Cancer Institute [NO1-CM-42216, NO1-CM91001-03, CA21765, CA108786] FX Grant sponsor: National Cancer Institute; Grant numbers: NO1-CM-42216; NO1-CM91001-03; CA21765; CA108786 NR 16 TC 10 Z9 10 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2014 VL 61 IS 8 BP 1486 EP 1489 DI 10.1002/pbc.24989 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AJ5CK UT WOS:000337698600033 PM 24623675 ER PT J AU Carol, H Maris, JM Kang, MH Reynolds, CP Kolb, EA Gorlick, R Keir, ST Wu, JR Kurmasheva, RT Houghton, PJ Smith, MA Lock, RB AF Carol, Hernan Maris, John M. Kang, Min H. Reynolds, C. Patrick Kolb, E. Anders Gorlick, Richard Keir, Stephen T. Wu, Jianrong Kurmasheva, Raushan T. Houghton, Peter J. Smith, Malcolm A. Lock, Richard B. TI Initial testing (stage 1) of the notch inhibitor PF-03084014, by the pediatric preclinical testing program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; notch inhibitors; preclinical testing ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CLINICAL-TRIAL; PHASE-I; CANCER; MODELS AB PF-03084014, a -secretase inhibitor, was tested against the PPTP in vitro cell line panel (1.0nM to 10M) and against the in vivo xenograft panels (administered orally twice daily on Days 1-7 and 15-21). PF-03084014 demonstrated limited in vitro activity, with no cell line achieving 50% inhibition. PF-03084014 induced significant differences in EFS distribution in 14 of 35 (40%) solid tumor xenografts, and 1 of 9 ALL xenografts (which lacked a NOTCH1 mutation), but objective responses were not observed. PF-03084014 demonstrated limited single agent activity in vitro and in vivo against the pediatric preclinical models studied. Pediatr Blood Cancer 2014; 61:1493-1496. (c) 2014 Wiley Periodicals, Inc. C1 [Carol, Hernan; Lock, Richard B.] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Kang, Min H.; Reynolds, C. Patrick] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Wu, Jianrong] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Kurmasheva, Raushan T.; Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Lock, RB (reprint author), Childrens Canc Inst Australia, Leukaemia Biol Program, Randwick, NSW 2031, Australia. EM rlock@ccia.unsw.edu.au RI Lock, Richard/G-4253-2013; OI Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NO1-CM-42216, CA21765, CA108786] FX Grant sponsor: National Cancer Institute; Grant numbers: NO1-CM-42216; CA21765; CA108786 NR 23 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2014 VL 61 IS 8 BP 1493 EP 1496 DI 10.1002/pbc.25026 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AJ5CK UT WOS:000337698600035 PM 24664981 ER PT J AU Smith, MA AF Smith, Malcolm A. TI Lessons learned from adult clinical experience to inform evaluations of VEGF pathway inhibitors in children with cancer SO PEDIATRIC BLOOD & CANCER LA English DT Review DE anti-angiogenesis; kinase inhibitors; vascular endothelial growth factor ID RENAL-CELL CARCINOMA; PHASE-III TRIAL; METASTATIC COLORECTAL-CANCER; REFRACTORY SOLID TUMORS; PRECLINICAL TESTING PROGRAM; SOFT PART SARCOMA; OXALIPLATIN-BASED CHEMOTHERAPY; BEVACIZUMAB PLUS IRINOTECAN; I CONSORTIUM REPORT; ADVANCED HEPATOCELLULAR-CARCINOMA AB Agents targeting the vascular endothelial growth factor (VEGF) pathway have been studied in adults with cancer for nearly two decades. It is important to assess the lessons learned from this adult experience and to see how these lessons can help inform pediatric development of agents in this class. The benefit achieved from the use of VEGF pathway targeted agents for adult cancers has primarily been to delay for several months disease progression and less commonly time to death for conditions in which cure is not a reasonable expectation. VEGF pathway targeted agents have shown no efficacy when applied in the adjuvant setting. For adults with advanced cancer, prolongation of survival by 2-3 months is considered an important achievement in some settings. However, the primary goal of pediatric oncology clinical research is to identify treatments that allow children to be cured of their cancer and to grow to adulthood without treatment-induced limitations that lower their quality of survival. An important question for the pediatric oncology research community, pharmaceutical companies, and regulatory agencies to address in planning for future clinical trials is whether existing data support a role for VEGF pathway targeted agents in contributing to a therapeutic pathway to cure for children with cancer. Pediatr Blood Cancer 2014; 61:1497-1505. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. C1 NCI, Bethesda, MD 20892 USA. RP Smith, MA (reprint author), NCI, 9609 Med Ctr Dr,RM 5-W414,MSC 9737, Bethesda, MD 20892 USA. EM Malcolm.Smith@nih.gov NR 147 TC 1 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2014 VL 61 IS 8 BP 1497 EP 1505 DI 10.1002/pbc.25036 PG 9 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AJ5CK UT WOS:000337698600036 PM 24760743 ER PT J AU Ghirlando, R Zhao, HY Balbo, A Piszczek, G Curth, U Brautigam, CA Schuck, P AF Ghirlando, Rodolfo Zhao, Huaying Balbo, Andrea Piszczek, Grzegorz Curth, Ute Brautigam, Chad A. Schuck, Peter TI Measurement of the temperature of the resting rotor in analytical ultracentrifugation SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Sedimentation velocity; Hydrodynamics; Temperature calibration ID ACCURACY; PROTEINS AB Accurate measurements of rotor temperature are critical for the interpretation of hydrodynamic parameters in analytical ultracentrifugation. We have recently developed methods for a more accurate determination of the temperature of a spinning rotor using iButton temperature loggers. Here we report that the temperature measured with the iButton on the counterbalance of a resting rotor, following thermal equilibration under high vacuum, closely corresponded to the temperature of the spinning rotor with a precision better than 0.2 degrees C. This strategy offers an inexpensive and straightforward approach to monitor the accuracy of the temperature calibration and determine corrective temperature offsets. Published by Elsevier Inc. C1 [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Zhao, Huaying; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. [Balbo, Andrea] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Piszczek, Grzegorz] NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Curth, Ute] Hannover Med Sch, Inst Biophys Chem, D-30625 Hannover, Germany. [Brautigam, Chad A.] Univ Texas SW Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA. RP Ghirlando, R (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM rodolfo.ghirlando@nih.gov; schuckp@mail.nih.gov OI Schuck, Peter/0000-0002-8859-6966 FU Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute of the National Institutes of Health FX We thank Erby Perdue and William Brenneman for their expert advice and for taking excellent care of our analytical ultracentrifuges. This work was supported by the Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Heart, Lung, and Blood Institute of the National Institutes of Health. NR 15 TC 3 Z9 3 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 EI 1096-0309 J9 ANAL BIOCHEM JI Anal. Biochem. PD AUG 1 PY 2014 VL 458 BP 37 EP 39 DI 10.1016/j.ab.2014.04.029 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AJ3FC UT WOS:000337550900007 PM 24799348 ER PT J AU Sonoda, S Nagineni, CN Kitamura, M Spee, C Kannan, R Hinton, DR AF Sonoda, Shozo Nagineni, Chandrasekharam N. Kitamura, Mizuki Spee, Christine Kannan, Ram Hinton, David R. TI Ceramide inhibits connective tissue growth factor expression by human retinal pigment epithelial cells SO CYTOKINE LA English DT Article DE Retinal pigment epithelium; Ceramide; TGF-beta; CTGF; Retinal fibrosis ID CHOROIDAL NEOVASCULARIZATION; PATHOGENESIS AB Connective tissue growth factor (CTGF) is known to be involved in retinal fibrotic disorders. We used human retinal pigment epithelial cells (HRPE), which play critical roles in retinal fibrosis, to examine the expression of CTGF and its regulation by ceramide and TGF-beta. Real-time PCR analysis showed downregulation of CTGF mRNA by C-2 ceramide and upregulation by TGF-beta. C-2 ceramide also inhibited constitutive and TGF-beta-enhanced CTGF secretion by HRPE cells. Predominant secretion (>80% of total) of CTGF from the apical side was observed in highly polarized HRPE cells. Fumonosin, an inhibitor of ceramide synthesis, stimulated CTGF secretion while 4HPR, an activator of ceramide synthesis, downregulated CTGF secretion. Based on these results demonstrating ceramide regulation of CTGF secretion by HRPE, we suggest that ceramide may have therapeutic potential for the treatment of retinal fibrotic diseases by inhibiting CTGF production. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Sonoda, Shozo; Kitamura, Mizuki; Kannan, Ram] Doheny Eye Inst, Arnold & Mabel Beckman Macular Res Ctr, Los Angeles, CA 90033 USA. [Nagineni, Chandrasekharam N.] NEI, Immunol Lab, Bethesda, MD 20892 USA. [Spee, Christine; Hinton, David R.] USC, Keck Sch Med, Dept Ophthalmol, Los Angeles, CA USA. [Spee, Christine; Hinton, David R.] USC, Keck Sch Med, Dept Pathol, Los Angeles, CA USA. RP Hinton, DR (reprint author), Univ So Calif, Keck Sch, Dept Pathol, 2011 Zonal Ave,HMR 209, Los Angeles, CA 90089 USA. EM dhinton@usc.edu OI Kannan, Ram/0000-0002-1583-3414 FU Intramural and extramural NIH [EY01545, EY03040]; Research to Prevent Blindness, Inc.; Arnold and Mabel Beckman Foundation FX We thank Ernesto Barron for assistance with the figures. This work was supported by Intramural and extramural NIH Grants (EY01545; EY03040) and Grants from Research to Prevent Blindness, Inc. and Arnold and Mabel Beckman Foundation. NR 14 TC 1 Z9 1 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD AUG PY 2014 VL 68 IS 2 BP 137 EP 140 DI 10.1016/j.cyto.2014.03.011 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA AI8YA UT WOS:000337211700010 PM 24758915 ER PT J AU Ehsani, JP Simons-Morton, B Xie, YL Klauer, SG Albert, PS AF Ehsani, Johnathon P. Simons-Morton, Bruce Xie, Yunlong Klauer, Sheila G. Albert, Paul S. TI The association between kinematic risky driving among parents and their teenage children: Moderation by shared personality characteristics SO ACCIDENT ANALYSIS AND PREVENTION LA English DT Article DE Parent; Teenager; Family; Driving behavior; Naturalistic driving ID SENSATION SEEKING; DRIVERS; BEHAVIOR; PREDICTION; CRASHES; EVENTS AB This study examined the driving behavior of 42 parent-teenager dyads for 18 months, under naturalistic driving conditions. At baseline participants' personality characteristics were assessed. Objective risky driving measures (kinematic risky driving) were captured by accelerometers for the duration of the study. To estimate teenage and parent correlations in kinematic risky driving, separate Poisson regression models were fit for teenagers and parents. Standardized residuals were computed for each trip for each individual. Correlations were obtained by estimating the Spearman rank correlations of the individual average residuals across teenagers and parents. The bootstrap technique was used to estimate the standard errors associated with the parent-teenager correlations. The overall correlation between teenage and parent kinematic risky driving for the 18-month study period was positive, but weak (r=0.18). When the association between parent and teenagers' risky driving was adjusted for shared personality characteristics, the correlation reduced to 0.09. Although interesting, the 95% confidence intervals on the difference between these two estimates overlapped zero. We conclude that the weak similarity in parent-teen kinematic risky driving was partly explained by shared personality characteristics. Published by Elsevier Ltd. C1 [Ehsani, Johnathon P.; Simons-Morton, Bruce; Xie, Yunlong; Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Klauer, Sheila G.] Virginia Tech, Transportat Inst, Blacksburg, VA USA. RP Ehsani, JP (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. EM johnathon.ehsani@nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural NIH HHS [Z01 HD001707-10, Z99 HD999999]; NICHD NIH HHS [N01-HD-5-3405] NR 30 TC 3 Z9 3 U1 1 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0001-4575 EI 1879-2057 J9 ACCIDENT ANAL PREV JI Accid. Anal. Prev. PD AUG PY 2014 VL 69 SI SI BP 56 EP 61 DI 10.1016/j.aap.2014.03.015 PG 6 WC Ergonomics; Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary; Transportation SC Engineering; Public, Environmental & Occupational Health; Social Sciences - Other Topics; Transportation GA AI2OF UT WOS:000336697100008 PM 24745931 ER PT J AU Samuel, W Kutty, RK Duncan, T Vijayasarathy, C Kuo, BC Chapa, KM Redmond, TM AF Samuel, William Kutty, R. Krishnan Duncan, Todd Vijayasarathy, Camasamudram Kuo, Bryan C. Chapa, Krysten M. Redmond, T. Michael TI Fenretinide Induces Ubiquitin-Dependent Proteasomal Degradation of Stearoyl-CoA Desaturase in Human Retinal Pigment Epithelial Cells SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; INDUCED INSULIN-RESISTANCE; COENZYME-A DESATURASE; ACTIVATING ENZYME E1; FATTY-ACIDS; DIHYDROCERAMIDE DESATURASE; SKELETAL-MUSCLE; SERINE PALMITOYLTRANSFERASE; CERAMIDE BIOSYNTHESIS; ENDOTHELIAL-CELLS AB Stearoyl-CoA desaturase (SCD, SCD1), an endoplasmic reticulum (ER) resident protein and a rate-limiting enzyme in monounsaturated fatty acid biosynthesis, regulates cellular functions by controlling the ratio of saturated to monounsaturated fatty acids. Increase in SCD expression is strongly implicated in the proliferation and survival of cancer cells, whereas its decrease is known to impair proliferation, induce apoptosis, and restore insulin sensitivity. We examined whether fenretinide, (N-(4-hydroxyphenyl)retinamide, 4HPR), which induces apoptosis in cancer cells and recently shown to improve insulin sensitivity, can modulate the expression of SCD. We observed that fenretinide decreased SCD protein and enzymatic activity in the ARPE-19 human retinal pigment epithelial cell line. Increased expression of BiP/GRP78, ATF4, and GADD153 implicated ER stress. Tunicamycin and thapsigargin, compounds known to induce ER stress, also decreased the SCD protein. This decrease was completely blocked by the proteasome inhibitor MG132. In addition, PYR41, an inhibitor of ubiquitin activating enzyme E1, blocked the fenretinide-mediated decrease in SCD. Immunoprecipitation analysis using anti-ubiquitin and anti-SCD antibodies and the blocking of SCD loss by PYR41 inhibition of ubiquitination further corroborate that fenretinide mediates the degradation of SCD in human RPE cells via the ubiquitin-proteasome dependent pathway. Therefore, the effect of fenretinide on SCD should be considered in its potential therapeutic role against cancer, type-2 diabetes, and retinal diseases. J. Cell. Physiol. 229: 1028-1038, 2014. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. C1 [Samuel, William; Kutty, R. Krishnan; Duncan, Todd; Kuo, Bryan C.; Chapa, Krysten M.; Redmond, T. Michael] NEI, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Vijayasarathy, Camasamudram] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. RP Samuel, W (reprint author), NEI, Lab Retinal Cell & Mol Biol, NIH, Bldg 6 Room 112A,6 Ctr Dr, Bethesda, MD 20892 USA. EM samuelw@nei.nih.gov OI Redmond, T. Michael/0000-0002-1813-5291 FU Intramural Research Program of the National Eye Institute, National Institutes of Health FX Contract grant sponsor: Intramural Research Program of the National Eye Institute, National Institutes of Health. NR 72 TC 3 Z9 3 U1 0 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9541 EI 1097-4652 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD AUG PY 2014 VL 229 IS 8 BP 1028 EP 1038 DI 10.1002/jcp.24527 PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA AF7SV UT WOS:000334915900008 PM 24357007 ER PT J AU Song, N Choi, JY Sung, H Chung, S Song, M Park, SK Han, W Lee, JW Kim, MK Yoo, KY Ahn, SH Noh, DY Kang, D AF Song, Nan Choi, Ji-Yeob Sung, Hyuna Chung, Seokang Song, Minkyo Park, Sue K. Han, Wonshik Lee, Jong Won Kim, Mi Kyung Yoo, Keun-Young Ahn, Sei-Hyun Noh, Dong-Young Kang, Daehee TI Heterogeneity of epidemiological factors by breast tumor subtypes in Korean women: A case-case study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE epidemiological factors; heterogeneity; breast cancer; tumor subtypes; case-case study ID CANCER ASSOCIATION CONSORTIUM; BODY-MASS INDEX; RISK-FACTORS; CLINICAL-IMPLICATIONS; REPRODUCTIVE FACTORS; MOLECULAR SUBTYPES; CHINESE WOMEN; AGE; DISEASE; SUSCEPTIBILITY AB Breast cancer is heterogeneous in clinical behavior by subtypes; however, it is unclear how this heterogeneity is related to epidemiological factors. To evaluate the differences in epidemiological factors by breast tumor subtypes, we investigated the associations of epidemiological factors between tumor subtypes in Korean women. From the Seoul Breast Cancer Study, a total of 3,058 patients with breast cancer were included in the analyses. Tumor subtypes were classified based on hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) statuses. The epidemiological factors of each subtype were compared through case-case analyses using multivariate a polytomous logistic regression model adjusted for age and recruiting centers. The distribution of the subtypes was as follows: 1,714 HR+ HER2- (56.0%), 414 HR+ HER2+ (13.5%), 423 HR- HER2+ (13.9%) and 507 HR- HER2- (16.6%) patients with breast cancer. There were significant differences in age, menopausal status, age at menarche, number of children, age at first full-term pregnancy (FFTP), duration of breastfeeding and duration of endogenous estrogen exposure between tumor subtypes (p < 0.05). Compared to HR+ HER2- patients, the other subtype patients showed more frequency in having more numbers of children and less frequency in having earlier menarche, later FFTP and longer endogenous estrogen exposure. Although HR- HER2+ patients were less obese, HR- HER2- patients were younger and more obese. In conclusion, age, body mass index and reproductive factors were differentially associated with breast tumor subtypes suggesting a possible distinct etiology for tumor progression. C1 [Song, Nan; Choi, Ji-Yeob; Park, Sue K.; Han, Wonshik; Noh, Dong-Young; Kang, Daehee] Seoul Natl Univ, Canc Res Inst, Coll Med, Seoul 110799, South Korea. [Choi, Ji-Yeob; Sung, Hyuna; Chung, Seokang; Song, Minkyo; Park, Sue K.; Kang, Daehee] Seoul Natl Univ, Dept Biomed Sci, Coll Med, Seoul 110799, South Korea. [Choi, Ji-Yeob; Song, Minkyo; Park, Sue K.; Yoo, Keun-Young; Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul 110799, South Korea. [Sung, Hyuna] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Han, Wonshik; Noh, Dong-Young] Seoul Natl Univ, Dept Surg, Coll Med, Seoul 110799, South Korea. [Lee, Jong Won; Ahn, Sei-Hyun] Univ Ulsan, Coll Med, Dept Surg, Seoul, South Korea. [Lee, Jong Won; Ahn, Sei-Hyun] ASAN Med Ctr, Seoul, South Korea. [Kim, Mi Kyung] Natl Canc Ctr, Div Canc Epidemiol & Management, Goyang Si, Gyeonggi Do, South Korea. RP Choi, JY (reprint author), Seoul Natl Univ, Dept Biomed Sci, Coll Med, 103 Daehak Ro, Seoul 110799, South Korea. EM jiyeob.choi@gmail.com RI Han, Wonshik/B-3699-2008; OI Song, Minkyo/0000-0002-9412-2871 FU Ministry of Education, Science and Technology (Basic Research Laboratory Program through the National Research Foundation of Korea) [2012-0000347] FX Grant sponsor: Ministry of Education, Science and Technology (Basic Research Laboratory Program through the National Research Foundation of Korea); Grant number: 2012-0000347 NR 48 TC 2 Z9 2 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD AUG 1 PY 2014 VL 135 IS 3 BP 669 EP 681 DI 10.1002/ijc.28685 PG 13 WC Oncology SC Oncology GA AH2IX UT WOS:000335945800014 PM 24916400 ER PT J AU Dantuma, NP Bott, LC AF Dantuma, Nico P. Bott, Laura C. TI The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution SO FRONTIERS IN MOLECULAR NEUROSCIENCE LA English DT Review DE neurodegeneration; ubiquitin; proteasome; proteolysis; protein quality control ID BULBAR MUSCULAR-ATROPHY; AMYOTROPHIC-LATERAL-SCLEROSIS; TRANSGENIC MOUSE MODEL; DEUBIQUITINATING ENZYME ATAXIN-3; REGULATES AGGRESOME FORMATION; ANDROGEN RECEPTOR TOXICITY; VALOSIN-CONTAINING PROTEIN; GREEN FLUORESCENT PROTEIN; MOTOR-NEURON DEGENERATION; INCLUSION-BODY FORMATION AB The ubiquitin-proteasome system (UPS) has been implicated in neurodegenerative diseases based on the presence of deposits consisting of ubiquitylated proteins in affected neurons. It has been postulated that aggregation-prone proteins associated with these disorders, such as alpha-synuclein, beta-amyloid peptide, and polyglutamine proteins, compromise UPS function, and delay the degradation of other proteasome substrates. Many of these substrates play important regulatory roles in signaling, cell cycle progression, or apoptosis, and their inadvertent stabilization due to an overloaded and improperly functioning UPS may thus be responsible for cellular demise in neurodegeneration. Over the past decade, numerous studies have addressed the UPS dysfunction hypothesis using various model systems and techniques that differ in their readout and sensitivity. While an inhibitory effect of some disease proteins on the UPS has been demonstrated, increasing evidence attests that the UPS remains operative in many disease models, which opens new possibilities for treatment. In this review, we will discuss the paradigm shift that repositioned the UPS from being a prime suspect in the pathophysiology of neurodegeneration to an attractive therapeutic target that can be harnessed to accelerate the clearance of disease-linked proteins. C1 [Dantuma, Nico P.; Bott, Laura C.] Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden. [Bott, Laura C.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Dantuma, NP (reprint author), Karolinska Inst, Dept Cell & Mol Biol, Eulers Vag 3, S-17177 Stockholm, Sweden. EM nico.dantuma@ki.se OI Dantuma, Nico/0000-0002-6090-4170 FU Swedish Research Council; Swedish Cancer Society; Karolinska Institute FX We thank Florian Salomons and Emily Foran for critical reading of the manuscript. The Dantuma lab is supported by the Swedish Research Council, the Swedish Cancer Society and the Karolinska Institute. NR 219 TC 42 Z9 42 U1 3 U2 11 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5099 J9 FRONT MOL NEUROSCI JI Front. Molec. Neurosci. PD JUL 31 PY 2014 VL 7 AR 70 DI 10.3389/fnmo1.2014.00070 PG 18 WC Neurosciences SC Neurosciences & Neurology GA AZ2LI UT WOS:000348064700001 PM 25132814 ER PT J AU Koupenova, M Vitseva, O MacKay, CR Beaulieu, LM Benjamin, EJ Mick, E Kurt-Jones, EA Ravid, K Freedman, JE AF Koupenova, Milka Vitseva, Olga MacKay, Christopher R. Beaulieu, Lea M. Benjamin, Emelia J. Mick, Eric Kurt-Jones, Evelyn A. Ravid, Katya Freedman, Jane E. TI Platelet-TLR7 mediates host survival and platelet count during viral infection in the absence of platelet-dependent thrombosis SO BLOOD LA English DT Article ID IMMUNODEFICIENCY-VIRUS-INFECTION; HUMAN BLOOD PLATELETS; B-CELL RESPONSES; P-SELECTIN; SIGNALING PATHWAY; IN-VIVO; INNATE IMMUNITY; RECEPTOR 7; ACTIVATION; NEUTROPHILS AB Viral infections have been associated with reduced platelet counts, the biological significance of which has remained elusive. Here, we show that infection with encephalomyocarditis virus (EMCV) rapidly reduces platelet count, and this response is attributed to platelet Toll-like receptor 7 (TLR7). Platelet-TLR7 stimulation mediates formation of large platelet-neutrophil aggregates, both in mouse and human blood. Intriguingly, this process results in internalization of platelet CD41-fragments by neutrophils, as assessed biochemically and visualized by microscopy, with no influence on platelet prothrombotic properties. The mechanism includes TLR7-mediated platelet granule release, translocation of P-selectin to the cellsurface, and a consequent increase in platelet-neutrophil adhesion. Viral infection of platelet-depleted mice also led to increased mortality. Transfusion of wild-type, TLR7-expressing platelets into TLR7-deficient mice caused a drop in platelet count and increased survival post EMCV infection. Thus, this study identifies a new link between platelets and their response to single-stranded RNA viruses that involves activation of TLR7. Finally, platelet-TLR7 stimulation is independent of thrombosis and has implications to the host immune response and survival. C1 [Koupenova, Milka; Vitseva, Olga; Beaulieu, Lea M.; Freedman, Jane E.] Univ Massachusetts, Sch Med, Dept Med, Div Cardiovasc Med, Worcester, MA 01605 USA. [Koupenova, Milka; Benjamin, Emelia J.; Ravid, Katya] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Koupenova, Milka; Benjamin, Emelia J.; Ravid, Katya] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [MacKay, Christopher R.; Kurt-Jones, Evelyn A.] Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, Dept Med, Worcester, MA 01605 USA. [Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Benjamin, Emelia J.] Boston Univ, Framingham Heart Inst, Framingham, MA USA. [Mick, Eric] Univ Massachusetts, Sch Med, Dept Med, Div Quantitat Hlth Sci, Worcester, MA 01605 USA. [Ravid, Katya] Boston Univ, Sch Med, Evans Ctr Interdisciplinary Biomed Res, Boston, MA 02118 USA. RP Freedman, JE (reprint author), Univ Massachusetts, Sch Med, Albert Sherman Ctr, 368 Plantat St,S7-1051, Worcester, MA 01605 USA. EM Jane.Freedman@umassmed.edu OI Benjamin, Emelia/0000-0003-4076-2336; Mick, Eric/0000-0001-8505-8145 FU National Institutes of Health, National Heart, Lung, and Blood Institute [HL-112311-02, HL087201, RFA-HL-12-008, HL80442, N01-HC 25195, 1R01AG028321]; National Institute of Allergy and Infectious Diseases [P01 AI078894, AI083215]; National Heart, Lung, and Blood Institute T32 grant [HL007224] FX This work was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute (HL-112311-02 to J.E.F., HL087201 to J.E.F., RFA-HL-12-008 to J.E.F., HL80442 to K. R., N01-HC 25195 to E.J.B., 1R01AG028321 to E.J.B.), National Institute of Allergy and Infectious Diseases (P01 AI078894 to J.E.F. and L. M. B., AI083215 to E.A.K.-J.), and National Heart, Lung, and Blood Institute T32 grant HL007224 to M.K. NR 51 TC 35 Z9 36 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 31 PY 2014 VL 124 IS 5 BP 791 EP 802 DI 10.1182/blood-2013-11-536003 PG 12 WC Hematology SC Hematology GA AQ2MG UT WOS:000342619900023 PM 24755410 ER PT J AU Gao, F Bonsignori, M Liao, HX Kumar, A Xia, SM Lu, XZ Cai, FP Hwang, KK Song, HS Zhou, TQ Lynch, RM Alam, SM Moody, MA Ferrari, G Berrong, M Kelsoe, G Shaw, GM Hahn, BH Montefiori, DC Kamanga, G Cohen, MS Hraber, P Kwong, PD Korber, BT Mascola, JR Kepler, TB Haynes, BF AF Gao, Feng Bonsignori, Mattia Liao, Hua-Xin Kumar, Amit Xia, Shi-Mao Lu, Xiaozhi Cai, Fangping Hwang, Kwan-Ki Song, Hongshuo Zhou, Tongqing Lynch, Rebecca M. Alam, S. Munir Moody, M. Anthony Ferrari, Guido Berrong, Mark Kelsoe, Garnett Shaw, George M. Hahn, Beatrice H. Montefiori, David C. Kamanga, Gift Cohen, Myron S. Hraber, Peter Kwong, Peter D. Korber, Bette T. Mascola, John R. Kepler, Thomas B. Haynes, Barton F. TI Cooperation of B Cell Lineages in Induction of HIV-1-Broadly Neutralizing Antibodies SO CELL LA English DT Article ID CD4 BINDING-SITE; HIV-1-INFECTED INDIVIDUALS; CONFORMATIONAL EPITOPE; MONOCLONAL-ANTIBODIES; BROAD NEUTRALIZATION; IMMUNE-RESPONSES; GERMINAL-CENTERS; HIV-1 INFECTION; AFFINITY; MUTATIONS AB Development of strategies for induction of HIV-1 broadly neutralizing antibodies (bnAbs) by vaccines is a priority. Determining the steps of bnAb induction in HIV-1-infected individuals who make bnAbs is a key strategy for immunogen design. Here, we study the B cell response in a bnAb-producing individual and report cooperation between two B cell lineages to drive bnAb development. We isolated a virus-neutralizing antibody lineage that targeted an envelope region (loop D) and selected virus escape mutants that resulted in both enhanced bnAb lineage envelope binding and escape mutant neutralization-traits associated with increased B cell antigen drive. Thus, in this individual, two B cell lineages cooperated to induce the development of bnAbs. Design of vaccine immunogens that simultaneously drive both helper and broadly neutralizing B cell lineages may be important for vaccine-induced recapitulation of events that transpire during the maturation of neutralizing antibodies in HIV-1-infected individuals. C1 [Gao, Feng; Bonsignori, Mattia; Liao, Hua-Xin; Kumar, Amit; Xia, Shi-Mao; Lu, Xiaozhi; Cai, Fangping; Hwang, Kwan-Ki; Song, Hongshuo; Alam, S. Munir; Moody, M. Anthony; Ferrari, Guido; Berrong, Mark; Kelsoe, Garnett; Montefiori, David C.; Haynes, Barton F.] Duke Univ, Sch Med, Human Vaccine Inst, Dept Med, Durham, NC 27710 USA. [Gao, Feng; Bonsignori, Mattia; Liao, Hua-Xin; Kumar, Amit; Xia, Shi-Mao; Lu, Xiaozhi; Cai, Fangping; Hwang, Kwan-Ki; Song, Hongshuo; Alam, S. Munir; Moody, M. Anthony; Ferrari, Guido; Berrong, Mark; Kelsoe, Garnett; Montefiori, David C.; Haynes, Barton F.] Duke Univ, Sch Med, Human Vaccine Inst, Dept Surg, Durham, NC 27710 USA. [Gao, Feng; Bonsignori, Mattia; Liao, Hua-Xin; Kumar, Amit; Xia, Shi-Mao; Lu, Xiaozhi; Cai, Fangping; Hwang, Kwan-Ki; Song, Hongshuo; Alam, S. Munir; Moody, M. Anthony; Ferrari, Guido; Berrong, Mark; Kelsoe, Garnett; Montefiori, David C.; Haynes, Barton F.] Duke Univ, Sch Med, Human Vaccine Inst, Dept Pediat & Immunol, Durham, NC 27710 USA. [Gao, Feng; Bonsignori, Mattia; Liao, Hua-Xin; Kumar, Amit; Xia, Shi-Mao; Lu, Xiaozhi; Cai, Fangping; Hwang, Kwan-Ki; Song, Hongshuo; Alam, S. Munir; Moody, M. Anthony; Ferrari, Guido; Berrong, Mark; Kelsoe, Garnett; Montefiori, David C.; Haynes, Barton F.] Duke Univ, Ctr HIV AIDS Vaccine Immunol Immunogen Discovery, Durham, NC 27710 USA. [Zhou, Tongqing; Lynch, Rebecca M.; Kwong, Peter D.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Shaw, George M.; Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Shaw, George M.; Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Kamanga, Gift] UNC Project, Lilongwe, Malawi. [Kamanga, Gift] Univ N Carolina, Dept Hlth Policy, Chapel Hill, NC 27599 USA. [Kamanga, Gift] Univ N Carolina, Dept Management, Chapel Hill, NC 27599 USA. [Cohen, Myron S.] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. [Cohen, Myron S.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Cohen, Myron S.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Hraber, Peter; Korber, Bette T.] Los Alamos Natl Lab, Div Theoret, Los Alamos, NM 87544 USA. [Kepler, Thomas B.] Boston Univ, Dept Microbiol, Boston, MA 02215 USA. RP Gao, F (reprint author), Duke Univ, Sch Med, Human Vaccine Inst, Dept Med, Durham, NC 27710 USA. EM fgao@duke.edu; barton.haynes@duke.edu RI Zhou, Tongqing/A-6880-2010; Ferrari, Guido/A-6088-2015; OI Zhou, Tongqing/0000-0002-3935-4637; Korber, Bette/0000-0002-2026-5757; Hraber, Peter/0000-0002-2920-4897 FU Center For HIV/AIDS Vaccine Immunology-Immunogen Discovery grant (CHAVI-ID) [UM1 AI100645]; Duke University Center for AIDS Research (CFAR) [P30-AI-64518]; intramural research program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH FX This study was supported by the Center For HIV/AIDS Vaccine Immunology-Immunogen Discovery grant (CHAVI-ID; UM1 AI100645), the Duke University Center for AIDS Research (CFAR; P30-AI-64518), and the intramural research program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH. We thank Mark Hallen and Jiang Zhu for assistance and discussion on calculation of binding affinity and Daniel M Kozink, Abby Cooper, and Florence Perrin for technical assistance. Provisional patents have been filed by B. F. H., H.-X. L., R. M. L., T.Z., F. G., G. M. S., B. H. H., T. B. K., B. T. K., P. D. K., J.R.M., and P. H. M. S. C. served at Advisory Board of Roche Molecular Systems, Expert Advisory Panel of Gates Foundation, and Pipeline Advisory Board of Janssen Global Services. NR 51 TC 78 Z9 81 U1 2 U2 31 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 31 PY 2014 VL 158 IS 3 BP 481 EP 491 DI 10.1016/j.cell.2014.06.022 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9RB UT WOS:000340944300004 PM 25065977 ER PT J AU Gerard, A Patino-Lopez, G Beemiller, P Nambiar, R Ben-Aissa, K Liu, Y Totah, FJ Tyska, MJ Shaw, S Krummel, MF AF Gerard, Audrey Patino-Lopez, Genaro Beemiller, Peter Nambiar, Rajalakshmi Ben-Aissa, Khadija Liu, Yin Totah, Fadi J. Tyska, Matthew J. Shaw, Stephen Krummel, Matthew F. TI Detection of Rare Antigen-Presenting Cells through T Cell-Intrinsic Meandering Motility, Mediated by Myo1g SO CELL LA English DT Article ID MYOSIN-I; LYMPH-NODES; MEMBRANE TENSION; PLASMA-MEMBRANE; DENDRITIC CELLS; IMMUNE-SYSTEM; LEVY WALKS; MIGRATION; LYMPHOCYTES; CHEMOKINES AB To mount an immune response, T lymphocytes must successfully search for foreign material bound to the surface of antigen-presenting cells. How T cells optimize their chances of encountering and responding to these antigens is unknown. T cell motility in tissues resembles a random or Levy walk and is regulated in part by external factors including chemokines and lymph-node topology, but motility parameters such as speed and propensity to turn may also be cell intrinsic. Here we found that the unconventional myosin 1g (Myo1g) motor generates membrane tension, enforces cell-intrinsic meandering search, and enhances T-DC interactions during lymph-node surveillance. Increased turning and meandering motility, as opposed to ballistic motility, is enhanced by Myo1g. Myo1g acts as a "turning motor'' and generates a form of cellular "flanerie.'' Modeling and antigen challenges show that these intrinsically programmed elements of motility search are critical for the detection of rare cognate antigen-presenting cells. C1 [Gerard, Audrey; Beemiller, Peter; Totah, Fadi J.; Krummel, Matthew F.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [Patino-Lopez, Genaro; Ben-Aissa, Khadija; Liu, Yin; Shaw, Stephen] NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. [Nambiar, Rajalakshmi; Tyska, Matthew J.] Vanderbilt Univ, Sch Med, Dept Cell & Dev Biol, Nashville, TN 37205 USA. RP Krummel, MF (reprint author), Univ Calif San Francisco, Dept Pathol, 513 Parnassus Ave,HSW512, San Francisco, CA 94143 USA. EM matthew.krummel@ucsf.edu OI Patino-Lopez, Genaro/0000-0002-8716-722X FU NIH [DK075555, AI052116]; American Heart Association; NIH Intramural Research Program FX We thank the Biological Imaging Development Center personnel for technical assistance with imaging. We thank G. A. Bizarri, F. Bartumeus, G. Altan-Bonnet, D. Barber D. Erle, and S. Dumont for helpful comments and suggestions and the ImmGen consortium for array data. We thank M. B. Headley for critical reading of the manuscript. This work was supported by grants from NIH (DK075555) and American Heart Association to M.J.T., The NIH Intramural Research Program to S. S., and NIH (AI052116) to M. F. K. NR 53 TC 22 Z9 23 U1 2 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 31 PY 2014 VL 158 IS 3 BP 492 EP 505 DI 10.1016/j.cell.2014.05.044 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9RB UT WOS:000340944300005 PM 25083865 ER PT J AU Nair-Gupta, P Baccarini, A Tung, N Seyffer, F Florey, O Huang, YJ Banerjee, M Overholtzer, M Roche, PA Tampe, R Brown, BD Amsen, D Whiteheart, SW Blander, JM AF Nair-Gupta, Priyanka Baccarini, Alessia Tung, Navpreet Seyffer, Fabian Florey, Oliver Huang, Yunjie Banerjee, Meenakshi Overholtzer, Michael Roche, Paul A. Tampe, Robert Brown, Brian D. Amsen, Derk Whiteheart, Sidney W. Blander, J. Magarian TI TLR Signals Induce Phagosomal MHC-I Delivery from the Endosomal Recycling Compartment to Allow Cross-Presentation SO CELL LA English DT Article ID DENDRITIC CELLS; ANTIGEN; MATURATION; MEMBRANE; IMMUNITY; SNAP-23; CROSSPRESENTATION; PHOSPHORYLATION; RECOGNITION; ACTIVATION AB Adaptation of the endoplasmic reticulum (ER) pathway for MHC class I (MHC-I) presentation in dendritic cells enables cross-presentation of peptides derived from phagocytosed microbes, infected cells, or tumor cells to CD8 T cells. How these peptides intersect with MHC-I molecules remains poorly understood. Here, we show that MHC-I selectively accumulate within phagosomes carrying microbial components, which engage Toll-like receptor (TLR) signaling. Although cross-presentation requires Sec22b-mediated phagosomal recruitment of the peptide loading complex from the ER-Golgi intermediate compartment (ERGIC), this step is independent of TLR signaling and does not deliver MHC-I. Instead, MHC-I are recruited from an endosomal recycling compartment (ERC), which is marked by Rab11a, VAMP3/cellubrevin, and VAMP8/endobrevin and holds large reserves of MHC-I. While Rab11a activity stocks ERC stores with MHC-I, MyD88-dependent TLR signals drive I kappa B-kinase (IKK) 2-mediated phosphorylation of phagosome-associated SNAP23. Phospho-SNAP23 stabilizes SNARE complexes orchestrating ERC-phagosome fusion, enrichment of phagosomes with ERC-derived MHC-I, and subsequent cross-presentation during infection. C1 [Nair-Gupta, Priyanka; Baccarini, Alessia; Tung, Navpreet; Brown, Brian D.; Blander, J. Magarian] Icahn Sch Med Mt Sinai, Inst Immunol, New York, NY 10029 USA. [Tung, Navpreet; Brown, Brian D.; Blander, J. Magarian] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Nair-Gupta, Priyanka; Tung, Navpreet; Blander, J. Magarian] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [Baccarini, Alessia; Brown, Brian D.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Nair-Gupta, Priyanka; Tung, Navpreet] Icahn Sch Med Mt Sinai, Grad Sch Biol Sci, New York, NY 10029 USA. [Seyffer, Fabian; Tampe, Robert] Goethe Univ Frankfurt, Inst Biochem, Bioctr, Cluster Excellence Macromol Complexes, D-60438 Frankfurt, Germany. [Florey, Oliver; Overholtzer, Michael] Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10065 USA. [Huang, Yunjie; Banerjee, Meenakshi; Whiteheart, Sidney W.] Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA. [Roche, Paul A.] NCI, Expt Cell Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Amsen, Derk] Sanquin Res & Landsteiner Lab, Dept Hematopoiesis, NL-1066 CX Amsterdam, Netherlands. RP Blander, JM (reprint author), Icahn Sch Med Mt Sinai, Inst Immunol, New York, NY 10029 USA. EM julie.blander@mssm.edu RI Fachbereich14, Dekanat/C-8553-2015; OI Whiteheart, Sidney/0000-0001-5577-0473 FU NIH [5R24 CA095823-04, S10 RR0 9145-01, AI073899, HL56652, HL082193, AI104848, CA154649, DK072201, AI095245]; NSF [DBI-9724504]; German Research Foundation-Membrane Transport and Communication [SFB 807, TA157/7]; Landsteiner Foundation for Blood Research; Dutch Organization for Science; Burroughs Wellcome Fund; American Cancer Society [117254] FX We thank E. S. Trombetta, T. Moran, A. Garcia-Sastre, C. Harding, R. Germain, N. Aronin, M. M. DiFiglia, I. Verma, K. Suzuki, and S. Amigorena for reagents. We are grateful to E. Kavalali, B. Trinite, F. Gebhardt, H. Peche, current J.M.B. laboratory members, H. Gupta, M. Blander, and S.J. Blander for technical assistance, discussions, and support. ISMMS-Microscopy Shared Resource Facility was supported by NIH grants 5R24 CA095823-04, S10 RR0 9145-01, and NSF DBI-9724504. This work was supported by NIH grants AI073899 to J.M.B., HL56652 and HL082193 to S. W. W., AI104848 to B. D. B., CA154649 to M.O., German Research Foundation grants SFB 807-Membrane Transport and Communication and TA157/7 to R. T., and grants from the Landsteiner Foundation for Blood Research and The Dutch Organization for Science to D. A. J.M.B. is supported by NIH grants DK072201 and AI095245, the Burroughs Wellcome Fund, and American Cancer Society grant 117254. NR 34 TC 56 Z9 57 U1 3 U2 26 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 31 PY 2014 VL 158 IS 3 BP 506 EP 521 DI 10.1016/j.cell.2014.04.054 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9RB UT WOS:000340944300006 PM 25083866 ER PT J AU Satpute-Krishnan, P Ajinkya, M Bhat, S Itakura, E Hegde, RS Lippincott-Schwartz, J AF Satpute-Krishnan, Prasanna Ajinkya, Monica Bhat, Savithri Itakura, Eisuke Hegde, Ramanujan S. Lippincott-Schwartz, Jennifer TI ER Stress-Induced Clearance of Misfolded GPI-Anchored Proteins via the Secretory Pathway SO CELL LA English DT Article ID ENDOPLASMIC-RETICULUM; QUALITY-CONTROL; PRION PROTEIN; PLASMA-MEMBRANE; TRANSCRIPTION FACTOR; CELL; RECEPTOR; TRANSPORT; GOLGI; TRAFFICKING AB Proteins destined for the cell surface are first assessed in the endoplasmic reticulum (ER) for proper folding before release into the secretory pathway. This ensures that defective proteins are normally prevented from entering the extracellular environment, where they could be disruptive. Here, we report that, when ER folding capacity is saturated during stress, misfolded glycosylphosphatidylinositol-anchored proteins dissociate from resident ER chaperones, engage export receptors, and quantitatively leave the ER via vesicular transport to the Golgi. Clearance from the ER commences within minutes of acute ER stress, before the transcriptional component of the unfolded protein response is activated. These aberrant proteins then access the cell surface transiently before destruction in lysosomes. Inhibiting this stress-induced pathway by depleting the ER-export receptors leads to aggregation of the ER-retained misfolded protein. Thus, this rapid response alleviates the elevated burden of misfolded proteins in the ER at the onset of ER stress, promoting protein homeostasis in the ER. C1 [Satpute-Krishnan, Prasanna; Ajinkya, Monica; Bhat, Savithri; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. [Itakura, Eisuke; Hegde, Ramanujan S.] MRC, Mol Biol Lab, Cambridge CB2 0QH, England. RP Hegde, RS (reprint author), MRC, Mol Biol Lab, Francis Crick Ave, Cambridge CB2 0QH, England. EM rhegde@mrc-lmb.cam.ac.uk; lippincj@mail.nih.gov OI Hegde, Ramanujan/0000-0001-8338-852X FU Intramural Research Program of the National Institutes of Health; HHMI summer research grant at Swarthmore College; UK Medical Research Council [MC_UP_A022_1007]; JSPS postdoctoral fellowship FX Weare grateful to Drs. Prabuddha Sengupta, Schuyler Van Engelenburg, Angelika Rambold, Peter Kim, Dale Hailey, Aarthi Ashok, Carolyn Suzuki, Yihong Ye, Linda Hendershot, Graham Diering, Michael Lizardo, and Chand Khanna for critical discussions, reagents, and assistance. We are grateful to Dr. Ajay Sharma, Nora Tsai, and Rafael Villasmil of the NEI Flow Cytometry Core Facility for invaluable technical support. This work was supported by the Intramural Research Program of the National Institutes of Health (J.L.-S. and P.S.-K.), the HHMI summer research grant at Swarthmore College (M. A.), the UK Medical Research Council (MC_UP_A022_1007 to R.S.H.), and a JSPS postdoctoral fellowship (E. I.). NR 49 TC 29 Z9 29 U1 4 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 31 PY 2014 VL 158 IS 3 BP 522 EP 533 DI 10.1016/j.cell.2014.06.026 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9RB UT WOS:000340944300007 PM 25083867 ER PT J AU Tschaharganeh, DF Xue, W Calvisi, DF Evert, M Michurina, TV Dow, LE Banito, A Katz, SF Kastenhuber, ER Weissmueller, S Huang, CH Lechel, A Andersen, JB Capper, D Zender, L Longerich, T Enikolopov, G Lowe, SW AF Tschaharganeh, Darjus F. Xue, Wen Calvisi, Diego F. Evert, Matthias Michurina, Tatyana V. Dow, Lukas E. Banito, Ana Katz, Sarah F. Kastenhuber, Edward R. Weissmueller, Susann Huang, Chun-Hao Lechel, Andre Andersen, Jesper B. Capper, David Zender, Lars Longerich, Thomas Enikolopov, Grigori Lowe, Scott W. TI p53-Dependent Nestin Regulation Links Tumor Suppression to Cellular Plasticity in Liver Cancer SO CELL LA English DT Article ID INTERMEDIATE-FILAMENT NESTIN; STEM-CELLS; INTRAHEPATIC CHOLANGIOCARCINOMA; IN-VIVO; P53; EXPRESSION; MICE; GROWTH; DEDIFFERENTIATION; DIFFERENTIATION AB The p53 tumor suppressor coordinates a series of antiproliferative responses that restrict the expansion of malignant cells, and as a consequence, p53 is lost or mutated in the majority of human cancers. Here, we show that p53 restricts expression of the stem and progenitor-cell-associated protein nestin in an Sp1/3 transcription-factor-dependent manner and that Nestin is required for tumor initiation in vivo. Moreover, loss of p53 facilitates dedifferentiation of mature hepatocytes into nestin-positive progenitor-like cells, which are poised to differentiate into hepatocellular carcinomas (HCCs) or cholangiocarcinomas (CCs) in response to lineage-specific mutations that target Wnt and Notch signaling, respectively. Many human HCCs and CCs show elevated nestin expression, which correlates with p53 loss of function and is associated with decreased patient survival. Therefore, transcriptional repression of Nestin by p53 restricts cellular plasticity and tumorigenesis in liver cancer. C1 [Tschaharganeh, Darjus F.; Dow, Lukas E.; Banito, Ana; Kastenhuber, Edward R.; Weissmueller, Susann; Huang, Chun-Hao; Lowe, Scott W.] Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10065 USA. [Xue, Wen; Michurina, Tatyana V.; Weissmueller, Susann; Zender, Lars; Enikolopov, Grigori; Lowe, Scott W.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Calvisi, Diego F.; Evert, Matthias] Univ Med, Inst Pathol, D-17487 Greifswald, Germany. [Katz, Sarah F.; Lechel, Andre] Univ Ulm, Dept Internal Med 1, D-89070 Ulm, Germany. [Andersen, Jesper B.] NCI, Lab Expt Carcinogenesis, CCR, NIH, Bethesda, MD 20892 USA. [Andersen, Jesper B.] Univ Copenhagen, BRIC, DK-2200 Copenhagen, Denmark. [Capper, David; Longerich, Thomas] Univ Heidelberg Hosp, Inst Pathol, D-69120 Heidelberg, Germany. [Capper, David] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, D-69120 Heidelberg, Germany. [Lowe, Scott W.] Howard Hughes Med Inst, New York, NY 10065 USA. RP Lowe, SW (reprint author), Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10065 USA. EM lowes@mskcc.org OI Enikolopov, Grigori/0000-0001-8178-8917; Andersen , Jesper B/0000-0003-1760-5244 FU National Cancer Institute; National Center for Tumor Disease, Heidelberg; German Research Foundation (DFG) [SFB/TRR77]; German Cancer Aid; German Research Foundation (DFG) FX We thank all members of the Lowe lab for stimulating discussion and, in particular, Dr. Charles J. Sherr for important suggestions and editing the manuscript. We thank D. Grace, J. Simon, the MSKCC animal facility, and MSKCC molecular cytology core for outstanding technical support. This work was supported by program project grants from the National Cancer Institute (S.W.L.). This study was supported by the National Center for Tumor Disease, Heidelberg, and grants of the German Research Foundation (DFG, SFB/TRR77) and the German Cancer Aid (T.L.). D.F.T. is funded by a postdoctoral fellowship of the German Research Foundation (DFG). S.W.L. is the Geoffrey Beene Chair for Cancer Biology and a Howard Hughes Medical Institute investigator. NR 53 TC 32 Z9 34 U1 1 U2 34 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 31 PY 2014 VL 158 IS 3 BP 579 EP 592 DI 10.1016/j.cell.2014.05.051 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9RB UT WOS:000340944300011 PM 25083869 ER PT J AU Masri, S Rigor, P Cervantes, M Ceglia, N Sebastian, C Xiao, CY Roqueta-Rivera, M Deng, CX Osborne, TF Mostoslavsky, R Baldi, P Sassone-Corsi, P AF Masri, Selma Rigor, Paul Cervantes, Marlene Ceglia, Nicholas Sebastian, Carlos Xiao, Cuiying Roqueta-Rivera, Manuel Deng, Chuxia Osborne, Timothy F. Mostoslavsky, Raul Baldi, Pierre Sassone-Corsi, Paolo TI Partitioning Circadian Transcription by SIRT6 Leads to Segregated Control of Cellular Metabolism SO CELL LA English DT Article ID REGULATORY MOTIF SITES; LARGE GENE LISTS; DEACETYLASE SIRT6; GENOMIC INSTABILITY; MOUSE-LIVER; CHROMATIN; CLOCK; EXPRESSION; SIRTUINS; PROMOTER AB Circadian rhythms are intimately linked to cellular metabolism. Specifically, the NAD(+)-dependent deacetylase SIRT1, the founding member of the sirtuin family, contributes to clock function. Whereas SIRT1 exhibits diversity in deacetylation targets and subcellular localization, SIRT6 is the only constitutively chromatin-associated sirtuin and is prominently present at transcriptionally active genomic loci. Comparison of the hepatic circadian transcriptomes reveals that SIRT6 and SIRT1 separately control transcriptional specificity and therefore define distinctly partitioned classes of circadian genes. SIRT6 interacts with CLOCK:BMAL1 and, differently from SIRT1, governs their chromatin recruitment to circadian gene promoters. Moreover, SIRT6 controls circadian chromatin recruitment of SREBP-1, resulting in the cyclic regulation of genes implicated in fatty acid and cholesterol metabolism. This mechanism parallels a phenotypic disruption in fatty acid metabolism in SIRT6 null mice as revealed by circadian metabolome analyses. Thus, genomic partitioning by two independent sirtuins contributes to differential control of circadian metabolism. C1 [Masri, Selma; Cervantes, Marlene; Baldi, Pierre; Sassone-Corsi, Paolo] Univ Calif Irvine, Ctr Epigenet & Metab, Irvine, CA 92697 USA. [Masri, Selma; Cervantes, Marlene; Baldi, Pierre; Sassone-Corsi, Paolo] Univ Calif Irvine, Dept Biol Chem, Irvine, CA 92697 USA. [Rigor, Paul; Ceglia, Nicholas; Baldi, Pierre] Univ Calif Irvine, Dept Comp Sci, Irvine, CA 92697 USA. [Rigor, Paul; Ceglia, Nicholas; Baldi, Pierre; Sassone-Corsi, Paolo] Univ Calif Irvine, Inst Genom & Bioinformat, Irvine, CA 92697 USA. [Sebastian, Carlos; Mostoslavsky, Raul] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Xiao, Cuiying; Deng, Chuxia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Roqueta-Rivera, Manuel; Osborne, Timothy F.] Sanford Burnham Med Res Inst, Metabol Dis Program, Orlando, FL 32827 USA. RP Sassone-Corsi, P (reprint author), Univ Calif Irvine, Ctr Epigenet & Metab, Irvine, CA 92697 USA. EM psc@uci.edu RI deng, chuxia/N-6713-2016; OI Roqueta-Rivera, Manuel/0000-0001-6011-0226 FU NIH [GM097899, LM010235, LM07443, AG043745]; NSF [IIS-1321053]; Merieux Research Grant [53923]; Sirtris Pharmaceuticals [SP-48984] FX We thank Katrin Chua for reagents and helpful discussions. We thank all members of the Sassone-Corsi lab and Melanie Oakes, Seung-Ah Chung, Valentina Ciobanu, Yuzo Kanomata, and Andrea Eckhart for helpful discussion and technical assistance. Funding for S.M. was provided by NIH postdoctoral fellowship GM097899. Funding for P.B. was provided by NSF (IIS-1321053) and NIH (LM010235 and LM07443). Financial support for P.S.-C. was provided by NIH (AG043745), Merieux Research Grant (53923), and Sirtris Pharmaceuticals (SP-48984). NR 59 TC 60 Z9 60 U1 3 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 31 PY 2014 VL 158 IS 3 BP 659 EP 672 DI 10.1016/j.cell.2014.06.050 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9RB UT WOS:000340944300017 PM 25083875 ER PT J AU Wen, XB Wen, K Cao, DJ Li, GH Jones, RW Li, JP Szu, SS Hoshino, Y Yuan, LJ AF Wen, Xiaobo Wen, Ke Cao, Dianjun Li, Guohua Jones, Ronald W. Li, Jianping Szu, Shousun Hoshino, Yasutaka Yuan, Lijuan TI Inclusion of a universal tetanus toxoid CD4(+) T cell epitope P2 significantly enhanced the immunogenicity of recombinant rotavirus Delta VP8* subunit parenteral vaccines SO VACCINE LA English DT Article DE Human rotavirus; Subunit vaccine; T cell epitope; Immunogenicity; Protective efficacy; Diarrhea; Gnotobiotic pigs ID GNOTOBIOTIC PIG MODEL; WA HUMAN ROTAVIRUS; PROTECTIVE IMMUNITY; ANTIBODY-RESPONSES; SEROTYPIC CHARACTERIZATION; PORCINE CIRCOVIRUS; INFECTION; DIARRHEA; STRAIN; GASTROENTERITIS AB Currently available live oral rotavirus vaccines, Rotarix (R) and RotaTeq (R), are highly efficacious in developed countries. However, the immunogenicity and efficacy of such vaccines in some developing countries are low. We reported previously that bacterially-expressed rotavirus Delta VP8* subunit vaccine candidates with P[8], P[4] or P[6] specificity elicited high-titer virus neutralizing antibodies in animals immunized intramuscularly. Of note was the finding that antibodies induced with the P[8]Delta VP8* vaccine neutralized both homotypic P[8] and heterotypic P[4] rotavirus strains to high titer. To further improve its vaccine potential, a tetanus toxoid universal CD4(+) T cell epitope P2 was introduced into P[8] or P[6]Delta VP8* construct. The resulting recombinant fusion proteins expressed in Escherichia coli were of high solubility and were produced with high yield. Two doses (10 or 20 mu g/dose) of the P2-P[8]Delta VP8* vaccine or P2-P[6]Delta VP8* vaccine with aluminum phosphate adjuvant elicited significantly higher geometric mean homologous neutralizing antibody titers than the vaccines without P2 in intramuscularly immunized guinea pigs. Interestingly, high levels of neutralizing antibody responses induced in guinea pigs with 3 doses of the P2-P[8]Delta VP8* vaccine persisted for at least 6 months. Furthermore, in the gnotobiotic piglet challenge study, three intramuscular doses (50 mu g/dose) of the P2-P[8]Delta VP8* vaccine with aluminum phosphate adjuvant significantly delayed the onset of diarrhea and significantly reduced the duration of diarrhea and the cumulative diarrhea score after oral challenge with virulent human rotavirus Wa (GI P[8]) strain. The P2-P[8]Delta VP8* vaccine induced serum virus neutralizing antibody and VP4-specific IgG antibody production prechallenge, and primed the pigs for higher antibody and intestinal and systemic virus-specific IFN-gamma producing CD4(+) T cell responses postchallenge. These two subunit vaccines could be used at a minimum singly or preferably in bivalent formulation to provide antigenic coverage of most of the G types of global importance. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Wen, Xiaobo; Cao, Dianjun; Jones, Ronald W.; Hoshino, Yasutaka] NIAID, Rotavirus Vaccine Dev Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Wen, Ke; Cao, Dianjun; Li, Jianping; Szu, Shousun] Virginia Polytech Inst & State Univ, Virginia Maryland Reg Coll Vet Med, Dept Biomed Sci & Pathobiol, Blacksburg, VA 24061 USA. [Li, Jianping; Szu, Shousun] NICHHD, NIH, Lab Dev & Mol Immun, Bethesda, MD 20892 USA. RP Yuan, LJ (reprint author), Virginia Polytech Inst & State Univ, Virginia Maryland Reg Coll Vet Med, Dept Biomed Sci & Pathobiol, 1981 Kraft Dr,Integrated Life Sci Bldg, Blacksburg, VA 24061 USA. EM thoshino@niaid.nih.gov; lyuan@vt.edu FU Intramural Research Program; National Center of Complementary and Alternative Medicine [R01AT004789]; National Institutes of Health, USA FX We thank Elias Gonzales, Muqun Bai, Jacob Kocher, Xingdong Yang, Mariah Weiss for technical assistance; Dr. Marlice Vonck, Dr. Kevin Pelzer, Pete Jobst, Andrea Aman, Kimberly Allen, and Shannon Viers for animal care; and Cindy Clark, NIH Library Writing Center, for manuscript editing assistance. We extend our appreciation to late Dr. Albert Z. Kapikian for his support to this project. This work was supported by the Intramural Research Program (YH) and R01AT004789 from the National Center of Complementary and Alternative Medicine (LY), National Institutes of Health, USA. NR 40 TC 7 Z9 7 U1 3 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUL 31 PY 2014 VL 32 IS 35 BP 4420 EP 4427 DI 10.1016/j.vaccine.2014.06.060 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AM8QD UT WOS:000340141200009 PM 24962749 ER PT J AU Kim, SH Paldurai, A Xiao, S Collins, PL Samal, SK AF Kim, Shin-Hee Paldurai, Anandan Xiao, Sa Collins, Peter L. Samal, Siba K. TI Modified Newcastle disease virus vectors expressing the H5 hemagglutinin induce enhanced protection against highly pathogenic H5N1 avian influenza virus in chickens SO VACCINE LA English DT Article DE Newcastle disease virus; Vectored vaccine; Hemagglutinin; H5N1 highly virulent avian influenza virus ID RESPIRATORY-TRACT; VACCINE VECTOR; FOREIGN GENE; WEST-AFRICA; IMMUNIZATION; CHALLENGE; PRIMATES; PROTEIN; HUMANS; STRAIN AB Naturally-occurring attenuated strains of Newcastle disease virus (NDV) are being developed as vaccine vectors for use in poultry and humans. However, some NDV strains, such as Beaudette C (BC), may retain too much virulence in poultry for safe use, and more highly attenuated strains may be suboptimally immunogenic. We therefore modified the BC strain by changing the multibasic cleavage site sequence of the F protein to the dibasic sequence of avirulent strain LaSota. Additionally, the BC, F, and HN proteins were modified in several ways to enhance virus replication. These modified BC-derived vectors and the LaSota strain were engineered to express the hemagglutin (HA) protein of H5N1 highly pathogenic influenza virus (HPAIV). In general, the modified BC-based vectors expressing HA replicated better than LaSota/HA, and expressed higher levels of HA protein. Pathogenicity tests indicated that all the modified viruses were highly attenuated in chickens. Based on in vitro characterization, two of the modified BC vectors were chosen for evaluation in chickens as vaccine vectors against H5N1 HPAIV A/Vietnam/1203/04. Immunization of chickens with rNDV vector vaccines followed by challenge with HPAIV demonstrated high levels of protection against clinical disease and mortality. However, only those chickens immunized with modified BC/HA in which residues 271-330 from the F protein had been replaced with the corresponding sequence from the NDV AKO strain conferred complete protection against challenge virus shedding. Our findings suggest that this modified rNDV can be used safely as a vaccine vector with enhanced replication, expression, and protective efficacy in avian species, and potentially in humans. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Kim, Shin-Hee; Paldurai, Anandan; Xiao, Sa; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, College Pk, MD USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, 8075 Greenmead Dr, College Pk, MD 20742 USA. EM ssamal@umd.edu FU National Institute of Allergy and Infectious Diseases (NIAID) [N01A060009]; NIAID, National Institutes of Health (NIH) FX We thank Daniel Rockemann, Girmay Gebreluul, Yonas Araya, Andrea Ferrero-Perez, and our laboratory members for excellent technical assistance; and Dr. Bernard Moss (NIAID, NIH) for providing the vaccinia T7 recombinant virus and the pTM1 plasmid. This research was supported by National Institute of Allergy and Infectious Diseases (NIAID) contract no N01A060009 (85% support) and NIAID, National Institutes of Health (NIH) Intramural Research Program (15% support). The views expressed herein do not necessarily reflect the official policies of the Department of Health and Human Services, nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government. NR 21 TC 8 Z9 8 U1 0 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUL 31 PY 2014 VL 32 IS 35 BP 4428 EP 4435 DI 10.1016/j.vaccine.2014.06.061 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AM8QD UT WOS:000340141200010 PM 24968158 ER PT J AU Ashley, EA Dhorda, M Fairhurst, RM Amaratunga, C Lim, P Suon, S Sreng, S Anderson, JM Mao, S Sam, B Sopha, C Chuor, CM Nguon, C Sovannaroth, S Pukrittayakamee, S Jittamala, P Chotivanich, K Chutasmit, K Suchatsoonthorn, C Runcharoen, R Hien, TT Thuy-Nhien, NT Thanh, NV Phu, NH Htut, Y Han, KT Aye, KH Mokuolu, OA Olaosebikan, RR Folaranmi, OO Mayxay, M Khanthavong, M Hongvanthong, B Newton, PN Onyamboko, MA Fanello, CI Tshefu, AK Mishra, N Valecha, N Phyo, AP Nosten, F Yi, P Tripura, R Borrmann, S Bashraheil, M Peshu, J Faiz, MA Ghose, A Hossain, MA Samad, R Rahman, MR Hasan, MM Islam, A Miotto, O Amato, R MacInnis, B Stalker, J Kwiatkowski, DP Bozdech, Z Jeeyapant, A Cheah, PY Sakulthaew, T Chalk, J Intharabut, B Silamut, K Lee, SJ Vihokhern, B Kunasol, C Imwong, M Tarning, J Taylor, WJ Yeung, S Woodrow, CJ Flegg, JA Das, D Smith, J Venkatesan, M Plowe, CV Stepniewska, K Guerin, PJ Dondorp, AM Day, NP White, NJ AF Ashley, E. A. Dhorda, M. Fairhurst, R. M. Amaratunga, C. Lim, P. Suon, S. Sreng, S. Anderson, J. M. Mao, S. Sam, B. Sopha, C. Chuor, C. M. Nguon, C. Sovannaroth, S. Pukrittayakamee, S. Jittamala, P. Chotivanich, K. Chutasmit, K. Suchatsoonthorn, C. Runcharoen, R. Hien, T. T. Thuy-Nhien, N. T. Thanh, N. V. Phu, N. H. Htut, Y. Han, K-T. Aye, K. H. Mokuolu, O. A. Olaosebikan, R. R. Folaranmi, O. O. Mayxay, M. Khanthavong, M. Hongvanthong, B. Newton, P. N. Onyamboko, M. A. Fanello, C. I. Tshefu, A. K. Mishra, N. Valecha, N. Phyo, A. P. Nosten, F. Yi, P. Tripura, R. Borrmann, S. Bashraheil, M. Peshu, J. Faiz, M. A. Ghose, A. Hossain, M. A. Samad, R. Rahman, M. R. Hasan, M. M. Islam, A. Miotto, O. Amato, R. MacInnis, B. Stalker, J. Kwiatkowski, D. P. Bozdech, Z. Jeeyapant, A. Cheah, P. Y. Sakulthaew, T. Chalk, J. Intharabut, B. Silamut, K. Lee, S. J. Vihokhern, B. Kunasol, C. Imwong, M. Tarning, J. Taylor, W. J. Yeung, S. Woodrow, C. J. Flegg, J. A. Das, D. Smith, J. Venkatesan, M. Plowe, C. V. Stepniewska, K. Guerin, P. J. Dondorp, A. M. Day, N. P. White, N. J. TI Spread of Artemisinin Resistance in Plasmodium falciparum Malaria SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PARASITE CLEARANCE; WESTERN CAMBODIA; SUSCEPTIBILITY; ARTESUNATE; EFFICACY; PROVINCE; RATES AB BACKGROUND Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. METHODS Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. RESULTS The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing in-fections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U. K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.) C1 [Ashley, E. A.; Fanello, C. I.; Phyo, A. P.; Nosten, F.; Tripura, R.; Miotto, O.; Jeeyapant, A.; Cheah, P. Y.; Sakulthaew, T.; Intharabut, B.; Silamut, K.; Lee, S. J.; Vihokhern, B.; Kunasol, C.; Tarning, J.; Taylor, W. J.; Woodrow, C. J.; Dondorp, A. M.; Day, N. P.; White, N. J.] Mahidol Univ, Mahidol Oxford Trop Med Res Unit, Bangkok 10400, Thailand. [Pukrittayakamee, S.; Jittamala, P.; Chotivanich, K.; Imwong, M.] Mahidol Univ, Fac Trop Med, Bangkok 10400, Thailand. [Chutasmit, K.] Phusing Hosp, Srisaket, Thailand. [Runcharoen, R.] Khunhan Hosp, Srisaket, Thailand. [Suchatsoonthorn, C.] Kraburi Hosp, Ranong, Thailand. [Phyo, A. P.; Nosten, F.] Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Shoklo Malaria Res Unit, Mae Sot, Thailand. [Ashley, E. A.; Dhorda, M.; Hien, T. T.; Mayxay, M.; Newton, P. N.; Onyamboko, M. A.; Fanello, C. I.; Phyo, A. P.; Nosten, F.; Cheah, P. Y.; Chalk, J.; Lee, S. J.; Tarning, J.; Taylor, W. J.; Woodrow, C. J.; Flegg, J. A.; Das, D.; Smith, J.; Venkatesan, M.; Stepniewska, K.; Guerin, P. J.; Dondorp, A. M.; Day, N. P.; White, N. J.] Univ Oxford, Ctr Trop Med, Oxford, England. [Dhorda, M.; Flegg, J. A.; Das, D.; Smith, J.; Venkatesan, M.; Stepniewska, K.; Guerin, P. J.] Univ Oxford, Ctr Trop Med, Worldwide Antimalarial Resistance Network, Oxford, England. [Miotto, O.; Amato, R.; MacInnis, B.; Stalker, J.; Kwiatkowski, D. P.] Univ Oxford, Nuffield Dept Med, Med Res Council Ctr Genom & Global Hlth, Oxford, England. [Amato, R.; Kwiatkowski, D. P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Miotto, O.; MacInnis, B.; Stalker, J.; Kwiatkowski, D. P.] Wellcome Trust Sanger Inst, Cambridge, England. [Yeung, S.] London Sch Hyg & Trop Med, Fac Publ Hlth & Policy, Dept Global Hlth & Dev, London WC1, England. [Yeung, S.] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Policy & Clin Res Dept, London WC1, England. [Dhorda, M.; Smith, J.; Venkatesan, M.; Plowe, C. V.] Univ Maryland, Sch Med, Howard Hughes Med Inst, Malaria Grp,Ctr Vaccine Dev, Baltimore, MD 21201 USA. [Fairhurst, R. M.; Amaratunga, C.; Lim, P.; Anderson, J. M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Lim, P.; Suon, S.; Sreng, S.; Chuor, C. M.; Nguon, C.; Sovannaroth, S.; Yi, P.] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia. [Mao, S.] Sampov Meas Referral Hosp, Pursat, Cambodia. [Sam, B.] Ratanakiri Referral Hosp, Ratanakiri, Cambodia. [Sopha, C.] Makara 16 Referral Hosp, Preah Vihear, Cambodia. [Hien, T. T.; Thuy-Nhien, N. T.; Thanh, N. V.; Phu, N. H.] Oxford Univ Clin Res Unit, Hosp Trop Dis, Ho Chi Minh City, Vietnam. [Htut, Y.; Han, K-T.; Aye, K. H.] Dept Med Res, Lower Myanmar, Yangon, Myanmar. [Mokuolu, O. A.; Olaosebikan, R. R.] Univ Ilorin, Dept Paediat & Child Hlth, Ilorin, Nigeria. [Folaranmi, O. O.] Univ Ilorin, Teaching Hosp, Dept Histopathol, Ilorin, Nigeria. [Mayxay, M.; Newton, P. N.] Mahosot Hosp, Lao Oxford Mahosot Hosp Wellcome Trust Res Unit, Viangchan, Laos. [Mayxay, M.] Univ Hlth Sci, Fac Postgrad Studies, Viangchan, Laos. [Khanthavong, M.; Hongvanthong, B.] Ctr Malariol Parasitol & Entomol, Viangchan, Laos. [Onyamboko, M. A.; Tshefu, A. K.] Kinshasa Sch Publ Hlth, Kinshasa, Zaire. [Mishra, N.; Valecha, N.] Indian Council Med Res, Natl Inst Malaria Res, Sect 8, New Delhi, India. [Borrmann, S.; Bashraheil, M.; Peshu, J.] Kenya Govt Med Res Ctr, Wellcome Trust Res Programme, Kilifi, Kenya. [Borrmann, S.] Univ Tubingen, Inst Trop Med, Tubingen, Germany. [Borrmann, S.] German Ctr Infect Res, Tubingen, Germany. [Faiz, M. A.; Ghose, A.; Hossain, M. A.; Samad, R.; Rahman, M. R.] Malaria Res Grp, Dhaka, Bangladesh. [Faiz, M. A.; Ghose, A.; Hossain, M. A.; Samad, R.; Rahman, M. R.] Dev Care Fdn, Dhaka, Bangladesh. [Rahman, M. R.] Shaheed Suhrawardy Med Coll, Dhaka, Bangladesh. [Ghose, A.; Hossain, M. A.; Samad, R.; Hasan, M. M.] Chittagong Med Coll, Chittagong, Bangladesh. [Islam, A.] Ramu Upazila Hlth Complex, Coxs Bazar, Bangladesh. [Bozdech, Z.] Nanyang Technol Univ, Sch Biol Sci, Singapore 639798, Singapore. RP White, NJ (reprint author), Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, 420-6 Rajvithi Rd, Bangkok 10400, Thailand. EM nickw@tropmedres.ac RI Bozdech, Zbynek/A-2205-2011; Mishra, Dr. Neelima/D-3924-2017; OI Borrmann, Steffen/0000-0001-9189-4393; Flegg, Jennifer/0000-0002-8809-726X; Miotto, Olivo/0000-0001-8060-6771; Amato, Roberto/0000-0001-8633-9221; Nosten, Francois/0000-0002-7951-0745; Kwiatkowski, Dominic/0000-0002-5023-0176; Guerin, Philippe/0000-0002-6008-2963; Pyae Phyo, Aung/0000-0002-0383-9624; Woodrow, Charles/0000-0002-5134-7165 FU U.K. Department for International Development; Worldwide Antimalarial Resistance Network; National Institute of Allergy and Infectious Diseases of the National Institutes of Health; Bill and Melinda Gates Foundation; Wellcome Trust of Great Britain FX Supported by grants from the U.K. Department for International Development, the Worldwide Antimalarial Resistance Network, the Intramural Research Program of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, and the Bill and Melinda Gates Foundation. The Mahidol-University Oxford Tropical Medicine Research Programme is funded by the Wellcome Trust of Great Britain. NR 36 TC 422 Z9 432 U1 11 U2 91 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 31 PY 2014 VL 371 IS 5 BP 411 EP 423 DI 10.1056/NEJMoa1314981 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA AM0SK UT WOS:000339556900006 PM 25075834 ER PT J AU Pai, SY Logan, BR Griffith, LM Buckley, RH Parrott, RE Dvorak, CC Kapoor, N Hanson, IC Filipovich, AH Jyonouchi, S Sullivan, KE Small, TN Burroughs, L Skoda-Smith, S Haight, AE Grizzle, A Pulsipher, MA Chan, KW Fuleihan, RL Haddad, E Loechelt, B Aquino, VM Gillio, A Davis, J Knutsen, A Smith, AR Moore, TB Schroeder, ML Goldman, FD Connelly, JA Porteus, MH Xiang, Q Shearer, WT Fleisher, TA Kohn, DB Puck, JM Notarangelo, LD Cowan, MJ O'Reilly, RJ AF Pai, Sung-Yun Logan, Brent R. Griffith, Linda M. Buckley, Rebecca H. Parrott, Roberta E. Dvorak, Christopher C. Kapoor, Neena Hanson, Imelda C. Filipovich, Alexandra H. Jyonouchi, Soma Sullivan, Kathleen E. Small, Trudy N. Burroughs, Lauri Skoda-Smith, Suzanne Haight, Ann E. Grizzle, Audrey Pulsipher, Michael A. Chan, Ka Wah Fuleihan, Ramsay L. Haddad, Elie Loechelt, Brett Aquino, Victor M. Gillio, Alfred Davis, Jeffrey Knutsen, Alan Smith, Angela R. Moore, Theodore B. Schroeder, Marlis L. Goldman, Frederick D. Connelly, James A. Porteus, Matthew H. Xiang, Qun Shearer, William T. Fleisher, Thomas A. Kohn, Donald B. Puck, Jennifer M. Notarangelo, Luigi D. Cowan, Morton J. O'Reilly, Richard J. TI Transplantation Outcomes for Severe Combined Immunodeficiency, 2000-2009 SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; SOYBEAN AGGLUTININ; THYMIC OUTPUT; RECONSTITUTION; LYMPHOCYTES; DEFICIENCY; EXPERIENCE; CHILDREN; DISEASE AB BACKGROUND The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth. METHODS We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009). RESULTS Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell-depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myelo-ablative pretransplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin-induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival. CONCLUSIONS Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.) C1 [Pai, Sung-Yun] Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA USA. [Notarangelo, Luigi D.] Harvard Stem Cell Inst, Manton Ctr Orphan Dis Res, Div Immunol, Boston, MA USA. [Pai, Sung-Yun] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Logan, Brent R.; Xiang, Qun] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Small, Trudy N.; O'Reilly, Richard J.] Mem Sloan Kettering Canc Ctr, Bone Marrow Transplant Program, New York, NY 10065 USA. [Griffith, Linda M.] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. [Fleisher, Thomas A.] NIAID, Ctr Clin, Dept Lab Med, NIH, Bethesda, MD 20892 USA. [Buckley, Rebecca H.; Parrott, Roberta E.] Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. [Buckley, Rebecca H.; Parrott, Roberta E.] Duke Univ, Med Ctr, Dept Immunol, Durham, NC USA. [Dvorak, Christopher C.; Puck, Jennifer M.; Cowan, Morton J.] Univ Calif San Francisco, Benioff Childrens Hosp, Div Allergy Immunol Blood & Marrow Transplantat, San Francisco, CA 94143 USA. [Kapoor, Neena] Childrens Hosp Los Angeles, Dept Pediat, Los Angeles, CA 90027 USA. [Hanson, Imelda C.; Shearer, William T.] Texas Childrens Hosp, Sect Pediat Immunol Allergy & Rheumatol, Baylor Coll Med, Houston, TX 77030 USA. [Filipovich, Alexandra H.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Jyonouchi, Soma; Sullivan, Kathleen E.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Burroughs, Lauri; Skoda-Smith, Suzanne] Seattle Childrens Hosp, Div Clin Res, Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Haight, Ann E.; Grizzle, Audrey] Childrens Healthcare Atlanta, Aflac Canc & Blood Disorders Ctr, Atlanta, GA USA. Emory Univ, Sch Med, Atlanta, GA USA. [Pulsipher, Michael A.] Univ Utah, Huntsman Canc Inst, Primary Childrens Hosp, Div Hematol, Salt Lake City, UT USA. [Chan, Ka Wah] Texas Transplant Inst, San Antonio, TX USA. [Chan, Ka Wah] Methodist Childrens Hosp South Texas, San Antonio, TX USA. [Fuleihan, Ramsay L.] Northwestern Univ, Feinberg Sch Med, Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [Haddad, Elie] Univ Montreal, Ctr Hosp Univ St Justine, Montreal, PQ, Canada. [Loechelt, Brett] Childrens Natl Med Ctr, Div Blood & Marrow Transplantat & Allergy & Immun, Washington, DC 20010 USA. [Aquino, Victor M.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Gillio, Alfred] Hackensack Univ, Med Ctr, Pediat Blood & Marrow Transplant Program, Hackensack, NJ USA. [Davis, Jeffrey] BC Childrens Hosp, Dept Pediat, Vancouver, BC, Canada. [Schroeder, Marlis L.] Univ Manitoba, Dept Pediat & Child Hlth, Winnipeg, MB R3T 2N2, Canada. [Knutsen, Alan] St Louis Univ, Cardinal Glennon Childrens Med Ctr, Div Pediat Allergy & Immunol, St Louis, MO 63103 USA. [Smith, Angela R.] Univ Minnesota, Div Pediat Blood & Marrow Transplantat, Minneapolis, MN USA. [Moore, Theodore B.; Kohn, Donald B.] Univ Calif Los Angeles, Mattel Childrens Hosp, Los Angeles, CA USA. [Goldman, Frederick D.] Univ Alabama Birmingham, Childrens Alabama, Dept Pediat, Birmingham, AL USA. [Connelly, James A.] Univ Michigan, Dept Pediat Hematol Oncol, Ann Arbor, MI 48109 USA. [Porteus, Matthew H.] Stanford Univ, Div Hematol Oncol Stem Cell Transplantat, Stanford, CA 94305 USA. RP O'Reilly, RJ (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA. EM oreillyr@mskcc.org RI Notarangelo, Luigi/F-9718-2016; OI Notarangelo, Luigi/0000-0002-8335-0262; Haddad, Elie/0000-0003-2446-6879 FU NIAID [1U54AI082973]; NIH Office of Rare Diseases Research, National Center for Advancing Translational Sciences [R13AI094943]; National Cancer Institute [CA23766]; David Center, Texas Children's Hospital; National Heart, Lung, and Blood Institute (NHLBI) [HL085288, HL36444]; NHLBI [2U01HL069254]; St. Baldrick's Foundation FX Supported by grants from the NIAID (1U54AI082973) and the NIH Office of Rare Diseases Research, National Center for Advancing Translational Sciences (R13AI094943), a Translational Investigator Service Award (to Dr. Pai), and grants from the National Cancer Institute (CA23766, to Dr. O'Reilly), the David Center, Texas Children's Hospital (to Dr. Shearer), and the National Heart, Lung, and Blood Institute (NHLBI) (HL085288 and HL36444, to Dr. Burroughs). Activities of the Pediatric Blood and Marrow Transplant Consortium, a core group representing 19 centers participating in this study, were also partially supported by grants from the NHLBI (2U01HL069254) and the St. Baldrick's Foundation. NR 37 TC 89 Z9 93 U1 6 U2 23 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 31 PY 2014 VL 371 IS 5 BP 434 EP 446 DI 10.1056/NEJMoa1401177 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA AM0SK UT WOS:000339556900008 PM 25075835 ER PT J AU van Montfrans, J Zavialov, A Zhou, Q AF van Montfrans, Joris Zavialov, Andrey Zhou, Qing TI Mutant ADA2 in Vasculopathies SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [van Montfrans, Joris] Univ Med Ctr Utrecht, Utrecht, Netherlands. [Zavialov, Andrey] Univ Turku, Turku, Finland. [Zhou, Qing] NIH, Bethesda, MD 20892 USA. RP van Montfrans, J (reprint author), Univ Med Ctr Utrecht, Utrecht, Netherlands. EM j.vanmontfrans@umcutrecht.nl RI Yu, Xiaomin/I-6407-2016 NR 2 TC 13 Z9 13 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 31 PY 2014 VL 371 IS 5 BP 478 EP 478 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AM0SK UT WOS:000339556900017 PM 25075845 ER PT J AU Kastner, DL Zhou, Q Aksentijevich, I AF Kastner, Daniel L. Zhou, Qing Aksentijevich, Ivona TI Mutant ADA2 in Vasculopathies Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Kastner, Daniel L.; Zhou, Qing; Aksentijevich, Ivona] NHGRI, Bethesda, MD 20892 USA. RP Kastner, DL (reprint author), NHGRI, Bethesda, MD 20892 USA. RI Yu, Xiaomin/I-6407-2016 NR 0 TC 5 Z9 5 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 31 PY 2014 VL 371 IS 5 BP 480 EP 481 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AM0SK UT WOS:000339556900021 PM 25075844 ER PT J AU Goncalves, BP Fried, M Duffy, PE AF Goncalves, Bronner P. Fried, Michal Duffy, Patrick E. TI Parasite Burden and Severity of Malaria in Tanzanian Children Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Goncalves, Bronner P.; Fried, Michal; Duffy, Patrick E.] NIAID, Rockville, MD 20852 USA. RP Goncalves, BP (reprint author), NIAID, Rockville, MD 20852 USA. EM patrick.duffy@nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 5 TC 3 Z9 3 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 31 PY 2014 VL 371 IS 5 BP 482 EP 482 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AM0SK UT WOS:000339556900024 PM 25075849 ER PT J AU Borges, AH Weitz, JI Collins, G Baker, JV Levy, Y Davey, RT Phillips, AN Neaton, JD Lundgren, JD Deeks, SG AF Borges, Alvaro H. Weitz, Jeffrey I. Collins, Gary Baker, Jason V. Levy, Yves Davey, Richard T., Jr. Phillips, Andrew N. Neaton, James D. Lundgren, Jens D. Deeks, Steven G. CA INSIGHT SILCAAT Sci Comm TI Markers of inflammation and activation of coagulation are associated with anaemia in antiretroviral-treated HIV disease SO AIDS LA English DT Article DE anaemia; coagulation; C-reactive protein; D-dimer; HIV; interleukin-6; inflammation ID HUMAN-IMMUNODEFICIENCY-VIRUS; THERAPY; INTERLEUKIN-6; INFECTION; SURVIVAL; HEPCIDIN; EUROPE; COHORT; AIDS AB Objective: The objective of this study is to determine the relationship between inflammatory interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP)] and coagulation (D-dimer) biomarkers and the presence and type of anaemia among HIV-positive individuals. Design: A cross-sectional study. Methods: Combination antiretroviral therapy (cART)-treated adults participating in an international HIV trial with haemoglobin and mean corpuscular volume (MCV) measurements at entry were categorized by presence of anaemia (haemoglobin <= 14 g/dl in men and <= 12 g/dl in women) and, for those with anaemia, by type [microcytic (MCV < 80 fl), normocytic (80-100 fl), macrocytic (> 100 fl)]. We analysed the association between inflammation (IL-6 and hsCRP) and coagulation (D-dimer) and haemoglobin, controlling for demographics (age, race and sex), BMI, HIV plasma RNA levels, CD4(+) T-cell counts (nadir and baseline), Karnofsky score, previous AIDS diagnosis, hepatitis B/C coinfection and use of zidovudine. Results: Among 1410 participants, 313 (22.2%) had anaemia. Of these, 4.1, 27.2 and 68.7% had microcytic, normocytic and macrocytic anaemia, respectively. When compared with participants with normal haemoglobin values, those with anaemia were more likely to be older, black, male and on zidovudine. They also had lower baseline CD4(+) T-cell counts and lower Karnofsky scores. Adjusted relative odds of anaemia per two-fold higher biomarker levels were 1.22 (P = 0.007) for IL-6, 0.99 for hsCRP (P = 0.86) and 1.35 (P < 0.001) for D-dimer. Similar associations were seen in those with normal and high MCV values. Conclusion: Persistent inflammation and hypercoagulation appear to be associated with anaemia. Routine measurements of haemoglobin might provide insights into the inflammatory state of treated HIV infection. (C) 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins C1 [Borges, Alvaro H.; Lundgren, Jens D.] Univ Copenhagen, Rigshosp, Dept Infect Dis & Reumathol, Ctr Hlth & Infect Dis Res CHIP, DK-2100 Copenhagen O, Denmark. [Weitz, Jeffrey I.] Thrombosis & Atherosclerosis Res Inst, Hamilton, ON, Canada. [Weitz, Jeffrey I.] McMaster Univ, Hamilton, ON, Canada. [Collins, Gary; Neaton, James D.] Univ Minnesota, Dept Biostat, Minneapolis, MN USA. [Baker, Jason V.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Baker, Jason V.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Levy, Yves] Univ Paris Est Creteil, Fac Med, Equipe 16, INSERM,U955, Creteil, France. [Levy, Yves] Univ Paris Est Creteil, Fac Med, VRI, Creteil, France. [Levy, Yves] Hop Henri Mondor, AP HP, Serv Immunol Clin, F-94010 Creteil, France. [Davey, Richard T., Jr.] NIAID, NIH, Bethesda, MD 20892 USA. [Phillips, Andrew N.] UCL, Res Dept Infect & Populat Hlth, London, England. [Deeks, Steven G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Borges, AH (reprint author), Univ Copenhagen, Rigshosp, Sect 2100, CHIP,Dept Infect Dis, Blegdamsvej 9, DK-2100 Copenhagen O, Denmark. EM adb@cphiv.dk RI Phillips, Andrew/B-4427-2008; Borges, Alvaro /G-3231-2016; OI Phillips, Andrew/0000-0003-2384-4807; Borges, Alvaro /0000-0003-2020-3828; Lundgren, Jens/0000-0001-8901-7850 FU Gilead; ViiV; NIH [K24AI069994]; Chiron; Novartis FX J.V.B. has received research support from Gilead and ViiV. S.G.D. is supported by the NIH (K24AI069994).; SILCAAT was supported by grants from Chiron and Novartis. The funders had no role in study design, data collection and analysis, decision to publish or preparation of this manuscript. NR 25 TC 7 Z9 7 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUL 31 PY 2014 VL 28 IS 12 BP 1791 EP 1796 DI 10.1097/QAD.0000000000000344 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AL2XG UT WOS:000338988300009 PM 25003720 ER PT J AU Desai, SA Miller, LH AF Desai, Sanjay A. Miller, Louis H. TI MALARIA Protein-export pathway illuminated SO NATURE LA English DT Editorial Material ID PLASMODIUM-FALCIPARUM; HOST ERYTHROCYTES; VIRULENCE; PARASITES; MEMBRANE; REVEALS; CHANNEL; PTEX C1 [Desai, Sanjay A.; Miller, Louis H.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Desai, SA (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM sdesai@niaid.nih.gov; lmiller@niaid.nih.gov FU Intramural NIH HHS [ZIA AI000882-13] NR 16 TC 1 Z9 1 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUL 30 PY 2014 VL 511 IS 7511 BP 541 EP 542 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM0VT UT WOS:000339566300023 PM 25043009 ER PT J AU Collisson, EA Campbell, JD Brooks, AN Berger, AH Lee, W Chmielecki, J Beer, DG Cope, L Creighton, CJ Danilova, L Ding, L Getz, G Hammerman, PS Hayes, DN Hernandez, B Herman, JG Heymach, JV Jurisica, I Kucherlapati, R Kwiatkowski, D Ladanyi, M Robertson, G Schultz, N Shen, RL Sinha, R Sougnez, C Tsao, MS Travis, WD Weinstein, JN Wigle, DA Wilkerson, MD Chu, AD Cherniack, AD Hadjipanayis, A Rosenberg, M Weisenberger, DJ Laird, PW Radenbaugh, A Ma, SG Stuart, JM Byers, LA Baylin, SB Govindan, R Meyerson, M Rosenberg, M Gabriel, SB Cibulskis, K Sougnez, C Kim, J Stewart, C Lichtenstein, L Lander, ES Lawrence, MS Getz Kandoth, C Fulton, R Fulton, LL McLellan, MD Wilson, RK Ye, K Fronick, CC Maher, CA Miller, CA Wendl, MC Cabanski, C Ding, L Mardis, E Govindan, R Creighton, CJ Wheeler, D Balasundaram, M Butterfield, YSN Carlsen, R Chu, AD Chuah, E Dhalla, N Guin, R Hirst, C Lee, D Li, HYI Mayo, M Moore, RA Mungall, AJ Schein, JE Sipahimalani, P Tam, A Varhol, R Robertson, AG Wye, N Thiessen, N Holt, RA Jones, SJM Marra, MA Campbell, JD Brooks, AN Chmielecki, J Imielinski, M Onofrio, RC Hodis, E Zack, T Sougnez, C Helman, E Pedamallu, CS Mesirov, J Cherniack, AD Saksena, G Schumacher, SE Carter, SL Hernandez, B Garraway, L Beroukhim, R Gabriel, SB Getz, G Meyerson, M Hadjipanayis, A Lee, S Mahadeshwar, HS Pantazi, A Protopopov, A Ren, XJ Seth, S Song, XZ Tang, JB Yang, LX Zhang, JH Chen, PC Parfenov, M Xu, AW Santoso, N Chin, L Park, PJ Kucherlapati, R Hoadley, KA Auman, JT Meng, SW Shi, Y Buda, E Waring, S Veluvolu, U Tan, DH Mieczkowski, PA Jones, CD Simons, JV Soloway, MG Bodenheimer, T Jefferys, SR Roach, J Hoyle, AP Wu, JY Balu, S Singh, D Prins, JF Marron, JS Parker, JS Hayes, DN Perou, CM Liu, JZ Cope, L Danilova, L Weisenberger, DJ Maglinte, DT Lai, PH Bootwalla, MS Van Den Berg, DJ Triche, T Baylin, SB Laird, PW Rosenberg, M Chin, L Zhang, JH Cho, J DiCara, D Heiman, D Lin, P Mallard, W Voet, D Zhang, HL Zou, LH Noble, MS Lawrence, MS Saksena, G Gehlenborg, N Thorvaldsdottir, H Mesirov, J Nazaire, MD Robinson, J Getz, G Lee, W Aksoy, BA Ciriello, G Taylor, BS Dresdner, G Gao, JJ Gross, B Seshan, VE Ladanyi, M Reva, B Sinha, R Sumer, SO Weinhold, N Schultz, N Shen, RL Sander, C Ng, S Ma, S Zhu, JC Radenbaugh, A Stuart, JM Benz, CC Yau, C Haussler, D Spellman, PT Wilkerson, MD Parker, JS Hoadley, KA Kimes, PK Hayes, DN Perou, CM Broom, BM Wang, J Lu, YL Ng, PKS Diao, LX Byers, LA Liu, WB Heymach, JV Amos, CI Weinstein, JN Akbani, R Mills, GB Curley, E Paulauskis, J Lau, K Morris, S Shelton, T Mallery, D Gardner, J Penny, R Saller, C Tarvin, K Richards, WG Cerfolio, R Bryant, A Raymond, DP Pennell, NA Farver, C Czerwinski, C Huelsenbeck-Dill, L Iacocca, M Petrelli, N Rabeno, B Brown, J Bauer, T Dolzhanskiy, O Potapova, O Rotin, D Voronina, O Nemirovich-Danchenko, E Fedosenko, KV Gal, A Behera, M Ramalingam, SS Sica, G Flieder, D Boyd, J Weaver, J Kohl, B Thinh, DHQ Sandusky, G Juhl, H Duhig, E Illei, P Gabrielson, E Shin, J Lee, B Rogers, K Trusty, D Brock, MV Williamson, C Burks, E Rieger-Christ, K Holway, A Sullivan, T Wigle, DA Asiedu, MK Kosari, F Travis, WD Rekhtman, N Zakowski, M Rusch, VW Zippile, P Suh, J Pass, H Goparaju, C Owusu-Sarpong, Y Bartlett, JMS Kodeeswaran, S Parfitt, J Sekhon, H Albert, M Eckman, J Myers, JB Cheney, R Morrison, C Gaudioso, C Borgia, JA Bonomi, P Pool, M Liptay, MJ Moiseenko, F Zaytseva, I Dienemann, H Meister, M Schnabel, PA Muley, TR Peifer, M Gomez-Fernandez, C Herbert, L Egea, S Huang, M Thorne, LB Boice, L Salazar, AH Funkhouser, WK Rathmell, WK Dhir, R Yousem, SA Dacic, S Schneider, F Siegfried, JM Hajek, R Watson, MA McDonald, S Meyers, B Clarke, B Yang, IA Fong, KM Hunter, L Windsor, M Bowman, RV Peters, S Letovanec, I Khan, KZ Jensen, MA Snyder, EE Srinivasan, D Kahn, AB Baboud, J Pot, DA Shaw, KRM Sheth, M Davidsen, T Demchok, JA Yang, LM Wang, ZN Tarnuzzer, R Zenklusen, JC Ozenberger, BA Sofia, HJ Travis, WD Cheney, R Clarke, B Sanja Dacic Duhig, E Funkhouser, WK Illei, P Farver, C Rekhtman, N Sica, G Suh, J Tsao, MS AF Collisson, Eric A. Campbell, Joshua D. Brooks, Angela N. Berger, Alice H. Lee, William Chmielecki, Juliann Beer, David G. Cope, Leslie Creighton, Chad J. Danilova, Ludmila Ding, Li Getz, Gad Hammerman, Peter S. Hayes, D. Neil Hernandez, Bryan Herman, James G. Heymach, John V. Jurisica, Igor Kucherlapati, Raju Kwiatkowski, David Ladanyi, Marc Robertson, Gordon Schultz, Nikolaus Shen, Ronglai Sinha, Rileen Sougnez, Carrie Tsao, Ming-Sound Travis, William D. Weinstein, John N. Wigle, Dennis A. Wilkerson, Matthew D. Chu, Andy Cherniack, Andrew D. Hadjipanayis, Angela Rosenberg, Mara Weisenberger, Daniel J. Laird, Peter W. Radenbaugh, Amie Ma, Singer Stuart, Joshua M. Byers, Lauren Averett Baylin, Stephen B. Govindan, Ramaswamy Meyerson, Matthew Rosenberg, Mara Gabriel, Stacey B. Cibulskis, Kristian Sougnez, Carrie Kim, Jaegil Stewart, Chip Lichtenstein, Lee Lander, Eric S. Lawrence, Michael S. Getz Kandoth, Cyriac Fulton, Robert Fulton, Lucinda L. McLellan, Michael D. Wilson, Richard K. Ye, Kai Fronick, Catrina C. Maher, Christopher A. Miller, Christopher A. Wendl, Michael C. Cabanski, Christopher Ding, Li Mardis, Elaine Govindan, Ramaswamy Creighton, Chad J. Wheeler, David Balasundaram, Miruna Butterfield, Yaron S. N. Carlsen, Rebecca Chu, Andy Chuah, Eric Dhalla, Noreen Guin, Ranabir Hirst, Carrie Lee, Darlene Li, Haiyan I. Mayo, Michael Moore, Richard A. Mungall, Andrew J. Schein, Jacqueline E. Sipahimalani, Payal Tam, Angela Varhol, Richard Robertson, A. Gordon Wye, Natasja Thiessen, Nina Holt, Robert A. Jones, Steven J. M. Marra, Marco A. Campbell, Joshua D. Brooks, Angela N. Chmielecki, Juliann Imielinski, Marcin Onofrio, Robert C. Hodis, Eran Zack, Travis Sougnez, Carrie Helman, Elena Pedamallu, Chandra Sekhar Mesirov, Jill Cherniack, Andrew D. Saksena, Gordon Schumacher, Steven E. Carter, Scott L. Hernandez, Bryan Garraway, Levi Beroukhim, Rameen Gabriel, Stacey B. Getz, Gad Meyerson, Matthew Hadjipanayis, Angela Lee, Semin Mahadeshwar, Harshad S. Pantazi, Angeliki Protopopov, Alexei Ren, Xiaojia Seth, Sahil Song, Xingzhi Tang, Jiabin Yang, Lixing Zhang, Jianhua Chen, Peng-Chieh Parfenov, Michael Xu, Andrew Wei Santoso, Netty Chin, Lynda Park, Peter J. Kucherlapati, Raju Hoadley, Katherine A. Auman, J. Todd Meng, Shaowu Shi, Yan Buda, Elizabeth Waring, Scot Veluvolu, Umadevi Tan, Donghui Mieczkowski, Piotr A. Jones, Corbin D. Simons, Janae V. Soloway, Matthew G. Bodenheimer, Tom Jefferys, Stuart R. Roach, Jeffrey Hoyle, Alan P. Wu, Junyuan Balu, Saianand Singh, Darshan Prins, Jan F. Marron, J. S. Parker, Joel S. Hayes, D. Neil Perou, Charles M. Liu, Jinze Cope, Leslie Danilova, Ludmila Weisenberger, Daniel J. Maglinte, Dennis T. Lai, Philip H. Bootwalla, Moiz S. Van Den Berg, David J. Triche, Timothy, Jr. Baylin, Stephen B. Laird, Peter W. Rosenberg, Mara Chin, Lynda Zhang, Jianhua Cho, Juok DiCara, Daniel Heiman, David Lin, Pei Mallard, William Voet, Douglas Zhang, Hailei Zou, Lihua Noble, Michael S. Lawrence, Michael S. Saksena, Gordon Gehlenborg, Nils Thorvaldsdottir, Helga Mesirov, Jill Nazaire, Marc-Danie Robinson, Jim Getz, Gad Lee, William Aksoy, B. Arman Ciriello, Giovanni Taylor, Barry S. Dresdner, Gideon Gao, Jianjiong Gross, Benjamin Seshan, Venkatraman E. Ladanyi, Marc Reva, Boris Sinha, Rileen Sumer, S. Onur Weinhold, Nils Schultz, Nikolaus Shen, Ronglai Sander, Chris Sam Ng Ma, Singer Zhu, Jingchun Radenbaugh, Amie Stuart, Joshua M. Benz, Christopher C. Yau, Christina Haussler, David Spellman, Paul T. Wilkerson, Matthew D. Parker, Joel S. Hoadley, Katherine A. Kimes, Patrick K. Hayes, D. Neil Perou, Charles M. Broom, Bradley M. Wang, Jing Lu, Yiling Patrick Kwok Shing Ng Diao, Lixia Byers, Lauren Averett Liu, Wenbin Heymach, John V. Amos, Christopher I. Weinstein, John N. Akbani, Rehan Mills, Gordon B. Curley, Erin Paulauskis, Joseph Lau, Kevin Morris, Scott Shelton, Troy Mallery, David Gardner, Johanna Penny, Robert Saller, Charles Tarvin, Katherine Richards, William G. Cerfolio, Robert Bryant, Ayesha Raymond, Daniel P. Pennell, Nathan A. Farver, Carol Czerwinski, Christine Huelsenbeck-Dill, Lori Iacocca, Mary Petrelli, Nicholas Rabeno, Brenda Brown, Jennifer Bauer, Thomas Dolzhanskiy, Oleg Potapova, Olga Rotin, Daniil Voronina, Olga Nemirovich-Danchenko, Elena Fedosenko, Konstantin V. Gal, Anthony Behera, Madhusmita Ramalingam, Suresh S. Sica, Gabriel Flieder, Douglas Boyd, Jeff Weaver, JoEllen Kohl, Bernard Dang Huy Quoc Thinh Sandusky, George Juhl, Hartmut Duhig, Edwina Illei, Peter Gabrielson, Edward Shin, James Lee, Beverly Rogers, Kristen Trusty, Dante Brock, Malcolm V. Williamson, Christina Burks, Eric Rieger-Christ, Kimberly Holway, Antonia Sullivan, Travis Wigle, Dennis A. Asiedu, Michael K. Kosari, Farhad Travis, William D. Rekhtman, Natasha Zakowski, Maureen Rusch, Valerie W. Zippile, Paul Suh, James Pass, Harvey Goparaju, Chandra Owusu-Sarpong, Yvonne Bartlett, John M. S. Kodeeswaran, Sugy Parfitt, Jeremy Sekhon, Harmanjatinder Albert, Monique Eckman, John Myers, Jerome B. Cheney, Richard Morrison, Carl Gaudioso, Carmelo Borgia, Jeffrey A. Bonomi, Philip Pool, Mark Liptay, Michael J. Moiseenko, Fedor Zaytseva, Irina Dienemann, Hendrik Meister, Michael Schnabel, Philipp A. Muley, Thomas R. Peifer, Martin Gomez-Fernandez, Carmen Herbert, Lynn Egea, Sophie Huang, Mei Thorne, Leigh B. Boice, Lori Salazar, Ashley Hill Funkhouser, William K. Rathmell, W. Kimryn Dhir, Rajiv Yousem, Samuel A. Dacic, Sanja Schneider, Frank Siegfried, Jill M. Hajek, Richard Watson, Mark A. McDonald, Sandra Meyers, Bryan Clarke, Belinda Yang, Ian A. Fong, Kwun M. Hunter, Lindy Windsor, Morgan Bowman, Rayleen V. Peters, Solange Letovanec, Igor Khan, Khurram Z. Jensen, Mark A. Snyder, Eric E. Srinivasan, Deepak Kahn, Ari B. Baboud, Julien Pot, David A. Shaw, Kenna R. Mills Sheth, Margi Davidsen, Tanja Demchok, John A. Yang, Liming Wang, Zhining Tarnuzzer, Roy Zenklusen, Jean Claude Ozenberger, Bradley A. Sofia, Heidi J. Travis, William D. Cheney, Richard Clarke, Belinda Dacic, Sanja Duhig, Edwina Funkhouser, William K. Illei, Peter Farver, Carol Rekhtman, Natasha Sica, Gabriel Suh, James Tsao, Ming-Sound CA Canc Genome Atlas Res Network TI Comprehensive molecular profiling of lung adenocarcinoma SO NATURE LA English DT Article ID CANCER GENOME; CELL-LINES; MUTATIONS; EXPRESSION; GENE; REVEALS; CLASSIFICATION; INACTIVATION; LANDSCAPE; DISCOVERY AB Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen(mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis. C1 [Collisson, Eric A.; Taylor, Barry S.] Univ Calif San Francisco, San Francisco, CA 94158 USA. [Brooks, Angela N.; Garraway, Levi; Beroukhim, Rameen; Meyerson, Matthew; Spellman, Paul T.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Brooks, Angela N.; Lee, William; Ladanyi, Marc; Schultz, Nikolaus; Shen, Ronglai; Travis, William D.; Aksoy, B. Arman; Ciriello, Giovanni; Dresdner, Gideon; Gao, Jianjiong; Gross, Benjamin; Seshan, Venkatraman E.; Reva, Boris; Sinha, Rileen; Sumer, S. Onur; Weinhold, Nils; Schultz, Nikolaus; Sander, Chris; Rekhtman, Natasha; Zakowski, Maureen; Rusch, Valerie W.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Beer, David G.] Univ Michigan, Ann Arbor, MI 48109 USA. [Cope, Leslie; Danilova, Ludmila; Herman, James G.; Baylin, Stephen B.; Illei, Peter; Gabrielson, Edward; Shin, James; Lee, Beverly; Rogers, Kristen; Trusty, Dante; Brock, Malcolm V.] Johns Hopkins Univ, Baltimore, MD 21287 USA. [Creighton, Chad J.; Wheeler, David] Baylor Coll Med, Houston, TX 77030 USA. [Ding, Li; Govindan, Ramaswamy; Kandoth, Cyriac; Fulton, Robert; Fulton, Lucinda L.; McLellan, Michael D.; Wilson, Richard K.; Ye, Kai; Fronick, Catrina C.; Maher, Christopher A.; Miller, Christopher A.; Wendl, Michael C.; Cabanski, Christopher; Mardis, Elaine; Watson, Mark A.; McDonald, Sandra; Meyers, Bryan] Washington Univ, St Louis, MO 63108 USA. [Getz, Gad; Kucherlapati, Raju; Hadjipanayis, Angela; Getz; Imielinski, Marcin; Hodis, Eran; Garraway, Levi; Beroukhim, Rameen; Meyerson, Matthew; Hadjipanayis, Angela; Lee, Semin; Pantazi, Angeliki; Ren, Xiaojia; Yang, Lixing; Chen, Peng-Chieh; Parfenov, Michael; Xu, Andrew Wei; Santoso, Netty; Park, Peter J.; Kucherlapati, Raju] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Getz, Gad; Getz; Imielinski, Marcin] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hayes, D. Neil; Wilkerson, Matthew D.; Hoadley, Katherine A.; Auman, J. Todd; Meng, Shaowu; Shi, Yan; Buda, Elizabeth; Waring, Scot; Veluvolu, Umadevi; Tan, Donghui; Mieczkowski, Piotr A.; Jones, Corbin D.; Simons, Janae V.; Soloway, Matthew G.; Bodenheimer, Tom; Jefferys, Stuart R.; Roach, Jeffrey; Hoyle, Alan P.; Wu, Junyuan; Balu, Saianand; Singh, Darshan; Prins, Jan F.; Marron, J. S.; Parker, Joel S.; Perou, Charles M.; Kimes, Patrick K.; Huang, Mei; Thorne, Leigh B.; Boice, Lori; Salazar, Ashley Hill; Funkhouser, William K.; Rathmell, W. Kimryn] Univ N Carolina, Chapel Hill, NC 27599 USA. [Heymach, John V.; Sinha, Rileen; Weinstein, John N.; Byers, Lauren Averett; Holt, Robert A.; Mahadeshwar, Harshad S.; Protopopov, Alexei; Seth, Sahil; Song, Xingzhi; Tang, Jiabin; Zhang, Jianhua; Chin, Lynda; Broom, Bradley M.; Wang, Jing; Lu, Yiling; Patrick Kwok Shing Ng; Diao, Lixia; Liu, Wenbin; Amos, Christopher I.; Akbani, Rehan; Mills, Gordon B.; Hajek, Richard] Univ Texas MD Anderson Canc Ctr, Houston, TX 77054 USA. [Jurisica, Igor; Tsao, Ming-Sound] Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada. [Kwiatkowski, David; Hadjipanayis, Angela; Lee, Semin; Pantazi, Angeliki; Parfenov, Michael; Xu, Andrew Wei; Santoso, Netty; Park, Peter J.; Kucherlapati, Raju; Richards, William G.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Robertson, Gordon; Chu, Andy; Balasundaram, Miruna; Butterfield, Yaron S. N.; Carlsen, Rebecca; Chuah, Eric; Dhalla, Noreen; Guin, Ranabir; Hirst, Carrie; Lee, Darlene; Li, Haiyan I.; Mayo, Michael; Moore, Richard A.; Mungall, Andrew J.; Schein, Jacqueline E.; Sipahimalani, Payal; Tam, Angela; Varhol, Richard; Robertson, A. Gordon; Wye, Natasja; Thiessen, Nina; Jones, Steven J. M.; Marra, Marco A.] BC Canc Agcy, Vancouver, BC V5Z 4S6, Canada. [Wigle, Dennis A.; Asiedu, Michael K.; Kosari, Farhad] Mayo Clin, Rochester, MN 55905 USA. [Weisenberger, Daniel J.; Laird, Peter W.; Maglinte, Dennis T.; Lai, Philip H.; Bootwalla, Moiz S.; Van Den Berg, David J.; Triche, Timothy, Jr.] Univ So Calif, Los Angeles, CA 90033 USA. [Radenbaugh, Amie; Ma, Singer; Stuart, Joshua M.; Sam Ng; Zhu, Jingchun; Radenbaugh, Amie; Haussler, David] Univ Calif Santa Cruz, Santa Cruz, CA 95064 USA. [Lander, Eric S.] MIT, Cambridge, MA 02142 USA. [Liu, Jinze] Univ Kentucky, Lexington, KY 40515 USA. [Benz, Christopher C.; Yau, Christina] Buck Inst Age Res, Novato, CA 94945 USA. [Haussler, David] Univ Calif Santa Cruz, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA. [Spellman, Paul T.] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Curley, Erin; Paulauskis, Joseph; Lau, Kevin; Morris, Scott; Shelton, Troy; Mallery, David; Gardner, Johanna; Penny, Robert] Int Genom Consortium, Phoenix, AZ 85004 USA. [Saller, Charles; Tarvin, Katherine] Analyt Biol Serv Inc, Wilmington, DE 19801 USA. [Cerfolio, Robert; Bryant, Ayesha] Univ Alabama Birmingham, Birmingham, AL 35294 USA. [Raymond, Daniel P.; Pennell, Nathan A.; Farver, Carol] Cleveland Clin, Cleveland, OH 44195 USA. [Czerwinski, Christine; Huelsenbeck-Dill, Lori; Iacocca, Mary; Petrelli, Nicholas; Rabeno, Brenda; Brown, Jennifer; Bauer, Thomas] Christiana Care, Newark, DE 19713 USA. [Dolzhanskiy, Oleg; Potapova, Olga; Rotin, Daniil; Voronina, Olga; Nemirovich-Danchenko, Elena; Fedosenko, Konstantin V.] Cureline Inc, San Francisco, CA 94080 USA. [Gal, Anthony; Behera, Madhusmita; Ramalingam, Suresh S.; Sica, Gabriel] Emory Univ, Atlanta, GA 30322 USA. [Flieder, Douglas; Boyd, Jeff; Weaver, JoEllen] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Kohl, Bernard; Dang Huy Quoc Thinh] ILSbio, Chestertown, MD 21620 USA. [Sandusky, George] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Juhl, Hartmut] Individumed, Silver Spring, MD 20910 USA. [Duhig, Edwina; Clarke, Belinda; Yang, Ian A.; Fong, Kwun M.; Hunter, Lindy; Windsor, Morgan; Bowman, Rayleen V.; Duhig, Edwina] Prince Charles Hosp, Brisbane, Qld 4032, Australia. [Duhig, Edwina; Clarke, Belinda; Fong, Kwun M.; Hunter, Lindy; Windsor, Morgan; Bowman, Rayleen V.; Duhig, Edwina] Univ Queensland, Thorac Res Ctr, Brisbane, Qld 4032, Australia. [Duhig, Edwina] Sullivan Nicolaides Pathol, Tugun 4680, Australia. [Duhig, Edwina] John Flynn Hosp, Tugun 4680, Australia. [Williamson, Christina; Burks, Eric; Rieger-Christ, Kimberly; Holway, Antonia; Sullivan, Travis] Lahey Hosp & Med Ctr, Burlington, MA 01805 USA. [Zippile, Paul; Suh, James; Pass, Harvey; Goparaju, Chandra; Owusu-Sarpong, Yvonne] NYU Langone Med Ctr, New York, NY 10016 USA. [Bartlett, John M. S.; Kodeeswaran, Sugy; Parfitt, Jeremy; Sekhon, Harmanjatinder; Albert, Monique] Ontario Inst Canc Res, Ontario Tumour Bank, Toronto, ON M5G 0A3, Canada. [Eckman, John; Myers, Jerome B.] Penrose St Francis Hlth Serv, Colorado Springs, CO 80907 USA. [Cheney, Richard; Morrison, Carl; Gaudioso, Carmelo] Roswel Pk Canc Ctr, Buffalo, NY 14263 USA. [Borgia, Jeffrey A.; Bonomi, Philip; Pool, Mark; Liptay, Michael J.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Moiseenko, Fedor; Zaytseva, Irina] St Petersburg Acad Univ, St Petersburg 199034, Russia. [Dienemann, Hendrik; Meister, Michael; Muley, Thomas R.] Univ Klinikum Heidelberg, Thoraxklin, D-69126 Heidelberg, Germany. [Schnabel, Philipp A.] Heidelberg Univ, D-69120 Heidelberg, Germany. [Peifer, Martin] Univ Cologne, D-50931 Cologne, Germany. [Gomez-Fernandez, Carmen; Herbert, Lynn; Egea, Sophie] Univ Miami, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA. [Dhir, Rajiv; Yousem, Samuel A.; Dacic, Sanja; Schneider, Frank; Siegfried, Jill M.] Univ Pittsburgh, Pittsburgh, PA 15213 USA. [Peters, Solange; Letovanec, Igor] CHU Vaudois, Lausanne & European Thorac Oncol Platform, CH-1011 Lausanne, Switzerland. [Khan, Khurram Z.] Ziauddin Univ Hosp, Karachi 75300, Pakistan. [Jensen, Mark A.; Snyder, Eric E.; Srinivasan, Deepak; Kahn, Ari B.; Baboud, Julien; Pot, David A.] SRA Int Inc, Fairfax, VA 22033 USA. [Shaw, Kenna R. Mills; Sheth, Margi; Davidsen, Tanja; Demchok, John A.; Yang, Liming; Wang, Zhining; Tarnuzzer, Roy; Zenklusen, Jean Claude] NCI, NIH, Bethesda, MD 20892 USA. [Ozenberger, Bradley A.; Sofia, Heidi J.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Meyerson, M (reprint author), Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. EM matthew_meyerson@dfci.harvard.edu RI Ye, Kai/B-3640-2012; Laird, Peter/G-8683-2012; Schein, Jacquie/G-3674-2015; Jones, Steven/C-3621-2009; Lee, Semin/S-2629-2016; Yang, Ian/B-9609-2008; Marra, Marco/B-5987-2008; Holt, Robert/C-3303-2009; OI Moiseenko, Fedor/0000-0003-2544-9042; Lee, William/0000-0001-9582-4413; Pot, David/0000-0002-1480-9826; Sinha, Rileen/0000-0001-5497-5055; Lee, Semin/0000-0002-9015-6046; Yang, Ian/0000-0001-8338-1993; Schultz, Nikolaus/0000-0002-0131-4904; Kandoth, Cyriac/0000-0002-1345-3573; Perou, Charles/0000-0001-9827-2247 FU NIH [U24 CA126561, U24 CA126551, U24 CA126554, U24 CA126543, U24 CA126546, U24 CA137153, U24 CA126563, U24 CA126544, U24 CA143845, U24 CA143858, U24 CA144025, U24 CA143882, U24 CA143866]; The NIH [U24 CA143867, U24 CA143848, U24 CA143840, U24 CA143835, U24 CA143799, U24 CA143883, U24 CA143843, U54 HG003067, U54 HG003079, U54 HG003273] FX This study was supported by NIH grants: U24 CA126561, U24 CA126551, U24 CA126554, U24 CA126543, U24 CA126546, U24 CA137153, U24 CA126563, U24 CA126544, U24 CA143845, U24 CA143858, U24 CA144025, U24 CA143882, U24 CA143866, U24 CA143867, U24 CA143848, U24 CA143840, U24 CA143835, U24 CA143799, U24 CA143883, U24 CA143843, U54 HG003067, U54 HG003079 and U54 HG003273. We thank K. Guebert and L. Gaffney for assistance and C. Gunter for review. NR 42 TC 432 Z9 434 U1 27 U2 129 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUL 30 PY 2014 VL 511 IS 7511 BP 543 EP 550 DI 10.1038/nature13385 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM0VT UT WOS:000339566300025 ER PT J AU Sandler, NG Bosinger, SE Estes, JD Zhu, RTR Tharp, GK Boritz, E Levin, D Wijeyesinghe, S Makamdop, KN del Prete, GQ Hill, BJ Timmer, JK Reiss, E Yarden, G Darko, S Contijoch, E Todd, JP Silvestri, G Nason, M Norgren, RB Keele, BF Rao, S Langer, JA Lifson, JD Schreiber, G Douek, DC AF Sandler, Netanya G. Bosinger, Steven E. Estes, Jacob D. Zhu, Richard T. R. Tharp, Gregory K. Boritz, Eli Levin, Doron Wijeyesinghe, Sathi Makamdop, Krystelle Nganou del Prete, Gregory Q. Hill, Brenna J. Timmer, J. Katherina Reiss, Emma Yarden, Ganit Darko, Samuel Contijoch, Eduardo Todd, John Paul Silvestri, Guido Nason, Martha Norgren, Robert B., Jr. Keele, Brandon F. Rao, Srinivas Langer, Jerome A. Lifson, Jeffrey D. Schreiber, Gideon Douek, Daniel C. TI Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression SO NATURE LA English DT Article ID PERSISTENT LCMV INFECTION; CD4(+) T-CELLS; HIV-1 INFECTION; ALPHA; REPLICATION; ACQUISITION; ACTIVATION; BLOCKADE; THERAPY; GENES AB Inflammation in HIV infection is predictive of non-AIDS morbidity and death(1), higher set point plasma virus load(2) and virus acquisition3; thus, therapeutic agents are in development to reduce its causes and consequences. However, inflammation may simultaneously confer both detrimental and beneficial effects. This dichotomy is particularly applicable to type I interferons (IFN-I) which, while contributing to innate control of infection(4-10), also provide target cells for the virus during acute infection, impair CD4 T-cell recovery, and are associated with disease progression(6,11-19). Here we manipulated IFN-I signalling in rhesus macaques (Macaca mulatta) during simian immunodeficiency virus (Sly) transmission and acute infection with two complementary in vivo interventions. We show that blockade of the IFN-I receptor caused reduced antiviral gene expression, increased SIV reservoir size and accelerated CD4 T-cell depletion with progression to AIDS despite decreased T-cell activation. In contrast, IFN-a2a administration initially upreg-ulated expression of antiviral genes and prevented systemic infection. However, continued IFN-a2a treatment induced IFN-I desensitization and decreased antiviral gene expression, enabling infection with increased SIV reservoir size and accelerated CD4 T-cell loss. Thus, the timing of IFN-induced innate responses in acute SIV infection profoundly affects overall disease course and outweighs the detrimental consequences of increased immune activation. Yet, the clinical consequences of manipulation of IFN signalling are difficult to predict in vivo and therapeutic interventions in human studies should be approached with caution. C1 [Sandler, Netanya G.; Zhu, Richard T. R.; Boritz, Eli; Wijeyesinghe, Sathi; Makamdop, Krystelle Nganou; Hill, Brenna J.; Timmer, J. Katherina; Reiss, Emma; Darko, Samuel; Contijoch, Eduardo; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Bosinger, Steven E.; Tharp, Gregory K.; Silvestri, Guido] Yerkes Natl Primate Res Ctr, Emory Vaccine Ctr, Div Microbiol & Immunol, Atlanta, GA 30322 USA. [Bosinger, Steven E.; Tharp, Gregory K.] Emory Univ, Robert W Woodruff Hlth Sci Ctr, Yerkes Natl Primate Res Ctr, Nonhuman Primate Genom Core, Atlanta, GA 30322 USA. [Estes, Jacob D.; del Prete, Gregory Q.; Keele, Brandon F.; Lifson, Jeffrey D.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab, Frederick, MD 21702 USA. [Levin, Doron; Yarden, Ganit; Schreiber, Gideon] Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. [Todd, John Paul; Rao, Srinivas] NIAID, Lab Anim Med, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Nason, Martha] NIAID, Biostat Res Branch, Div Clin Res, NIH, Bethesda, MD 20892 USA. [Norgren, Robert B., Jr.] Univ Nebraska Med Ctr, Dept Genet Cell Biol & Anat, Omaha, NE 68198 USA. [Langer, Jerome A.] Rutgers Robert Wood Johnson Med Sch, Dept Pharmacol, Piscataway, NJ 08854 USA. RP Douek, DC (reprint author), NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ddouek@mail.nih.gov OI Langer, Jerome/0000-0002-4617-3260; Utay, Netanya/0000-0002-6407-8670 FU NIH Intramural Funding; NCI/NIH [HHSN261200800001E]; NIH [R24 RR017444, AI-076174]; I-CORE Program of the Planning and Budgeting Committee; Israel Science Foundation grant [1775/12] FX We would like to acknowledge A. Zimin for his work in creating the MuSuRCA rhesus assembly, C. Miller for the gift of 6 rhesus macaques and Y. Peleg and S. Albeck at the Israel Structure Proteomic Center and G. Jona from Weizmann Institute Biological services for helping with protein production and purification; A. Roque and N. Haining for initial work on the pilot study; N. Modi, D. Ambrozak, R. Koup, M. Ghosh, I. Srivastava, R. Schwartz, F. Villinger, K. Zoon, J. Bekisz, K. Ghneim, A. Filali, R. Sekaly, L. Mach and L. Shen for their assistance on the current project; and A. Somasunderam for additional support This project was supported by NIH Intramural Funding, federal funds from NCI/NIH Contract HHSN261200800001E, NIH R24 RR017444, NIH AI-076174, I-CORE Program of the Planning and Budgeting Committee and the Israel Science Foundation grant No. 1775/12. NR 34 TC 121 Z9 121 U1 3 U2 27 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUL 30 PY 2014 VL 511 IS 7511 BP 601 EP + DI 10.1038/nature13554 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM0VT UT WOS:000339566300037 PM 25043006 ER PT J AU Sellier, C Usdin, K Pastori, C Peschansky, VJ Tassone, F Charlet-Berguerand, N AF Sellier, Chantal Usdin, Karen Pastori, Chiara Peschansky, Veronica J. Tassone, Flora Charlet-Berguerand, Nicolas TI The multiple molecular facets of fragile X-associated tremor/ataxia syndrome SO JOURNAL OF NEURODEVELOPMENTAL DISORDERS LA English DT Review ID LONG NONCODING RNAS; CGG-REPEAT LENGTH; NATURAL ANTISENSE TRANSCRIPTS; FMR1 MESSENGER-RNA; PREMUTATION CARRIERS; FULL MUTATION; SYNDROME FXTAS; MOUSE MODEL; MEDIATED NEURODEGENERATION; INTRANUCLEAR INCLUSIONS AB Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset inherited neurodegenerative disorder characterized by intentional tremor, gait ataxia, autonomic dysfunction, and cognitive decline. FXTAS is caused by the presence of a long CGG repeat tract in the 5' UTR of the FMR1 gene. In contrast to Fragile X syndrome, in which the FMR1 gene harbors over 200 CGG repeats but is transcriptionally silent, the clinical features of FXTAS arise from a toxic gain of function of the elevated levels of FMR1 transcript containing the long CGG tract. However, how this RNA leads to neuronal cell dysfunction is unknown. Here, we discuss the latest advances in the current understanding of the possible molecular basis of FXTAS. C1 [Sellier, Chantal; Charlet-Berguerand, Nicolas] IGBMC, INSERM, Dept Translat Med, U964, Illkirch Graffenstaden, France. [Usdin, Karen] NIDDK, Sect Gene Struct & Dis, NIH, Bethesda, MD 20892 USA. [Pastori, Chiara; Peschansky, Veronica J.] Univ Miami, Miller Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33136 USA. [Pastori, Chiara; Peschansky, Veronica J.] Univ Miami, Miller Sch Med, Ctr Therapeut Innovat, Hussman Inst Human Genom, Miami, FL 33136 USA. [Tassone, Flora] Univ Calif Davis, Med Ctr, Dept Biochem & Mol Med, Sacramento, CA 95817 USA. [Tassone, Flora] Univ Calif Davis, Med Ctr, MIND Inst, Sacramento, CA 95817 USA. [Charlet-Berguerand, Nicolas] Univ Strasbourg, Inst Genet & Biol Mol & Cellulaire, CNRS, UMR7104,INSERM,U964, F-67404 Illkirch Graffenstaden, France. RP Charlet-Berguerand, N (reprint author), IGBMC, INSERM, Dept Translat Med, U964, Illkirch Graffenstaden, France. EM ncharlet@igbmc.fr RI Charlet-Berguerand, Nicolas/I-6727-2016; OI Charlet-Berguerand, Nicolas/0000-0002-4423-4920; Peschansky, Veronica/0000-0002-5096-4161 FU INSERM; ANR; E-RARE 'CURE FXTAS'; ERC 'RNA DISEASES'; National Institute of Mental Health [5R01MH084880-05]; National Institute of Diabetes and Digestive and Kidney Diseases (NIH) [DK057808-05] FX We thank Paul Hagerman and Peter Todd for invaluable and fruitful discussions. We sincerely apologize to all colleagues whose work could not be cited due to space limitations. This work was supported by INSERM (NCB), ANR and E-RARE 'CURE FXTAS' (NCB), ERC 'RNA DISEASES' (NCB), the National Institute of Mental Health (grant number 5R01MH084880-05) and the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIH; DK057808-05). NR 84 TC 7 Z9 7 U1 2 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1866-1947 EI 1866-1955 J9 J NEURODEV DISORD JI J. Neurodev. Disord. PD JUL 30 PY 2014 VL 6 AR 23 DI 10.1186/1866-1955-6-23 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AO2PC UT WOS:000341166200002 PM 25161746 ER PT J AU Park, JY Mott, M Williams, T Ikeda, H Wen, H Linhoff, M Ono, F AF Park, Jee-Young Mott, Meghan Williams, Tory Ikeda, Hiromi Wen, Hua Linhoff, Michael Ono, Fumihito TI A Single Mutation in the Acetylcholine Receptor delta-Subunit Causes Distinct Effects in Two Types of Neuromuscular Synapses SO JOURNAL OF NEUROSCIENCE LA English DT Article DE acetylcholine receptors; neuromuscular diseases; zebrafish ID CONGENITAL MYASTHENIC SYNDROME; ALPHA-BUNGAROTOXIN; RAPSYN CLUSTERS; ZEBRAFISH MODEL; EPSILON-SUBUNIT; BINDING-SITE; MUSCLE; SLOW; MUTANT; IDENTIFICATION AB Mutations in AChR subunits, expressed as pentamers in neuromuscular junctions (NMJs), cause various types of congenital myasthenic syndromes. In AChR pentamers, the adult epsilon subunit gradually replaces the embryonic gamma subunit as the animal develops. Because of this switch in subunit composition, mutations in specific subunits result in synaptic phenotypes that change with developmental age. However, a mutation in any AChR subunit is considered to affect the NMJs of all muscle fibers equally. Here, we report a zebrafish mutant of the AChR delta subunit that exhibits two distinct NMJ phenotypes specific to two muscle fiber types: slow or fast. Homozygous fish harboring a point mutation in the delta subunit form functional AChRs in slow muscles, whereas receptors in fast muscles are nonfunctional. To test the hypothesis that different subunit compositions in slow and fast muscles underlie distinct phenotypes, we examined the presence of epsilon/gamma subunits in NMJs using specific antibodies. Both wild-type and mutant larvae lacked epsilon/gamma subunits in slow muscle synapses. These findings in zebrafish suggest that some mutations in human congenital myasthenic syndromes may affect slow and fast muscle fibers differently. C1 [Park, Jee-Young; Mott, Meghan; Williams, Tory; Ikeda, Hiromi; Ono, Fumihito] NIAAA, Sect Model Synapt Syst, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. [Wen, Hua; Linhoff, Michael] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Ono, Fumihito] Osaka Med Coll, Dept Physiol, Takatsuki, Osaka 5690801, Japan. RP Ono, F (reprint author), NIAAA, NIH, MSC9411, Bethesda, MD 20892 USA. EM onof@mail.nih.gov FU intramural program at the National Institute on Alcohol Abuse and Alcoholism FX This work was supported by the intramural program at the National Institute on Alcohol Abuse and Alcoholism. We thank Drs. Alex Nechiporuk and Paul Brehm for kindly providing the love sofa mutant; and members of the Laboratory of Molecular Physiology for helpful discussions. NR 48 TC 4 Z9 4 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 30 PY 2014 VL 34 IS 31 BP 10211 EP 10218 DI 10.1523/JNEUROSCI.0426-14.2014 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AO0OK UT WOS:000341009500007 PM 25080583 ER PT J AU Berman, RF Buijsen, RAM Usdin, K Pintado, E Kooy, F Pretto, D Pessah, IN Nelson, DL Zalewski, Z Charlet-Bergeurand, N Willemsen, R Hukema, RK AF Berman, Robert F. Buijsen, Ronald A. M. Usdin, Karen Pintado, Elizabeth Kooy, Frank Pretto, Dalyir Pessah, Isaac N. Nelson, David L. Zalewski, Zachary Charlet-Bergeurand, Nicholas Willemsen, Rob Hukema, Renate K. TI Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome SO JOURNAL OF NEURODEVELOPMENTAL DISORDERS LA English DT Review DE CGG trinucleotide repeat; FMR1; FMRP; Fragile X premutation; FXTAS; Intranuclear inclusions; Mouse models; RNA toxicity ID KNOCK-IN MICE; CGG-REPEAT LENGTH; PUR-ALPHA BINDS; FMR1 GENE; INTRANUCLEAR INCLUSIONS; MYOTONIC-DYSTROPHY; DENDRITIC SPINE; SYNDROME FXTAS; DNA-DAMAGE; MEDIATED NEURODEGENERATION AB Carriers of the fragile X premutation (FPM) have CGG trinucleotide repeat expansions of between 55 and 200 in the 5'-UTR of FMR1, compared to a CGG repeat length of between 5 and 54 for the general population. Carriers were once thought to be without symptoms, but it is now recognized that they can develop a variety of early neurological symptoms as well as being at risk for developing the late onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Several mouse models have contributed to our understanding of FPM and FXTAS, and findings from studies using these models are summarized here. This review also discusses how this information is improving our understanding of the molecular and cellular abnormalities that contribute to neurobehavioral features seen in some FPM carriers and in patients with FXTAS. Mouse models show much of the pathology seen in FPM carriers and in individuals with FXTAS, including the presence of elevated levels of Fmr1 mRNA, decreased levels of fragile X mental retardation protein, and ubiquitin-positive intranuclear inclusions. Abnormalities in dendritic spine morphology in several brain regions are associated with neurocognitive deficits in spatial and temporal memory processes, impaired motor performance, and altered anxiety. In vitro studies have identified altered dendritic and synaptic architecture associated with abnormal Ca2+ dynamics and electrical network activity. FPM mice have been particularly useful in understanding the roles of Fmr1 mRNA, fragile X mental retardation protein, and translation of a potentially toxic polyglycine peptide in pathology. Finally, the potential for using these and emerging mouse models for preclinical development of therapies to improve neurological function in FXTAS is considered. C1 [Berman, Robert F.] Univ Calif Davis, Dept Neurol Surg, Davis, CA 95618 USA. [Buijsen, Ronald A. M.; Willemsen, Rob; Hukema, Renate K.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Usdin, Karen] NIDDK, NIH, Bethesda, MD 20892 USA. [Pintado, Elizabeth] Univ Seville, Sch Med, Seville, Spain. [Kooy, Frank] Univ Antwerp, Dept Med Genet, B-2020 Antwerp, Belgium. [Pretto, Dalyir] Univ Calif Davis, MIND Inst, Sacramento, CA USA. [Pessah, Isaac N.] Univ Calif Davis, Dept Mol Biosci, Davis, CA 95618 USA. [Nelson, David L.; Zalewski, Zachary] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Charlet-Bergeurand, Nicholas] IGBMC, Dept Translat Med, Illkirch Graffenstaden, France. RP Berman, RF (reprint author), Univ Calif Davis, Dept Neurol Surg, Room 502C,1515 Newton Court, Davis, CA 95618 USA. EM rfberman@ucdavis.edu RI Hukema, Renate/E-1422-2013; Kooy, Frank/F-5276-2014 OI Hukema, Renate/0000-0002-1580-4154; Kooy, Frank/0000-0003-2024-0485 FU NICHD [P30 HD24064-15 S1]; Dutch Brain Foundation; NIDDK, NIH; NIEHS [ES011269]; DOD [PR120921]; E-Rare grant; Belgian National Fund for Scientific Research, Flanders; Ministry of Health, Spain; [NS079775] FX The assistance of Andreea Pop with the editing of this manuscript is appreciated. The following funding sources supported the writing of this manuscript: NS079775 (RFB, RW); NICHD P30 HD24064-15 S1 (DLN); Dutch Brain Foundation (RW); the Intramural Program of NIDDK, NIH (KU), NIEHS ES011269 and DOD PR120921(INP); E-Rare grant (RKH); Belgian National Fund for Scientific Research, Flanders (RFK), Ministry of Health, Spain (EP). NR 117 TC 10 Z9 10 U1 2 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1866-1947 EI 1866-1955 J9 J NEURODEV DISORD JI J. Neurodev. Disord. PD JUL 30 PY 2014 VL 6 AR 25 DI 10.1186/1866-1955-6-25 PG 16 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AN4XF UT WOS:000340592300001 PM 25136376 ER PT J AU Choi, J Song, N Han, S Chung, S Sung, H Lee, JY Jung, S Park, SK Yoo, KY Han, W Lee, JW Noh, DY Kang, D Choi, JY AF Choi, Jaesung Song, Nan Han, Sohee Chung, Seokang Sung, Hyuna Lee, Ji-young Jung, Sunjae Park, Sue K. Yoo, Keun-Young Han, Wonshik Lee, Jong Won Noh, Dong-Young Kang, Daehee Choi, Ji-Yeob TI The Associations between Immunity-Related Genes and Breast Cancer Prognosis in Korean Women SO PLOS ONE LA English DT Article ID CELL LUNG-CANCER; SINGLE NUCLEOTIDE POLYMORPHISMS; THYMIC STROMAL LYMPHOPOIETIN; HEPATOCYTE GROWTH-FACTOR; LYMPHOMA SURVIVAL; BLADDER-CANCER; RECEPTOR; RISK; EXPRESSION; VARIANTS AB We investigated the role of common genetic variation in immune-related genes on breast cancer disease-free survival (DFS) in Korean women. 107 breast cancer patients of the Seoul Breast Cancer Study (SEBCS) were selected for this study. A total of 2,432 tag single nucleotide polymorphisms (SNPs) in 283 immune-related genes were genotyped with the GoldenGate Oligonucleotide pool assay (OPA). A multivariate Cox-proportional hazard model and polygenic risk score model were used to estimate the effects of SNPs on breast cancer prognosis. Harrell's C index was calculated to estimate the predictive accuracy of polygenic risk score model. Subsequently, an extended gene set enrichment analysis (GSEA-SNP) was conducted to approximate the biological pathway. In addition, to confirm our results with current evidence, previous studies were systematically reviewed. Sixty-two SNPs were statistically significant at p-value less than 0.05. The most significant SNPs were rs1952438 in SOCS4 gene (hazard ratio (HR) = 11.99, 95% CI = 3.62-39.72, P = 4.84E-05), rs2289278 in TSLP gene (HR = 4.25, 95% CI = 2.10-8.62, P = 5.99E-05) and rs2074724 in HGF gene (HR = 4.63, 95% CI = 2.18-9.87, P = 7.04E-05). In the polygenic risk score model, the HR of women in the 3rd tertile was 6.78 (95% CI = 1.48-31.06) compared to patients in the 1st tertile of polygenic risk score. Harrell's C index was 0.813 with total patients and 0.924 in 4-fold cross validation. In the pathway analysis, 18 pathways were significantly associated with breast cancer prognosis (P<0.1). The IL-6R, IL-8, IL-10RB, IL-12A, and IL-12B was associated with the prognosis of cancer in data of both our study and a previous study. Therefore, our results suggest that genetic polymorphisms in immune-related genes have relevance to breast cancer prognosis among Korean women. C1 [Choi, Jaesung; Chung, Seokang; Park, Sue K.; Kang, Daehee; Choi, Ji-Yeob] Seoul Natl Univ, Dept Biomed Sci, Grad Sch, Seoul, South Korea. [Song, Nan; Park, Sue K.; Han, Wonshik; Noh, Dong-Young; Kang, Daehee; Choi, Ji-Yeob] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea. [Han, Sohee; Jung, Sunjae; Park, Sue K.; Yoo, Keun-Young; Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Sung, Hyuna] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lee, Ji-young] Yonsei Univ Hlth Syst, Cardiovasc Res Inst, Seoul, South Korea. [Lee, Ji-young] Yonsei Univ Hlth Syst, Cardiovasc Genome Ctr, Seoul, South Korea. [Han, Wonshik; Noh, Dong-Young] Seoul Natl Univ, Dept Surg, Coll Med, Seoul, South Korea. [Lee, Jong Won] Univ Ulsan, Dept Surg, Coll Med, Seoul, South Korea. [Lee, Jong Won] ASAN Med Ctr, Seoul, South Korea. RP Choi, JY (reprint author), Seoul Natl Univ, Dept Biomed Sci, Grad Sch, Seoul, South Korea. EM jiyeob.choi@gmail.com RI Han, Wonshik/B-3699-2008; OI Lee, Ji-Young/0000-0002-7784-1401 FU Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health & Welfare, Republic of Korea [HI14C0065] FX This research was supported by a grant of Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C0065). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 1 Z9 2 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 30 PY 2014 VL 9 IS 7 AR e103593 DI 10.1371/journal.pone.0103593 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM7EZ UT WOS:000340028800066 PM 25075970 ER PT J AU Cook, MB Corley, DA Murray, LJ Liao, LM Kamangar, F Ye, WM Gammon, MD Risch, HA Casson, AG Freedman, ND Chow, WH Wu, AH Bernstein, L Nyren, O Pandeya, N Whiteman, DC Vaughan, TL AF Cook, Michael B. Corley, Douglas A. Murray, Liam J. Liao, Linda M. Kamangar, Farin Ye, Weimin Gammon, Marilie D. Risch, Harvey A. Casson, Alan G. Freedman, Neal D. Chow, Wong-Ho Wu, Anna H. Bernstein, Leslie Nyren, Olof Pandeya, Nirmala Whiteman, David C. Vaughan, Thomas L. TI Gastroesophageal Reflux in Relation to Adenocarcinomas of the Esophagus: A Pooled Analysis from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) SO PLOS ONE LA English DT Article ID GASTRIC CARDIA; ESOPHAGOGASTRIC JUNCTION; SOCIOECONOMIC-FACTORS; UNITED-STATES; BODY-SIZE; RISK; ALCOHOL; CANCER; SYMPTOMS; SMOKING AB Background: Previous studies have evidenced an association between gastroesophageal reflux and esophageal adenocarcinoma (EA). It is unknown to what extent these associations vary by population, age, sex, body mass index, and cigarette smoking, or whether duration and frequency of symptoms interact in predicting risk. The Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) allowed an in-depth assessment of these issues. Methods: Detailed information on heartburn and regurgitation symptoms and covariates were available from five BEACON case-control studies of EA and esophagogastric junction adenocarcinoma (EGJA). We conducted single-study multivariable logistic regressions followed by random-effects meta-analysis. Stratified analyses, meta-regressions, and sensitivity analyses were also conducted. Results: Five studies provided 1,128 EA cases, 1,229 EGJA cases, and 4,057 controls for analysis. All summary estimates indicated positive, significant associations between heartburn/regurgitation symptoms and EA. Increasing heartburn duration was associated with increasing EA risk; odds ratios were 2.80, 3.85, and 6.24 for symptom durations of <10 years, 10 to,20 years, and >= 20 years. Associations with EGJA were slighter weaker, but still statistically significant for those with the highest exposure. Both frequency and duration of heartburn/regurgitation symptoms were independently associated with higher risk. We observed similar strengths of associations when stratified by age, sex, cigarette smoking, and body mass index. Conclusions: This analysis indicates that the association between heartburn/regurgitation symptoms and EA is strong, increases with increased duration and/or frequency, and is consistent across major risk factors. Weaker associations for EGJA suggest that this cancer site has a dissimilar pathogenesis or represents a mixed population of patients. C1 [Cook, Michael B.; Liao, Linda M.; Kamangar, Farin; Freedman, Neal D.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Corley, Douglas A.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Corley, Douglas A.] Kaiser Permanente No Calif, Oakland Med Ctr, Oakland, CA USA. [Murray, Liam J.] Queens Univ, Ctr Publ Hlth, Belfast, Antrim, North Ireland. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. [Ye, Weimin; Nyren, Olof] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Gammon, Marilie D.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Risch, Harvey A.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Casson, Alan G.] Univ Saskatchewan, Dept Surg, Saskatoon, SK, Canada. [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Wu, Anna H.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA. [Bernstein, Leslie] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Pandeya, Nirmala; Whiteman, David C.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Vaughan, Thomas L.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. RP Cook, MB (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. EM michael.cook@nih.gov RI Freedman, Neal/B-9741-2015; Cook, Michael/A-5641-2009; Whiteman, David/P-2728-2014; Pandeya, Nirmala/F-8054-2010 OI Freedman, Neal/0000-0003-0074-1098; Cook, Michael/0000-0002-0533-7302; Whiteman, David/0000-0003-2563-9559; Liao, Linda/0000-0002-1923-5294; Pandeya, Nirmala/0000-0003-1462-4968 FU Intramural Research Program of the National Institutes of Health; Queensland Cancer Fund; National Health and Medical Research Council (NHMRC) of Australia [199600]; California Tobacco Related Research Program [3RT-0122, 10RT-0251]; National Cancer Institute [CA59636]; Northern Ireland Research & Development Office; Health Research Board, Ireland; [U01-CA57949]; [U01-CA57983]; [U01-CA57923]; [R01 CA57947-03]; [RO1 DK63616- 01]; [R21 DK077742] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health. The US Multi-Center Study was funded by grants U01-CA57949 (awarded to TLV), U01-CA57983 (awarded to MDG), and U01-CA57923 (awarded to HAR). The Australian Cancer Study was supported by the Queensland Cancer Fund and the National Health and Medical Research Council (NHMRC) of Australia (Program no. 199600, awarded to DCW, Adele C. Green, Nicholas K. Hayward, Peter G. Parsons, David M. Purdie, and Penelope M. Webb). The Swedish Esophageal Cancer Study was funded by grant number R01 CA57947-03 (awarded to ON and Hans-Olov Adami). The Los Angeles County Multi-ethnic Case-control Study was funded by grants 3RT-0122 ('Smoking and Risk of Proximal Vs. Distal Gastric Cancer', awarded to AHW) and 10RT-0251 ('Smoking, microsatellite instability & gastric cancers', awarded to AHW) from the California Tobacco Related Research Program and grant CA59636 (awarded to LB) from the National Cancer Institute. The Factors Influencing the Barrett's Adenocarcinoma Relationship (FINBAR) study was funded by an Ireland-Northern Ireland Co-operation Research Project Grant sponsored by the Northern Ireland Research & Development Office, and the Health Research Board, Ireland (All-Ireland case-control study of Oesophageal Adenocarcinoma and Barrett's Oesophagus, awardedto LJM and Harry Comber). DAC was supported by RO1 DK63616- 01, R21 DK077742. The funders of the individual studies had no role in the design, analysis or interpretation of the data, or in writing or publication decisions related to this manuscript. NR 28 TC 23 Z9 24 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 30 PY 2014 VL 9 IS 7 AR e103508 DI 10.1371/journal.pone.0103508 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM7EZ UT WOS:000340028800056 PM 25075959 ER PT J AU Escalera-Zamudio, M Nelson, MI Guemes, AGC Lopez-Martinez, I Cruz-Ortiz, N Iguala-Vidales, M Garcia, ER Barrera-Badillo, G Diaz-Quinonez, JA Lopez, S Arias, CF Isa, P AF Escalera-Zamudio, Marina Nelson, Martha I. Cobian Gueemes, Ana Georgina Lopez-Martinez, Irma Cruz-Ortiz, Natividad Iguala-Vidales, Miguel Rodriguez Garcia, Elvia Barrera-Badillo, Gisela Alberto Diaz-Quinonez, Jose Lopez, Susana Arias, Carlos F. Isa, Pavel CA Colegio Pediat Estado Veracruz TI Molecular Epidemiology of Influenza A/H3N2 Viruses Circulating in Mexico from 2003 to 2012 SO PLOS ONE LA English DT Article ID A H3N2 VIRUSES; UNITED-STATES; SEQUENCE ALIGNMENT; GENETIC EVOLUTION; VACCINE; UPDATE; SEASON; REASSORTMENT; HEMAGGLUTININ; ORIGIN AB In this work, nineteen influenza A/H3N2 viruses isolated in Mexico between 2003 and 2012 were studied. Our findings show that different human A/H3N2 viral lineages co-circulate within a same season and can also persist locally in between different influenza seasons, increasing the chance for genetic reassortment events. A novel minor cluster was also identified, named here as Korea, that circulated worldwide during 2003. Frequently, phylogenetic characterization did not correlate with the determined antigenic identity, supporting the need for the use of molecular evolutionary tools additionally to antigenic data for the surveillance and characterization of viral diversity during each flu season. This work represents the first long-term molecular epidemiology study of influenza A/H3N2 viruses in Mexico based on the complete genomic sequences and contributes to the monitoring of evolutionary trends of A/H3N2 influenza viruses within North and Central America. C1 [Escalera-Zamudio, Marina; Cobian Gueemes, Ana Georgina; Lopez, Susana; Arias, Carlos F.; Isa, Pavel] Univ Nacl Autonoma Mexico, Inst Biotecnol, Cuernavaca 62191, Morelos, Mexico. [Nelson, Martha I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Lopez-Martinez, Irma; Cruz-Ortiz, Natividad; Iguala-Vidales, Miguel; Rodriguez Garcia, Elvia; Barrera-Badillo, Gisela; Alberto Diaz-Quinonez, Jose] Inst Diagnost & Referencia Epidemiol, Mexico City, DF, Mexico. RP Isa, P (reprint author), Univ Nacl Autonoma Mexico, Inst Biotecnol, Cuernavaca 62191, Morelos, Mexico. EM pavel@ibt.unam.mx OI Diaz-Quinonez, Jose Alberto/0000-0002-3503-7079 FU Instituto de Ciencia y Tecnologia del Distrito Federal, Mexico [PICOSI09-209]; Consejo Nacional de Ciencia y Tecnologia CONACyT-Mexico [S0008-126823]; CONACyT-Mexico FX This work was partially supported by grant PICOSI09-209 from the Instituto de Ciencia y Tecnologia del Distrito Federal to PI, Mexico and S0008-126823 from Consejo Nacional de Ciencia y Tecnologia CONACyT-Mexico to CFA. Marina Escalera-Zamudio y Ana Georgina Cobian Guemes were supported by a scholarship from CONACyT-Mexico. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 0 Z9 1 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 30 PY 2014 VL 9 IS 7 AR e102453 DI 10.1371/journal.pone.0102453 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM7EZ UT WOS:000340028800012 PM 25075517 ER PT J AU Colegate, SM Welsh, SL Gardner, DR Betz, JM Panter, KE AF Colegate, Steven M. Welsh, Stanley L. Gardner, Dale R. Betz, Joseph M. Panter, Kip E. TI Profiling of Dehydropyrrolizidine Alkaloids and their N-Oxides in Herbarium-Preserved Specimens of Amsinckia Species Using HPLC-esi(+)MS SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE Amsinckia; herbarium samples; dehydropyrrolizidine alkaloids; HPLC-esiMS; MS/MS; lycopsamine; intermedine ID PYRROLIZIDINE ALKALOIDS; MS AB Species of the Amsinckia genus (Boraginaceae) are known to produce potentially hepato-, pneumo-, and/or genotoxic dehydropyrrolizidine alkaloids. However, the taxonomic differentiation of Amsinckia species can be very subtle and there seems to be marked differences in toxicity toward grazing livestock. Methanol extracts of mass-limited leaf samples from herbarium specimens (collected from 1899 to 2013) of 10 Amsinckia species and one variety were analyzed using HPLC-esi(+)MS and MS/MS for the presence of potentially toxic dehydropyrrolizidine alkaloids and/or their N-oxides. Dehydropyrrolizidine alkaloids were detected in all specimens examined ranging from about 1 to 4000 mu g/g of plant. Usually occurring mainly as their N-oxides, the predominant alkaloids were the epimeric lycopsamine and intermedine. Also sometimes observed in higher concentrations were the 3'- and 7-acetyl derivatives of lycopsamine/intermedine and their N-oxides. Within a designated species, an inconsistent profile was often observed that may be due to natural variation, taxonomic misassignment, or nonuniform degradation due to plant collection and storage differences. C1 [Colegate, Steven M.; Gardner, Dale R.; Panter, Kip E.] ARS, Poisonous Plant Res Lab, USDA, Logan, UT 84341 USA. [Welsh, Stanley L.] Brigham Young Univ, Stanley L Welsh Herbarium, Provo, UT 84602 USA. [Betz, Joseph M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Colegate, SM (reprint author), ARS, Poisonous Plant Res Lab, USDA, 1150 East 1400 North, Logan, UT 84341 USA. EM steven.colegate@ars.usda.gov FU Agricultural Research Service of U.S. Department of Agriculture; Office of Dietary Supplements of the National Institutes of Health FX This research is supported by the Agricultural Research Service of the U.S. Department of Agriculture and an Interagency Agreement with the Office of Dietary Supplements of the National Institutes of Health. NR 14 TC 1 Z9 1 U1 1 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 EI 1520-5118 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD JUL 30 PY 2014 VL 62 IS 30 BP 7382 EP 7392 DI 10.1021/jf500425v PG 11 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA AM2PW UT WOS:000339694300009 PM 24655304 ER PT J AU Medrano-Gracia, P Cowan, BR Ambale-Venkatesh, B Bluemke, DA Eng, J Finn, JP Fonseca, CG Lima, JAC Suinesiaputra, A Young, AA AF Medrano-Gracia, Pau Cowan, Brett R. Ambale-Venkatesh, Bharath Bluemke, David A. Eng, John Finn, John Paul Fonseca, Carissa G. Lima, Joao A. C. Suinesiaputra, Avan Young, Alistair A. TI Left ventricular shape variation in asymptomatic populations: the multi-ethnic study of atherosclerosis SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Cardiovascular magnetic resonance; Atlas; Principal component analysis ID CARDIOVASCULAR MAGNETIC-RESONANCE; MYOCARDIAL-INFARCTION; PROGNOSTIC IMPLICATIONS; HEART-FAILURE; ATLAS; DISEASE; MASS; DEFORMATION; DILATATION; GEOMETRY AB Background: Although left ventricular cardiac geometric indices such as size and sphericity characterize adverse remodeling and have prognostic value in symptomatic patients, little is known of shape distributions in subclinical populations. We sought to quantify shape variation across a large number of asymptomatic volunteers, and examine differences among sub-cohorts. Methods: An atlas was constructed comprising 1,991 cardiovascular magnetic resonance (CMR) cases contributed from the Multi-Ethnic Study of Atherosclerosis baseline examination. A mathematical model describing regional wall motion and shape was used to establish a coordinate map registered to the cardiac anatomy. The model was automatically customized to left ventricular contours and anatomical landmarks, corrected for breath-hold mis-registration between image slices. Mathematical techniques were used to characterize global shape distributions, after removal of translations, rotations, and scale due to height. Differences were quantified among ethnicity, sex, smoking, hypertension and diabetes sub-cohorts. Results: The atlas construction process yielded accurate representations of global shape (errors between manual and automatic surface points in 244 validation cases were less than the image pixel size). After correction for height, the dominant shape component was associated with heart size, explaining 32% of the total shape variance at end-diastole and 29% at end-systole. After size, the second dominant shape component was sphericity at end-diastole (13%), and concentricity at end-systole (10%). The resulting shape components distinguished differences due to ethnicity and risk factors with greater statistical power than traditional mass and volume indices. Conclusions: We have quantified the dominant components of global shape variation in the adult asymptomatic population. The data and results are available at cardiacatlas.org. Shape distributions were principally explained by size, sphericity and concentricity, which are known correlates of adverse outcomes. Atlas-based global shape analysis provides a powerful method for quantifying left ventricular shape differences in asymptomatic populations. C1 [Medrano-Gracia, Pau; Cowan, Brett R.; Suinesiaputra, Avan; Young, Alistair A.] Univ Auckland, Dept Anat Radiol, Auckland 1, New Zealand. [Ambale-Venkatesh, Bharath; Eng, John; Lima, Joao A. C.] Johns Hopkins Univ, Donald W Reynolds Cardiovasc Clin Res Ctr, Baltimore, MD USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. [Finn, John Paul; Fonseca, Carissa G.] Univ Calif Los Angeles, Dept Radiol, Los Angeles, CA USA. RP Young, AA (reprint author), Univ Auckland, Dept Anat Radiol, Auckland 1, New Zealand. EM a.young@auckland.ac.nz RI Ambale Venkatesh, Bharath/F-4941-2016; OI Ambale Venkatesh, Bharath/0000-0002-2330-2373; Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute, NIH [R01HL087773] FX R01HL087773 from the National Heart, Lung, and Blood Institute, NIH. NR 40 TC 18 Z9 18 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD JUL 30 PY 2014 VL 16 AR 56 DI 10.1186/s12968-014-0056-2 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AM4TE UT WOS:000339847600001 PM 25160814 ER PT J AU Stan, C Astefanoaei, C Pretegiani, E Optican, L Creanga, D Rufa, A Cristescu, CP AF Stan, C. Astefanoaei, C. Pretegiani, E. Optican, L. Creanga, D. Rufa, A. Cristescu, C. P. TI Nonlinear analysis of saccade speed fluctuations during combined action and perception tasks SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Saccade speed peak; Action-perception task; Multifractal properties; Lempel-Ziv complexity ID LEMPEL-ZIV COMPLEXITY; EYE-MOVEMENT; TIME-SERIES; SEQUENCES; DYNAMICS; LENGTH; BRAIN; MODEL AB Background: Saccades are rapid eye movements used to gather information about a scene which requires both action and perception. These are usually studied separately, so that how perception influences action is not well understood. In a dual task, where the subject looks at a target and reports a decision, subtle changes in the saccades might be caused by action perception interactions. Studying saccades might provide insight into how brain pathways for action and for perception interact. New method: We applied two complementary methods, multifractal detrended fluctuation analysis and Lempel-Ziv complexity index to eye peak speed recorded in two experiments, a pure action task and a combined action perception task. Results: Multifractality strength is significantly different in the two experiments, showing smaller values for dual decision task saccades compared to simple-task saccades. The normalized Lempel-Ziv complexity index behaves similarly i.e. is significantly smaller in the decision saccade task than in the simple task. Comparison with existing methods: Compared to the usual statistical and linear approaches, these analyses emphasize the character of the dynamics involved in the fluctuations and offer a sensitive tool for quantitative evaluation of the multifractal features and of the complexity measure in the saccades peak speeds when different brain circuits are involved. Conclusion: Our results prove that the peak speed fluctuations have multifractal characteristics with lower magnitude for the multifractality strength and for the complexity index when two neural pathways are simultaneously activated, demonstrating the nonlinear interaction in the brain pathways for action and perception. (C) 2014 Elsevier B.V. All rights reserved. C1 [Stan, C.; Cristescu, C. P.] Univ Politehn Bucuresti, Dept Phys, RO-060042 Bucharest, Romania. [Astefanoaei, C.; Creanga, D.] Univ Alexandru Ioan Cuza, Dept Phys, Iasi 700506, Romania. [Pretegiani, E.; Rufa, A.] Univ Siena, Dept Med Surg & Neurosci, Eye Tracking & Visual Applicat Lab EVALab, I-53100 Siena, Italy. [Optican, L.] NEI, Sensorimotor Res Lab, IRP, DHHS, Bethesda, MD 20892 USA. RP Creanga, D (reprint author), Univ Alexandru Ioan Cuza, Dept Phys, 11 Blvd Carol 1, Iasi 700506, Romania. EM cstan@physics.pub.ro; corina_astefanoaei@yahoo.com; elena.pretegiani@nih.gov; lmo@lsr.nei.nih.gov; dorina.creanga@gmail.com; rufa@unisi.it; cpcris@physics.pub.ro RI Stan, Cristina/B-5722-2012; Stan, Cristina/O-2180-2016 OI Stan, Cristina/0000-0003-1757-4011; Stan, Cristina/0000-0003-1757-4011 FU FP 7 Project IRSES People [269263] FX This research was supported by FP 7 Project IRSES People 269263 "CERVISO". NR 33 TC 0 Z9 0 U1 1 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD JUL 30 PY 2014 VL 232 BP 102 EP 109 DI 10.1016/j.jneumeth.2014.05.010 PG 8 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AL4ZW UT WOS:000339144300013 PM 24854830 ER PT J AU Baker, SG AF Baker, Stuart G. TI Instrumental variable methods for causal inference: early work and recent developments SO STATISTICS IN MEDICINE LA English DT Letter ID IDENTIFICATION C1 NCI, Biometry Res Grp, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, Biometry Res Grp, Bethesda, MD 20892 USA. EM sb16i@nih.gov NR 11 TC 0 Z9 0 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUL 30 PY 2014 VL 33 IS 17 BP 3058 EP 3059 DI 10.1002/sim.6168 PG 2 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA AL3ZO UT WOS:000339071900013 PM 24989339 ER PT J AU Viboud, C Charu, V Olson, D Ballesteros, S Gog, J Khan, F Grenfell, B Simonsen, L AF Viboud, Cecile Charu, Vivek Olson, Donald Ballesteros, Sebastien Gog, Julia Khan, Farid Grenfell, Bryan Simonsen, Lone TI Demonstrating the Use of High-Volume Electronic Medical Claims Data to Monitor Local and Regional Influenza Activity in the US SO PLOS ONE LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; UNITED-STATES; PANDEMIC INFLUENZA; VACCINE UPTAKE; CHILDREN; MORTALITY; SURVEILLANCE; PNEUMONIA; EPIDEMICS; COVERAGE AB Introduction: Fine-grained influenza surveillance data are lacking in the US, hampering our ability to monitor disease spread at a local scale. Here we evaluate the performances of high-volume electronic medical claims data to assess local and regional influenza activity. Material and Methods: We used electronic medical claims data compiled by IMS Health in 480 US locations to create weekly regional influenza-like-illness (ILI) time series during 2003-2010. IMS Health captured 62% of US outpatient visits in 2009. We studied the performances of IMS-ILI indicators against reference influenza surveillance datasets, including CDC-ILI outpatient and laboratory-confirmed influenza data. We estimated correlation in weekly incidences, peak timing and seasonal intensity across datasets, stratified by 10 regions and four age groups (< 5, 5-29, 30-59, and 60+ years). To test IMS-Health performances at the city level, we compared IMS-ILI indicators to syndromic surveillance data for New York City. We also used control data on laboratory-confirmed Respiratory Syncytial Virus (RSV) activity to test the specificity of IMS-ILI for influenza surveillance. Results: Regional IMS-ILI indicators were highly synchronous with CDC's reference influenza surveillance data (Pearson correlation coefficients rho >= 0.89; range across regions, 0.80-0.97, P < 0.001). Seasonal intensity estimates were weakly correlated across datasets in all age data (rho <= 0.52), moderately correlated among adults (rho >= 0.64) and uncorrelated among school-age children. IMS-ILI indicators were more correlated with reference influenza data than control RSV indicators (rho = 0.93 with influenza v. rho = 0.33 with RSV, P < 0.05). City-level IMS-ILI indicators were highly consistent with reference syndromic data (rho >= 0.86). Conclusion: Medical claims-based ILI indicators accurately capture weekly fluctuations in influenza activity in all US regions during inter-pandemic and pandemic seasons, and can be broken down by age groups and fine geographical areas. Medical claims data provide more reliable and fine-grained indicators of influenza activity than other high-volume electronic algorithms and should be used to augment existing influenza surveillance systems. C1 [Viboud, Cecile; Charu, Vivek; Gog, Julia; Grenfell, Bryan; Simonsen, Lone] Fogarty Int Ctr, NIH, Bethesda, MD 20892 USA. [Charu, Vivek] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Olson, Donald] New York City Dept Hlth & Mental Hyg, New York, NY USA. [Ballesteros, Sebastien; Grenfell, Bryan] Princeton Univ, Dept Evolut Biol, Princeton, NJ 08544 USA. [Gog, Julia] Univ Cambridge, Dept Appl Math & Theoret Phys, Cambridge CB3 9EW, England. [Khan, Farid] IMS Hlth, Plymouth, PA USA. [Simonsen, Lone] George Washington Univ, Sch Publ Hlth & Hlth Serv, Washington, DC USA. RP Viboud, C (reprint author), Fogarty Int Ctr, NIH, Bethesda, MD 20892 USA. EM viboudc@mail.nih.gov OI Simonsen, Lone/0000-0003-1535-8526 FU Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This study was supported by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security (to JG, LS, BG), and the in-house influenza program of the Fogarty International Center, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 14 Z9 14 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 29 PY 2014 VL 9 IS 7 AR e102429 DI 10.1371/journal.pone.0102429 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO4KU UT WOS:000341307600012 PM 25072598 ER PT J AU Lavi, O Skinner, J Gottesman, MM AF Lavi, Orit Skinner, Jeff Gottesman, Michael M. TI Network features suggest new hepatocellular carcinoma treatment strategies SO BMC SYSTEMS BIOLOGY LA English DT Article DE Co-expression network; Pathway network; Robustness; Redundancy; Resistance; Cancer therapy ID CHROMATOGRAPHY-MASS SPECTROMETRY; COEXPRESSION NETWORK; SIGNALING PATHWAYS; DATA SETS; CANCER; CLASSIFICATION; RESISTANCE; DISCOVERY; EPIDEMIOLOGY; SIGNATURES AB Background: Resistance to therapy remains a major cause of the failure of cancer treatment. A major challenge in cancer therapy is to design treatment strategies that circumvent the higher-level homeostatic functions of the robust cellular network that occurs in resistant cells. There is a lack of understanding of mechanisms responsible for the development of cancer and the basis of therapy-resistance mechanisms. Cellular signaling networks have an underlying architecture guided by universal principles. A robust system, such as cancer, has the fundamental ability to survive toxic anticancer drug treatments or a stressful environment mainly due to its mechanisms of redundancy. Consequently, inhibition of a single component/pathway would probably not constitute a successful cancer therapy. Results: We developed a computational method to study the mechanisms of redundancy and to predict communications among the various pathways based on network theory, using data from gene expression profiles of hepatocellular carcinoma (HCC) of patients with poor and better prognosis cancers. Our results clearly indicate that immune system pathways tightly regulate most cancer pathways, and when those pathways are targeted by drugs, the network connectivity is dramatically changed. We examined the main HCC targeted treatments that are currently being evaluated in clinical trials. One prediction of our study is that Sorafenib combined with immune system treatments will be a more effective combination strategy than Sorafenib combined with any other targeted drugs. Conclusions: We developed a computational framework to analyze gene expression data from HCC tumors with varying degrees of responsiveness and non-tumor samples, based on both Gene and Pathway Co-expression Networks. Our hypothesis is that redundancy is one of the major causes of drug resistance, and can be described as a function of the network structure and its properties. From this perspective, we believe that integration of the redundant variables could lead to the development of promising new methodologies to selectively identify and target the most significant resistance mechanisms of HCC. We describe three mechanisms of redundancy based on their levels of generalization and study the possible impact of those redundancy mechanisms on HCC treatments. C1 [Lavi, Orit; Gottesman, Michael M.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Skinner, Jeff] NIAID, Lab Immunogenet LIG, NIH, Rockville, MD USA. RP Lavi, O (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM orit.lavi@nih.gov OI Skinner, Jeff/0000-0001-5697-0442 FU Intramural Research Program of the National Institutes of Health FX We would like to thank George Leiman for editorial assistance. The authors thank Snorri Thorgeirsson, Teresa Przytycka and Yoram Louzoun for their helpful discussions and comments on the manuscript. This research was funded by the Intramural Research Program of the National Institutes of Health. NR 52 TC 1 Z9 2 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD JUL 29 PY 2014 VL 8 AR 88 DI 10.1186/s12918-014-0088-0 PG 15 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AN5RN UT WOS:000340649100001 PM 25070212 ER PT J AU Gelijns, AC Moskowitz, AJ Acker, MA Argenziano, M Geller, NL Puskas, JD Perrault, LP Smith, PK Kron, IL Michler, RE Miller, MA Gardner, TJ Ascheim, DD Ailawadi, G Lackner, P Goldsmith, LA Robichaud, S Miller, RA Rose, EA Ferguson, TB Horvath, KA Moquete, EG Parides, MK Bagiella, E O'Gara, PT Blackstone, EH AF Gelijns, Annetine C. Moskowitz, Alan J. Acker, Michael A. Argenziano, Michael Geller, Nancy L. Puskas, John D. Perrault, Louis P. Smith, Peter K. Kron, Irving L. Michler, Robert E. Miller, Marissa A. Gardner, Timothy J. Ascheim, Deborah D. Ailawadi, Gorav Lackner, Pamela Goldsmith, Lyn A. Robichaud, Sophie Miller, Rachel A. Rose, Eric A. Ferguson, T. Bruce, Jr. Horvath, Keith A. Moquete, Ellen G. Parides, Michael K. Bagiella, Emilia O'Gara, Patrick T. Blackstone, Eugene H. CA Cardiothoracic Surgical Trials Net TI Management Practices and Major Infections After Cardiac Surgery SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiac surgery; infection; risk factors ID SURGICAL-SITE INFECTIONS; BLOOD-STREAM INFECTIONS; PRACTICE GUIDELINE SERIES; INTENSIVE-CARE UNITS; ANTIBIOTIC-PROPHYLAXIS; STAPHYLOCOCCUS-AUREUS; METAANALYSIS; INTERVENTION; DURATION; OUTCOMES AB BACKGROUND Infections are the most common noncardiac complication after cardiac surgery, but their incidence across a broad range of operations, as well as the management factors that shape infection risk, remain unknown. OBJECTIVES This study sought to prospectively examine the frequency of post-operative infections and associated mortality, and modifiable management practices predictive of infections within 65 days from cardiac surgery. METHODS This study enrolled 5,158 patients and analyzed independently adjudicated infections using a competing risk model (with death as the competing event). RESULTS Nearly 5% of patients experienced major infections. Baseline characteristics associated with increased infection risk included chronic lung disease (hazard ratio [HR]: 1.66; 95% confidence interval [CI]: 1.21 to 2.26), heart failure (HR: 1.47; 95% CI: 1.11 to 1.95), and longer surgery (HR: 1.31; 95% CI: 1.21 to 1.41). Practices associated with reduced infection risk included prophylaxis with second-generation cephalosporins (HR: 0.70; 95% CI: 0.52 to 0.94), whereas post-operative antibiotic duration >48 h (HR: 1.92; 95% CI: 1.28 to 2.88), stress hyperglycemia (HR: 1.32; 95% CI: 1.01 to 1.73); intubation time of 24 to 48 h (HR: 1.49; 95% CI: 1.04 to 2.14); and ventilation >48 h (HR: 2.45; 95% CI: 1.66 to 3.63) were associated with increased risk. HRs for infection were similar with either <24 h or <48 h of antibiotic prophylaxis. There was a significant but differential effect of transfusion by surgery type (excluding left ventricular assist device procedures/transplant) (HR: 1.13; 95% CI: 1.07 to 1.20). Major infections substantially increased mortality (HR: 10.02; 95% CI: 6.12 to 16.39). CONCLUSIONS Major infections dramatically affect survival and readmissions. Second-generation cephalosporins were strongly associated with reduced major infection risk, but optimal duration of antibiotic prophylaxis requires further study. Given practice variations, considerable opportunities exist for improving outcomes and preventing readmissions. (Management Practices and Risk of Infection Following Cardiac Surgery; NCT01089712) (C) 2014 by the American College of Cardiology Foundation C1 [Gelijns, Annetine C.; Moskowitz, Alan J.; Ascheim, Deborah D.; Rose, Eric A.; Moquete, Ellen G.; Parides, Michael K.; Bagiella, Emilia] Icahn Sch Med Mt Sinai, Dept Hlth Evidence & Policy, Int Ctr Hlth Outcomes & Innovat Res InCHOIR, New York, NY 10029 USA. [Acker, Michael A.] Univ Penn, Sch Med, Dept Surg, Div Cardiovasc Surg, Philadelphia, PA 19104 USA. [Argenziano, Michael; Goldsmith, Lyn A.] Columbia Univ Coll Phys & Surg, Dept Surg, Div Cardiothorac Surg, New York, NY 10032 USA. [Geller, Nancy L.] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Puskas, John D.] Emory Univ, Sch Med, Div Cardiothorac Surg, Clin Res Unit, Atlanta, GA 30322 USA. [Perrault, Louis P.; Robichaud, Sophie] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [Smith, Peter K.] Duke Univ, Med Ctr, Dept Surg, Div Cardiovasc & Thorac Surg, Durham, NC 27710 USA. [Kron, Irving L.; Ailawadi, Gorav] Univ Virginia, Sch Med, Div Thorac & Cardiovasc Surg, Charlottesville, VA 22908 USA. [Michler, Robert E.] Albert Einstein Coll Med, Montefiore Med Ctr, Dept Cardiothorac Surg, New York, NY USA. [Miller, Marissa A.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Gardner, Timothy J.] Christiana Care Hlth Syst, Ctr Heart & Vasc Hlth, Newark, DE USA. [Lackner, Pamela; Blackstone, Eugene H.] Cleveland Clin Fdn, Dept Thorac & Cardiovasc Surg, Cleveland, OH 44195 USA. [Miller, Rachel A.] Univ Iowa, Carver Coll Med, Div Infect Dis, Dept Med, Iowa City, IA USA. [Ferguson, T. Bruce, Jr.] E Carolina Univ, East Carolina Heart Inst, Dept Cardiovasc Sci, Greenville, NC USA. [Horvath, Keith A.] Suburban Hosp, NIH Heart Ctr, Bethesda, MD USA. [O'Gara, Patrick T.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. RP Gelijns, AC (reprint author), Icahn Sch Med Mt Sinai, Dept Hlth Evidence & Policy, One Gustave L Levy Pl,Box 1077, New York, NY 10029 USA. EM annetine.gelijns@mssm.edu OI Moskowitz, Alan/0000-0002-4412-9450 FU National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke [7U01 HL088942]; Canadian Institutes of Health Research FX The research was supported by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke (Grant no. 7U01 HL088942), and the Canadian Institutes of Health Research. Dr. Gelijns has served as a member of the Research Council of InHealth in 2010 and 2011. Dr. Perrault has received honoraria from Bayer and Somahlution. Dr. Ascheim is a member of the BackBeat Medical, Data & Safety Monitoring Board. Dr. Acker is a consultant for Thoratec and Heartware. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 23 TC 20 Z9 21 U1 1 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 29 PY 2014 VL 64 IS 4 BP 372 EP 381 DI 10.1016/j.jacc.2014.04.052 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM9ZN UT WOS:000340240700007 PM 25060372 ER PT J AU Padron, A Molina-Cruz, A Quinones, M Ribeiro, JMC Ramphul, U Rodrigues, J Shen, K Haile, A Ramirez, JL Barillas-Mury, C AF Padron, Alejandro Molina-Cruz, Alvaro Quinones, Mariam Ribeiro, Jose M. C. Ramphul, Urvashi Rodrigues, Janneth Shen, Kui Haile, Ashley Ramirez, Jose Luis Barillas-Mury, Carolina TI In depth annotation of the Anopheles gambiae mosquito midgut transcriptome SO BMC GENOMICS LA English DT Article ID PLASMODIUM-FALCIPARUM; RNA-SEQ; DROSOPHILA-MELANOGASTER; PROTEIN DATABASE; GENOME; GENERATION; VITRO; DIFFERENTIATION; PARASITES; SEQUENCE AB Background: Genome sequencing of Anopheles gambiae was completed more than ten years ago and has accelerated research on malaria transmission. However, annotation needs to be refined and verified experimentally, as most predicted transcripts have been identified by comparative analysis with genomes from other species. The mosquito midgut-the first organ to interact with Plasmodium parasites-mounts effective antiplasmodial responses that limit parasite survival and disease transmission. High-throughput Illumina sequencing of the midgut transcriptome was used to identify new genes and transcripts, contributing to the refinement of An. gambiae genome annotation. Results: We sequenced similar to 223 million reads from An. gambiae midgut cDNA libraries generated from susceptible (G3) and refractory (L35) mosquito strains. Mosquitoes were infected with either Plasmodium berghei or Plasmodium falciparum, and midguts were collected after the first or second Plasmodium infection. In total, 22,889 unique midgut transcript models were generated from both An. gambiae strain sequences combined, and 76% are potentially novel. Of these novel transcripts, 49.5% aligned with annotated genes and appear to be isoforms or pre-mRNAs of reference transcripts, while 50.5% mapped to regions between annotated genes and represent novel intergenic transcripts (NITs). Predicted models were validated for midgut expression using qRT-PCR and microarray analysis, and novel isoforms were confirmed by sequencing predicted intron-exon boundaries. Coding potential analysis revealed that 43% of total midgut transcripts appear to be long non-coding RNA (IncRNA), and functional annotation of NITs showed that 68% had no homology to current databases from other species. Reads were also analyzed using de novo assembly and predicted transcripts compared with genome mapping-based models. Finally, variant analysis of G3 and L35 midgut transcripts detected 160,742 variants with respect to the An. gambiae PEST genome, and 74% were new variants. Intergenic transcripts had a higher frequency of variation compared with non-intergenic transcripts. Conclusion: This in-depth Illumina sequencing and assembly of the An. gambiae midgut transcriptome doubled the number of known transcripts and tripled the number of variants known in this mosquito species. It also revealed existence of a large number of IncRNA and opens new possibilities for investigating the biological function of many newly discovered transcripts. C1 [Padron, Alejandro; Molina-Cruz, Alvaro; Ribeiro, Jose M. C.; Ramphul, Urvashi; Rodrigues, Janneth; Haile, Ashley; Ramirez, Jose Luis; Barillas-Mury, Carolina] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20817 USA. [Quinones, Mariam; Shen, Kui] NIAID, Bioinformat & Computat Biosci Branch, NIH, Rockville, MD USA. RP Molina-Cruz, A (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20817 USA. EM amolina-cruz@niaid.nih.gov; cbarillas@niaid.nih.gov RI Shen, Kui/E-2764-2015; Ribeiro, Jose/J-7011-2015; OI Ribeiro, Jose/0000-0002-9107-0818 FU Intramural Research Program of the Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health FX We appreciate the technical assistance of Andre Laughinghouse and Kevin Lee for mosquito rearing; Liguo Wang for verifying the R script generated by CPAT; Alice Young for Illumina sequencing; Timothy Myers, Qin Su, and the NIAID Genomic Technologies Section for hybridization and scanning the microarray; and Brenda Rae Marshall, DPSS, for editorial assistance. This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 42 TC 9 Z9 9 U1 0 U2 25 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUL 29 PY 2014 VL 15 AR 636 DI 10.1186/1471-2164-15-636 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AM5QT UT WOS:000339915800001 PM 25073905 ER PT J AU Wang, X Ouyang, YY Liu, J Zhu, MM Zhao, G Bao, W Hu, FB AF Wang, Xia Ouyang, Yingying Liu, Jun Zhu, Minmin Zhao, Gang Bao, Wei Hu, Frank B. TI Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; CORONARY-HEART-DISEASE; ALL-CAUSE MORTALITY; MEDITERRANEAN DIET; PUBLICATION BIAS; ELDERLY POPULATION; TREND ESTIMATION; MAGNESIUM INTAKE; BLOOD-PRESSURE; EUROPEAN MEN AB Objective To examine and quantify the potential dose-response relation between fruit and vegetable consumption and risk of all cause, cardiovascular, and cancer mortality. Data sources Medline, Embase, and the Cochrane library searched up to 30 August 2013 without language restrictions. Reference lists of retrieved articles. Study selection Prospective cohort studies that reported risk estimates for all cause, cardiovascular, and cancer mortality by levels of fruit and vegetable consumption. Data synthesis Random effects models were used to calculate pooled hazard ratios and 95% confidence intervals and to incorporate variation between studies. The linear and non-linear dose-response relations were evaluated with data from categories of fruit and vegetable consumption in each study. Results Sixteen prospective cohort studies were eligible in this meta-analysis. During follow-up periods ranging from 4.6 to 26 years there were 56 423 deaths (11 512 from cardiovascular disease and 16 817 from cancer) among 833 234 participants. Higher consumption of fruit and vegetables was significantly associated with a lower risk of all cause mortality. Pooled hazard ratios of all cause mortality were 0.95 (95% confidence interval 0.92 to 0.98) for an increment of one serving a day of fruit and vegetables (P=0.001), 0.94 (0.90 to 0.98) for fruit (P=0.002), and 0.95 (0.92 to 0.99) for vegetables (P=0.006). There was a threshold around five servings of fruit and vegetables a day, after which the risk of all cause mortality did not reduce further. A significant inverse association was observed for cardiovascular mortality (hazard ratio for each additional serving a day of fruit and vegetables 0.96, 95% confidence interval 0.92 to 0.99), while higher consumption of fruit and vegetables was not appreciably associated with risk of cancer mortality. Conclusions This meta-analysis provides further evidence that a higher consumption of fruit and vegetables is associated with a lower risk of all cause mortality, particularly cardiovascular mortality. C1 [Wang, Xia] Shandong Univ, Sch Publ Hlth, Dept Maternal & Child Hlth Care, Jinan 250100, Peoples R China. [Wang, Xia; Ouyang, Yingying; Liu, Jun] Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, Dept Nutr & Food Hyg, Wuhan 430074, Peoples R China. [Zhu, Minmin] Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, Dept Epidemiol & Biostat, Wuhan 430074, Peoples R China. [Zhao, Gang] Shandong Univ, Shandong Prov Hosp, Dept Cardiovasc Sci, Jinan 250100, Peoples R China. [Bao, Wei] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Hu, FB (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. EM wei.bao@nih.gov; nhbfh@channing.harvard.edu OI Bao, Wei/0000-0002-7301-5786 FU National Natural Science Foundation of China [NSFC 81071081]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was funded by National Natural Science Foundation (NSFC 81071081) of China. WB was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The funders had no role in study design, data collection and analysis, preparation of the manuscript, or decision to publish. NR 67 TC 167 Z9 174 U1 18 U2 69 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD JUL 29 PY 2014 VL 349 AR g4490 DI 10.1136/bmj.g4490 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA AM5NG UT WOS:000339906000001 PM 25073782 ER PT J AU Boutin, C Labedan, P Dimidschstein, J Richard, F Cremer, H Andre, P Yang, YZ Montcouquiol, M Goffinet, AM Tissir, F AF Boutin, Camille Labedan, Paul Dimidschstein, Jordane Richard, Fabrice Cremer, Harold Andre, Philipp Yang, Yingzi Montcouquiol, Mireille Goffinet, Andre M. Tissir, Fadel TI A dual role for planar cell polarity genes in ciliated cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BASAL BODIES; MOTILE CILIA; AIRWAY CILIA; IN-VIVO; HYDROCEPHALUS; CILIOGENESIS; EXPRESSION; CELSR3; POLARIZATION; FOREBRAIN AB In the nervous system, cilia dysfunction perturbs the circulation of the cerebrospinal fluid, thus affecting neurogenesis and brain homeostasis. A role for planar cell polarity (PCP) signaling in the orientation of cilia (rotational polarity) and ciliogenesis is established. However, whether and how PCP regulates cilia positioning in the apical domain (translational polarity) in radial progenitors and ependymal cells remain unclear. By analysis of a large panel of mutant mice, we show that two PCP signals are operating in ciliated cells. The first signal, controlled by cadherin, EGF-like, laminin G-like, seven-pass, G-type receptor (Celsr) 2, Celsr3, Frizzled3 (Fzd3) and Van Gogh like2 (Vangl2) organizes multicilia in individual cells (single-cell polarity), whereas the second signal, governed by Celsr1, Fzd3, and Vangl2, coordinates polarity between cells in both radial progenitors and ependymal cells (tissue polarity). Loss of either of these signals is associated with specific defects in the cytoskeleton. Our data reveal unreported functions of PCP and provide an integrated view of planar polarization of the brain ciliated cells. C1 [Boutin, Camille; Goffinet, Andre M.; Tissir, Fadel] Catholic Univ Louvain, Inst Neurosci Dev Neurobiol, B-1200 Brussels, Belgium. [Labedan, Paul] PLab, B-1200 Brussels, Belgium. [Dimidschstein, Jordane] Univ Libre Brussels, Inst Rech Biol Humaine & Mol, B-1070 Brussels, Belgium. [Richard, Fabrice; Cremer, Harold] Aix Marseille Univ, CNRS, Inst Biol Developpement Marseille Luminy, Unite Mixte Rech 7288, F-13288 Marseille, France. [Andre, Philipp; Yang, Yingzi] Natl Human Genome Res Inst, Genet Dis Res Branch, Dev Genet Sect, Bethesda, MD 20892 USA. [Montcouquiol, Mireille] Inst Natl Sante & Rech Med, Planar Polar & Plast Grp, U862, F-33077 Bordeaux, France. RP Tissir, F (reprint author), Catholic Univ Louvain, Inst Neurosci Dev Neurobiol, B-1200 Brussels, Belgium. EM fadel.tissir@uclouvain.be OI montcouquiol, mireille/0000-0001-8739-6519 FU Fonds de la Recherche Scientifique Medicale Grant [3.4550.11]; Belgian National Fund for Scientific Research Grant [T0002.13]; Actions de Recherches Concertees Grant [ARC-10/15-026]; Fondation medicale Reine Elisabeth grant; Fondation JED-Belgique grant; Desordres Inflamatoires dans les Affections Neurologiques grant; Welbio grant from the Region wallonne; Inter-University Poles of Attraction Grant [PAI P7/20]; Belgian National Fund for Scientific Research FX We thank Jean Hebert for the Foxg1-Cre line, Gerard Dougherty for Clamp antibodies, and Isabelle Lambermont, Esther Paitre, and Rachid El Kaddouri for technical assistance. This work was supported by Fonds de la Recherche Scientifique Medicale Grant 3.4550.11, Belgian National Fund for Scientific Research Grant T0002.13, Actions de Recherches Concertees Grant ARC-10/15-026, a Fondation medicale Reine Elisabeth grant, a Fondation JED-Belgique grant, a Desordres Inflamatoires dans les Affections Neurologiques grant, a Welbio grant from the Region wallonne, and Inter-University Poles of Attraction Grant PAI P7/20. F. T. is a senior research associate of the Belgian National Fund for Scientific Research. NR 49 TC 30 Z9 30 U1 2 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 29 PY 2014 VL 111 IS 30 BP E3129 EP E3138 DI 10.1073/pnas.1404988111 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL9YT UT WOS:000339500200014 PM 25024228 ER PT J AU Volkow, ND Wang, GJ Telang, F Fowler, JS Alexoff, D Logan, J Jayne, M Wong, C Tomasi, D AF Volkow, Nora D. Wang, Gene-Jack Telang, Frank Fowler, Joanna S. Alexoff, David Logan, Jean Jayne, Millard Wong, Christopher Tomasi, Dardo TI Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE nucleus accumbens; amotivation; cannabinoid 1 receptors; brain imaging; midbrain ID POSITRON-EMISSION-TOMOGRAPHY; D-2/D-3 RECEPTOR AVAILABILITY; CANNABINOID CB1; CONCURRENT STIMULATION; ORAL METHYLPHENIDATE; GLUCOSE-METABOLISM; VENTRAL STRIATUM; RELEASE; USERS; DEPENDENCE AB Moves to legalize marijuana highlight the urgency to investigate effects of chronic marijuana in the human brain. Here, we challenged 48 participants (24 controls and 24 marijuana abusers) with methylphenidate (MP), a drug that elevates extracellular dopamine (DA) as a surrogate for probing the reactivity of the brain to DA stimulation. We compared the subjective, cardiovascular, and brain DA responses (measured with PET and [C-11]raclopride) to MP between controls and marijuana abusers. Although baseline (placebo) measures of striatal DA D2 receptor availability did not differ between groups, the marijuana abusers showed markedly blunted responses when challenged with MP. Specifically, compared with controls, marijuana abusers had significantly attenuated behavioral ("self-reports" for high, drug effects, anxiety, and restlessness), cardiovascular (pulse rate and diastolic blood pressure), and brain DA [reduced decreases in distribution volumes (DVs) of [C-11]raclopride, although normal reductions in striatal nondisplaceable binding potential (BPND)]responses to MP. In ventral striatum (key brain reward region), MP-induced reductions in DVs and BPND (reflecting DA increases) were inversely correlated with scores of negative emotionality, which were significantly higher for marijuana abusers than controls. In marijuana abusers, DA responses in ventral striatum were also inversely correlated with addiction severity and craving. The attenuated responses to MP, including reduced decreases in striatal DVs, are consistent with decreased brain reactivity to the DA stimulation in marijuana abusers that might contribute to their negative emotionality (increased stress reactivity and irritability) and addictive behaviors. C1 [Volkow, Nora D.; Wang, Gene-Jack; Telang, Frank; Jayne, Millard; Wong, Christopher; Tomasi, Dardo] NIAAA, Lab Neuroimaging, Rockville, MD 20857 USA. [Volkow, Nora D.] NIDA, Rockville, MD 20857 USA. [Fowler, Joanna S.; Alexoff, David] Brookhaven Natl Lab, Dept Biosci, Upton, NY 11973 USA. [Logan, Jean] NYU, Langone Med Ctr, Dept Radiol, New York, NY 10016 USA. RP Volkow, ND (reprint author), NIAAA, Lab Neuroimaging, Rockville, MD 20857 USA. EM nvolkow@nida.nih.gov; fowler@bnl.gov RI Tomasi, Dardo/J-2127-2015 FU National Institute of Health's Intramural Research Program (National Institute on Alcohol Abuse and Alcoholism); Brookhaven National Laboratory [DE-AC02-98CH10886] FX We thank Lisa Muench, Colleen Shea, and Youwen Xu for radiopharmaceutical preparation and quality control, Pauline Carter and Barbara Hubbard for subject care and protocol oversight, Karen Apelskog for protocol coordination, Michael Schueller for cyclotron operations, and Ruben Baler for assistance in manuscript preparation. We also thank the subjects who volunteered to participate in this study. Research was supported by the National Institute of Health's Intramural Research Program (National Institute on Alcohol Abuse and Alcoholism) and was carried out using the infrastructure of Brookhaven National Laboratory under Contract DE-AC02-98CH10886. NR 80 TC 27 Z9 27 U1 4 U2 45 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 29 PY 2014 VL 111 IS 30 BP E3149 EP E3156 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL9YT UT WOS:000339500200016 PM 25024177 ER PT J AU Trinchieri, G AF Trinchieri, Giorgio TI Critical role for CX(3)CR1(+) mononuclear phagocytes in intestinal homeostasis SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Editorial Material C1 NCI, NIH, Bethesda, MD 20892 USA. RP Trinchieri, G (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM trinchig@mail.nih.gov NR 0 TC 1 Z9 1 U1 1 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JUL 28 PY 2014 VL 211 IS 8 BP 1500 EP 1501 DI 10.1084/jem.2118insight2 PG 2 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AQ4DV UT WOS:000342743500002 PM 25071160 ER PT J AU Margulies, D AF Margulies, David TI The in-betweeners: MAIT cells join the innate-like lymphocytes gang SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Editorial Material C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Margulies, D (reprint author), NIAID, NIH, Bethesda, MD 20892 USA. EM dhm@nih.gov OI Margulies, David/0000-0001-8530-7375 NR 0 TC 3 Z9 3 U1 1 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JUL 28 PY 2014 VL 211 IS 8 BP 1501 EP 1502 DI 10.1084/jem.2118insight3 PG 2 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AQ4DV UT WOS:000342743500003 PM 25071161 ER PT J AU Gold, MC McLaren, JE Reistetter, JA Smyk-Pearson, S Ladell, K Swarbrick, GM Yu, YYL Hansen, TH Lund, O Nielsen, M Gerritsen, B Kesmir, C Miles, JJ Lewinsohn, DA Price, DA Lewinsohn, DM AF Gold, Marielle C. McLaren, James E. Reistetter, Joseph A. Smyk-Pearson, Sue Ladell, Kristin Swarbrick, Gwendolyn M. Yu, Yik Y. L. Hansen, Ted H. Lund, Ole Nielsen, Morten Gerritsen, Bram Kesmir, Can Miles, John J. Lewinsohn, Deborah A. Price, David A. Lewinsohn, David M. TI MR1-restricted MAIT cells display ligand discrimination and pathogen selectivity through distinct T cell receptor usage SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID VITAMIN-B METABOLITES; BACTERIAL-INFECTION; ALPHA-CHAIN; RECOGNITION; MR1; EXPRESSION AB Mucosal-associated invariant T (MAIT) cells express a semi-invariant T cell receptor (TCR) that detects microbial metabolites presented by the nonpolymorphic major histocompatibility complex (MHC)-like molecule MR1. The highly conserved nature of MR1 in conjunction with biased MAIT TCR. chain usage is widely thought to indicate limited ligand presentation and discrimination within a pattern-like recognition system. Here, we evaluated the TCR repertoire of MAIT cells responsive to three classes of microbes. Substantial diversity and heterogeneity were apparent across the functional MAIT cell repertoire as a whole, especially for TCR beta chain sequences. Moreover, different pathogen-specific responses were characterized by distinct TCR usage, both between and within individuals, suggesting that MAIT cell adaptation was a direct consequence of exposure to various exogenous MR1-restricted epitopes. In line with this interpretation, MAIT cell clones with distinct TCRs responded differentially to a riboflavin metabolite. These results suggest that MAIT cells can discriminate between pathogen-derived ligands in a clonotype-dependent manner, providing a basis for adaptive memory via recruitment of specific repertoires shaped by microbial exposure.\ C1 [Gold, Marielle C.; Reistetter, Joseph A.; Smyk-Pearson, Sue; Lewinsohn, David M.] Oregon Hlth & Sci Univ, Div Pulm & Crit Care Med, Portland, OR 97239 USA. [Gold, Marielle C.; Lewinsohn, Deborah A.; Lewinsohn, David M.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97239 USA. [Swarbrick, Gwendolyn M.; Lewinsohn, Deborah A.] Oregon Hlth & Sci Univ, Dept Pediat, Portland, OR 97239 USA. [Gold, Marielle C.; Lewinsohn, David M.] Portland VA Med Ctr, Portland, OR 97239 USA. [McLaren, James E.; Ladell, Kristin; Miles, John J.; Price, David A.] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [Yu, Yik Y. L.; Hansen, Ted H.] Washington Univ, St Louis Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Lund, Ole; Nielsen, Morten] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Nielsen, Morten] Univ Nacl San Martin, Inst Invest Biotecnol, RA-1650 Buenos Aires, DF, Argentina. [Gerritsen, Bram; Kesmir, Can] Univ Utrecht, Theoret Biol & Bioinformat Grp, NL-3584 CH Utrecht, Netherlands. [Miles, John J.] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia. [Price, David A.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Gold, MC (reprint author), Oregon Hlth & Sci Univ, Div Pulm & Crit Care Med, Portland, OR 97239 USA. EM goldm@ohsu.edu; lewinsod@ohsu.edu RI Lund, Ole/F-4437-2014; Price, David/C-7876-2013; Ladell, Kristin/C-8301-2013; Kesmir, Can/B-9410-2011; Lewinsohn, David/I-4936-2013; OI Lund, Ole/0000-0003-1108-0491; Price, David/0000-0001-9416-2737; Ladell, Kristin/0000-0002-9856-2938; Lewinsohn, David/0000-0001-9906-9494; Nielsen, Morten/0000-0001-7885-4311 FU Department of Veterans Affairs with resources and facility access provided by the Portland VA Medical Center; National Institutes of Health (NIH) via the Mucosal Immunology Studies Team (MIST) - National Institute of Allergy and Infectious Diseases (NIH grant) [U01 AI095776-01, AI046553]; Wellcome Trust (UK); Wellcome Trust Senior Investigator FX This work was supported by the Department of Veterans Affairs with resources and facility access provided by the Portland VA Medical Center, the National Institutes of Health (NIH) via the Mucosal Immunology Studies Team (MIST) U01 AI095776-01 funded by the National Institute of Allergy and Infectious Diseases (NIH grant AI046553), and the Wellcome Trust (UK). D.A. Price is a Wellcome Trust Senior Investigator. NR 29 TC 49 Z9 49 U1 4 U2 16 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JUL 28 PY 2014 VL 211 IS 8 BP 1601 EP 1610 DI 10.1084/jem.20140507 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AQ4DV UT WOS:000342743500010 PM 25049333 ER PT J AU Ghosh, HS Ceribelli, M Matos, I Lazarovici, A Bussemaker, HJ Lasorella, A Hiebert, SW Liu, K Staudt, LM Reizis, B AF Ghosh, Hiyaa S. Ceribelli, Michele Matos, Ines Lazarovici, Allan Bussemaker, Harmen J. Lasorella, Anna Hiebert, Scott W. Liu, Kang Staudt, Louis M. Reizis, Boris TI ETO family protein Mtg16 regulates the balance of dendritic cell subsets by repressing Id2 SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID TRANSCRIPTION FACTOR E2-2; NATURAL-KILLER-CELL; FACTOR SPI-B; STEADY-STATE; BONE-MARROW; IN-VIVO; LINEAGE; DIFFERENTIATION; PROGENITORS; EXPRESSION AB Dendritic cells (DCs) comprise two major subsets, the interferon (IFN)-producing plasmacytoid DCs (pDCs) and antigen-presenting classical DCs (cDCs). The development of pDCs is promoted by E protein transcription factor E2-2, whereas E protein antagonist Id2 is specifically absent from pDCs. Conversely, Id2 is prominently expressed in cDCs and promotes CD8(+) cDC development. The mechanisms that control the balance between E and Id proteins during DC subset specification remain unknown. We found that the loss of Mtg16, a transcriptional cofactor of the ETO protein family, profoundly impaired pDC development and pDC-dependent IFN response. The residual Mtg16-deficient pDCs showed aberrant phenotype, including the expression of myeloid marker CD11b. Conversely, the development of cDC progenitors (pre-DCs) and of CD8(+) cDCs was enhanced. Genome-wide expression and DNA-binding analysis identified Id2 as a direct target of Mtg16. Mtg16-deficient cDC progenitors and pDCs showed aberrant induction of Id2, and the deletion of Id2 facilitated the impaired development of Mtg16-deficient pDCs. Thus, Mtg16 promotes pDC differentiation and restricts cDC development in part by repressing Id2, revealing a cell-intrinsic mechanism that controls subset balance during DC development. C1 [Ghosh, Hiyaa S.; Matos, Ines; Liu, Kang; Reizis, Boris] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA. [Bussemaker, Harmen J.] Columbia Univ, Med Ctr, Ctr Computat Biol & Bioinformat, New York, NY 10032 USA. [Lasorella, Anna] Columbia Univ, Med Ctr, Inst Canc Genet, New York, NY 10032 USA. [Lasorella, Anna] Columbia Univ, Med Ctr, Dept Pathol, New York, NY 10032 USA. [Lasorella, Anna] Columbia Univ, Med Ctr, Dept Pediat, New York, NY 10032 USA. [Lazarovici, Allan; Bussemaker, Harmen J.] Columbia Univ, Dept Biol Sci, New York, NY 10032 USA. [Lazarovici, Allan] Columbia Univ, Dept Elect Engn, New York, NY 10032 USA. [Staudt, Louis M.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hiebert, Scott W.] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA. RP Reizis, B (reprint author), Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA. EM bvr2101@columbia.edu OI Reizis, Boris/0000-0003-1140-7853 FU National Institutes of Health (NIH) [AI072571]; New York State Dept. of Health [N09G-22]; American Society of Hematology Postdoctoral Fellowship; NIH [AI101251, AR044535, HG003008, CA121852]; Dana Foundation Neuroimmunology grant FX This work was supported by National Institutes of Health (NIH) grant AI072571 and New York State Dept. of Health grant N09G-22 (to B. Reizis), an American Society of Hematology Postdoctoral Fellowship (to H.S. Ghosh), NIH grants AI101251 and AR044535 and the Dana Foundation Neuroimmunology grant (to K. Liu), and NIH grants HG003008 and CA121852 (to H.J. Bussemaker). NR 53 TC 12 Z9 12 U1 1 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JUL 28 PY 2014 VL 211 IS 8 BP 1623 EP 1635 DI 10.1084/jem.20132121 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AQ4DV UT WOS:000342743500012 PM 24980046 ER PT J AU Guo, W Shugart, YY AF Guo, Wei Shugart, Yin Yao TI The power comparison of the haplotype-based collapsing tests and the variant-based collapsing tests for detecting rare variants in pedigrees SO BMC GENOMICS LA English DT Article DE Haplotype; Pedigree disequilibrium test; Rare variants; Weights; Association ID KERNEL ASSOCIATION TEST; QUANTITATIVE TRAITS; HDL CHOLESTEROL; COMPLEX TRAITS; COMMON; CONTRIBUTE; FAMILY; PROMOTER; DISEASES; GENES AB Background: Both common and rare genetic variants have been shown to contribute to the etiology of complex diseases. Recent genome-wide association studies (GWAS) have successfully investigated how common variants contribute to the genetic factors associated with common human diseases. However, understanding the impact of rare variants, which are abundant in the human population (one in every 17 bases), remains challenging. A number of statistical tests have been developed to analyze collapsed rare variants identified by association tests. Here, we propose a haplotype-based approach. This work inspired by an existing statistical framework of the pedigree disequilibrium test (PDT), which uses genetic data to assess the effects of variants in general pedigrees. We aim to compare the performance between the haplotype-based approach and the rare variant-based approach for detecting rare causal variants in pedigrees. Results: Extensive simulations in the sequencing setting were carried out to evaluate and compare the haplotype-based approach with the rare variant methods that drew on a more conventional collapsing strategy. As assessed through a variety of scenarios, the haplotype-based pedigree tests had enhanced statistical power compared with the rare variants based pedigree tests when the disease of interest was mainly caused by rare haplotypes(with multiple rare alleles), and vice versa when disease was caused by rare variants acting independently. For most of other situations when disease was caused both by haplotypes with multiple rare alleles and by rare variants with similar effects, these two approaches provided similar power in testing for association. Conclusions: The haplotype-based approach was designed to assess the role of rare and potentially causal haplotypes. The proposed rare variants-based pedigree tests were designed to assess the role of rare and potentially causal variants. This study clearly documented the situations under which either method performs better than the other. All tests have been implemented in a software, which was submitted to the Comprehensive R Archive Network (CRAN) for general use as a computer program named rvHPDT. C1 [Guo, Wei; Shugart, Yin Yao] NIMH, Div Intramural Div Program, NIH, Bethesda, MD 20892 USA. RP Shugart, YY (reprint author), NIMH, Div Intramural Div Program, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM kay1yao@mail.nih.gov FU Intramural Research Programs of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH); [MH002930-03] FX Drs. Guo and Shugart gratefully acknowledge the support of the Intramural Research Programs of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) and Project number MH002930-03. Ioline Henter (NIMH) provided invaluable editorial assistance. The views expressed in this presentation do not necessarily represent the views of the NIMH, NIH, HHS, or the United States Government. NR 32 TC 0 Z9 0 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUL 28 PY 2014 VL 15 AR 632 DI 10.1186/1471-2164-15-632 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AN5ND UT WOS:000340637300001 PM 25070353 ER PT J AU Chau, M Lui, JLC Landman, EBM Spath, SS Vortkamp, A Baron, J Nilsson, O AF Chau, Michael Lui, Julian C. Landman, Ellie B. M. Spath, Stephan-Stanislaw Vortkamp, Andrea Baron, Jeffrey Nilsson, Ola TI Gene Expression Profiling Reveals Similarities between the Spatial Architectures of Postnatal Articular and Growth Plate Cartilage SO PLOS ONE LA English DT Article ID KNEE-JOINT; SYNOVIAL JOINT; CHONDROCYTES; CHONDROGENESIS; OSTEOARTHRITIS; IDENTIFICATION; CELLS; DIFFERENTIATION; NORMALIZATION; ANGIOGENESIS AB Articular and growth plate cartilage are discrete tissues but arise from a common cartilaginous condensation and have comparable spatial architectures consisting of distinct layers of chondrocytes. To investigate similarities and differences between articular and growth plate cartilage and to explore transcriptional changes that occur during the onset of their divergence, we performed manual microdissection of 10-day-old rat proximal tibias, microarray analysis, bioinformatics, and real-time PCR to compare gene expression profiles in individual cartilage layers. We found that many genes that were spatially upregulated in the intermediate/deep zone of articular cartilage were also spatially upregulated in the resting zone of growth plate cartilage (overlap greater than expected by chance, P<0.001). Interestingly, the superficial zone of articular cartilage showed an expression profile with similarities to both the proliferative and hypertrophic zones of growth plate cartilage (P<0.001 each). Additionally, significant numbers of known proliferative zone markers (3 out of 6) and hypertrophic zone markers (27 out of 126) were spatially upregulated in the superficial zone (more than expected by chance, P<0.001 each). In conclusion, we provide evidence that the intermediate/deep zone of articular cartilage has a gene expression profile more similar to that of the resting zone of growth plate cartilage, whereas the superficial zone has a gene expression profile more similar to those of the proliferative and hypertrophic zones. These findings suggest that the superficial zone chondrocytes of articular cartilage differentiate according to a program that is not completely different from but instead has distinct similarities to the hypertrophic differentiation program of growth plate chondrocytes. We also present functional signaling pathways implicated by differential gene expression between articular and growth plate cartilage during their initial separation by the secondary ossification center. C1 [Chau, Michael; Landman, Ellie B. M.; Spath, Stephan-Stanislaw; Nilsson, Ola] Karolinska Inst, Dept Womens & Childrens Hlth, Pediat Endocrinol Unit, Stockholm, Sweden. [Chau, Michael; Landman, Ellie B. M.; Spath, Stephan-Stanislaw; Nilsson, Ola] Univ Hosp, Stockholm, Sweden. [Chau, Michael; Lui, Julian C.; Landman, Ellie B. M.; Spath, Stephan-Stanislaw; Baron, Jeffrey; Nilsson, Ola] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Vortkamp, Andrea] Univ Duisburg Essen, Fac Biol, Dept Dev Biol, Essen, Germany. [Vortkamp, Andrea] Univ Duisburg Essen, Ctr Med Biotechnol, Essen, Germany. RP Nilsson, O (reprint author), Karolinska Inst, Dept Womens & Childrens Hlth, Pediat Endocrinol Unit, Stockholm, Sweden. EM ola.nilsson@ki.se RI Lui, Chun Kin Julian/E-2253-2012; OI Nilsson, Ola/0000-0002-9986-8138 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH, Bethesda, MD, USA; Sallskapet Barnavard; Karolinska Institutet, Stockholm, SWE; Deutsche Forschungsgemeinschaft, Bonn, DEU [Vo-620/10]; ESPE Research Fellowship; Swedish Research Council; Stockholm County Council; Swedish Society of Medicine; HKH Kronprinsessan Lovisas forening for barnasjukvard; Stiftelsen Frimurare Barnhuset i Stockholm, FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA. MC was supported by a grant from Sallskapet Barnavard and the Karolinska Institutet, Stockholm, SWE. AV was supported by a grant from the Deutsche Forschungsgemeinschaft (Vo-620/10), Bonn, DEU. ON was supported by an ESPE Research Fellowship Grant and grants from the Swedish Research Council, the Stockholm County Council, the Swedish Society of Medicine, HKH Kronprinsessan Lovisas forening for barnasjukvard, Sallskapet Barnavard, Stiftelsen Frimurare Barnhuset i Stockholm, and the Karolinska Institutet, Stockholm, SWE. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 3 Z9 3 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 28 PY 2014 VL 9 IS 7 AR e103061 DI 10.1371/journal.pone.0103061 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM6RZ UT WOS:000339993700031 PM 25068449 ER PT J AU Chu, M Wang, LB Wang, H Shen, T Yang, YQ Sun, Y Tang, NN Ni, T Zhu, J Mailman, RB Wang, Y AF Chu, Min Wang, Libo Wang, Huan Shen, Ting Yang, Yanqin Sun, Yun Tang, Nannan Ni, Ting Zhu, Jun Mailman, Richard B. Wang, Yuan TI A Novel Role of CDX1 in Embryonic Epicardial Development SO PLOS ONE LA English DT Article ID GENE-EXPRESSION; STEM-CELLS; SMOOTH-MUSCLE; HOX GENES; HEART; MOUSE; DIFFERENTIATION; HEMATOPOIESIS; TRANSCRIPTION; PROGENITORS AB The molecular mechanism that regulates epicardial development has yet to be understood. In this study, we explored the function of CDX1, a Caudal-related family member, in epicardial epithelial-to-mesenchymal transition (EMT) and in the migration and the differentiation of epicardium-derived progenitors into vascular smooth muscle cells. We detected a transient expression of CDX1 in murine embryonic hearts at 11.5 days post coitum (dpc). Using a doxycycline-inducible CDX1 mouse model, primary epicardium, and ex vivo heart culture, we further demonstrated that ectopic expression of CDX1 promoted epicardial EMT. In addition, a low-dose CDX1 induction led to enhanced migration and differentiation of epicardium-derived cells into alpha-SMA+ vascular smooth muscles. In contrast, either continued high-level induction of CDX1 or CDX1 deficiency attenuated the ability of epicardium-derived cells to migrate and to mature into smooth muscles induced by TGF-beta 1. Further RNA-seq analyses showed that CDX1 induction altered the transcript levels of genes involved in neuronal development, angiogenesis, and cell adhesions required for EMT. Our data have revealed a previously undefined role of CDX1 during epicardial development, and suggest that transient expression of CDX1 promotes epicardial EMT, whereas subsequent down-regulation of CDX1 after 11.5 dpc in mice is necessary for further subepicardial invasion of EPDCs and contribution to coronary vascular endothelium or smooth muscle cells. C1 [Chu, Min; Wang, Libo; Wang, Huan; Sun, Yun; Tang, Nannan; Wang, Yuan] E China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200062, Peoples R China. [Chu, Min; Wang, Libo; Wang, Huan; Sun, Yun; Tang, Nannan; Wang, Yuan] E China Normal Univ, Sch Life Sci, Shanghai 200062, Peoples R China. [Shen, Ting; Ni, Ting] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. [Shen, Ting; Ni, Ting] Fudan Univ, Sch Life Sci, MOE Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China. [Yang, Yanqin; Zhu, Jun] NHLBI, Syst Biol Ctr, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Mailman, Richard B.] Penn State Coll Med, Dept Pharmacol, Hershey, PA USA. RP Wang, Y (reprint author), E China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200062, Peoples R China. EM ywang@bio.ecnu.edu.cn OI Mailman, Richard/0000-0003-1353-2738 FU Ministry of Science and Technology of China [2010CB945403, 2014CB964800]; National Science Foundation of China [31271589, 30971522]; Science and Technology Commission of Shanghai Municipality [11DZ2260300, 13JC1406402]; intramural research program at the National Heart Lung and Blood Institute (USA) FX This work was supported by grants from the Ministry of Science and Technology of China (2010CB945403 and 2014CB964800), the National Science Foundation of China (31271589 and 30971522), the Science and Technology Commission of Shanghai Municipality (11DZ2260300 and 13JC1406402), and the intramural research program at the National Heart Lung and Blood Institute (USA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 4 Z9 5 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 28 PY 2014 VL 9 IS 7 AR e103271 DI 10.1371/journal.pone.0103271 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM6RZ UT WOS:000339993700053 PM 25068460 ER PT J AU Cho, H Chung, JY Song, KH Noh, KH Kim, BW Chung, EJ Ylaya, K Kim, JH Kim, TW Hewitt, SM Kim, JH AF Cho, Hanbyoul Chung, Joon-Yong Song, Kwon-Ho Noh, Kyung Hee Kim, Bo Wook Chung, Eun Joo Ylaya, Kris Kim, Jin Hee Kim, Tae Woo Hewitt, Stephen M. Kim, Jae-Hoon TI Apoptosis inhibitor-5 overexpression is associated with tumor progression and poor prognosis in patients with cervical cancer SO BMC CANCER LA English DT Article DE API5; pERK1/2; Prognosis; Cervical cancer; Tissue microarray; Immunohistochemistry ID RISK HUMAN-PAPILLOMAVIRUS; ACTIVATED PROTEIN-KINASE; GROWTH-FACTOR RECEPTOR; EXPRESSION LEVELS; IN-VIVO; AAC-11; CELLS; INTERACTS; INVASION; CASCADE AB Background: The apoptosis inhibitor-5 (API5), anti-apoptosis protein, is considered a key molecule in the tumor progression and malignant phenotype of tumor cells. Here, we investigated API5 expression in cervical cancer, its clinical significance, and its relationship with phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2) in development and progression of cervical cancer. Methods: API5 effects on cell growth were assessed in cervical cancer cell lines. API5 and pERK1/2 immunohistochemical staining were performed on a cervical cancer tissue microarray consisting of 173 primary cervical cancers, 306 cervical intraepithelial neoplasias (CINs), and 429 matched normal tissues. Results: API5 overexpression promoted cell proliferation and colony formation in CaSki cells, whereas API5 knockdown inhibited the both properties in HeLa cells. Immunohistochemical staining showed that API5 expression increased during the normal to tumor transition of cervical carcinoma (P < 0.001), and this increased expression was significantly associated with tumor stage (P = 0.004), tumor grade (P < 0.001), and chemo-radiation response (P = 0.004). API5 expression levels were positively associated with pERK1/2 in cervical cancer (P < 0.001) and high grade CIN (P = 0.031). In multivariate analysis, API5+ (P = 0.039) and combined API5+/pERK1/2+ (P = 0.032) were independent prognostic factors for overall survival. Conclusions: API5 expression is associated with pERK1/2 in a subset of cervical cancer patients and its expression predicts poor overall survival, supporting that API5 may be a promising novel target for therapeutic interventions. C1 [Cho, Hanbyoul; Kim, Jae-Hoon] Yonsei Univ, Gangnam Severance Hosp, Coll Med, Dept Obstet & Gynecol, Seoul 135720, South Korea. [Cho, Hanbyoul; Chung, Joon-Yong; Kim, Bo Wook; Ylaya, Kris; Hewitt, Stephen M.] NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Song, Kwon-Ho; Noh, Kyung Hee; Kim, Jin Hee; Kim, Tae Woo] Korea Univ, Grad Sch Med, Dept Biomed Sci, Seoul, South Korea. [Song, Kwon-Ho; Noh, Kyung Hee; Kim, Jin Hee; Kim, Tae Woo] Korea Univ, Coll Med, Dept Biochem, Seoul 136705, South Korea. [Chung, Eun Joo] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hewitt, SM (reprint author), NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM genejock@helix.nih.gov; jaehoonkim@yuhs.ac OI Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 FU Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2013M3A9D3045881, 2011-0005230, 2011-0010286, 2011-0007146]; Yonsei University College of Medicine [6-2014-0072]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work was supported in part by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2013M3A9D3045881, 2011-0005230, 2011-0010286, and 2011-0007146), faculty research grants from Yonsei University College of Medicine for 2014 (6-2014-0072), and Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 36 TC 6 Z9 7 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JUL 28 PY 2014 VL 14 AR 545 DI 10.1186/1471-2407-14-545 PG 12 WC Oncology SC Oncology GA AM6JW UT WOS:000339971800005 PM 25070070 ER PT J AU Khare, R Wei, CH Mao, YQ Leaman, R Lu, ZY AF Khare, Ritu Wei, Chih-Hsuan Mao, Yuqing Leaman, Robert Lu, Zhiyong TI tmBioC: improving interoperability of text-mining tools with BioC SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID GENE NORMALIZATION; BIOCREATIVE III; INFORMATION; IDENTIFICATION; CORPUS AB The lack of interoperability among biomedical text-mining tools is a major bottleneck in creating more complex applications. Despite the availability of numerous methods and techniques for various text-mining tasks, combining different tools requires substantial efforts and time owing to heterogeneity and variety in data formats. In response, BioC is a recent proposal that offers a minimalistic approach to tool interoperability by stipulating minimal changes to existing tools and applications. BioC is a family of XML formats that define how to present text documents and annotations, and also provides easy-to-use functions to read/write documents in the BioC format. In this study, we introduce our text-mining toolkit, which is designed to perform several challenging and significant tasks in the biomedical domain, and repackage the toolkit into BioC to enhance its interoperability. Our toolkit consists of six state-of-the-art tools for named-entity recognition, normalization and annotation (PubTator) of genes (GenNorm), diseases (DNorm), mutations (tmVar), species (SR4GN) and chemicals (tmChem). Although developed within the same group, each tool is designed to process input articles and output annotations in a different format. We modify these tools and enable them to read/write data in the proposed BioC format. We find that, using the BioC family of formats and functions, only minimal changes were required to build the newer versions of the tools. The resulting BioC wrapped toolkit, which we have named tmBioC, consists of our tools in BioC, an annotated full-text corpus in BioC, and a format detection and conversion tool. Furthermore, through participation in the 2013 BioCreative IV Interoperability Track, we empirically demonstrate that the tools in tmBioC can be more efficiently integrated with each other as well as with external tools: Our experimental results show that using BioC reduces >60% in lines of code for text-mining tool integration. The tmBioC toolkit is publicly available at http://www.ncbi.nlm.nih.gov/CBBresearch/Lu/Demo/tmTools/. C1 [Khare, Ritu; Wei, Chih-Hsuan; Mao, Yuqing; Leaman, Robert; Lu, Zhiyong] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. RP Lu, ZY (reprint author), NIH, Natl Ctr Biotechnol Informat, 8600 Rockville Pike, Bethesda, MD 20892 USA. EM zhiyong.lu@nih.gov FU Intramural Research Program of the NIH, National Library of Medicine FX This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 37 TC 2 Z9 2 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD JUL 25 PY 2014 AR bau073 DI 10.1093/database/bau073 PG 10 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AM4BN UT WOS:000339796800001 ER PT J AU Lee, YH Morrison, BL Bottaro, DP AF Lee, Young H. Morrison, Bethanie L. Bottaro, Donald P. TI Synergistic Signaling of Tumor Cell Invasiveness by Hepatocyte Growth Factor and Hypoxia SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RENAL-CARCINOMA CELLS; BETA-CATENIN; MESENCHYMAL TRANSITION; CANCER CELLS; E-CADHERIN; IN-VITRO; C-JUN; AUTOPHAGY; ACTIVATION; MET AB Hepatocyte growth factor (HGF) signaling promotes tumor invasiveness in renal cell carcinoma (RCC) and other cancers. In clear cell RCC, VHL loss generates pseudohypoxia that exacerbates HGF-driven invasion through beta-catenin deregulation. Hypoxia also enhances HGF-driven invasiveness by papillary RCC cells, but in the absence of VHL, loss signaling integration involves three parallel routes: 1) hypoxia-induced reactive oxygen species production and decreased DUSP2 expression, leading to enhanced mitogen-activated protein kinase (MAPK) cascade activation; 2) reactive oxygen species-induced diacylglycerol production by phospholipase C gamma, leading to protein kinase C activation and increased protein phosphatase-2A activity, thereby suppressing HGF-induced Akt activation; and 3) a profound shift from HGF-enhanced, proliferation-oriented metabolism to autophagy-dependent invasion and suppression of proliferation. This tripartite signaling integration was not unique to RCC or HGF; in RCC cells, invasive synergy induced by the combination of hypoxia and epidermal growth factor occurred through the same mechanism, and in estrogen receptor-positive breast cancer cells, this mechanism was suppressed in the absence of estrogen. These results define the molecular basis of growth factor and hypoxia invasive synergy in VHL-competent papillary RCC cells, illustrate the plasticity of invasive and proliferative tumor cell states, and provide signaling profiles by which they may be predicted. C1 [Lee, Young H.; Bottaro, Donald P.] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Morrison, Bethanie L.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bottaro, DP (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bldg 10 CRC Rm 2-3952,10 Ctr Dr MSC 1107, Bethesda, MD 20892 USA. EM dbottaro@helix.nih.gov OI Bottaro, Donald/0000-0002-5057-5334 FU National Institutes of Health Intramural Research Program, NCI, Center for Cancer Research FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program, NCI, Center for Cancer Research. NR 49 TC 8 Z9 8 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 25 PY 2014 VL 289 IS 30 BP 20448 EP 20461 DI 10.1074/jbc.M114.580597 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AL8NS UT WOS:000339396600004 PM 24914205 ER PT J AU Restifo, NP AF Restifo, Nicholas P. TI Big bang theory of stem-like T cells confirmed SO BLOOD LA English DT Editorial Material ID MEMORY; EFFECTOR; DIFFERENTIATION AB In this issue of Blood, Stemberger et al show that the progeny of a single CD62L(hi) cell can provide protection against bacterial challenge and that ultra-low doses of cytomegalovirus (CMV)-specific CD8(+) T cells can expand greatly in humans.(1) C1 NCI, Bethesda, MD 20892 USA. RP Restifo, NP (reprint author), NCI, Bethesda, MD 20892 USA. OI Restifo, Nicholas P./0000-0003-4229-4580 NR 10 TC 4 Z9 4 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 24 PY 2014 VL 124 IS 4 BP 476 EP 477 DI 10.1182/blood-2014-06-578989 PG 4 WC Hematology SC Hematology GA AQ2MD UT WOS:000342619600008 PM 25061170 ER PT J AU Diamond, EL Dagna, L Hyman, DM Cavalli, G Janku, F Estrada-Veras, J Ferrarini, M Abdel-Wahab, O Heaney, ML Scheel, PJ Feeley, NK Ferrero, E McClain, KL Vaglio, A Colby, T Arnaud, L Haroche, J AF Diamond, Eli L. Dagna, Lorenzo Hyman, David M. Cavalli, Giulio Janku, Filip Estrada-Veras, Juvianee Ferrarini, Marina Abdel-Wahab, Omar Heaney, Mark L. Scheel, Paul J. Feeley, Nancy K. Ferrero, Elisabetta McClain, Kenneth L. Vaglio, Augusto Colby, Thomas Arnaud, Laurent Haroche, Julien TI Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease SO BLOOD LA English DT Review ID LANGERHANS-CELL HISTIOCYTOSIS; CENTRAL-NERVOUS-SYSTEM; OF-THE-LITERATURE; TC-99M MDP BONE; IMATINIB MESYLATE; INTERFERON-ALPHA; CARDIAC INVOLVEMENT; MAGNETIC-RESONANCE; BRAF MUTATION; INFILTRATION AB Erdheim-Chester disease (ECD) is a rare, non-Langerhans histiocytosis. Recent findings suggest that ECD is a clonal disorder, marked by recurrent BRAFV600E mutations in >50% of patients, in which chronic uncontrolled inflammation is an important mediator of disease pathogenesis. Although similar to 500 to 550 cases have been described in the literature to date, increased physician awareness has driven a dramatic increase in ECD diagnoses over the last decade. ECD frequently involves multiple organ systems and has historically lacked effective therapies. Given the protean clinical manifestations and the lack of a consensus-derived approach for the management of ECD, we provide here the first multidisciplinary consensus guidelines for the clinical management of ECD. These recommendations were outlined at the First International Medical Symposium for ECD, comprised of a comprehensive group of international academicians with expertise in the pathophysiology and therapy of ECD. Detailed recommendations on the initial clinical, laboratory, and radiographic assessment of ECD patients are presented in addition to treatment recommendations based on critical appraisal of the literature and clinical experience. These formalized consensus descriptions will hopefully facilitate ongoing and future research efforts in this disorder. C1 [Diamond, Eli L.] Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY 10021 USA. [Dagna, Lorenzo; Cavalli, Giulio] Ist Ricovero & Cura, Unit Med & Clin Immunol, Milan, Italy. [Dagna, Lorenzo; Cavalli, Giulio; Ferrarini, Marina; Ferrero, Elisabetta] Carattere Sci San Raffaele Sci Inst, Milan, Italy. [Hyman, David M.] Mem Sloan Kettering Canc Ctr, Dev Therapeut Unit, New York, NY 10021 USA. [Janku, Filip] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Phase Clin Trials Program 1, Houston, TX 77030 USA. [Estrada-Veras, Juvianee] NHGRI, Med Genet Branch, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Estrada-Veras, Juvianee] NHGRI, Hematol Sect, Dept Lab Med, NIH, Bethesda, MD 20892 USA. [Ferrarini, Marina; Ferrero, Elisabetta] Ist Ricovero & Cura, Dept Oncol, Milan, Italy. [Abdel-Wahab, Omar] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Abdel-Wahab, Omar] Mem Sloan Kettering Canc Ctr, Leukemia Serv, New York, NY 10021 USA. [Heaney, Mark L.] Columbia Univ Med Ctr, Div Hematol Oncol, New York, NY USA. [Scheel, Paul J.; Feeley, Nancy K.] Johns Hopkins Univ Sch Med, Div Nephrol, Baltimore, MD USA. [McClain, Kenneth L.] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. [McClain, Kenneth L.] Baylor Coll Med, Hematol Ctr, Houston, TX 77030 USA. [Vaglio, Augusto] Univ Hosp Parma, Parma, Italy. [Colby, Thomas] Mayo Clin Arizona, Lab Med & Pathol, Scottsdale, AZ USA. [Arnaud, Laurent; Haroche, Julien] Hop La Pitie Salpetriere, AP HP, French Reference Ctr Autoimmune Dis, Dept Internal Med, Paris, France. RP Diamond, EL (reprint author), Dept Neurol, Box 52,1275 York Ave, New York, NY 10065 USA. EM diamone1@mskcc.org OI Abdel-Wahab, Omar/0000-0002-3907-6171; Vaglio, Augusto/0000-0002-3814-9172; Dagna, Lorenzo/0000-0002-7428-315X; Cavalli, Giulio/0000-0001-8728-3004; Diamond, Eli/0000-0001-5456-5961 FU ECD Global Alliance; Italian Ministry of Health [GR-2009-1594586]; Geoffrey Beene Cancer Research Foundation FX J.H., L.A., E.D., O.A.-W., and D.H. are supported by funding from the ECD Global Alliance. L.D. is supported by funding from the Italian Ministry of Health (GR-2009-1594586). E.D., O.A.-W., and D.H. are supported by the Geoffrey Beene Cancer Research Foundation. NR 94 TC 85 Z9 86 U1 4 U2 9 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 24 PY 2014 VL 124 IS 4 BP 483 EP 492 DI 10.1182/blood-2014-03-561381 PG 10 WC Hematology SC Hematology GA AQ2MD UT WOS:000342619600011 PM 24850756 ER PT J AU Hosnijeh, FS Lan, Q Rothman, N Liu, CS Cheng, WL Nieters, A Guldberg, P Tjonneland, A Campa, D Martino, A Boeing, H Trichopoulou, A Lagiou, P Trichopoulos, D Krogh, V Tumino, R Panico, S Masala, G Weiderpass, E Castano, JMH Ardanaz, E Sala, N Dorronsoro, M Quiros, JR Sanchez, MJ Melin, B Johansson, AS Malm, J Borgquist, S Peeters, PH Bueno-de-Mesquita, HB Wareham, N Khaw, KT Travis, RC Brennan, P Siddiq, A Riboli, E Vineis, P Vermeulen, R AF Hosnijeh, Fatemeh Saberi Lan, Qing Rothman, Nathaniel Liu, Chin San Cheng, Wen-Ling Nieters, Alexandra Guldberg, Per Tjonneland, Anne Campa, Daniele Martino, Alessandro Boeing, Heiner Trichopoulou, Antonia Lagiou, Pagona Trichopoulos, Dimitrios Krogh, Vittorio Tumino, Rosario Panico, Salvatore Masala, Giovanna Weiderpass, Elisabete Castano, Jose Maria Huerta Ardanaz, Eva Sala, Nuria Dorronsoro, Miren Quiros, J. Ramon Sanchez, Maria-Jose Melin, Beatrice Johansson, Ann Sofie Malm, Johan Borgquist, Signe Peeters, Petra H. Bueno-de-Mesquita, H. Bas Wareham, Nick Khaw, Kay-Tee Travis, Ruth C. Brennan, Paul Siddiq, Afshan Riboli, Elio Vineis, Paolo Vermeulen, Roel TI Mitochondrial DNA copy number and future risk of B-cell lymphoma in a nested case-control study in the prospective EPIC cohort SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NON-HODGKIN-LYMPHOMA; GENETIC-VARIANTS; OXIDATIVE STRESS; BENZENE EXPOSURE; CANCER RISK; GENOME; ASSOCIATION; BIOGENESIS; INCREASE AB It has been suggested that mitochondrial dysfunction and DNA damage are involved in lymphomagenesis. Increased copy number of mitochondrial DNA (mtDNA) as a compensatory mechanism of mitochondrial dysfunction previously has been associated with B-cell lymphomas, in particular chronic lymphocytic leukemia (CLL). However, current evidence is limited and based on a relatively small number of cases. Using a nested case-control study, we extended these findings with a focus on subtype-specific analyses. Relative mtDNA copy number was measured in the buffy coat of prospectively collected blood of 469 lymphoma cases and 469 matched controls. The association between mtDNA copy number and the risk of developing lymphoma and histologic subtypes was examined using logistic regression models. We found no overall association between mtDNA and risk of lymphoma. Subtype analyses revealed significant increased risks of CLL (n=102) with increasing mtDNA copy number (odds ratio=1.34, 1.44, and 1.80 for quartiles 2-4, respectively; Ptrend=.001). mtDNA copy number was not associated with follow-up time, suggesting that this observation is not strongly influenced by indolent disease status. This study substantially strengthens the evidence that mtDNA copy number is related to risk of CLL and supports the importance of mitochondrial dysfunction as a possible mechanistic pathway in CLL ontogenesis. C1 [Hosnijeh, Fatemeh Saberi; Vermeulen, Roel] Univ Utrecht, Div Environm Epidemiol, Inst Risk Assessment Sci, NL-3508 TD Utrecht, Netherlands. [Hosnijeh, Fatemeh Saberi] Zanjan Univ Med Sci, Zanjan, Iran. [Lan, Qing; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Liu, Chin San] Changhua Christian Hosp, Dept Neurol, Changhua, Taiwan. [Liu, Chin San] Changhua Christian Hosp, Vasc & Genom Ctr, Changhua, Taiwan. [Liu, Chin San] China Med Univ, Coll Chinese Med, Grad Inst Integrated Med, Taichung, Taiwan. [Cheng, Wen-Ling] Chunghua Christian Hosp, Lab Mitochondrial Med, Taipei, Taiwan. [Nieters, Alexandra] Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, Freiburg, Germany. [Guldberg, Per; Tjonneland, Anne] Danish Canc Soc Res Ctr, Copenhagen, Denmark. [Campa, Daniele; Martino, Alessandro] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Boeing, Heiner] German Inst Human Nutr, Dept Epidemiol, Potsdam, Nuthetal, Germany. [Trichopoulou, Antonia; Trichopoulos, Dimitrios] Hellen Hlth Fdn, Athens, Greece. [Trichopoulou, Antonia; Lagiou, Pagona] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, WHO Collaborating Ctr Food & Nutr Policies, GR-11527 Athens, Greece. [Lagiou, Pagona; Trichopoulos, Dimitrios] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Lagiou, Pagona; Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Krogh, Vittorio] Fdn IRCCS Ist Nazl Tumori, Epidemiol & Prevent Unit, Milan, Italy. [Tumino, Rosario] Civ MP Arezzo Hosp, Canc Registry & Histopathol Unit, Asp Ragusa, Italy. [Panico, Salvatore] Univ Naples Federico II, Dept Clin Med & Surg, Naples, Italy. [Masala, Giovanna] ISPO Canc Res & Prevent Inst, Mol & Nutr Epidemiol Unit, Florence, Italy. [Weiderpass, Elisabete] Univ Tromso, Dept Community Med, Fac Hlth Sci, Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, Dept Res, Oslo, Norway. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, Elisabete] Samfundet Folkhalsan, Helsinki, Finland. [Castano, Jose Maria Huerta] Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain. [Castano, Jose Maria Huerta; Ardanaz, Eva; Sanchez, Maria-Jose] CIBER Epidemiol & Publ Hlth CIBERESP, Barcelona, Spain. [Ardanaz, Eva] Navarre Publ Hlth Inst, Pamplona, Spain. [Sala, Nuria] Biomed Res Inst IDIBELL, Catalan Inst Oncol, Translat Res Lab, Barcelona, Spain. [Sala, Nuria] Biomed Res Inst IDIBELL, Catalan Inst Oncol, Unit Nutr, Environm & Canc Res Program Canc Epidemiol, Barcelona, Spain. [Dorronsoro, Miren] Basque Reg Hlth Dept, Publ Hlth Direct, Vitoria, Spain. [Dorronsoro, Miren] Basque Reg Hlth Dept, Biodonostia Res Inst Ciberesp, Vitoria, Spain. [Quiros, J. Ramon] Publ Hlth Directorate, Asturias, Spain. [Sanchez, Maria-Jose] Andalusian Sch Publ Hlth, Granada, Spain. [Sanchez, Maria-Jose] Inst Invest Biosanitario Granada, Granada, Spain. [Melin, Beatrice; Johansson, Ann Sofie] Oncol Umea Univ, Dept Radiat Sci, Umea, Sweden. [Malm, Johan] Lund Univ, Dept Lab Med, Malmo, Sweden. [Malm, Johan] Skane Univ Hosp, Malmo, Sweden. [Borgquist, Signe] Lund Univ, Dept Clin Sci, Div Oncol, Malmo, Sweden. [Peeters, Petra H.; Vermeulen, Roel] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, Utrecht, Netherlands. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Bueno-de-Mesquita, H. Bas; Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Wareham, Nick] Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England. [Wareham, Nick; Khaw, Kay-Tee] Univ Cambridge, Sch Clin Med, Cambridge, England. [Travis, Ruth C.] Univ Oxford, Canc Epidemiol Unit, Oxford, England. [Brennan, Paul] Int Agcy Res Canc, Genet Sect, F-69372 Lyon, France. [Siddiq, Afshan] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London, England. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Vineis, Paolo] Human Genet Fdn, Turin, Italy. RP Vermeulen, R (reprint author), Univ Utrecht, Div Environm Epidemiol, Inst Risk Assessment Sci, POB 80178, NL-3508 TD Utrecht, Netherlands. EM r.c.h.vermeulen@uu.nl RI SANCHEZ-PEREZ, MARIA JOSE/D-1087-2011; Huerta, Jose Maria/N-8654-2015; Campa, Daniele/K-1617-2016; Krogh, Vittorio/K-2628-2016; Panico, Salvatore/K-6506-2016; Weiderpass, Elisabete/M-4029-2016; Saberi Hosnijeh, Fatemeh/N-6684-2013; Vermeulen, Roel/F-8037-2011; OI Masala, Giovanna/0000-0002-5758-9069; SANCHEZ-PEREZ, MARIA JOSE/0000-0003-4817-0757; Huerta, Jose Maria/0000-0002-9637-3869; Campa, Daniele/0000-0003-3220-9944; Krogh, Vittorio/0000-0003-0122-8624; Panico, Salvatore/0000-0002-5498-8312; Weiderpass, Elisabete/0000-0003-2237-0128; Vermeulen, Roel/0000-0003-4082-8163; Sala, Nuria/0000-0003-3585-7613 FU 'Europe Against Cancer Programme' of the European Commission (SANCO); French League against Cancer (LNCC); National Institute for Health and Medical Research (INSERM), France; Mutuelle Generale de l'Education Nationale (MGEN) (France); 3M Co (France); Gustave Roussy Institute (IGR) (France); General Councils of France (France); German Cancer Aid (Germany); German Cancer Research Centre (Germany); German Federal Ministry of Education and Research (Germany); Danish Cancer Society (Denmark); Health Research Fund (FIS) of the Spanish Ministry of Health [Exp P10710130]; Regional Government of Andalucia; Regional Government of Asturias; Regional Government of Basque Country; Regional Government of Murcia [6236]; Regional Government of Navarra; Catalan Institute of Oncology, La Caixa (Spain) [BM 06-130, RTICC-RD06/0020]; Cancer Research UK; Medical Research Council (UK); Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (Italy); Italian National Research Council (Italy); Fondazione-Istituto Banco Napoli (Italy); Compagnia di San Paolo (Italy); Dutch Ministry of Public Health, Welfare and Sports (the Netherlands); Dutch Prevention Funds (the Netherlands); LK Research Funds (the Netherlands); Dutch ZON (Zorg Onderzoek Nederland) (the Netherlands); World Cancer Research Fund; Swedish Cancer Society (Sweden); Swedish Scientific Council (Sweden); Regional Government of Skane (Sweden); European Research Council (Norway); Norwegian Research Council (Norway); Norwegian Cancer Society (Norway) FX This work was supported by the 'Europe Against Cancer Programme' of the European Commission (SANCO); French League against Cancer (LNCC); National Institute for Health and Medical Research (INSERM), France; Mutuelle Generale de l'Education Nationale (MGEN), 3M Co, Gustave Roussy Institute (IGR), General Councils of France (France); German Cancer Aid, German Cancer Research Centre, German Federal Ministry of Education and Research (Germany); Danish Cancer Society (Denmark); Health Research Fund (FIS) of the Spanish Ministry of Health (Exp P10710130), Regional Governments of Andalucia, Asturias, Basque Country, Murcia (no. 6236), Navarra, and the Catalan Institute of Oncology, La Caixa (BM 06-130), RTICC-RD06/0020 (Spain); Cancer Research UK, Medical Research Council (UK); the Hellenic Health Foundation (Greece); Italian Association for Research on Cancer, Italian National Research Council, Fondazione-Istituto Banco Napoli, Compagnia di San Paolo (Italy); Dutch Ministry of Public Health, Welfare and Sports, Dutch Prevention Funds, LK Research Funds, Dutch ZON (Zorg Onderzoek Nederland) (the Netherlands); World Cancer Research Fund; Swedish Cancer Society, Swedish Scientific Council, Regional Government of Skane (Sweden); and European Research Council, Norwegian Research Council, Norwegian Cancer Society (Norway). NR 24 TC 11 Z9 11 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 24 PY 2014 VL 124 IS 4 BP 530 EP 535 DI 10.1182/blood-2013-10-532085 PG 6 WC Hematology SC Hematology GA AQ2MD UT WOS:000342619600016 PM 24899624 ER PT J AU Fertrin, KY van Beers, EJ Samsel, L Mendelsohn, LG Saiyed, R Nichols, JS Hepp, DA Brantner, CA Daniels, MP McCoy, JP Kato, GJ AF Fertrin, Kleber Yotsumoto van Beers, Eduard J. Samsel, Leigh Mendelsohn, Laurel G. Saiyed, Rehan Nichols, James S. Hepp, David A. Brantner, Christine A. Daniels, Mathew P. McCoy, J. Philip Kato, Gregory J. TI Imaging flow cytometry documents incomplete resistance of human sickle F-cells to ex vivo hypoxia-induced sickling SO BLOOD LA English DT Letter ID FETAL-HEMOGLOBIN; HYDROXYUREA; DISEASE; ANEMIA C1 [Fertrin, Kleber Yotsumoto; van Beers, Eduard J.; Mendelsohn, Laurel G.; Saiyed, Rehan; Nichols, James S.] NHLBI, Sickle Cell Vasc Dis Sect, Hematol Branch, Bethesda, MD 20892 USA. [Samsel, Leigh; McCoy, J. Philip] NHLBI, Flow Cytometry Core Facil, Bethesda, MD 20892 USA. [Hepp, David A.; Brantner, Christine A.; Daniels, Mathew P.] NHLBI, Electron Microscopy Core Facil, Bethesda, MD 20892 USA. [Kato, Gregory J.] Univ Pittsburgh, Dept Med, Div Hematol Oncol, Pittsburgh, PA 15261 USA. [Kato, Gregory J.] Univ Pittsburgh, Heart Lung Blood & Vasc Med Inst, Pittsburgh, PA 15261 USA. RP Kato, GJ (reprint author), Univ Pittsburgh, Dept Med, Div Hematol Oncol, 200 Lothrop St,BST E1240, Pittsburgh, PA 15261 USA. EM katogj@upmc.edu RI van Beers, Eduard/I-3561-2012; Kato, Gregory/I-7615-2014; OI van Beers, Eduard/0000-0002-3934-7189; Kato, Gregory/0000-0003-4465-3217; Brantner, Christine/0000-0001-8172-901X NR 4 TC 3 Z9 3 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 24 PY 2014 VL 124 IS 4 BP 658 EP 660 DI 10.1182/blood-2014-03-559054 PG 5 WC Hematology SC Hematology GA AQ2MD UT WOS:000342619600032 PM 25061174 ER PT J AU Cha, J Bartos, A Park, C Sun, XF Li, YJ Cha, SW Ajima, R Ho, HYH Yamaguchi, TP Dey, SK AF Cha, Jeeyeon Bartos, Amanda Park, Craig Sun, Xiaofei Li, Yingju Cha, Sang-Wook Ajima, Rieko Ho, Hsin-Yi Henry Yamaguchi, Terry P. Dey, Sudhansu K. TI Appropriate Crypt Formation in the Uterus for Embryo Homing and Implantation Requires Wnt5a-ROR Signaling SO CELL REPORTS LA English DT Article ID PLANAR CELL POLARITY; RECEPTOR TYROSINE KINASES; MOUSE UTERUS; BLASTOCYST IMPLANTATION; SKELETAL ABNORMALITIES; UTERINE RECEPTIVITY; INDIAN HEDGEHOG; MICE; EXPRESSION; PATHWAY AB Embryo homing and implantation occur within a crypt (implantation chamber) at the antimesometrial (AM) pole along the uterus. The mechanism by which this is achieved is not known. Here, we show that villi-like epithelial projections from the main uterine lumen toward the AM pole at regularly spaced intervals that form crypts for embryo implantation were disrupted in mice with uterine loss or gain of function of Wnt5a, or loss of function of both Ror1 and Ror2. This disruption of Wnt5a-ROR signaling resulted in disorderly epithelial projections, crypt formation, embryo spacing, and impaired implantation. These early disturbances under abnormal Wnt5a-ROR signaling were reflected in adverse late pregnancy events, including defective decidualization and placentation, ultimately leading to compromised pregnancy outcomes. This study presents deeper insight regarding the formation of organized epithelial projections for crypt formation and embryo implantation for pregnancy success. C1 [Cha, Jeeyeon; Bartos, Amanda; Park, Craig; Sun, Xiaofei; Li, Yingju; Dey, Sudhansu K.] Cincinnati Childrens Hosp Med Ctr, Div Reprod Sci, Cincinnati, OH 45229 USA. [Cha, Jeeyeon; Cha, Sang-Wook; Dey, Sudhansu K.] Cincinnati Childrens Hosp Med Ctr, Div Dev Biol, Cincinnati, OH 45229 USA. [Ajima, Rieko; Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Ajima, Rieko] Natl Inst Genet, Div Mammalian Dev, Mishima, Shizuoka 4118540, Japan. [Ho, Hsin-Yi Henry] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Ho, Hsin-Yi Henry] Univ Calif Davis, Sch Med, Dept Cell Biol & Human Anat, Davis, CA 95616 USA. RP Dey, SK (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Reprod Sci, Cincinnati, OH 45229 USA. EM sk.dey@cchmc.org FU NIH [HD068524, DA06668]; March of Dimes [21-FY12-127, 22-FY13-543]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; University of Cincinnati MSTP [F30AG040858]; Lalor Foundation FX We thank Michael Greenberg (Harvard) for generously providing the Ror1 and Ror2 floxed mice and Francesco DeMayo and John B. Lydon (Baylor) for the Pgr-Cre mice. The ROR2 antibody was kindly provided by Yasuhiro Minami (Kyoto) and the phospho-Smad1/Smad5/Smad8 antibody by Dan Vasiliauskas, Susan Morton, Tom Jessell, and Ed Laufer (Columbia). We are thankful to Barbara Fegley and the Electron Microscopy Research Lab (University of Kansas Medical Center) for assistance with electron microscopy experiments (9P20GM104936). This work was supported in part by grants from the NIH (HD068524 and DA06668) and March of Dimes (21-FY12-127 and 22-FY13-543) (to S.K.D.) and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (to T.P.Y.). J.C. is a National Research Service Award fellow (F30AG040858) of the University of Cincinnati MSTP, and X.S. was supported by a Lalor Foundation Postdoctoral Fellowship. NR 39 TC 25 Z9 25 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUL 24 PY 2014 VL 8 IS 2 BP 381 EP 391 DI 10.1016/j.celrep.2014.06.027 PG 11 WC Cell Biology SC Cell Biology GA AO7YT UT WOS:000341569800008 PM 25043182 ER PT J AU Fedorova, EV Buryakina, AV Zakharov, AV Filimonov, DA Lagunin, AA Poroikov, VV AF Fedorova, Elena V. Buryakina, Anna V. Zakharov, Alexey V. Filimonov, Dmitry A. Lagunin, Alexey A. Poroikov, Vladimir V. TI Design, Synthesis and Pharmacological Evaluation of Novel Vanadium-Containing Complexes as Antidiabetic Agents SO PLOS ONE LA English DT Article ID ACUTE TOXICITY; PREDICTION; QSAR; METABOLISM; MECHANISM; SULFATE; SERIES; RATS AB Based on the data about structure and antidiabetic activity of twenty seven vanadium and zinc coordination complexes collected from literature we developed QSAR models using the GUSAR program. These QSAR models were applied to 10 novel vanadium coordination complexes designed in silico in order to predict their hypoglycemic action. The five most promising substances with predicted potent hypoglycemic action were selected for chemical synthesis and pharmacological evaluation. The selected coordination vanadium complexes were synthesized and tested in vitro and in vivo for their hypoglycemic activities and acute rat toxicity. Estimation of acute rat toxicity of these five vanadium complexes was performed using a freely available web-resource (http://way2drug.com/GUSAR/acutoxpredict.html). It has shown that the selected compounds belong to the class of moderate toxic pharmaceutical agents, according to the scale of Hodge and Sterner. Comparison with the predicted data has demonstrated a reasonable correspondence between the experimental and predicted values of hypoglycemic activity and toxicity. Bis{tert-butyl[amino(imino) methyl]carbamato}oxovanadium (IV) and sodium(2,2'-Bipyridyl)oxo-diperoxovanadate(V) octahydrate were identified as the most potent hypoglycemic agents among the synthesized compounds. C1 [Fedorova, Elena V.; Buryakina, Anna V.] Minist Healthcare & Social Dev Russian Federat, St Petersburg State Chem Pharmaceut Acad, St Petersburg, Russia. [Zakharov, Alexey V.] NCI, NIH, Frederick, MD 21701 USA. [Zakharov, Alexey V.; Filimonov, Dmitry A.; Lagunin, Alexey A.; Poroikov, Vladimir V.] Russian Acad Med Sci, Orekhovich Inst Biomed Chem, Moscow, Russia. RP Fedorova, EV (reprint author), Minist Healthcare & Social Dev Russian Federat, St Petersburg State Chem Pharmaceut Acad, St Petersburg, Russia. EM elena.fedorova@pharminnotech.com RI Lagunin, Alexey/G-3745-2010; Poroikov, Vladimir/O-2769-2013 OI Lagunin, Alexey/0000-0003-1757-8004; Poroikov, Vladimir/0000-0001-7937-2621 FU Ministry of Education and Science of the Russian Federation [1.2.1.]; Russian Foundation for Basic Research [02-07-90322] FX This work was supported by Ministry of Education and Science of the Russian Federation on the main academic programs of higher professional education, program 1.2.1. (fcpk.ru). We also acknowledge the support of the Russian Foundation for Basic Research (http://www.rfbr.ru/rffi/ru/) in the payment of the license for using the Cambridge Structural Database, project no. 02-07-90322. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 7 Z9 7 U1 0 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 24 PY 2014 VL 9 IS 7 AR e100386 DI 10.1371/journal.pone.0100386 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO5BG UT WOS:000341354800002 PM 25057899 ER PT J AU Gusenleitner, D Auerbach, SS Melia, T Gomez, HF Sherr, DH Monti, S AF Gusenleitner, Daniel Auerbach, Scott S. Melia, Tisha Gomez, Harold F. Sherr, David H. Monti, Stefano TI Genomic Models of Short-Term Exposure Accurately Predict Long-Term Chemical Carcinogenicity and Identify Putative Mechanisms of Action SO PLOS ONE LA English DT Article ID NATIONAL-TOXICOLOGY-PROGRAM; ABERRANT LIPID-METABOLISM; GENE-EXPRESSION; HEPATOCELLULAR-CARCINOMA; POTENCY-DATABASE; LIVER-TUMORS; CANCER; RAT; RISK; HEPATOCARCINOGENS AB Background: Despite an overall decrease in incidence of and mortality from cancer, about 40% of Americans will be diagnosed with the disease in their lifetime, and around 20% will die of it. Current approaches to test carcinogenic chemicals adopt the 2-year rodent bioassay, which is costly and time-consuming. As a result, fewer than 2% of the chemicals on the market have actually been tested. However, evidence accumulated to date suggests that gene expression profiles from model organisms exposed to chemical compounds reflect underlying mechanisms of action, and that these toxicogenomic models could be used in the prediction of chemical carcinogenicity. Results: In this study, we used a rat-based microarray dataset from the NTP DrugMatrix Database to test the ability of toxicogenomics to model carcinogenicity. We analyzed 1,221 gene-expression profiles obtained from rats treated with 127 well-characterized compounds, including genotoxic and non-genotoxic carcinogens. We built a classifier that predicts a chemical's carcinogenic potential with an AUC of 0.78, and validated it on an independent dataset from the Japanese Toxicogenomics Project consisting of 2,065 profiles from 72 compounds. Finally, we identified differentially expressed genes associated with chemical carcinogenesis, and developed novel data-driven approaches for the molecular characterization of the response to chemical stressors. Conclusion: Here, we validate a toxicogenomic approach to predict carcinogenicity and provide strong evidence that, with a larger set of compounds, we should be able to improve the sensitivity and specificity of the predictions. We found that the prediction of carcinogenicity is tissue-dependent and that the results also confirm and expand upon previous studies implicating DNA damage, the peroxisome proliferator-activated receptor, the aryl hydrocarbon receptor, and regenerative pathology in the response to carcinogen exposure. C1 [Gusenleitner, Daniel; Melia, Tisha; Gomez, Harold F.; Monti, Stefano] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. [Gusenleitner, Daniel; Monti, Stefano] Boston Univ, Dept Computat Biomed, Boston, MA 02215 USA. [Auerbach, Scott S.] NIEHS, Biomol Screening Branch, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Sherr, David H.] Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. RP Monti, S (reprint author), Boston Univ, Bioinformat Program, Boston, MA 02215 USA. EM smonti@bu.edu FU National Institutes of Health (NIH) [P42 RFA-ES-10-010]; Evans Center for Interdisciplinary Biomedical Research ARC on "Computational Genomic Models of Environmental Chemical Carcinogenicity'' at Boston University; National Center for Advancing Translational Sciences, NIH, through BU-CTSI Grant [UL1 TR000157]; Art BeCAUSE Breast Cancer Foundation FX This work was partially supported by the National Institutes of Health (NIH)-funded Boston University Superfund Research Program (P42 RFA-ES-10-010), the Evans Center for Interdisciplinary Biomedical Research ARC on "Computational Genomic Models of Environmental Chemical Carcinogenicity'' at Boston University (http://www.bumc.bu.edu/evanscenteribr/), the National Center for Advancing Translational Sciences, NIH, through BU-CTSI Grant Number UL1 TR000157, and the Art BeCAUSE Breast Cancer Foundation. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 10 Z9 10 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 24 PY 2014 VL 9 IS 7 AR e102579 DI 10.1371/journal.pone.0102579 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO5BG UT WOS:000341354800026 PM 25058030 ER PT J AU Brouwer, C Jenko, K Zoghbi, SS Innis, RB Pike, VW AF Brouwer, Chad Jenko, Kimberly Zoghbi, Sami S. Innis, Robert B. Pike, Victor W. TI Development of N-Methyl-(2-arylquinolin-4-yl)oxypropanamides as Leads to PET Radioligands for Translocator Protein (18 kDa) SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID BENZODIAZEPINE BINDING-SITES; POSITRON-EMISSION-TOMOGRAPHY; MULTIPLE-SCLEROSIS PATIENTS; IN-VIVO; HUMAN-BRAIN; MICROGLIAL ACTIVATION; GENETIC-POLYMORPHISM; HEALTHY HUMANS; RECEPTOR; NEUROINFLAMMATION AB Translocator protein (18 kDa), known as TSPO, is a recognized biomarker of neuroinflammation. Radioligands with PET accurately quantify TSPO in neuroinflammatory conditions. However, the existence of three human TSPO genotypes that show differential affinity to almost all useful TSPO PET radioligands hampers such studies. There is an unmet need for genotype-insensitive, high-affinity, and moderately lipophilic TSPO ligands that may serve as leads for PET radioligand development. To address this need, we varied the known high-affinity TSPO ligand (l)-N,N-diethyl-2-methyl-3-(2-phenylquinolin-4-yl)propanamide in its aryl scaffold, side chain tether, and pendant substituted amido group while retaining an N-methyl group as a site for labeling with carbon-11. From this effort, oxygen-tethered N-methyl-aryloxypropanamides emerged as new high-affinity TSPO ligands with attenuated lipophilicity, including one example with attractive properties for PET radioligand development, namely N-methyl-N-phenyl-2-{[2-(pyridin-2-yl)quinolin-4-yl]oxy}propanamide (22a; rat K-i = 0.10 nM; human TSPO genotypes K-i = 1.4 nM; clogD = 4.18). C1 [Brouwer, Chad; Jenko, Kimberly; Zoghbi, Sami S.; Innis, Robert B.; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Pike, VW (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Room B3 C346A,10 Ctr Dr, Bethesda, MD 20892 USA. EM pikev@mail.nih.gov FU National Institutes of Health (NIH), National Institute of Mental Health FX This study was supported by the Intramural Research Program of the National Institutes of Health (NIH), specifically the National Institute of Mental Health. We thank the NIH PET Department for radioisotope production. NR 62 TC 7 Z9 7 U1 0 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD JUL 24 PY 2014 VL 57 IS 14 BP 6240 EP 6251 DI 10.1021/jm5007947 PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AM0MX UT WOS:000339540800031 PM 24949670 ER PT J AU Bhirde, AA Hassan, SA Harr, E Chen, XY AF Bhirde, Ashwinkumar A. Hassan, Sergio A. Harr, Erick Chen, Xiaoyuan TI Role of Albumin in the Formation and Stabilization of Nanoparticle Aggregates in Serum Studied by Continuous Photon Correlation Spectroscopy and Multiscale Computer Simulations SO JOURNAL OF PHYSICAL CHEMISTRY C LA English DT Article ID GOLD NANOPARTICLES; PROTEIN CORONA; LIGHT-SCATTERING; PREDICTION; SURFACES; PROGRAM; DENSITY; FORCES AB Recently, small (<5 nm diameter) nanoparticles (NPs) have shown improved in vivo biocompatibility compared to that of larger (>10 nm) NPs. However, the fate of small NPs under physiological conditions is poorly understood and remains unexplored. Here, the long-term aggregation behavior of gold nanoparticles (AuNPs) exposed to serum proteins in a near-physiological setup is studied using continuous photon correlation spectroscopy and computer simulations. It is found that the medium, temperature, and NP concentration affect the aggregation of AuNPs, but the observed aggregates are much smaller than previously reported. Simulations show that a single layer of albumin is deposited on the NP surface, but the properties of the aggregates (size, shape, and internal structure) depend critically on the charge distribution on the proteins, which changes with the conditions of the solution. These results explain the seemingly conflicting data reported in the literature regarding the size of aggregates and the morphology of the albumin corona. The simulations suggest that controlling the concentration of NPs as well as the pH and ionic strength of the solution prior to intravenous administration may help to preserve properties of the functionalized NPs in the bloodstream. C1 [Bhirde, Ashwinkumar A.; Harr, Erick; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, Bethesda, MD 20892 USA. [Hassan, Sergio A.] NIH, Ctr Mol Modeling, Div Computat Biosci, CIT, Bethesda, MD 20892 USA. RP Hassan, SA (reprint author), NIH, Ctr Mol Modeling, Div Computat Biosci, CIT, Bldg 10, Bethesda, MD 20892 USA. EM hassan@mail.nih.gov; shawn.chen@nih.gov FU National Institute of Biomedical Imaging and Bioengineering (NIBIB); Center for Information Technology at the National Institutes of Health (NIH); NIH-NIBIB/NIST NRC FX This study utilized the high-performance computer capabilities of the Biowulf PC/Linux cluster at the NIH. This work was supported, in part, by the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), and Center for Information Technology at the National Institutes of Health (NIH). A.B. was supported by a postdoctoral fellowship from NIH-NIBIB/NIST NRC. The authors thank Peter Steinbach for reading the manuscript. NR 44 TC 6 Z9 6 U1 3 U2 25 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1932-7447 J9 J PHYS CHEM C JI J. Phys. Chem. C PD JUL 24 PY 2014 VL 118 IS 29 BP 16199 EP 16208 DI 10.1021/jp5034068 PG 10 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA AM0MW UT WOS:000339540700072 PM 25221633 ER PT J AU Ripke, S Neale, BM Corvin, A Walters, JTR Farh, KH Holmans, PA Lee, P Bulik-Sullivan, B Collier, DA Huang, HL Pers, TH Agartz, I Agerbo, E Albus, M Alexander, M Amin, F Bacanu, SA Begemann, M Belliveau, RA Bene, J Bergen, SE Bevilacqua, E Bigdeli, TB Black, DW Bruggeman, R Buccola, NG Buckner, RL Byerley, W Cahn, W Cai, GQ Campion, D Cantor, RM Carr, VJ Carrera, N Catts, SV Chambert, KD Chan, RCK Chen, RYL Chen, EYH Cheng, W Cheung, EFC Chong, SA Cloninger, CR Cohen, D Cohen, N Cormican, P Craddock, N Crowley, JJ Curtis, D Davidson, M Davis, KL Degenhardt, F Del Favero, J Demontis, D Dikeos, D Dinan, T Djurovic, S Donohoe, G Drapeau, E Duan, J Dudbridge, F Durmishi, N Eichhammer, P Eriksson, J Escott-Price, V Essioux, L Fanous, AH Farrell, MS Frank, J Franke, L Freedman, R Freimer, NB Friedl, M Friedman, JI Fromer, M Genovese, G Georgieva, L Giegling, I Giusti-Rodriguez, P Godard, S Goldstein, JI Golimbet, V Gopal, S Gratten, J de Haan, L Hammer, C Hamshere, ML Hansen, M Hansen, T Haroutunian, V Hartmann, AM Henskens, FA Herms, S Hirschhorn, JN Hoffmann, P Hofman, A Hollegaard, MV Hougaard, DM Ikeda, M Joa, I Julia, A Kahn, RS Kalaydjieva, L Karachanak-Yankova, S Karjalainen, J Kavanagh, D Keller, MC Kennedy, JL Khrunin, A Kim, Y Klovins, J Knowles, JA Konte, B Kucinskas, V Kucinskiene, ZA Kuzelova-Ptackova, H Kahler, AK Laurent, C Keong, JLC Lee, SH Legge, SE Lerer, B Li, MX Li, T Liang, KY Lieberman, J Limborska, S Loughland, CM Lubinski, J Lonnqvist, J Macek, M Magnusson, PKE Maher, BS Maier, W Mallet, J Marsal, S Mattheisen, M Mattingsdal, M McCarley, RW McDonald, C McIntosh, AM Meier, S Meijer, CJ Melegh, B Melle, I Mesholam-Gately, RI Metspalu, A Michie, PT Milani, L Milanova, V Mokrab, Y Morris, DW Mors, O Murphy, KC Murray, RM Myin-Germeys, I Muller-Myhsok, B Nelis, M Nenadic, I Nertney, DA Nestadt, G Nicodemus, KK Nikitina-Zake, L Nisenbaum, L Nordin, A O'Callaghan, E O'Dushlaine, C O'Neill, FA Oh, SY Olincy, A Olsen, L Van Os, J Pantelis, C Papadimitriou, GN Papiol, S Parkhomenko, E Pato, MT Paunio, T Pejovic-Milovancevic, M Perkins, DO Pietilainen, O Pimm, J Pocklington, AJ Powell, J Price, A Pulver, AE Purcell, SM Quested, D Rasmussen, HB Reichenberg, A Reimers, MA Richards, AL Roffman, JL Roussos, P Ruderfer, DM Salomaa, V Sanders, AR Schall, U Schubert, CR Schulze, TG Schwab, SG Scolnick, EM Scott, RJ Seidman, LJ Shi, JX Sigurdsson, E Silagadze, T Silverman, JM Sim, K Slominsky, P Smoller, JW So, HC Spencer, CCA Stahl, EA Stefansson, H Steinberg, S Stogmann, E Straub, RE Strengman, E Strohmaier, J Stroup, TS Subramaniam, M Suvisaari, J Svrakic, DM Szatkiewicz, JP Soderman, E Thirumalai, S Toncheva, D Tosato, S Veijola, J Waddington, J Walsh, D Wang, D Wang, Q Webb, BT Weiser, M Wildenauer, DB Williams, NM Williams, S Witt, SH Wolen, AR Wong, EHM Wormley, BK Xi, HS Zai, CC Zheng, XB Zimprich, F Wray, NR Stefansson, K Visscher, PM Adolfsson, R Andreassen, OA Blackwood, DHR Bramon, E Buxbaum, JD Borglum, AD Cichon, S Darvasi, A Domenici, E Ehrenreich, H Esko, T Gejman, PV Gill, M Gurling, H Hultman, CM Iwata, N Jablensky, AV Jonsson, EG Kendler, KS Kirov, G Knight, J Lencz, T Levinson, DF Li, QQS Liu, JJ Malhotra, AK McCarroll, SA McQuillin, A Moran, JL Mortensen, PB Mowry, BJ Nothen, MM Ophoff, RA Owen, MJ Palotie, A Pato, CN Petryshen, TL Posthuma, D Rietschel, M Riley, BP Rujescu, D Sham, PC Sklar, P St Clair, D Weinberger, DR Wendland, JR Werge, T Daly, MJ Sullivan, PF O'Donovan, MC AF Ripke, Stephan Neale, Benjamin M. Corvin, Aiden Walters, James T. R. Farh, Kai-How Holmans, Peter A. Lee, Phil Bulik-Sullivan, Brendan Collier, David A. Huang, Hailiang Pers, Tune H. Agartz, Ingrid Agerbo, Esben Albus, Margot Alexander, Madeline Amin, Farooq Bacanu, Silviu A. Begemann, Martin Belliveau, Richard A., Jr. Bene, Judit Bergen, Sarah E. Bevilacqua, Elizabeth Bigdeli, Tim B. Black, Donald W. Bruggeman, Richard Buccola, Nancy G. Buckner, Randy L. Byerley, William Cahn, Wiepke Cai, Guiqing Campion, Dominique Cantor, Rita M. Carr, Vaughan J. Carrera, Noa Catts, Stanley V. Chambert, Kimberly D. Chan, Raymond C. K. Chen, Ronald Y. L. Chen, Eric Y. H. Cheng, Wei Cheung, Eric F. C. Chong, Siow Ann Cloninger, C. Robert Cohen, David Cohen, Nadine Cormican, Paul Craddock, Nick Crowley, James J. Curtis, David Davidson, Michael Davis, Kenneth L. Degenhardt, Franziska Del Favero, Jurgen Demontis, Ditte Dikeos, Dimitris Dinan, Timothy Djurovic, Srdjan Donohoe, Gary Drapeau, Elodie Duan, Jubao Dudbridge, Frank Durmishi, Naser Eichhammer, Peter Eriksson, Johan Escott-Price, Valentina Essioux, Laurent Fanous, Ayman H. Farrell, Martilias S. Frank, Josef Franke, Lude Freedman, Robert Freimer, Nelson B. Friedl, Marion Friedman, Joseph I. Fromer, Menachem Genovese, Giulio Georgieva, Lyudmila Giegling, Ina Giusti-Rodriguez, Paola Godard, Stephanie Goldstein, Jacqueline I. Golimbet, Vera Gopal, Srihari Gratten, Jacob de Haan, Lieuwe Hammer, Christian Hamshere, Marian L. Hansen, Mark Hansen, Thomas Haroutunian, Vahram Hartmann, Annette M. Henskens, Frans A. Herms, Stefan Hirschhorn, Joel N. Hoffmann, Per Hofman, Andrea Hollegaard, Mads V. Hougaard, David M. Ikeda, Masashi Joa, Inge Julia, Antonio Kahn, Rene S. Kalaydjieva, Luba Karachanak-Yankova, Sena Karjalainen, Juha Kavanagh, David Keller, Matthew C. Kennedy, James L. Khrunin, Andrey Kim, Yunjung Klovins, Janis Knowles, James A. Konte, Bettina Kucinskas, Vaidutis Kucinskiene, Zita Ausrele Kuzelova-Ptackova, Hana Kahler, Anna K. Laurent, Claudine Keong, Jimmy Lee Chee Lee, S. Hong Legge, Sophie E. Lerer, Bernard Li, Miaoxin Li, Tao Liang, Kung-Yee Lieberman, Jeffrey Limborska, Svetlana Loughland, Carmel M. Lubinski, Jan Lonnqvist, Jouko Macek, Milan, Jr. Magnusson, Patrik K. E. Maher, Brion S. Maier, Wolfgang Mallet, Jacques Marsal, Sara Mattheisen, Manuel Mattingsdal, Morten McCarley, Robert W. McDonald, Colm McIntosh, Andrew M. Meier, Sandra Meijer, Carin J. Melegh, Bela Melle, Ingrid Mesholam-Gately, Raquelle I. Metspalu, Andres Michie, Patricia T. Milani, Lili Milanova, Vihra Mokrab, Younes Morris, Derek W. Mors, Ole Murphy, Kieran C. Murray, Robin M. Myin-Germeys, Inez Mueller-Myhsok, Bertram Nelis, Mari Nenadic, Igor Nertney, Deborah A. Nestadt, Gerald Nicodemus, Kristin K. Nikitina-Zake, Liene Nisenbaum, Laura Nordin, Annelie O'Callaghan, Eadbhard O'Dushlaine, Colm O'Neill, F. Anthony Oh, Sang-Yun Olincy, Ann Olsen, Line Van Os, Jim Pantelis, Christos Papadimitriou, George N. Papiol, Sergi Parkhomenko, Elena Pato, Michele T. Paunio, Tiina Pejovic-Milovancevic, Milica Perkins, Diana O. Pietilainen, Olli Pimm, Jonathan Pocklington, Andrew J. Powell, John Price, Alkes Pulver, Ann E. Purcell, Shaun M. Quested, Digby Rasmussen, Henrik B. Reichenberg, Abraham Reimers, Mark A. Richards, Alexander L. Roffman, Joshua L. Roussos, Panos Ruderfer, Douglas M. Salomaa, Veikko Sanders, Alan R. Schall, Ulrich Schubert, Christian R. Schulze, Thomas G. Schwab, Sibylle G. Scolnick, Edward M. Scott, Rodney J. Seidman, Larry J. Shi, Jianxin Sigurdsson, Engilbert Silagadze, Teimuraz Silverman, Jeremy M. Sim, Kang Slominsky, Petr Smoller, Jordan W. So, Hon-Cheong Spencer, Chris C. A. Stahl, Eli A. Stefansson, Hreinn Steinberg, Stacy Stogmann, Elisabeth Straub, Richard E. Strengman, Eric Strohmaier, Jana Stroup, T. Scott Subramaniam, Mythily Suvisaari, Jaana Svrakic, Dragan M. Szatkiewicz, Jin P. Soderman, Erik Thirumalai, Srinivas Toncheva, Draga Tosato, Sarah Veijola, Juha Waddington, John Walsh, Dermot Wang, Dai Wang, Qiang Webb, Bradley T. Weiser, Mark Wildenauer, Dieter B. Williams, Nigel M. Williams, Stephanie Witt, Stephanie H. Wolen, Aaron R. Wong, Emily H. M. Wormley, Brandon K. Xi, Hualin Simon Zai, Clement C. Zheng, Xuebin Zimprich, Fritz Wray, Naomi R. Stefansson, Kari Visscher, Peter M. Adolfsson, Rolf Andreassen, Ole A. Blackwood, Douglas H. R. Bramon, Elvira Buxbaum, Joseph D. Borglum, Anders D. Cichon, Sven Darvasi, Ariel Domenici, Enrico Ehrenreich, Hannelore Esko, Tonu Gejman, Pablo V. Gill, Michael Gurling, Hugh Hultman, Christina M. Iwata, Nakao Jablensky, Assen V. Jonsson, Erik G. Kendler, Kenneth S. Kirov, George Knight, Jo Lencz, Todd Levinson, Douglas F. Li, Qingqin S. Liu, Jianjun Malhotra, Anil K. McCarroll, Steven A. McQuillin, Andrew Moran, Jennifer L. Mortensen, Preben B. Mowry, Bryan J. Noethen, Markus M. Ophoff, Roel A. Owen, Michael J. Palotie, Aarno Pato, Carlos N. Petryshen, Tracey L. Posthuma, Danielle Rietschel, Marcella Riley, Brien P. Rujescu, Dan Sham, Pak C. Sklar, Pamela St Clair, David Weinberger, Daniel R. Wendland, Jens R. Werge, Thomas Daly, Mark J. Sullivan, Patrick F. O'Donovan, Michael C. CA Psychiat Genomics Consortium Psychosis Endophenotypes Int Conso Wellcome Trust Case-Control Consor TI Biological insights from 108 schizophrenia-associated genetic loci SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; COMMON VARIANTS; PSYCHIATRIC-DISORDERS; BIPOLAR DISORDER; CONFERRING RISK; DISEASE; IDENTIFICATION; METAANALYSIS; MUTATIONS; FRAMEWORK AB Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia. C1 [Ripke, Stephan; Neale, Benjamin M.; Farh, Kai-How; Lee, Phil; Bulik-Sullivan, Brendan; Huang, Hailiang; Fromer, Menachem; Goldstein, Jacqueline I.; Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Ripke, Stephan; Neale, Benjamin M.; Lee, Phil; Bulik-Sullivan, Brendan; Belliveau, Richard A., Jr.; Bergen, Sarah E.; Bevilacqua, Elizabeth; Chambert, Kimberly D.; Fromer, Menachem; Genovese, Giulio; O'Dushlaine, Colm; Scolnick, Edward M.; Smoller, Jordan W.; McCarroll, Steven A.; Moran, Jennifer L.; Palotie, Aarno; Petryshen, Tracey L.; Daly, Mark J.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Neale, Benjamin M.; Huang, Hailiang; Pers, Tune H.; Goldstein, Jacqueline I.; Hirschhorn, Joel N.; Price, Alkes; Stahl, Eli A.; Esko, Tonu; Daly, Mark J.] Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA 02142 USA. [Neale, Benjamin M.; Lee, Phil; Fromer, Menachem; Smoller, Jordan W.; Palotie, Aarno] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Corvin, Aiden; Cormican, Paul; Donohoe, Gary; Morris, Derek W.; Gill, Michael] Univ Ireland Trinity Coll, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin 8, Ireland. [Walters, James T. R.; Holmans, Peter A.; Carrera, Noa; Craddock, Nick; Escott-Price, Valentina; Georgieva, Lyudmila; Hamshere, Marian L.; Kavanagh, David; Legge, Sophie E.; Pocklington, Andrew J.; Richards, Alexander L.; Ruderfer, Douglas M.; Williams, Nigel M.; Kirov, George; Owen, Michael J.; O'Donovan, Michael C.] Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Genom, Inst Psychol Med & Clin Neurosci, Cardiff CF24 4HQ, S Glam, Wales. [Holmans, Peter A.; Craddock, Nick; Owen, Michael J.; O'Donovan, Michael C.] Cardiff Univ, Natl Ctr Mental Hlth, Cardiff CF24 4HQ, S Glam, Wales. [Collier, David A.; Mokrab, Younes] Eli Lilly & Co Ltd, Erl Wood Manor, Windlesham GU20 6PH, Surrey, England. [Collier, David A.] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London SE5 8AF, England. [Pers, Tune H.] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Pers, Tune H.; Hirschhorn, Joel N.; Esko, Tonu] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Pers, Tune H.; Hirschhorn, Joel N.; Esko, Tonu] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA. [Agartz, Ingrid; Soderman, Erik; Jonsson, Erik G.] Karolinska Inst, Psychiat Sect, Dept Clin Neurosci, SE-17176 Stockholm, Sweden. [Agartz, Ingrid] Diakonhjemmet Hosp, Dept Psychiat, N-0319 Oslo, Norway. [Agartz, Ingrid; Djurovic, Srdjan; Mattingsdal, Morten; Melle, Ingrid; Andreassen, Ole A.; Jonsson, Erik G.] Univ Oslo, Inst Clin Med, KG Jebsen Ctr Psychosis Res, NORMENT, N-0424 Oslo, Norway. [Agerbo, Esben; Mortensen, Preben B.] Aarhus Univ, CIRRAU, Ctr Integrat Register Based Res, DK-8210 Aarhus, Denmark. [Agerbo, Esben; Mortensen, Preben B.] Aarhus Univ, Natl Ctr Register Based Res, DK-8210 Aarhus, Denmark. [Agerbo, Esben; Demontis, Ditte; Hansen, Thomas; Mattheisen, Manuel; Mors, Ole; Olsen, Line; Rasmussen, Henrik B.; Borglum, Anders D.; Mortensen, Preben B.; Werge, Thomas] Lundbeck Fdn Initiat Integrat Psychiat Res, iPSYCH, Aarhus, Denmark. [Albus, Margot] State Mental Hosp, D-85540 Haar, Germany. [Alexander, Madeline; Laurent, Claudine; Levinson, Douglas F.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Amin, Farooq] Atlanta Vet Affairs Med Ctr, Dept Psychiat & Behav Sci, Atlanta, GA 30033 USA. [Amin, Farooq] Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. [Bacanu, Silviu A.; Bigdeli, Tim B.; Webb, Bradley T.; Wormley, Brandon K.] Virginia Commonwealth Univ, Dept Psychiat, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23298 USA. [Begemann, Martin; Hammer, Christian; Papiol, Sergi; Ehrenreich, Hannelore] Max Planck Inst Expt Med, D-37075 Gottingen, Germany. [Bene, Judit; Melegh, Bela] Univ Pecs, Dept Med Genet, H-7624 Pecs, Hungary. [Bene, Judit; Melegh, Bela] Univ Pecs, Szentagothai Res Ctr, H-7624 Pecs, Hungary. [Bergen, Sarah E.; Kahler, Anna K.; Magnusson, Patrik K. E.; Hultman, Christina M.; Sullivan, Patrick F.] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Black, Donald W.] Univ Iowa, Carver Coll Med, Dept Psychiat, Iowa City, IA 52242 USA. [Bruggeman, Richard] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9700 RB Groningen, Netherlands. [Buccola, Nancy G.] Louisiana State Univ, Hlth Sci Ctr, Sch Nursing, New Orleans, LA 70112 USA. 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[Campion, Dominique] INSERM, U1079, Fac Med, F-76301 Rouen, France. [Cantor, Rita M.; Ophoff, Roel A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Carr, Vaughan J.; Catts, Stanley V.; Henskens, Frans A.; Loughland, Carmel M.; Michie, Patricia T.; Pantelis, Christos; Schall, Ulrich; Scott, Rodney J.; Jablensky, Assen V.] Schizophrenia Res Inst, Sydney, NSW 2010, Australia. [Carr, Vaughan J.] Univ New S Wales, Sch Psychiat, Sydney, NSW 2031, Australia. [Catts, Stanley V.] Univ Queensland, Royal Brisbane & Womens Hosp, St Lucia, Qld 4072, Australia. [Chan, Raymond C. K.] Chinese Acad Sci, Inst Psychol, Beijing 100101, Peoples R China. [Chen, Ronald Y. L.; Chen, Eric Y. H.; Li, Miaoxin; So, Hon-Cheong; Wong, Emily H. M.; Sham, Pak C.] Univ Hong Kong, Li Ka Shing Fac Med, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China. [Chen, Eric Y. H.; Li, Miaoxin; Sham, Pak C.] Univ Hong Kong, Li Ka Shing Fac Med, State Key Lab Brain & Cognit Sci, Hong Kong, Hong Kong, Peoples R China. [Cheng, Wei] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27514 USA. [Cheung, Eric F. C.] Castle Peak Hosp, Hong Kong, Hong Kong, Peoples R China. [Chong, Siow Ann; Keong, Jimmy Lee Chee; Sim, Kang; Subramaniam, Mythily] Inst Mental Hlth, Singapore 539747, Singapore. [Cloninger, C. Robert; Svrakic, Dragan M.] Washington Univ, Dept Psychiat, St Louis, MO 63110 USA. [Cohen, David] Assistance Publ Hop Paris, Dept Child & Adolescent Psychiat, Pierre & Marie Curie Fac Med, F-75013 Paris, France. [Cohen, David] Inst Intelligent Syst & Robot, F-75013 Paris, France. [Cohen, Nadine] Blue Note Biosci, Princeton, NJ 08540 USA. [Crowley, James J.; Farrell, Martilias S.; Giusti-Rodriguez, Paola; Kim, Yunjung; Szatkiewicz, Jin P.; Williams, Stephanie; Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. 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[Dikeos, Dimitris; Papadimitriou, George N.] Univ Athens, Sch Med, Dept Psychiat 1, Athens 11528, Greece. [Dinan, Timothy] Univ Coll Cork, Dept Psychiat, Cork, Ireland. [Djurovic, Srdjan] Oslo Univ Hosp, Dept Med Genet, N-0424 Oslo, Norway. [Donohoe, Gary; Morris, Derek W.] Natl Univ Ireland Galway, Cognit Genet & Therapy Grp, Sch Psychol, Galway, Ireland. [Donohoe, Gary; Morris, Derek W.] Natl Univ Ireland Galway, Discipline Biochem, Galway, Ireland. [Duan, Jubao; Sanders, Alan R.; Gejman, Pablo V.] Univ Chicago, Dept Psychiat & Behav Neurosci, Chicago, IL 60637 USA. [Duan, Jubao; Sanders, Alan R.; Gejman, Pablo V.] NorthShore Univ HealthSyst, Dept Psychiat & Biobehav Sci, Evanston, IL 60201 USA. [Dudbridge, Frank] Univ London London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1E 7HT, England. [Durmishi, Naser] Univ Clin Psychiat, Dept Child & Adolescent Psychiat, Skopje 1000, Macedonia. [Eichhammer, Peter] Univ Regensburg, Dept Psychiat, D-93053 Regensburg, Germany. [Eriksson, Johan] Univ Helsinki, Cent Hosp, Dept Gen Practice, FI-00014 Helsinki, Finland. [Eriksson, Johan] Folkhalsan Res Ctr, Helsinki, Finland. [Eriksson, Johan] Biomedicum Helsinki 1, FI-00290 Helsinki, Finland. [Eriksson, Johan; Salomaa, Veikko] Natl Inst Hlth & Welf, FI-00271 Helsinki, Finland. [Essioux, Laurent] F Hoffmann La Roche & Co Ltd, Pharma Res & Early Dev, Translat Technol & Bioinformat, CH-4070 Basel, Switzerland. [Fanous, Ayman H.] Georgetown Univ, Sch Med, Dept Psychiat, Washington, DC 20057 USA. [Fanous, Ayman H.] Univ So Calif, Keck Sch Med, Dept Psychiat, Los Angeles, CA 90033 USA. [Fanous, Ayman H.] Virginia Commonwealth Univ, Sch Med, Dept Psychiat, Richmond, VA 23298 USA. [Fanous, Ayman H.] Washington VA Med Ctr, Washington, DC 20422 USA. [Frank, Josef; Meier, Sandra; Schulze, Thomas G.; Strohmaier, Jana; Witt, Stephanie H.; Rietschel, Marcella] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, D-68159 Mannheim, Germany. [Franke, Lude; Karjalainen, Juha] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. [Freedman, Robert; Olincy, Ann] Univ Colorado Denver, Dept Psychiat, Aurora, CO 80045 USA. [Freimer, Nelson B.; Ophoff, Roel A.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Ctr Neurobehav Genet, Los Angeles, CA 90095 USA. [Friedl, Marion; Giegling, Ina; Hartmann, Annette M.; Konte, Bettina; Rujescu, Dan] Univ Halle Wittenberg, Dept Psychiat, D-06112 Halle, Germany. [Fromer, Menachem; Purcell, Shaun M.; Roussos, Panos; Ruderfer, Douglas M.; Stahl, Eli A.; Sklar, Pamela] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY USA. [Giegling, Ina; Rujescu, Dan] Univ Munich, Dept Psychiat, D-80336 Munich, Germany. [Godard, Stephanie] Hop La Pitie Salpetriere, Dept Psychiat, INSERM, Inst Myol, F-75013 Paris, France. [Godard, Stephanie] Hop La Pitie Salpetriere, Dept Human & Mol Genet, INSERM, Inst Myol, F-75013 Paris, France. [Golimbet, Vera] Russian Acad Med Sci, Mental Hlth Res Ctr, Moscow 115522, Russia. [Gopal, Srihari; Wang, Dai; Li, Qingqin S.] Janssen Res & Dev, Neurosci Therapeut Area, Raritan, NJ 08869 USA. [Gratten, Jacob; Lee, S. Hong; Wray, Naomi R.; Visscher, Peter M.; Mowry, Bryan J.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. [de Haan, Lieuwe; Meijer, Carin J.] Univ Amsterdam, Acad Med Ctr, Dept Psychiat, NL-1105 AZ Amsterdam, Netherlands. [Hansen, Mark] Illumina, La Jolla, CA 92122 USA. [Hansen, Thomas; Olsen, Line; Rasmussen, Henrik B.; Werge, Thomas] Mental Hlth Serv Copenhagen, Mental Hlth Ctr Sct Hans, Inst Biol Psychiat, DK-4000 Roskilde, Denmark. 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[Julia, Antonio; Marsal, Sara] Vall dHebron Res Inst, Rheumatol Res Grp, Barcelona 08035, Spain. [Kalaydjieva, Luba] Univ Western Australia, Ctr Med Res, Perth, WA 6009, Australia. [Kalaydjieva, Luba; Jablensky, Assen V.] Univ Western Australia, Perkins Inst Med Res, Perth, WA 6009, Australia. [Karachanak-Yankova, Sena; Toncheva, Draga] Med Univ, Dept Med Genet, Sofia 1431, Bulgaria. [Keller, Matthew C.] Univ Colorado, Dept Psychol, Boulder, CO 80309 USA. [Kennedy, James L.; Zai, Clement C.; Knight, Jo] Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Res Inst, Toronto, ON M5T 1R8, Canada. [Kennedy, James L.; Zai, Clement C.; Knight, Jo] Univ Toronto, Dept Psychiat, Toronto, ON M5T 1R8, Canada. [Kennedy, James L.; Knight, Jo] Univ Toronto, Inst Med Sci, Toronto, ON M5S 1A8, Canada. [Khrunin, Andrey; Limborska, Svetlana; Slominsky, Petr] Russian Acad Sci, Inst Mol Genet, Moscow 123182, Russia. 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[Li, Miaoxin; Sham, Pak C.] Univ Hong Kong, Ctr Genom Sci, Hong Kong, Hong Kong, Peoples R China. [Li, Tao; Wang, Qiang] Sichuan Univ, Mental Hlth Ctr, Chengdu 610041, Sichuan, Peoples R China. [Li, Tao; Wang, Qiang] Sichuan Univ, West China Hosp, Psychiat Lab, Chengdu 610041, Sichuan, Peoples R China. [Liang, Kung-Yee] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Lieberman, Jeffrey; Stroup, T. Scott] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. [Loughland, Carmel M.; Schall, Ulrich] Univ Newcastle, Prior Ctr Translat Neurosci & Mental Hlth, Newcastle, NSW 2300, Australia. [Lubinski, Jan] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, PL-70453 Szczecin, Poland. [Lonnqvist, Jouko; Suvisaari, Jaana] Natl Inst Hlth & Welf, Dept Mental Hlth & Subst Abuse Serv, FI-00271 Helsinki, Finland. [Maher, Brion S.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD 21205 USA. [Maier, Wolfgang] Univ Bonn, Dept Psychiat, D-53127 Bonn, Germany. [Mallet, Jacques] Hop La Pitie Salpetriere, CNRS, Lab Genet Mol Neurotransmiss & Proc Neurodegenera, F-75013 Paris, France. [Mattheisen, Manuel] Univ Bonn, Dept Genom Math, D-53127 Bonn, Germany. [Mattingsdal, Morten] Sorlandet Hosp, Res Unit, N-4604 Kristiansand, Norway. [McCarley, Robert W.; Mesholam-Gately, Raquelle I.; Seidman, Larry J.; Petryshen, Tracey L.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [McCarley, Robert W.] VA Boston Hlth Care Syst, Brockton, MA 02301 USA. [McDonald, Colm] Natl Univ Ireland Galway, Dept Psychiat, Galway, Ireland. [McIntosh, Andrew M.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH16 4SB, Midlothian, Scotland. [McIntosh, Andrew M.; Blackwood, Douglas H. R.] Univ Edinburgh, Div Psychiat, Edinburgh EH16 4SB, Midlothian, Scotland. [Melle, Ingrid; Andreassen, Ole A.] Oslo Univ Hosp, Div Mental Hlth & Addict, N-0424 Oslo, Norway. [Mesholam-Gately, Raquelle I.; Seidman, Larry J.] Beth Israel Deaconess Med Ctr, Publ Psychiat Div, Massachusetts Mental Hlth Ctr, Boston, MA 02114 USA. [Metspalu, Andres; Milani, Lili; Nelis, Mari; Esko, Tonu] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Michie, Patricia T.] Univ Newcastle, Sch Psychol, Callaghan, NSW 2308, Australia. [Milanova, Vihra] Med Univ, Psychiat Clin 1, Sofia 1431, Bulgaria. [Mors, Ole; Borglum, Anders D.] Aarhus Univ Hosp, Dept P, DK-8240 Risskov, Denmark. [Murphy, Kieran C.] Royal Coll Surgeons Ireland, Dept Psychiat, Dublin 2, Ireland. [Murray, Robin M.; Powell, John] Kings Coll London, London SE5 8AF, England. [Myin-Germeys, Inez; Van Os, Jim] Maastricht Univ, Med Ctr, South Limburg Mental Hlth Res & Teaching Network, EURON, NL-6229 HX Maastricht, Netherlands. [Mueller-Myhsok, Bertram] Univ Liverpool, Inst Translat Med, Liverpool L69 3BX, Merseyside, England. [Mueller-Myhsok, Bertram] Max Planck Inst Psychiat, D-80336 Munich, Germany. [Mueller-Myhsok, Bertram] Munich Cluster Syst Neurol SyNergy, D-80336 Munich, Germany. [Nenadic, Igor] Jena Univ Hosp, Dept Psychiat & Psychotherapy, D-07743 Jena, Germany. [Nertney, Deborah A.] Univ Queensland, Queensland Brain Inst, Dept Psychiat, St Lucia, Qld 4072, Australia. [Nertney, Deborah A.] Univ Queensland, Queensland Ctr Mental Hlth Res, St Lucia, Qld 4072, Australia. [Nestadt, Gerald; Pulver, Ann E.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Nicodemus, Kristin K.] Univ Dublin Trinity Coll, Dept Psychiat, Dublin 2, Ireland. [Nisenbaum, Laura] Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA. [Nordin, Annelie; Adolfsson, Rolf] Umea Univ, Dept Clin Sci, SE-90187 Umea, Sweden. [O'Callaghan, Eadbhard] DETECT Early Intervent Serv Psychosis, Blackrock, Dublin, Ireland. [O'Neill, F. Anthony] Queens Univ Belfast, Inst Clin Sci, Ctr Publ Hlth, Belfast BT12 6AB, Antrim, North Ireland. 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[Reimers, Mark A.; Wolen, Aaron R.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23298 USA. [Roussos, Panos; Sklar, Pamela] Icahn Sch Med Mt Sinai, Inst Multiscale Biol, New York, NY 10029 USA. [Schubert, Christian R.; Wendland, Jens R.] Pfizer Worldwide Res & Dev, Pharma Therapeut Clin Res, Cambridge, MA 02139 USA. [Schulze, Thomas G.] Univ Gottingen, Dept Psychiat & Psychotherapy, D-37073 Gottingen, Germany. [Schwab, Sibylle G.] Univ Erlangen Nurnberg, Psychiat & Psychotherapy Clin, D-91054 Erlangen, Germany. [Scott, Rodney J.] Hunter New England Hlth Serv, Newcastle, NSW 2308, Australia. [Scott, Rodney J.] Univ Newcastle, Sch Biomed Sci, Newcastle, NSW 2308, Australia. [Shi, Jianxin] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Sigurdsson, Engilbert] Univ Iceland, Natl Univ Hosp, Landspitali, IS-101 Reykjavik, Iceland. [Silagadze, Teimuraz] Tbilisi State Med Univ TSMU, Dept Psychiat & Drug Addict, GE-0177 Tbilisi, Rep of Georgia. 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[Wildenauer, Dieter B.; Jablensky, Assen V.] Univ Western Australia, Sch Psychiat & Clin Neurosci, Perth, WA 6009, Australia. [Xi, Hualin Simon] Pfizer Worldwide Res & Dev, Computat Sci CoE, Cambridge, MA 02139 USA. [Zheng, Xuebin; Liu, Jianjun] ASTAR, Genome Inst Singapore, Singapore 138672, Singapore. [Bramon, Elvira] UCL, London WC1E 6BT, England. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Cichon, Sven] Res Ctr Juelich, Inst Neurosci & Med INM 1, D-52428 Julich, Germany. [Darvasi, Ariel] Hebrew Univ Jerusalem, Dept Genet, IL-91905 Jerusalem, Israel. [Domenici, Enrico] F Hoffmann La Roche & Co Ltd, Pharma Res & Early Dev, Neurosci Discovery & Translat Area, CH-4070 Basel, Switzerland. [Jablensky, Assen V.] Univ Western Australia, Sch Psychiat & Clin Neurosci, Ctr Clin Res Neuropsychiat, Perth, WA 6000, Australia. [Kendler, Kenneth S.; Riley, Brien P.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA 23298 USA. [Kendler, Kenneth S.; Riley, Brien P.] Virginia Commonwealth Univ, Dept Human & Mol Genet, Richmond, VA 23298 USA. [Lencz, Todd; Malhotra, Anil K.] Feinstein Inst Med Res, Manhasset, NY 11030 USA. [Lencz, Todd; Malhotra, Anil K.] Hofstra NS LIJ Sch Med, Hempstead, NY 11549 USA. [Lencz, Todd; Malhotra, Anil K.] Zucker Hillside Hosp, Glen Oaks, NY 11004 USA. [Liu, Jianjun] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117597, Singapore. [Mowry, Bryan J.] Univ Queensland, Queensland Ctr Mental Hlth Res, Brisbane, Qld 4076, Australia. [Petryshen, Tracey L.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Petryshen, Tracey L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Posthuma, Danielle] Erasmus Univ, Med Ctr, Dept Child & Adolescent Psychiat, NL-3000 Rotterdam, Netherlands. [Posthuma, Danielle] Vrije Univ Amsterdam, Med Ctr Amsterdam, Dept Complex Trait Genet, NL-1081 Amsterdam, Netherlands. [Posthuma, Danielle] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Funct Genom, NL-1081 Amsterdam, Netherlands. [St Clair, David] Univ Aberdeen, Inst Med Sci, Aberdeen AB25 2ZD, Scotland. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Inst Med Genet, Baltimore, MD 21205 USA. [Werge, Thomas] Univ Copenhagen, Dept Clin Med, DK-2200 Copenhagen, Denmark. RP O'Donovan, MC (reprint author), Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Genom, Inst Psychol Med & Clin Neurosci, Cardiff CF24 4HQ, S Glam, Wales. EM odonovanmc@cardiff.ac.uk RI McQuillin, Andrew/C-1623-2008; Magnusson, Patrik/C-4458-2017; Wray, Naomi/C-8639-2015; SCHALL, ULRICH/G-7452-2013; Mattheisen, Manuel/B-4949-2012; Catts, Stanley/G-6917-2013; Slominsky, Petr/B-4640-2016; So, Hon-Cheong/I-1100-2016; Pantelis, Christos/H-7722-2014; Domenici, Enrico/K-8194-2016; Ruderfer, Douglas/M-5795-2016; Roussos, Panos/J-7090-2013; Franke, Lude/P-7036-2016; Karjalainen, Juha/P-8624-2016; Lencz, Todd/J-3418-2014; Myin-Germeys, Inez /L-5106-2014; McDonald, Colm/C-1430-2009; McCarley, Robert/N-5562-2014; Jablensky, Assen/H-5116-2014; Lee, Sang Hong/A-2569-2011; Powell, John/G-4412-2011; Hansen, Thomas/O-5965-2014; Agerbo, Esben /A-2645-2012; Holmans, Peter/F-4518-2015; Mortensen, Preben /F-6758-2015; Hammer, Christian/C-5827-2014; Zai, Clement/G-7379-2015; Mortensen, Preben/D-2358-2015; Herms, Stefan/J-1949-2014; Stroup, Thomas/F-9188-2014; OI McQuillin, Andrew/0000-0003-1567-2240; Wray, Naomi/0000-0001-7421-3357; Bergen, Sarah/0000-0002-5888-0034; McCarroll, Steven/0000-0002-6954-8184; Buccola, Nancy/0000-0003-1378-4636; Stefansson, Hreinn/0000-0002-9331-6666; Corvin, Aiden/0000-0001-6717-4089; O'Donovan, Michael/0000-0001-7073-2379; Mattheisen, Manuel/0000-0002-8442-493X; Slominsky, Petr/0000-0003-3530-0655; Pantelis, Christos/0000-0002-9565-0238; Domenici, Enrico/0000-0001-7436-6919; Ruderfer, Douglas/0000-0002-2365-386X; Roussos, Panos/0000-0002-4640-6239; Franke, Lude/0000-0002-5159-8802; Lencz, Todd/0000-0001-8586-338X; McCarley, Robert/0000-0001-5705-7495; Lee, Sang Hong/0000-0001-9701-2718; Powell, John/0000-0001-6124-439X; Hansen, Thomas/0000-0001-6703-7762; Agerbo, Esben /0000-0002-2849-524X; Holmans, Peter/0000-0003-0870-9412; Mortensen, Preben /0000-0002-4782-1450; Hammer, Christian/0000-0003-4548-7548; Mortensen, Preben/0000-0002-5230-9865; Gratten, Jacob/0000-0003-1293-409X; Henskens, Frans/0000-0003-2358-5630; murray, robin/0000-0003-0829-0519; Visscher, Peter/0000-0002-2143-8760; Eriksson, Johan/0000-0002-2516-2060; Curtis, David/0000-0002-4089-9183; Knight, Joanne/0000-0002-7148-1660; McIntosh, Andrew/0000-0002-0198-4588; Dinan, Timothy/0000-0002-2316-7220; Goldstein, Jacqueline/0000-0003-1902-6916; Bruggeman, Richard/0000-0002-3238-8471; O'Neill, Francis Anthony/0000-0002-7531-7657; /0000-0002-8114-7615; Huang, Hailiang/0000-0003-1461-5762; Adolfsson, Rolf/0000-0001-9785-8473; Golimbet, Vera/0000-0002-9960-7114; Jonsson, Erik/0000-0001-8368-6332; Nothen, Markus/0000-0002-8770-2464; Donohoe, Gary/0000-0003-3037-7426; Webb, Bradley/0000-0002-0576-5366; Escott-Price, Valentina/0000-0003-1784-5483; Esko, Tonu/0000-0003-1982-6569; Murphy, Kieran/0000-0003-2930-4465; Julia Cano, Antonio/0000-0001-6064-3620; Moran, Jennifer/0000-0002-5664-4716; Walters, James/0000-0002-6980-4053; Suvisaari, Jaana/0000-0001-7167-0990; Buxbaum, Joseph/0000-0001-8898-8313; Agartz, Ingrid/0000-0002-9839-5391; Crowley, James/0000-0001-9051-1557; Golimbet, Vera/0000-0002-0114-4300; Herms, Stefan/0000-0002-2786-8200; Stroup, Thomas/0000-0002-3123-0672; Morris, Derek/0000-0002-3413-570X; Myin-Germeys, Inez/0000-0002-3731-4930; Andreassen, Ole A./0000-0002-4461-3568; Gill, Michael/0000-0003-0206-5337; Hollegaard, Mads Vilhelm/0000-0003-1061-0091 FU US National Institute of Mental Health [U01 MH094421] FX Core funding for the Psychiatric Genomics Consortium is from the US National Institute of Mental Health (U01 MH094421). We thank T. Lehner (NIMH). The work of the contributing groups was supported by numerous grants from governmental and charitable bodies as well as philanthropic donation. Details are provided in the Supplementary Notes. Membership of the Wellcome Trust Case Control Consortium and of the Psychosis Endophenotype International Consortium are provided in the Supplementary Notes. NR 50 TC 564 Z9 567 U1 50 U2 325 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUL 24 PY 2014 VL 511 IS 7510 BP 421 EP + DI 10.1038/nature13595 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL7SO UT WOS:000339335700037 ER PT J AU Chen, BYH Huang, CH Lin, YH Huang, CC Deng, CX Hsu, LC AF Chen, Bert Yu-Hung Huang, Cheng-Hsiang Lin, Ying-Hsi Huang, Ching-Chun Deng, Chu-Xia Hsu, Lih-Ching TI The K898E germline variant in the PP1-binding motif of BRCA1 causes defects in DNA Repair SO SCIENTIFIC REPORTS LA English DT Article ID NUCLEAR PHOSPHOPROTEIN; GENETIC INSTABILITY; TUMOR-SUPPRESSOR; BINDING DOMAIN; BREAST-CANCER; PROTEIN; HYPERSENSITIVITY; IDENTIFICATION; IRRADIATION; MUTATIONS AB BRCA1 is a phosphoprotein involved in many biological processes, including transcription, ubiquitination, checkpoint control, homologous recombination, and DNA repair. We have demonstrated that protein phosphatase 1 alpha (PP1 alpha) interacts with BRCA1 via a PP1-binding motif (KVTF901)-K-898, and can dephosphorylate multiple serine residues phosphorylated by checkpoint kinases. A K898E germline missense variant in the PP1-binding motif of BRCA1 has been found in an Ashkenazi patient and a non-Ashkenazi Argentinean patient with breast and ovarian cancer, but its clinical significance is still unknown. Here we report that the lysine residue in the PP1-binding motif of BRCA1 is highly conserved across many mammalian species. The K898E mutation interferes with the interaction between BRCA1 and PP1 alpha. Moreover, while the expression of wild-type BRCA1 in Brca1-deficient cells improved cell survival after DNA damage induced by ionizing radiation (IR), expression of BRCA1 K898E proved unable to enhance cell survival. DNA damage repair mechanisms remained defective in these BRCA1 K898E-reconstituted cells, as revealed by the comet assay and IR-induced Rad51 foci formation assay. These results reflect the significance of the interaction between BRCA1 and PP1, and indicate that the K898E variant may render carriers susceptible to DNA damage and malignant transformation. C1 [Chen, Bert Yu-Hung; Huang, Cheng-Hsiang; Lin, Ying-Hsi; Huang, Ching-Chun; Hsu, Lih-Ching] Natl Taiwan Univ, Coll Med, Sch Pharm, Taipei 10050, Taiwan. [Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Hsu, LC (reprint author), Natl Taiwan Univ, Coll Med, Sch Pharm, Taipei 10050, Taiwan. EM lhsu@ntu.edu.tw RI deng, chuxia/N-6713-2016; OI HSU, LIH-CHING/0000-0002-7816-3825 FU NCI [R01CA111436]; Taiwan National Science Council [97-2314-B-002-183-, 98-2320-B-002-055-]; National Taiwan University FX This study was supported by NCI Grant R01CA111436, Taiwan National Science Council grants 97-2314-B-002-183-and 98-2320-B-002-055-, and funds from the National Taiwan University (to L.C.H.). We would also like to acknowledge the National Taiwan University Hospital Sequencing Core Facility for providing DNA sequencing service. NR 26 TC 3 Z9 3 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 24 PY 2014 VL 4 AR 5812 DI 10.1038/srep05812 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL8WL UT WOS:000339420400003 PM 25056273 ER PT J AU Lim, JA Li, LS Raben, N AF Lim, Jeong-A Li, Lishu Raben, Nina TI Pompe disease: from pathophysiology to therapy and back again SO FRONTIERS IN AGING NEUROSCIENCE LA English DT Review DE autophagy; lysosome; Pompe disease; lipofuscin; enzyme replacement therapy ID ACID ALPHA-GLUCOSIDASE; ENZYME REPLACEMENT THERAPY; GLYCOGENOSIS TYPE-II; LYSOSOMAL STORAGE DISORDERS; SKELETAL-MUSCLE; MALTASE DEFICIENCY; GENE-THERAPY; MOUSE MODEL; AUTOPHAGIC DEGRADATION; GLOBULAR INCLUSIONS AB Pornpe disease is a lysosomal storage disorder in which acid alpha-glucosidase (GAA) is deficient or absent. Deficiency of this lysosomal enzyme results in progressive expansion of glycogen-filled lysosomes in multiple tissues, with cardiac and skeletal muscle being the most severely affected. The clinical spectrum ranges from fatal hypertrophic cardiomyopathy and skeletal muscle rnyopathy in infants to relatively attenuated forms, which manifest as a progressive myopathy without cardiac involvement. The currently available enzyme replacement therapy (ERT) proved to be successful in reversing cardiac but not skeletal muscle abnormalities. Although the overall understanding of the disease has progressed, the pathophysiology of muscle damage remains poorly understood. Lysosomal enlargement/rupture has long been considered a mechanism of relentless muscle damage in Pompe disease. In past years, it became clear that this simple view of the pathology is inadequate; the pathological cascade involves dysfunctional autophagy, a major lysosome-dependent intracellular degradative pathway. The autophagic process in Pornpe skeletal muscle is affected at the termination stage impaired autophagosomal-lysosomal fusion. Yet another abnormality in the diseased muscle is the accelerated production of large, unrelated to ageing, lipofuscin deposits a marker of cellular oxidative damage and a sign of mitochondrial dysfunction. The massive autophagic buildup and lipofuscin inclusions appear to cause a greater effect on muscle architecture than the enlarged lysosomes outside the autophagic regions. Furthermore, the dysfunctional autophagy affects the trafficking of the replacement enzyme and interferes with its delivery to the lysosomes. Several new therapeutic approaches have been tested in Pompe mouse models: substrate reduction therapy, lysosomal exocytosis following the overexpression of transcription factor EB and a closely related but distinct factor E3, and genetic manipulation of autophagy. C1 [Lim, Jeong-A; Li, Lishu; Raben, Nina] Natl Inst Arthritis & Musculoskeletal & Skin Dis, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Raben, N (reprint author), Natl Inst Arthritis & Musculoskeletal & Skin Dis, Lab Muscle Stem Cells & Gene Regulat, NIH, 50 South Dr,Bld 50 Room 1345, Bethesda, MD 20892 USA. EM rabenn@mail.nih.gov RI Li, Lishu /J-3191-2015 FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin diseases of the National Institutes of Health; CRADA; Acid Maltase Deficiency Association FX This research was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin diseases of the National Institutes of Health. Dr. Lim and Dr. Li are supported in part by a CRADA between NIH and Genzyme Corporation and by the Acid Maltase Deficiency Association. NR 137 TC 24 Z9 24 U1 0 U2 33 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1663-4365 J9 FRONT AGING NEUROSCI JI Front. Aging Neurosci. PD JUL 23 PY 2014 VL 6 AR 177 DI 10.3389/fnagi.2014.00177 PG 14 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA AN9AR UT WOS:000340898200001 PM 25183957 ER PT J AU Tovar-Moll, F de Oliveira-Souza, R Bramati, IE Zahn, R Cavanagh, A Tierney, M Moll, J Grafman, J AF Tovar-Moll, Fernanda de Oliveira-Souza, Ricardo Bramati, Ivanei Edson Zahn, Roland Cavanagh, Alyson Tierney, Michael Moll, Jorge Grafman, Jordan TI White Matter Tract Damage in the Behavioral Variant of Frontotemporal and Corticobasal Dementia Syndromes SO PLOS ONE LA English DT Article ID LOBAR DEGENERATION; ALZHEIMERS-DISEASE; PICKS-DISEASE; ATROPHY; BRAIN; TRACTOGRAPHY; DIAGNOSIS; PATHOLOGY; PATHWAYS; PATTERNS AB The phenotypes of the behavioral variant of frontotemporal dementia and the corticobasal syndrome present considerable clinical and anatomical overlap. The respective patterns of white matter damage in these syndromes have not been directly contrasted. Beyond cortical involvement, damage to white matter pathways may critically contribute to both common and specific symptoms in both conditions. Here we assessed patients with the behavioral variant of frontotemporal dementia and corticobasal syndrome with whole-brain diffusion tensor imaging to identify the white matter networks underlying these pathologies. Twenty patients with the behavioral variant of frontotemporal dementia, 19 with corticobasal syndrome, and 15 healthy controls were enrolled in the study. Differences in tract integrity between (i) patients and controls, and (ii) patients with the corticobasal syndrome and the behavioral variant of frontotemporal dementia were assessed with whole brain tract-based spatial statistics and analyses of regions of interest. Behavioral variant of frontotemporal dementia and the corticobasal syndrome shared a pattern of bilaterally decreased white matter integrity in the anterior commissure, genu and body of the corpus callosum, corona radiata and in the long intrahemispheric association pathways. Patients with the behavioral variant of frontotemporal dementia showed greater damage to the uncinate fasciculus, genu of corpus callosum and forceps minor. In contrast, corticobasal syndrome patients had greater damage to the midbody of the corpus callosum and perirolandic corona radiata. Whereas several compact white matter pathways were damaged in both the behavioral variant of frontotemporal dementia and corticobasal syndrome, the distribution and degree of white matter damage differed between them. These findings concur with the distinctive clinical manifestations of these conditions and may improve the in vivo neuroanatomical and diagnostic characterization of these disorders. C1 [Tovar-Moll, Fernanda; de Oliveira-Souza, Ricardo; Bramati, Ivanei Edson; Zahn, Roland; Moll, Jorge] DOr Inst Res & Educ IDOR, Rio De Janeiro, Brazil. [Tovar-Moll, Fernanda; Bramati, Ivanei Edson] Univ Fed Rio de Janeiro, Inst Biomed Sci, Rio De Janeiro, Brazil. [Tovar-Moll, Fernanda; Bramati, Ivanei Edson] Univ Fed Rio de Janeiro, Natl Ctr Struct Biol & Bioimaging CENABIO, Rio De Janeiro, Brazil. [Zahn, Roland] Kings Coll London, Inst Psychiat, London WC2R 2LS, England. [Cavanagh, Alyson; Tierney, Michael; Grafman, Jordan] NINDS, NIH, Bethesda, MD 20892 USA. [Grafman, Jordan] Rehabil Inst Chicago, Chicago, IL 60611 USA. RP Tovar-Moll, F (reprint author), DOr Inst Res & Educ IDOR, Rio De Janeiro, Brazil. EM fernanda.tovarmoll@idor.org; jgrafman@northwestern.edu RI Zahn, Roland/C-4665-2008 OI Zahn, Roland/0000-0002-8447-1453 FU National Institute of Neurological Disorders and Stroke, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 7 Z9 7 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 23 PY 2014 VL 9 IS 7 AR e102656 DI 10.1371/journal.pone.0102656 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM1NT UT WOS:000339614100043 PM 25054218 ER PT J AU Wu, XN Ye, YX Niu, JW Li, Y Li, X You, X Chen, H Zhao, LD Zeng, XF Zhang, FC Tang, FL He, W Cao, XT Zhang, X Lipsky, PE AF Wu, Xiang-ni Ye, Yan-xia Niu, Jing-wen Li, Yang Li, Xin You, Xin Chen, Hua Zhao, Li-dan Zeng, Xiao-feng Zhang, Feng-chun Tang, Fu-lin He, Wei Cao, Xue-tao Zhang, Xuan Lipsky, Peter E. TI Defective PTEN regulation contributes to B cell hyperresponsiveness in systemic lupus erythematosus SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID PROTEIN-KINASE B; TUMOR-SUPPRESSOR; INTERLEUKIN-21 RECEPTOR; PHOSPHOINOSITIDE 3-KINASE; SIGNALING PATHWAY; ANTIGEN RECEPTOR; IL-21; ACTIVATION; EXPRESSION; IDENTIFICATION AB PTEN regulates normal signaling through the B cell receptor (BCR). In systemic lupus erythematosus (SLE), enhanced BCR signaling contributes to increased B cell activity, but the role of PTEN in human SLE has remained unclear. We performed fluorescence-activated cell sorting analysis in B cells from SLE patients and found that all SLE B cell subsets, except for memory B cells, showed decreased expression of PTEN compared with B cells from healthy controls. Moreover, the level of PTEN expression was inversely correlated with disease activity. We then explored the mechanisms governing PTEN regulation in SLE B cells. Notably, in normal but not SLE B cells, interleukin-21 (IL-21) induced PTEN expression and suppressed Akt phosphorylation induced by anti-immunoglobulin M and CD40L stimulation. However, this deficit was not primarily at the signaling or the transcriptional level, because IL-21-induced STAT3 (signal transducer and activator of transcription 3) phosphorylation was intact and IL-21 up-regulated PTEN mRNA in SLE B cells. Therefore, we examined the expression of candidate microRNAs (miRs) that could regulate PTEN: SLE B cells were found to express increased levels of miR-7, miR-21, and miR-22. These miRs down-regulated the expression of PTEN, and IL-21 stimulation increased the expression of miR-7 and miR-22 in both normal and SLE B cells. Indeed, a miR-7 antagomir corrected PTEN-related abnormalities in SLE B cells in a manner dependent on PTEN. Therefore, defective miR-7 regulation of PTEN contributes to B cell hyperresponsiveness in SLE and could be a new target of therapeutic intervention. C1 [Wu, Xiang-ni; Ye, Yan-xia; Niu, Jing-wen; Li, Yang; Li, Xin; You, Xin; Chen, Hua; Zhao, Li-dan; Zeng, Xiao-feng; Zhang, Feng-chun; Tang, Fu-lin; Zhang, Xuan; Lipsky, Peter E.] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Rheumatol & Clin Immunol, Beijing 100730, Peoples R China. [Wu, Xiang-ni; Ye, Yan-xia; Niu, Jing-wen; Li, Yang; Li, Xin; You, Xin; Chen, Hua; Zhao, Li-dan; Zeng, Xiao-feng; Zhang, Feng-chun; Tang, Fu-lin; Zhang, Xuan; Lipsky, Peter E.] Peking Union Med Coll, Beijing 100730, Peoples R China. [He, Wei; Cao, Xue-tao] Peking Union Med Coll, Sch Basic Med, Dept Immunol, Beijing 100005, Peoples R China. [He, Wei; Cao, Xue-tao] Chinese Acad Med Sci, Inst Basic Med Sci, Beijing 100005, Peoples R China. [Lipsky, Peter E.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Zhang, X (reprint author), Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Rheumatol & Clin Immunol, Beijing 100730, Peoples R China. EM zxpumch2003@sina.com; peterlipsky@comcast.net OI zhang, xuan/0000-0001-8775-1699 FU National Natural Science Foundation of China [81325019, 81172859, 81273312, 81302594]; Beijing Municipal Natural Science Foundation [7141008, 7144208]; National Major Scientific and Technological Special Project [2012ZX09303006-002]; Research Special Fund for Public Welfare Industry of Health [20120217, 201302017]; Capital Health Research and Development of Special Fund [2011-4001-02]; National Laboratory Special Fund [2060204] FX Supported by grants from the National Natural Science Foundation of China (81325019, 81172859, 81273312, and 81302594), the Beijing Municipal Natural Science Foundation (7141008 and 7144208), the National Major Scientific and Technological Special Project (2012ZX09303006-002), the Research Special Fund for Public Welfare Industry of Health (20120217 and 201302017), the Capital Health Research and Development of Special Fund (2011-4001-02), and the National Laboratory Special Fund (2060204). NR 67 TC 18 Z9 19 U1 0 U2 14 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUL 23 PY 2014 VL 6 IS 246 AR 246ra99 DI 10.1126/scitranslmed.3009131 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AM2EH UT WOS:000339661400010 PM 25101889 ER PT J AU Fauci, AS Marston, HD Folkers, GK AF Fauci, Anthony S. Marston, Hilary D. Folkers, Gregory K. TI An HIV Cure Feasibility, Discovery, and Implementation SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CCR5 C1 [Fauci, Anthony S.; Marston, Hilary D.; Folkers, Gregory K.] NIAID, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM afauci@niaid.nih.gov NR 8 TC 17 Z9 17 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 23 PY 2014 VL 312 IS 4 BP 335 EP 336 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AL6QN UT WOS:000339257800013 PM 25038345 ER PT J AU Heidari, S Mofenson, LM Bekker, LG AF Heidari, Shirin Mofenson, Lynne M. Bekker, Linda-Gail TI Realization of an AIDS-Free Generation Ensuring Sustainable Treatment for Children SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID ANTIRETROVIRAL THERAPY C1 [Heidari, Shirin] Inforia, CH-1202 Geneva, Switzerland. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Bekker, Linda-Gail] Univ Cape Town, Desmond Tutu HIV Ctr, ZA-7925 Cape Town, South Africa. RP Heidari, S (reprint author), Inforia, Rue Henri Veyrassat 3, CH-1202 Geneva, Switzerland. EM shirin.heidari@inforia.org NR 8 TC 4 Z9 4 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 23 PY 2014 VL 312 IS 4 BP 339 EP 340 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AL6QN UT WOS:000339257800015 PM 25038347 ER PT J AU Philpott, CC Ryu, MS AF Philpott, Caroline C. Ryu, Moon-Suhn TI Special delivery: distributing iron in the cytosol of mammalian cells SO FRONTIERS IN PHARMACOLOGY LA English DT Review DE non-heme iron; diiron; glutathione; metallochaperone; iron chaperone; glutaredoxin; labile iron pool ID GLUTAREDOXIN 3 PICOT; SULFUR CLUSTER; SACCHAROMYCES-CEREVISIAE; DEOXYHYPUSINE HYDROXYLASE; SUPEROXIDE-DISMUTASE; COPPER CHAPERONE; LABILE IRON; HOMEOSTASIS; PROTEINS; TRAFFICKING AB Eukaryotic cells contain hundreds of proteins that require iron cofactors for activity. These iron enzymes are located in essentially every subcellular compartment; thus, iron cofactors must travel to every compartment in the cell. Iron cofactors exist in three basic forms: Heme, iron-sulfur clusters, and simple iron ions (also called non-heme iron). Iron ions taken up by the cell initially enter a kinetically labile, exchangeable pool that is referred to as the labile iron pool. The majority of the iron in this pool is delivered to mitochondria, where it is incorporated into heme and iron-sulfur clusters, as well as non-heme iron enzymes. These cofactors must then be distributed to nascent proteins in the mitochondria, cytosol, and membrane-bound organelles. Emerging evidence suggests that specific systems exist for the distribution of iron cofactors within the cell. These systems include membrane transporters, protein chaperones, specialized carriers, and small molecules. This review focuses on the distribution of iron ions in the cytosol and will highlight differences between the iron distribution systems of simple eukaryotes and mammalian cells. C1 [Philpott, Caroline C.; Ryu, Moon-Suhn] NIDDK, Genet & Metab Sect, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Philpott, CC (reprint author), NIDDK, Genet & Metab Sect, Liver Dis Branch, NIH, Bldg 10,Room 9B-16,10 Ctr Dr, Bethesda, MD 20892 USA. EM carolinep@intra.niddk.nih.gov NR 69 TC 16 Z9 16 U1 7 U2 22 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1663-9812 J9 FRONT PHARMACOL JI Front. Pharmacol. PD JUL 22 PY 2014 VL 5 AR UNSP 173 DI 10.3389/fphar.2014.00173 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AX7OF UT WOS:000347104300001 PM 25101000 ER PT J AU te Riele, ASJM James, CA Rastegar, N Bhonsale, A Murray, B Tichnell, C Judge, DP Bluemke, DA Zimmerman, SL Kamel, IR Calkins, H Tandri, H AF te Riele, Anneline S. J. M. James, Cynthia A. Rastegar, Neda Bhonsale, Aditya Murray, Brittney Tichnell, Crystal Judge, Daniel P. Bluemke, David A. Zimmerman, Stefan L. Kamel, Ihab R. Calkins, Hugh Tandri, Harikrishna TI Yield of Serial Evaluation in At-Risk Family Members of Patients With ARVD/C SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiomyopathy; electrocardiography; magnetic resonance imaging; progression; screening ID RIGHT-VENTRICULAR DYSPLASIA/CARDIOMYOPATHY; DESMOSOMAL MUTATION CARRIERS; TASK-FORCE CRITERIA; DIAGNOSTIC-CRITERIA; ARRHYTHMIC RISK; CARDIOMYOPATHY/DYSPLASIA; STRATIFICATION; PENETRANCE; DYSPLASIA; GENETICS AB BACKGROUND Incomplete penetrance and variable expressivity of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) complicate family screening. OBJECTIVES The objective of the present study was to determine the optimal approach to longitudinal follow-up regarding: 1) screening interval; and 2) testing strategy in at-risk relatives of ARVD/C patients. METHODS We included 117 relatives (45% male, age 33.3 +/- 16.3 years) from 64 families who were at risk of developing ARVD/C by virtue of their familial predisposition (72% mutation carriers [92% plakophilin-2]; 28% first-degree relatives of a mutation-negative proband). Subjects were evaluated by electrocardiography (ECG), Holter monitoring, signal-averaged ECG, and cardiac magnetic resonance (CMR). Disease progression was defined as the development of a new criterion by the 2010 Task Force Criteria (not the "Hamid criteria") at last follow-up that was absent at enrollment. RESULTS At first evaluation, 43 subjects (37%) fulfilled an ARVD/C diagnosis according to the 2010 Task Force Criteria. Among the remaining 74 subjects (63%), 11 of 37 (30%) with complete re-evaluation experienced disease progression during 4.1 +/- 2.3 years of follow-up. Electrical progression (n = 10 [27%], including by ECG [14%], Holter monitoring [11%], or signal-averaged ECG [14%]) was more frequently observed than structural progression (n 1 [3%] on CMR). All 5 patients (14%) with clinical ARVD/C diagnosis at last follow-up had an abnormal ECG or Holter monitor recording, and the only patient with an abnormal CMR already had an abnormal ECG at enrollment. CONCLUSIONS Over a mean follow-up of 4 years, our study showed that: 1) almost one-third of at-risk relatives have electrical progression; 2) structural progression is rare; and 3) electrical abnormalities precede detectable structural changes. This information could be valuable in determining family screening protocols. (C) 2014 by the American College of Cardiology Foundation. C1 [te Riele, Anneline S. J. M.] Univ Med Ctr Utrecht, Div Cardiol, Dept Med, Utrecht, Netherlands. [te Riele, Anneline S. J. M.; James, Cynthia A.; Bhonsale, Aditya; Murray, Brittney; Tichnell, Crystal; Judge, Daniel P.; Zimmerman, Stefan L.; Kamel, Ihab R.; Calkins, Hugh; Tandri, Harikrishna] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Rastegar, Neda; Bluemke, David A.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Bluemke, David A.] Natl Inst Hlth Clin Ctr, Bethesda, MD USA. RP Tandri, H (reprint author), Johns Hopkins Univ Hosp, Div Cardiol, Dept Med, 600 North Wolfe St,Carnegie 538, Baltimore, MD 21287 USA. EM htandri1@jhmi.edu OI Bluemke, David/0000-0002-8323-8086 FU Alexandre Suerman Stipend; National Heart, Lung, and Blood Institute [K23HL093350]; Dr. Francis P. Chiaramonte Private Foundation; St. Jude Medical Foundation; Medtronic Inc.; Bogle Foundation; Healing Hearts Foundation; Campanella family; Patrick J. Harrison Family; Peter French Memorial Foundation; Dr. Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins; St. Jude Medical; Wilmerding Endowments FX The authors wish to acknowledge funding from the Alexandre Suerman Stipend (to Dr. te Riele); the National Heart, Lung, and Blood Institute (K23HL093350 to Dr. Tandri); the Dr. Francis P. Chiaramonte Private Foundation; the St. Jude Medical Foundation; and Medtronic Inc. The Johns Hopkins ARVD/C Program is supported by the Bogle Foundation, the Healing Hearts Foundation, the Campanella family, the Patrick J. Harrison Family, the Peter French Memorial Foundation, the Wilmerding Endowments and the Dr. Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins. Dr. Calkins has received ARVD/C research support from Medtronic Inc. and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 21 TC 17 Z9 17 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 22 PY 2014 VL 64 IS 3 BP 293 EP 301 DI 10.1016/j.jacc.2014.04.044 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM9ZB UT WOS:000340238900011 PM 25034067 ER PT J AU King, TH Kemmler, CB Guo, ZM Mann, D Lu, YN Coeshott, C Gehring, AJ Bertoletti, A Ho, ZZ Delaney, W Gaggar, A Subramanian, GM McHutchison, JG Shrivastava, S Lee, YJL Kottilil, S Bellgrau, D Rodell, T Apelian, D AF King, Thomas H. Kemmler, Charles B. Guo, Zhimin Mann, Derrick Lu, Yingnian Coeshott, Claire Gehring, Adam J. Bertoletti, Antonio Ho, Zi Z. Delaney, William Gaggar, Anuj Subramanian, G. Mani McHutchison, John G. Shrivastava, Shikha Lee, Yu-Jin L. Kottilil, Shyamasundaran Bellgrau, Donald Rodell, Timothy Apelian, David TI A Whole Recombinant Yeast-Based Therapeutic Vaccine Elicits HBV X, S and Core Specific T Cells in Mice and Activates Human T Cells Recognizing Epitopes Linked to Viral Clearance SO PLOS ONE LA English DT Article ID HEPATITIS-B-VIRUS; IMMUNE-RESPONSE; DENDRITIC CELLS; SURFACE-ANTIGEN; INFECTION; TOLERANCE; PATHOGENESIS; INDIVIDUALS; MATURATION; CIRRHOSIS AB Chronic hepatitis B infection (CHB) is characterized by sub-optimal T cell responses to viral antigens. A therapeutic vaccine capable of restoring these immune responses could potentially improve HBsAg seroconversion rates in the setting of direct acting antiviral therapies. A yeast-based immunotherapy (Tarmogen) platform was used to make a vaccine candidate expressing hepatitis B virus (HBV) X, surface (S), and Core antigens (X-S-Core). Murine and human immunogenicity models were used to evaluate the type and magnitude of HBV-Ag specific T cell responses elicited by the vaccine. C57BL/6J, BALB/c, and HLA-A*0201 transgenic mice immunized with yeast expressing X-S-Core showed T cell responses to X, S and Core when evaluated by lymphocyte proliferation assay, ELISpot, intracellular cytokine staining (ICS), or tumor challenge assays. Both CD4(+) and CD8(+) T cell responses were observed. Human T cells transduced with HBc18-27 and HBs183-91 specific T cell receptors (TCRs) produced interferon gamma (IFN gamma following incubation with X-S-Core-pulsed dendritic cells (DCs). Furthermore, stimulation of peripheral blood mononuclear cells (PBMCs) isolated from CHB patients or from HBV vaccine recipients with autologous DCs pulsed with X-S-Core or a related product (S-Core) resulted in pronounced expansions of HBV Ag-specific T cells possessing a cytolytic phenotype. These data indicate that X-S-Core-expressing yeast elicit functional adaptive immune responses and supports the ongoing evaluation of this therapeutic vaccine in patients with CHB to enhance the induction of HBV-specific T cell responses. C1 [King, Thomas H.; Kemmler, Charles B.; Guo, Zhimin; Mann, Derrick; Lu, Yingnian; Coeshott, Claire; Bellgrau, Donald; Rodell, Timothy; Apelian, David] GlobeImmune Inc, Louisville, CO 80027 USA. [Bellgrau, Donald] Univ Colorado, Sch Med, Integrated Dept Immunol, Aurora, CO USA. [Delaney, William; Gaggar, Anuj; Subramanian, G. Mani; McHutchison, John G.] Gilead Sci Inc, Foster City, CA 94404 USA. [Gehring, Adam J.] St Louis Univ, Sch Med, St Louis, MO USA. [Gehring, Adam J.] St Louis Univ, Sch Med, Ctr Liver, St Louis, MO USA. [Gehring, Adam J.; Bertoletti, Antonio; Ho, Zi Z.] ASTAR, Singapore Inst Clin Sci, Singapore, Singapore. [Shrivastava, Shikha; Lee, Yu-Jin L.; Kottilil, Shyamasundaran] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP King, TH (reprint author), GlobeImmune Inc, Louisville, CO 80027 USA. EM tom.king@globeimmune.com OI Bertoletti, Antonio/0000-0002-2942-0485 FU Gilead Sciences, Inc.; GlobeImmune, Inc.; NIH [NIAID: AI000390-30]; Gilead FX This work was supported by Gilead Sciences, Inc. and GlobeImmune, Inc. Partial funding for work done by S.K. was provided by a intramural NIH grant (NIAID: AI000390-30). All members of each funding party participated in the study design, data collection and analysis, decision to publish or preparation of the manuscript. W.D., A.G., G.S., and J.M. are affiliated with (are employees and share holders of) the commercial company Gilead Sciences. Inc. T.K., C.K., Z.G., D.M., Y.L., C.C., D.B., T.R. and D.A. are or were paid employees of the commercial company GlobeImmune, Inc. at the time this work was performed. Work performed. GlobeImmuneco authors D.A. T.K., Z.G., and C.C. are inventors on patents # 8, 722, 054, PCT publication# WO 1012/109404, and related applications. One or more products described in the manuscript has the potential to be commercialised and GlobeImmune and/or Gilead and the employees and share holders therefore (including the co author listed above) could profit directly or indirectly from such commercialization. Work performed by A.J.G. and A.B. has funding agreements with Gilead and participates on Gilead advisory boards. These facts do not alter the authors' adherence to all PLOS ONE policies on sharing data and materials as detailed online in the PLOS ONE guide for authors, except for the one restriction regarding material as listed in Competing Interest section. NR 43 TC 17 Z9 17 U1 1 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 22 PY 2014 VL 9 IS 7 AR e101904 DI 10.1371/journal.pone.0101904 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM0QO UT WOS:000339551100016 PM 25051027 ER PT J AU Lee, J Gillman, AL Jang, H Ramachandran, S Kagan, BL Nussinov, R Arce, FT AF Lee, Joon Gillman, Alan L. Jang, Hyunbum Ramachandran, Srinivasan Kagan, Bruce L. Nussinov, Ruth Arce, Fernando Teran TI Role of the Fast Kinetics of Pyroglutamate-Modified Amyloid-beta Oligomers in Membrane Binding and Membrane Permeability SO BIOCHEMISTRY LA English DT Article ID ATOMIC-FORCE MICROSCOPY; ALZHEIMERS-DISEASE; ION CHANNELS; BILAYER-MEMBRANES; LIPID-MEMBRANES; A-BETA; MODEL MEMBRANES; ALPHA-SYNUCLEIN; PROTEIN; CHOLESTEROL AB Membrane permeability to ions and small molecules is believed to be a critical step in the pathology of Alzheimer's disease (AD). Interactions of oligomers formed by amyloid-beta (A beta) peptides with the plasma cell membrane are believed to play a fundamental role in the processes leading to membrane permeability. Among the family of A beta s, pyroglutamate (pE)-modified A beta peptides constitute the most abundant oligomeric species in the brains of AD patients. Although membrane permeability mechanisms have been studied for full-length A beta(1-40/42) peptides, these have not been sufficiently characterized for the more abundant A beta(pE3-42) fragment. Here we have compared the adsorbed and membrane-inserted oligomeric species of A beta(pE3-42) and A beta(1-42) Peptides. We find lower concentrations and larger dimensions for both species of membrane-associated A beta(pE3-42) oligomers. The larger dimensions are attributed to the faster self-assembly kinetics of A beta(pE3-42), and the lower concentrations are attributed to weaker interactions with zwitterionic lipid headgroups. While adsorbed oligomers produced little or no significant membrane structural damage, increased membrane permeabilization to ionic species is understood in terms of enlarged membrane-inserted oligomers. Membrane-inserted A beta(pE3-42) oligomers were also found to modify the mechanical properties of the membrane. Taken together, our results suggest that membrane-inserted oligomers are the primary species responsible for membrane permeability. C1 [Gillman, Alan L.; Ramachandran, Srinivasan; Arce, Fernando Teran] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Lee, Joon; Ramachandran, Srinivasan; Arce, Fernando Teran] Univ Calif San Diego, Dept Mech & Aerosp Engn, La Jolla, CA 92093 USA. [Lee, Joon; Ramachandran, Srinivasan; Arce, Fernando Teran] Univ Calif San Diego, Mat Sci Program, La Jolla, CA 92093 USA. [Jang, Hyunbum; Nussinov, Ruth] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Kagan, Bruce L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. RP Arce, FT (reprint author), Univ Calif San Diego, Dept Bioengn, PFBH 218,9500 Gilman Dr,MC 0412, La Jolla, CA 92093 USA. EM ftarce@ucsd.edu FU National Institutes of Health [R01AG028709]; National Institutes of Health Neuroplasticity of Aging Training Grant [T32 AG 000216]; Howard Hughes Medical Institute Med Into Grad Initiative; Federal from the Frederick National Laboratory for Cancer Research, National Institutes of Health (NIH) [HHSN261200800001E]; Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research FX Support by the National Institutes of Health (R01AG028709) is acknowledged. A.L.G. was supported in part by National Institutes of Health Neuroplasticity of Aging Training Grant T32 AG 000216 and the Howard Hughes Medical Institute Med Into Grad Initiative. This project has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health (NIH), under Contract HHSN261200800001E. This research was supported, in part, by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. NR 93 TC 12 Z9 12 U1 3 U2 31 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 22 PY 2014 VL 53 IS 28 BP 4704 EP 4714 DI 10.1021/bi500587p PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AL9LO UT WOS:000339462800020 PM 24950761 ER PT J AU Zhang, P Tu, B Wang, H Cao, ZY Tang, M Zhang, CH Gu, B Li, ZM Wang, LN Yang, Y Zhao, Y Wang, HY Luo, JY Deng, CX Gao, B Roeder, RG Zhu, WG AF Zhang, Ping Tu, Bo Wang, Hua Cao, Ziyang Tang, Ming Zhang, Chaohua Gu, Bo Li, Zhiming Wang, Lina Yang, Yang Zhao, Ying Wang, Haiying Luo, Jianyuan Deng, Chu-Xia Gao, Bin Roeder, Robert G. Zhu, Wei-Guo TI Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSCRIPTION FACTOR FOXO1; HEPATIC GLUCOSE-PRODUCTION; PROTEIN-KINASE; LIFE-SPAN; DEACETYLASE; MICE; GLYCOLYSIS; HOMEOSTASIS; INDUCTION; STRESS AB In mammalian cells, tumor suppressor p53 plays critical roles in the regulation of glucose metabolism, including glycolysis and oxidative phosphorylation, but whether and how p53 also regulates gluconeogenesis is less clear. Here, we report that p53 efficiently down-regulates the expression of phosphoenolpyruvate carboxykinase (PCK1) and glucose-6-phosphatase (G6PC), which encode rate-limiting enzymes in gluconeogenesis. Cell-based assays demonstrate the p53-dependent nuclear exclusion of forkhead box protein O1 (FoxO1), a key transcription factor that mediates activation of PCK1 and G6PC, with consequent alleviation of FoxO1-dependent gluconeogenesis. Further mechanistic studies show that p53 directly activates expression of the NAD+-dependent histone deacetylase sirtuin 6 (SIRT6), whose interaction with FoxO1 leads to FoxO1 deacetylation and export to the cytoplasm. In support of these observations, p53-mediated FoxO1 nuclear exclusion, down-regulation of PCK1 and G6PC expression, and regulation of glucose levels were confirmed in C57BL/J6 mice and in liver-specific Sirt6 conditional knockout mice. Our results provide insights into mechanisms of metabolism-related p53 functions that may be relevant to tumor suppression. C1 [Zhang, Ping; Tu, Bo; Cao, Ziyang; Tang, Ming; Zhang, Chaohua; Gu, Bo; Li, Zhiming; Wang, Lina; Yang, Yang; Zhao, Ying; Wang, Haiying; Luo, Jianyuan; Zhu, Wei-Guo] Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing 100191, Peoples R China. [Wang, Hua; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. [Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Roeder, Robert G.] Rockefeller Univ, Lab Biochem & Mol Biol, New York, NY 10065 USA. [Zhu, Wei-Guo] Peking Tsinghua Univ, Ctr Life Sci, Beijing 100871, Peoples R China. RP Roeder, RG (reprint author), Rockefeller Univ, Lab Biochem & Mol Biol, New York, NY 10065 USA. EM roeder@rockefeller.edu; zhuweiguo@bjmu.edu.cn RI zhu, wei-guo/E-1334-2012; deng, chuxia/N-6713-2016; OI Zhu, Wei-Guo/0000-0001-8385-6581 FU National Key Basic Research Program of China [2011CB504200, 2012CB517501, 2013CB911001]; National Natural Science Foundation of China [31070691, 81321003, 91319302]; Minister of Education of China "111 Project"; National Institutes of Health [CA129325] FX This work was supported by National Key Basic Research Program of China Grants 2011CB504200, 2012CB517501, and 2013CB911001; National Natural Science Foundation of China Grants 31070691, 81321003, and 91319302; Minister of Education of China "111 Project" (to W.-G.Z.); and the National Institutes of Health Grant CA129325 (to R.G.R.). NR 38 TC 43 Z9 43 U1 4 U2 34 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 22 PY 2014 VL 111 IS 29 BP 10684 EP 10689 DI 10.1073/pnas.1411026111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL7JS UT WOS:000339310700067 PM 25009184 ER PT J AU Deng, L Ma, L Virata-Theimer, ML Zhong, LL Yan, HL Zhao, Z Struble, E Feinstone, S Alter, H Zhang, P AF Deng, Lu Ma, Li Virata-Theimer, Maria Luisa Zhong, Lilin Yan, Hailing Zhao, Zhong Struble, Evi Feinstone, Stephen Alter, Harvey Zhang, Pei TI Discrete conformations of epitope II on the hepatitis C virus E2 protein for antibody-mediated neutralization and nonneutralization SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immunoglobulins; prophylaxis; vaccine ID GP120 V3 LOOP; ALTERNATIVE CONFORMATIONS; CORECEPTOR SELECTIVITY; BETA-HAIRPINS; BINDING; CD81; COMPLEXES; INFECTION; REGIONS; MODE AB The X-ray crystal structure of epitope II on the E2 protein of hepatitis C virus, in complex with nonneutralizing antibody mAb#12, has been solved at 2.90-angstrom resolution. The spatial arrangement of the essential components of epitope II (ie, the C-terminal a-helix and the N-terminal loop) was found to deviate significantly from that observed in those corresponding complexes with neutralizing antibodies. The distinct conformations are mediated largely by the flexibility of a highly conserved glycine residue that connects these components. Thus, it is the particular tertiary structure of epitope II, which is presented in a spatial and temporal manner, that determines the specificity of antibody recognition and, consequently, the outcome of neutralization or nonneutralization. C1 [Deng, Lu; Ma, Li; Virata-Theimer, Maria Luisa; Zhong, Lilin; Yan, Hailing; Zhao, Zhong; Struble, Evi; Zhang, Pei] US FDA, Ctr Biol Evaluat & Res, Off Blood Res & Review, Div Hematol, Bethesda, MD 20892 USA. [Feinstone, Stephen] George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Med, Washington, DC 20037 USA. [Alter, Harvey] Warren Grant Magnuson Clin Ctr, Dept Transfus Med, NIH, Bethesda, MD 20892 USA. RP Alter, H (reprint author), Warren Grant Magnuson Clin Ctr, Dept Transfus Med, NIH, Bethesda, MD 20892 USA. EM halter@dtm.cc.nih.gov; pei.zhang@fda.hhs.gov FU US Department of Energy Offices of Biological and Environmental Research and Basic Energy Sciences; National Center for Research Resources of the National Institutes of Health; CBER; FDA; Research Participation Program at CBER FX We thank Dr. John Finlayson for his comments on the manuscript, Dr. Tsan Xiao and Dr. Tengchuan Jin (National Institute of Allergy and Infectious Diseases) for providing the instrument for crystallization screening, Dr. Hongying Duan (CBER/FDA) for providing the monoclonal antibody reagents, and the FDA CBER Core Laboratory for assisting in protein sequence analysis. We also thank Howard Robinson (Brookhaven National Synchrotron Light Source) for X-ray data collection. Beamline X29 is supported by the US Department of Energy Offices of Biological and Environmental Research and Basic Energy Sciences and by the National Center for Research Resources of the National Institutes of Health. This study was funded by a Modernizing Science grant from CBER, FDA. L. M. and Z.Z. were supported by the Research Participation Program at CBER administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the FDA. NR 33 TC 14 Z9 14 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 22 PY 2014 VL 111 IS 29 BP 10690 EP 10695 DI 10.1073/pnas.1411317111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL7JS UT WOS:000339310700068 PM 25002515 ER PT J AU Qu, YB Huang, YH Feng, J Alvarez-Bolado, G Grove, EA Yang, YZ Tissir, F Zhou, LB Goffinet, AM AF Qu, Yibo Huang, Yuhua Feng, Jia Alvarez-Bolado, Gonzalo Grove, Elizabeth A. Yang, Yingzi Tissir, Fadel Zhou, Libing Goffinet, Andre M. TI Genetic evidence that Celsr3 and Celsr2, together with Fzd3, regulate forebrain wiring in a Vangl-independent manner SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Cre; anterior commissure; internal capsule; cortical barrels ID PLANAR CELL POLARITY; 7-PASS TRANSMEMBRANE CADHERIN; NEURAL-TUBE DEFECTS; ASYMMETRIC LOCALIZATION; ANTERIOR COMMISSURE; NERVOUS-SYSTEM; DROSOPHILA EYE; THALAMIC AXONS; BRAIN-STEM; HAIR-CELLS AB Celsr3 and Fzd3, members of "core planar cell polarity" (PCP) genes, were shown previously to control forebrain axon guidance and wiring by acting in axons and/or guidepost cells. Here, we show that Celsr2 acts redundantly with Celsr3, and that their combined mutation mimics that of Fzd3. The phenotypes generated upon inactivation of Fzd3 in different forebrain compartments are similar to those in conditional Celsr2-3 mutants, indicating that Fzd3 and Celsr2-3 act in the same population of cells. Inactivation of Celsr2-3 or Fzd3 in thalamus does not affect forebrain wiring, and joint inactivation in cortex and thalamus adds little to cortical inactivation alone in terms of thalamocortical projections. On the other hand, joint inactivation perturbs strongly the formation of the barrel field, which is unaffected upon single cortical or thalamic inactivation, indicating a role for interactions between thalamic axons and cortical neurons in cortical arealization. Unexpectedly, forebrain wiring is normal in mice defective in Vangl1 and Vangl2, showing that, contrary to epithelial PCP, axon guidance can be Vangl independent in some contexts. Our results suggest that Celsr2-3 and Fzd3 regulate axonal navigation in the forebrain by using mechanisms different from classical epithelial PCP, and require interacting partners other than Vangl1-2 that remain to be identified. C1 [Qu, Yibo; Huang, Yuhua; Feng, Jia; Zhou, Libing] Jinan Univ, Guangdong Hong Kong Macau Inst CNS Regenerat, Guangzhou 510632, Guangdong, Peoples R China. [Alvarez-Bolado, Gonzalo] Heidelberg Univ, Dept Neuroanat, D-69120 Heidelberg, Germany. [Grove, Elizabeth A.] Univ Chicago, Chicago, IL 60637 USA. [Yang, Yingzi] NHGRI, NIH, Bethesda, MD 20892 USA. [Tissir, Fadel; Goffinet, Andre M.] Univ Louvain, WELBIO Walloon Excellence Life Sci & Biotechnol, B-1200 Brussels, Belgium. [Tissir, Fadel; Goffinet, Andre M.] Univ Louvain, Inst Neurosci, B-1200 Brussels, Belgium. [Zhou, Libing] Univ Hong Kong, State Key Lab Brain & Cognit Sci, Hong Kong, Hong Kong, Peoples R China. RP Zhou, LB (reprint author), Jinan Univ, Guangdong Hong Kong Macau Inst CNS Regenerat, Guangzhou 510632, Guangdong, Peoples R China. EM tlibingzh@jnu.edu.cn; andre.goffinet@uclouvain.be OI Alvarez-Bolado, Gonzalo/0000-0002-3044-1603 FU National Natural Science Foundation of China [31200826, 31070955]; National Basic Research Program of China [973 Program] [2014CB542205, 2011CB504402]; Guangdong Natural Science Foundation [S2012040006744]; Guangzhou Science and Technology Project [13200068]; Jinan University Research and Innovation Foundation [21612345]; Belgian grants Actions de Recherches Concertees [ARC-10/15-026]; Fonds de la Recherche Scientifique Medicale [3.4550.11]; Fonds National de La Recherche Scientifique (FNRS) [T0002.13]; Interuniversity Poles of Attraction (Services Federaux des Affaires Scientifiques, Techniques, et Culturelles) [PAI p6/20, PAI7/20]; Fondation Medicale Reine Elisabeth; Fondation JED-Belgique; Region Wallonne [WELBIO-CR-2012A-07] FX We thank Jean Hebert, Kevin Jones, Nicoletta Kessaris, and Klaus Amin Nave for Cre mice; Nicolas Parmentier for help with Western blots; and Esther Paitre, Isabelle Lambermont, Valerie Bonte, and Rachid El Kaddouri for technical assistance. This work was supported by grants from the National Natural Science Foundation of China [31200826 (to Y.Q.) and 31070955 (to L.Z.)], National Basic Research Program of China [973 Program, 2014CB542205 (to Y.Q.) and 2011CB504402 (to L.Z.)], Guangdong Natural Science Foundation [S2012040006744 (to Y.Q.)], Guangzhou Science and Technology Project [13200068 (to Y.Q.)], and Jinan University Research and Innovation Foundation [21612345 (to Y.Q.)], and by Belgian grants Actions de Recherches Concertees (ARC-10/15-026), Fonds de la Recherche Scientifique Medicale 3.4550.11, Fonds National de La Recherche Scientifique (FNRS) T0002.13, Interuniversity Poles of Attraction (Services Federaux des Affaires Scientifiques, Techniques, et Culturelles, PAI p6/20 and PAI7/20), Fondation Medicale Reine Elisabeth, Fondation JED-Belgique, and WELBIO-CR-2012A-07 from the Region Wallonne (to F. T. and A. M. G.). F. T. is a senior research associate of the Belgian FNRS. NR 76 TC 15 Z9 15 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 22 PY 2014 VL 111 IS 29 BP E2996 EP E3004 DI 10.1073/pnas.1402105111 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL7JS UT WOS:000339310700011 PM 25002511 ER PT J AU Shen, W Li, WQ Hixon, JA Bouladoux, N Belkaid, Y Dzutzev, A Durum, SK AF Shen, Wei Li, Wenqing Hixon, Julie A. Bouladoux, Nicolas Belkaid, Yasmine Dzutzev, Amiran Durum, Scott K. TI Adaptive immunity to murine skin commensals SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE T lymphocyte; microbiome ID HYPER-IGE SYNDROME; MYCOBACTERIUM-TUBERCULOSIS INFECTION; CHRONIC MUCOCUTANEOUS CANDIDIASIS; REGULATORY T-CELLS; ATOPIC-DERMATITIS; LANGERHANS CELLS; TH17 CELLS; IN-VIVO; MUTATIONS; LYMPHOCYTES AB The adaptive immune system provides critical defense against pathogenic bacteria. Commensal bacteria have begun to receive much attention in recent years, especially in the gut where there is growing evidence of complex interactions with the adaptive immune system. In the present study, we observed that commensal skin bacteria are recognized by major populations of T cells in skin-draining lymph nodes of mice. Recombination activating gene 1 (Rag1)(-/-) mice, which lack adaptive immune cells, contained living skin-derived bacteria and bacterial sequences, especially mycobacteria, in their skin-draining lymph nodes. T cells from skin-draining lymph nodes of normal mice were shown, in vitro, to specifically recognize bacteria of several species that were grown from Rag1(-/-) lymph nodes. T cells from skin-draining lymph nodes, transferred into Rag1(-/-) mice proliferated in skin-draining lymph nodes, expressed a restricted T-cell receptor spectrotype and produced cytokines. Transfer of T cells into Rag1(-/-) mice had the effect of reducing bacterial sequences in skin-draining lymph nodes and in skin itself. Antibacterial effects of transferred T cells were dependent on IFN gamma and IL-17A. These studies suggest a previously unrecognized role for T cells in controlling skin commensal bacteria and provide a mechanism to account for cutaneous infections and mycobacterial infections in T-cell-deficient patients. C1 [Shen, Wei; Li, Wenqing; Hixon, Julie A.; Durum, Scott K.] NCI, Lab Immunoregulat, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Dzutzev, Amiran] NCI, Lab Expt Immunol, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Bouladoux, Nicolas; Belkaid, Yasmine] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20814 USA. RP Durum, SK (reprint author), NCI, Lab Immunoregulat, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. EM durums@mail.ncifcrf.gov FU National Cancer Institute; Ely and Edythe Broad Foundation FX We thank Drs. N. Boudaloux and Y. Belkaid for the generous gift of germ-free mice, and Drs. Mark Udey and Joost Oppenheim for helpful suggestions on the study and manuscript. The study was funded by the intramural program of the National Cancer Institute and a grant (to S.K.D.) from the Ely and Edythe Broad Foundation. NR 64 TC 17 Z9 17 U1 0 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 22 PY 2014 VL 111 IS 29 BP E2977 EP E2986 DI 10.1073/pnas.1401820111 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL7JS UT WOS:000339310700009 PM 25002505 ER PT J AU Zhang, J Tan, DZ DeRose, EF Perera, L Dominski, Z Marzluff, WF Tong, L Hall, TMT AF Zhang, Jun Tan, Dazhi DeRose, Eugene F. Perera, Lalith Dominski, Zbigniew Marzluff, William F. Tong, Liang Hall, Traci M. Tanaka TI Molecular mechanisms for the regulation of histone mRNA stem-loop-binding protein by phosphorylation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE X-ray crystallography; NMR; intrinsically disordered protein ID CELL-CYCLE REGULATION; AMBER FORCE-FIELD; 3' END; U7 SNRNP; PROCESSING SYSTEM; DROSOPHILA; 3'-END; HAIRPIN; MACROMOLECULES; EXPRESSION AB Replication-dependent histone mRNAs end with a conserved stem loop that is recognized by stem-loop-binding protein (SLBP). The minimal RNA-processing domain of SLBP is phosphorylated at an internal threonine, and Drosophila SLBP (dSLBP) also is phosphorylated at four serines in its 18-aa C-terminal tail. We show that phosphorylation of dSLBP increases RNA-binding affinity dramatically, and we use structural and biophysical analyses of dSLBP and a crystal structure of human SLBP phosphorylated on the internal threonine to understand the striking improvement in RNA binding. Together these results suggest that, although the C-terminal tail of dSLBP does not contact the RNA, phosphorylation of the tail promotes SLBP conformations competent for RNA binding and thereby appears to reduce the entropic penalty for the association. Increased negative charge in this C-terminal tail balances positively charged residues, allowing a more compact ensemble of structures in the absence of RNA. C1 [Zhang, Jun; DeRose, Eugene F.; Perera, Lalith; Hall, Traci M. Tanaka] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Tan, Dazhi; Tong, Liang] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Dominski, Zbigniew; Marzluff, William F.] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Dominski, Zbigniew; Marzluff, William F.] Univ N Carolina, Integrat Program Biol & Genome Sci, Chapel Hill, NC 27599 USA. RP Marzluff, WF (reprint author), Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. EM marzluff@med.unc.edu; ltong@columbia.edu; hall4@niehs.nih.gov RI Zhang, Jun/R-1502-2016; OI Zhang, Jun/0000-0002-5842-7424; Tong, Liang/0000-0002-0563-6468 FU Intramural Research Program of the National Institutes of Health (NIH); NIEHS; NIH [GM077175, GM58921, GM29832]; NIEHS, NIH [HHSN273200700046U]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX We thank X. C. Yang for expressing dSLBP and hSLBP in insect cells; J. Williams and the National Institute of Environmental Health Sciences (NIEHS) Protein Microcharacterization Facility for mass spectrometric analyses; L. Pedersen and the staff of the Southeast Regional Collaborative Access Team beamlines for assistance with X-ray data collection; R. Jackimowicz and H. Robinson for access to the X29A beamline at the National Synchrotron Light Source; the NIEHS NMR Group for advice and feedback regarding experimental design; and M. Sobhany for assistance with Isothermal Titration Calorimetry data collection. Fluorescence experiments were performed at the University of North Carolina Macromolecular Interactions Facility, and we thank A. Tripathy, Director of the facility, for his assistance. This work was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), NIEHS (T. M. T. H.), and NIH Grants GM077175 (to L. T.), GM58921 (to W. F. M.), and GM29832 (to Z.D. and W. F. M.). E. F. D. is supported by the NIEHS, NIH, under Delivery Order HHSN273200700046U. The Advanced Photon Source used for this study was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract W-31-109-Eng-38. NR 45 TC 2 Z9 2 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 22 PY 2014 VL 111 IS 29 BP E2937 EP E2946 DI 10.1073/pnas.1406381111 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL7JS UT WOS:000339310700005 PM 25002523 ER PT J AU Kwon, D Kim, S Shin, SY Chatr-aryamontri, A Wilbur, WJ AF Kwon, Dongseop Kim, Sun Shin, Soo-Yong Chatr-aryamontri, Andrew Wilbur, W. John TI Assisting manual literature curation for protein-protein interactions using BioQRator SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID TEXT; BIOLOGY; INFORMATION; ANNOTATION; ARTICLES AB The time-consuming nature of manual curation and the rapid growth of biomedical literature severely limit the number of articles that database curators can scrutinize and annotate. Hence, semi-automatic tools can be a valid support to increase annotation throughput. Although a handful of curation assistant tools are already available, to date, little has been done to formally evaluate their benefit to biocuration. Moreover, most curation tools are designed for specific problems. Thus, it is not easy to apply an annotation tool for multiple tasks. BioQRator is a publicly available web-based tool for annotating biomedical literature. It was designed to support general tasks, i. e. any task annotating entities and relationships. In the BioCreative IV edition, BioQRator was tailored for protein-protein interaction (PPI) annotation by migrating information from PIE the search. The results obtained from six curators showed that the precision on the top 10 documents doubled with PIE the search compared with PubMed search results. It was also observed that the annotation time for a full PPI annotation task decreased for a beginner-intermediate level annotator. This finding is encouraging because text-mining techniques were not directly involved in the full annotation task and BioQRator can be easily integrated with any text-mining resources. C1 [Kwon, Dongseop] Myongji Univ, Dept Comp Engn, Yongin 449728, South Korea. [Kim, Sun; Wilbur, W. John] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Shin, Soo-Yong] Asan Med Ctr, Dept Biomed Informat, Seoul 138736, South Korea. [Chatr-aryamontri, Andrew] Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada. RP Kwon, D (reprint author), Myongji Univ, Dept Comp Engn, Yongin 449728, South Korea. EM dongseop@mju.ac.kr; sun.kim@nih.gov FU National Research Foundation of Korea - Ministry of Education, Science and Technology [2012R1A1A2044389, 2011-0022437, 2012R1A1A2002804]; National Institutes of Health, National Library of Medicine FX Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012R1A1A2044389 and 2011-0022437 to D.K.) and (2012R1A1A2002804 to S.S.); Intramural Research Program of the National Institutes of Health, National Library of Medicine to S.K. and W.J.W. Funding for open access charge: Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 25 TC 7 Z9 7 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD JUL 22 PY 2014 AR bau067 DI 10.1093/database/bau067 PG 7 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AL8IP UT WOS:000339382100001 ER PT J AU Handel, A Lebarbenchon, C Stallknecht, D Rohani, P AF Handel, Andreas Lebarbenchon, Camille Stallknecht, David Rohani, Pejman TI Trade-offs between and within scales: environmental persistence and within-host fitness of avian influenza viruses SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE environmental persistence; avian influenza; mathematical model; multi-scale analysis ID A VIRUS; LIFE-HISTORY; CELL-CULTURE; TRANSMISSION; WATER; EVOLUTION; PATHOGENS; DYNAMICS; TEMPERATURE; INFECTIONS AB Trade-offs between different components of a pathogen's replication and transmission cycle are thought to be common. A number of studies have identified trade-offs that emerge across scales, reflecting the tension between strategies that optimize within-host proliferation and large-scale population spread. Most of these studies are theoretical in nature, with direct experimental tests of such cross-scale trade-offs still rare. Here, we report an analysis of avian influenza A viruses across scales, focusing on the phenotype of temperature-dependent viral persistence. Taking advantage of a unique dataset that reports both environmental virus decay rates and strain-specific viral kinetics from duck challenge experiments, we show that the temperature-dependent environmental decay rate of a strain does not impact within-host virus load. Hence, for this phenotype, the scales of within-host infection dynamics and between-host environmental persistence do not seem to interact: viral fitness may be optimized on each scale without cross-scale trade-offs. Instead, we confirm the existence of a temperature-dependent persistence trade-off on a single scale, with some strains favouring environmental persistence in water at low temperatures while others reduce sensitivity to increasing temperatures. We show that this temperature-dependent trade-off is a robust phenomenon and does not depend on the details of data analysis. Our findings suggest that viruses might employ different environmental persistence strategies, which facilitates the coexistence of diverse strains in ecological niches. We conclude that a better understanding of the transmission and evolutionary dynamics of influenza A viruses probably requires empirical information regarding both within-host dynamics and environmental traits, integrated within a combined ecological and within-host framework. C1 [Handel, Andreas] Univ Georgia, Coll Publ Hlth, Dept Epidemiol & Biostat, Athens, GA 30602 USA. [Stallknecht, David] Univ Georgia, Coll Vet Med, Dept Populat Hlth, Athens, GA 30602 USA. [Lebarbenchon, Camille] Univ Reun Isl, St Denis 97715, Reunion. [Rohani, Pejman] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Rohani, Pejman] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Handel, A (reprint author), Univ Georgia, Coll Publ Hlth, Dept Epidemiol & Biostat, Athens, GA 30602 USA. EM ahandel@uga.edu RI Lebarbenchon, Camille/H-7245-2013; OI Lebarbenchon, Camille/0000-0002-0922-7573; Handel, Andreas/0000-0002-4622-1146 FU James S. McDonnell Foundation; National Science Foundation [DEB-0917853]; RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX P.R. was supported by the James S. McDonnell Foundation, the National Science Foundation (DEB-0917853) and the RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. The opinions expressed herein are those of the author(s) and do not necessarily reflect the views of any of the funding agencies. NR 56 TC 8 Z9 8 U1 4 U2 34 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 EI 1471-2954 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD JUL 22 PY 2014 VL 281 IS 1787 AR 20133051 DI 10.1098/rspb.2013.3051 PG 9 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA AK3PC UT WOS:000338335800002 ER PT J AU Kikuchi, Y Horwitz, B Mishkin, M Rauschecker, JP AF Kikuchi, Yukiko Horwitz, Barry Mishkin, Mortimer Rauschecker, Josef P. TI Processing of harmonics in the lateral belt of macaque auditory cortex SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE communication calls; harmonics; macaques; auditory cortex; single-unit; multi-peaked neurons ID COMBINATION-SENSITIVE NEURONS; RHESUS-MONKEY; FUNCTIONAL SPECIALIZATION; RESPONSE PROPERTIES; SENSORY CONSONANCE; COMPLEX SOUNDS; TUNING CURVES; CAT; PERCEPTION; MUSIC AB Many speech sounds and animal vocalizations contain components, referred to as complex tones, that consist of a fundamental frequency (F0) and higher harmonics. In this study we examined single-unit activity recorded in the core (A1) and lateral belt (LB) areas of auditory cortex in two rhesus monkeys as they listened to pure tones and pitch-shifted conspecific vocalizations ("coos"). The latter consisted of complex-tone segments in which F0 was matched to a corresponding pure-tone stimulus. In both animals, neuronal latencies to pure-tone stimuli at the best frequency (BF) were similar to 10 to 15 ms longer in LB than in A1. This might be expected, since LB is considered to be at a hierarchically higher level than A1. On the other hand, the latency of LB responses to coos was similar to 10 to 20 ms shorter than to the corresponding pure-tone BE suggesting facilitation in LB by the harmonics. This latency reduction by coos was not observed in A1, resulting in similar coo latencies in A1 and LB. Multi-peaked neurons were present in both A1 and LB; however, harmonically-related peaks were observed in LB for both early and late response components, whereas in A1 they were observed only for late components. Our results suggest that harmonic features, such as relationships between specific frequency intervals of communication calls, are processed at relatively early stages of the auditory cortical pathway, but preferentially in LB. C1 [Kikuchi, Yukiko; Rauschecker, Josef P.] George Washington Univ, Med Ctr, Dept Neurosci, Washington, DC 20037 USA. [Kikuchi, Yukiko; Horwitz, Barry] Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, Voice Speech & Language Branch, NIH, Bethesda, MD USA. [Kikuchi, Yukiko; Mishkin, Mortimer] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Kikuchi, Y (reprint author), Newcastle Univ, Sch Med, Inst Neurosci, Henry Wellcome Bldg,Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. EM yukiko.kikuchi@newcastle.ac.uk FU National Institutes of Health [R01 N5052494, R56 N5052494-06A1]; National Science Foundation (FIRE) [OISE-0730255]; Intramural Research Program of NIMH; Intramural Research Program of NIDCD FX The authors thank M. Lawson, C. Silver, M. P. Mullarkey, and J. Lee for animal care and assistance with the experiments, P. Kusmierek for preparation of the acoustic stimuli, M. Ortiz for technical advice with AFNI, K. King for audiological screening, and P. Kusmierek, B. Scott, M. Sutter, S. Baumann, and M. Fukushima for discussion. This work was supported by grants from the National Institutes of Health (R01 N5052494, R56 N5052494-06A1) and the National Science Foundation (FIRE grant OISE-0730255) to Josef P. Rauschecker, and by the Intramural Research Programs of NIMH and NIDCD. NR 48 TC 6 Z9 6 U1 0 U2 3 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD JUL 21 PY 2014 VL 8 AR 204 DI 10.3389/fnins.2014.00204 PG 13 WC Neurosciences SC Neurosciences & Neurology GA AW8GQ UT WOS:000346499900002 PM 25100935 ER PT J AU Schovanek, J Martucci, V Wesley, R Fojo, T del Rivero, J Huynh, T Adams, K Kebebew, E Frysak, Z Stratakis, CA Pacak, K AF Schovanek, Jan Martucci, Victoria Wesley, Robert Fojo, Tito del Rivero, Jaydira Thanh Huynh Adams, Karen Kebebew, Electron Frysak, Zdenek Stratakis, Constantine A. Pacak, Karel TI The size of the primary tumor and age at initial diagnosis are independent predictors of the metastatic behavior and survival of patients with SDHB-related pheochromocytoma and paraganglioma: a retrospective cohort study SO BMC CANCER LA English DT Article DE Pheochromocytoma; Paraganglioma; Size; Age; SDHB; Metastatic; Survival ID GENE-MUTATIONS AB Background: Succinate dehydrogenase subunit B (SDHB) mutations are associated with aggressive pheochromocytoma (PHEO)/paraganglioma (PGL) behavior, often resulting in metastatic disease and fatal outcomes. These tumors are often larger, extra-adrenal, and contain lower catecholamine concentrations than other hereditary PHEOs/PGLs. This study evaluated the size and age at diagnosis of primary SDHB-related PHEOs/PGLs as independent predictors of their metastatic behavior and outcome (survival). Methods: One hundred six patients with SDHB mutation-related PHEO/PGL were included in this retrospective study. The recorded largest diameters, locations, and patient ages at initial diagnosis of SDHB-related primary tumors were analyzed in the context of time to metastasis and patient survival. Results: First, the development of metastatic disease in patients with primary tumors >= 4.5 cm was significantly earlier than in patients with smaller tumors (P = 0.003). Second, patients with primary tumors larger than 5.5 cm also had worse overall survival than patients with smaller tumors (P = 0.008). Third, age at initial diagnosis was found to be an independent predictor of patient survival (PHEOs: P = 0.041; PGLs: P < 0.001). Fourth, we did not observe a significant difference in survival based on the specific SDHB mutations or patient sex. Conclusion: Receiver operating characteristic curves established 4.5 cm as the best value to dichotomize the primary SDHB-related PHEO/PGL in order to evaluate the development of metastatic disease and 5.5 cm as the best value for survival prediction. Subsequently, the size of the primary tumor was found as an age-independent predictor of patient survival and metastases development in PGL. In both PHEO and PGL, age at diagnosis was found to be a size-independent predictor of patient survival. No significant difference was found in metastases development or patient survival between males and females or among specific SDHB mutations. This data further extends and supports previous recommendations that carriers with SDHB mutations must undergo early and regular evaluations to detect PHEO/PGL in order to achieve the best clinical outcome. C1 [Schovanek, Jan; Martucci, Victoria; del Rivero, Jaydira; Thanh Huynh; Adams, Karen; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, CRC, Bethesda, MD 20892 USA. [Schovanek, Jan; Frysak, Zdenek] Palacky Univ, Fac Med & Dent, Dept Internal Med Nephrol Rheumatol & Endocrinol, CR-77147 Olomouc, Czech Republic. [Wesley, Robert] NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Fojo, Tito] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, CRC, Bldg 10,Room 1E-3140,10 Ctr Dr MSC 1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver NICHD, NIH FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver NICHD, NIH. NR 24 TC 5 Z9 5 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JUL 21 PY 2014 VL 14 AR 523 DI 10.1186/1471-2407-14-523 PG 9 WC Oncology SC Oncology GA AM6JN UT WOS:000339970800002 PM 25048685 ER PT J AU Almeida-Suhett, CP Prager, EM Pidoplichko, V Figueiredo, TH Marini, AM Li, Z Eiden, LE Braga, MFM AF Almeida-Suhett, Camila P. Prager, Eric M. Pidoplichko, Volodymyr Figueiredo, Taiza H. Marini, Ann M. Li, Zheng Eiden, Lee E. Braga, Maria F. M. TI Reduced GABAergic Inhibition in the Basolateral Amygdala and the Development of Anxiety-Like Behaviors after Mild Traumatic Brain Injury SO PLOS ONE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; CONTROLLED CORTICAL IMPACT; NICOTINIC ACETYLCHOLINE-RECEPTORS; PANIC DISORDER; BENZODIAZEPINE-RECEPTOR; SYNAPTIC-TRANSMISSION; PREFRONTAL CORTEX; FUNCTIONAL MRI; BINDING; SENSITIVITY AB Traumatic brain injury (TBI) is a major public health concern affecting a large number of athletes and military personnel. Individuals suffering from a TBI risk developing anxiety disorders, yet the pathophysiological alterations that result in the development of anxiety disorders have not yet been identified. One region often damaged by a TBI is the basolateral amygdala (BLA); hyperactivity within the BLA is associated with increased expression of anxiety and fear, yet the functional alterations that lead to BLA hyperexcitability after TBI have not been identified. We assessed the functional alterations in inhibitory synaptic transmission in the BLA and one mechanism that modulates excitatory synaptic transmission, the alpha(7) containing nicotinic acetylcholine receptor (alpha(7)-nAChR), after mTBI, to shed light on the mechanisms that contribute to increased anxiety-like behaviors. Seven and 30 days after a mild controlled cortical impact (CCI) injury, animals displayed significantly greater anxiety-like behavior. This was associated with a significant loss of GABAergic interneurons and significant reductions in the frequency and amplitude of spontaneous and miniature GABA(A)-receptor mediated inhibitory postsynaptic currents (IPSCs). Decreases in the mIPSC amplitude were associated with reduced surface expression of alpha 1, beta 2, and gamma 2 GABA(A) receptor subunits. However, significant increases in the surface expression and current mediated by alpha(7)-nAChR, were observed, signifying increases in the excitability of principal neurons within the BLA. These results suggest that mTBI causes not only a significant reduction in inhibition in the BLA, but also an increase in neuronal excitability, which may contribute to hyperexcitability and the development of anxiety disorders. C1 [Almeida-Suhett, Camila P.; Prager, Eric M.; Marini, Ann M.; Braga, Maria F. M.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Program Neurosci, Bethesda, MD 20814 USA. [Pidoplichko, Volodymyr; Figueiredo, Taiza H.; Braga, Maria F. M.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. [Marini, Ann M.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Neurol, Bethesda, MD 20814 USA. [Almeida-Suhett, Camila P.; Marini, Ann M.; Li, Zheng; Eiden, Lee E.; Braga, Maria F. M.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Li, Zheng] NIMH, Sect Clin Studies, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Eiden, Lee E.] NIMH, Mol Neurosci Sect, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Braga, MFM (reprint author), Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Program Neurosci, Bethesda, MD 20814 USA. EM maria.braga@usuhs.edu RI Li, Zheng/I-8016-2014; Prager, Eric/O-1567-2015; OI Li, Zheng/0000-0002-2978-2531; Prager, Eric/0000-0002-3810-0985; Eiden, Lee/0000-0001-7524-944X FU Department of Defense in the Center for Neuroscience and Regenerative Medicine [G1702Z] FX The authors acknowledge the Department of Defense in the Center for Neuroscience and Regenerative Medicine for financially supporting the present work. Grant# G1702Z. URL of funder's website: http://www.usuhs.mil/cnrm/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 72 TC 17 Z9 17 U1 2 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 21 PY 2014 VL 9 IS 7 AR e102627 DI 10.1371/journal.pone.0102627 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM0SW UT WOS:000339558100054 PM 25047645 ER PT J AU Jain, M Zhang, L Boufraqech, M Liu-Chittenden, Y Bussey, K Demeure, MJ Wu, XL Su, L Pacak, K Stratakis, CA Kebebew, E AF Jain, Meenu Zhang, Lisa Boufraqech, Myriem Liu-Chittenden, Yi Bussey, Kimberly Demeure, Michael J. Wu, Xiaolin Su, Ling Pacak, Karel Stratakis, Constantine A. Kebebew, Electron TI ZNF367 Inhibits Cancer Progression and Is Targeted by miR-195 SO PLOS ONE LA English DT Article ID GROWTH; CELLS; TUMOR; GENE; IDENTIFICATION; INVASION; PROLIFERATION; ASSOCIATION; METASTASIS; RESISTANCE AB Background: Several members of the zinc finger protein family have been recently shown to have a role in cancer initiation and progression. Zinc finger protein 367 (ZNF367) is a member of the zinc finger protein family and is expressed in embryonic or fetal erythroid tissue but is absent in normal adult tissue. Methodology/Principal Findings: We show that ZNF367 is overexpressed in adrenocortical carcinoma, malignant pheochromocytoma/paraganglioma and thyroid cancer as compared to normal tissue and benign tumors. Using both functional knockdown and ectopic overexpression in multiple cell lines, we show that ZNF367 inhibits cellular proliferation, invasion, migration, and adhesion to extracellular proteins in vitro and in vivo. Integrated gene and microRNA expression analyses showed an inverse correlation between ZNF367 and miR-195 expression. Luciferase assays demonstrated that miR-195 directly regulates ZNF367 expression and that miR-195 regulates cellular invasion. Moreover, integrin alpha 3 (ITGA3) expression was regulated by ZNF367. Conclusions/Significance: Our findings taken together suggest that ZNF367 regulates cancer progression. C1 [Jain, Meenu; Zhang, Lisa; Boufraqech, Myriem; Liu-Chittenden, Yi; Kebebew, Electron] NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bussey, Kimberly; Demeure, Michael J.] Translat Genom Res Inst, Phoenix, AZ USA. [Wu, Xiaolin; Su, Ling] SAIC Frederick Inc, Lab Mol Technol, Frederick Natl Lab Canc Res, Frederick, MD USA. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth, Sect Med Neuroendocrinol, NIH, Bethesda, MD USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth, Sect Endocrinol & Genet, NIH, Bethesda, MD USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov RI Boufraqech, Myriem/E-4823-2016; OI Bussey, Kimberly/0000-0003-1001-8207; Liu-Chittenden, Yi/0000-0001-6357-5360 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 9 Z9 10 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 21 PY 2014 VL 9 IS 7 AR e101423 DI 10.1371/journal.pone.0101423 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM0SW UT WOS:000339558100009 PM 25047265 ER PT J AU Martins, I Hartmann, DO Alves, PC Martins, C Garcia, H Leclercq, CC Ferreira, R He, J Renaut, J Becker, JD Pereira, CS AF Martins, Isabel Hartmann, Diego O. Alves, Paula C. Martins, Celso Garcia, Helga Leclercq, Celine C. Ferreira, Rui He, Ji Renaut, Jenny Becker, Joerg D. Pereira, Cristina Silva TI Elucidating how the saprophytic fungus Aspergillus nidulans uses the plant polyester suberin as carbon source SO BMC GENOMICS LA English DT Article DE Aspergillus nidulans; beta-oxidation; Cutinase; Long chain fatty acids; Suberin; Whole-genome profiling ID SACCHAROMYCES-CEREVISIAE; SECONDARY METABOLISM; FUSARIUM-OXYSPORUM; IONIC LIQUIDS; ALKYLTRIBUTYLPHOSPHONIUM CHLORIDES; EXTRACELLULAR PROTEINASE; TRANSCRIPTOME ANALYSIS; SEXUAL DEVELOPMENT; ABC TRANSPORTERS; BETA-OXIDATION AB Background: Lipid polymers in plant cell walls, such as cutin and suberin, build recalcitrant hydrophobic protective barriers. Their degradation is of foremost importance for both plant pathogenic and saprophytic fungi. Regardless of numerous reports on fungal degradation of emulsified fatty acids or cutin, and on fungi-plant interactions, the pathways involved in the degradation and utilisation of suberin remain largely overlooked. As a structural component of the plant cell wall, suberin isolation, in general, uses harsh depolymerisation methods that destroy its macromolecular structure. We recently overcame this limitation isolating suberin macromolecules in a near-native state. Results: Suberin macromolecules were used here to analyse the pathways involved in suberin degradation and utilisation by Aspergillus nidulans. Whole-genome profiling data revealed the complex degrading enzymatic machinery used by this saprophytic fungus. Initial suberin modification involved ester hydrolysis and.-hydroxy fatty acid oxidation that released long chain fatty acids. These fatty acids were processed through peroxisomal beta-oxidation, leading to up-regulation of genes encoding the major enzymes of these pathways (e.g. faaB and aoxA). The obtained transcriptome data was further complemented by secretome, microscopic and spectroscopic analyses. Conclusions: Data support that during fungal growth on suberin, cutinase 1 and some lipases (e.g. AN8046) acted as the major suberin degrading enzymes (regulated by FarA and possibly by some unknown regulatory elements). Suberin also induced the onset of sexual development and the boost of secondary metabolism. C1 [Martins, Isabel; Hartmann, Diego O.; Alves, Paula C.; Martins, Celso; Garcia, Helga; Ferreira, Rui; Pereira, Cristina Silva] Univ Nova Lisboa, Inst Tecnol Quim & Biol, P-2780157 Oeiras, Portugal. [Martins, Celso; Pereira, Cristina Silva] Inst Biol Expt & Tecnol, P-2781901 Oeiras, Portugal. [Leclercq, Celine C.; Renaut, Jenny] Ctr Rech Publ Gabriel Lippmann, Prote Platform, Belvaux, Luxembourg. [He, Ji] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, NIH,DHHS, Gaithersburg, MD 20877 USA. [He, Ji] Samuel Roberts Noble Fdn Inc, Dept Comp Sci, Ardmore, OK USA. [Becker, Joerg D.] Inst Gulbenkian Ciencias, P-2780156 Oeiras, Portugal. RP Pereira, CS (reprint author), Univ Nova Lisboa, Inst Tecnol Quim & Biol, Av Republ, P-2780157 Oeiras, Portugal. EM spereira@itqb.unl.pt RI Martins, Celso/I-8391-2014; Ferreira, Rui/B-5550-2008; Martins, Isabel/I-7255-2012; Becker, Jorg/A-5930-2011; Silva Pereira, Cristina /F-3150-2011; Hartmann, Diego/E-6904-2013; OI Martins, Celso/0000-0002-8269-9550; Ferreira, Rui/0000-0002-0215-7197; Martins, Isabel/0000-0002-0136-1671; Becker, Jorg/0000-0002-6845-6122; Hartmann, Diego/0000-0002-6399-5020; Alves, Paula Cristina/0000-0001-7162-0053 FU Iceland, Liechtenstein and Norway through the EEA financial mechanism [PT015]; FCT [PEst-OE/EQB/LA0004/2013, PTDC/QUI-QUI/120982/2010, PTDC/AAC-CLI/119100/2010]; Fundacao para a Ciencia e a Tecnologia (FCT), Portugal [SFRH/BD/38378/2007, SFRH/BD/66396/2009, SFRH/BD/66030/2009, SFRH/BD/48286/2008]; Fundacao Calouste Gulbenkian, Portugal FX The work was partially supported by a grant from Iceland, Liechtenstein and Norway through the EEA financial mechanism (Project PT015), and FCT through the grants PEst-OE/EQB/LA0004/2013, PTDC/QUI-QUI/120982/2010 and PTDC/AAC-CLI/119100/2010.; IM, DOH, PCA and RF are grateful to Fundacao para a Ciencia e a Tecnologia (FCT), Portugal, for the fellowships SFRH/BD/38378/2007, SFRH/BD/66396/2009, SFRH/BD/66030/2009, SFRH/BD/48286/2008, respectively and HG to Fundacao Calouste Gulbenkian, Portugal for the fellowship 21-95587-B. We are thankful to Dr. Tiago Martins (ITQB), who read and critically commented the final manuscript. NR 103 TC 9 Z9 9 U1 3 U2 56 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUL 21 PY 2014 VL 15 AR 613 DI 10.1186/1471-2164-15-613 PG 19 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AM1EZ UT WOS:000339590500002 PM 25043916 ER PT J AU Wallen, GR Minniti, CP Krumlauf, M Eckes, E Allen, D Oguhebe, A Seamon, C Darbari, DS Hildesheim, M Yang, L Schulden, JD Kato, GJ Vi, JG AF Wallen, Gwenyth R. Minniti, Caterina P. Krumlauf, Michael Eckes, Ellen Allen, Darlene Oguhebe, Anna Seamon, Cassie Darbari, Deepika S. Hildesheim, Mariana Yang, Li Schulden, Jeffrey D. Kato, Gregory J. Taylor, James G. V., I TI Sleep disturbance, depression and pain in adults with sickle cell disease SO BMC PSYCHIATRY LA English DT Article DE Sickle cell disease; Sleep disturbance; Depression; Chronic pain; Patient reported outcomes; Bethesda sickle cell cohort study ID QUALITY-OF-LIFE; PISCES PROJECT; RISK-FACTORS; CHILDREN; ANEMIA; MANAGEMENT; INVENTORY; SEVERITY; ANXIETY; DEATH AB Background: Sleep disturbance and depression are commonly encountered in primary care. In sickle cell disease, depression is associated with pain, poor treatment compliance, and lower quality of life. The prevalence of sleep disturbance and its effect upon quality of life in adults with sickle cell disease is unknown. The goal of this study was to determine the prevalence of sleep disturbance and if it is associated with pain and depression in sickle cell disease. Methods: Three hundred twenty eight adults with sickle cell disease enrolled on the Bethesda Sickle Cell Cohort Study were assessed using the Pittsburgh Sleep Quality Index and Beck Depression Inventory II screening measures as a cross-sectional survey. Scores greater than 5 (Pittsburgh Sleep Quality Index) and 16 (Beck Depression Inventory II) defined sleep disturbance and depression, respectively. Clinical and laboratory parameters were also assessed. Results: The mean Pittsburgh Sleep Quality Index score was 8.4 (SD +/- 4.2) indicating a 71.2% prevalence of sleep disturbance. The mean Beck Depression Inventory II score was 8.0 (SD +/- 8.9). Sixty five (20.6%) participants had a score indicating depression, and half of these (10.0%) had thoughts of suicide. Both Pittsburgh Sleep Quality Index and Beck Depression Inventory II scores were significantly correlated (p < .001). The number of days with mild/moderate pain (p = .001) and a history of headaches (p = .005) were independently associated with depression by multivariate regression analysis. Patients with sleep disturbance were older (p = .002), had higher body mass index (p = .011), had more days of pain (p = .003) and more frequent severe acute painful events (emergency room visits and hospitalizations) during the previous 12 months (p < .001). Conclusions: More than 70 percent of adults with sickle cell disease had sleep disturbance, while 21 percent showed evidence of clinical depression. Sleep disturbance and depression were correlated, and were most common among those with more frequent pain. Providers caring for adults with sickle cell disease and frequent pain should consider screening for these common co-morbidities. Additional study is needed to confirm these findings and to determine if treatments for pain, depression or sleep disturbances will improve quality of life measures in this patient population. C1 [Wallen, Gwenyth R.; Krumlauf, Michael; Eckes, Ellen; Yang, Li] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Minniti, Caterina P.; Allen, Darlene; Oguhebe, Anna; Seamon, Cassie; Darbari, Deepika S.; Hildesheim, Mariana; Kato, Gregory J.; Taylor, James G. V., I] NHLBI, Hematol Branch, Genom Med Sect, Bethesda, MD 20892 USA. [Darbari, Deepika S.] Childrens Natl Med Ctr, Ctr Canc & Blood Dis, Washington, DC USA. [Schulden, Jeffrey D.] Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, NIH, Bethesda, MD USA. RP Vi, JG (reprint author), NHLBI, Hematol Branch, Genom Med Sect, Bldg 10-CRC,Room 5-5140 MSC 1476, Bethesda, MD 20892 USA. EM jamesta@mail.nih.gov RI Kato, Gregory/I-7615-2014; OI Kato, Gregory/0000-0003-4465-3217; Taylor, James/0000-0002-4421-1809 FU NHLBI Intramural Research program, National Institutes of Health [1 ZIA HL006012 04]; National Institutes of Health Clinical Center FX We thank the patients and their families for study participation and the OP7 Clinic Nursing staff at the NIH Clinical Center for providing exceptional clinical care during the course of this study. This work was supported by the NHLBI Intramural Research program, National Institutes of Health (1 ZIA HL006012 04) and the intramural program at the National Institutes of Health Clinical Center. NR 37 TC 11 Z9 11 U1 3 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-244X J9 BMC PSYCHIATRY JI BMC Psychiatry PD JUL 21 PY 2014 VL 14 AR 207 DI 10.1186/1471-244X-14-207 PG 8 WC Psychiatry SC Psychiatry GA AM0FR UT WOS:000339519900001 PM 25047658 ER PT J AU McGlinchey, RP Jiang, ZP Lee, JC AF McGlinchey, Ryan P. Jiang, Zhiping Lee, Jennifer C. TI Molecular Origin of pH-Dependent Fibril Formation of a Functional Amyloid SO CHEMBIOCHEM LA English DT Article DE melanin; Pmel17; repeat domains; transmission electron microscopy; tryptophan ID REPEAT DOMAIN; PMEL17; AGGREGATION; GRANULES; INSIGHTS; FIBERS AB Fibrils derived from Pmel17 are functional amyloids upon which melanin is deposited. Fibrils of the repeat domain (RPT) of Pmel17 form under strict melanosomal pH (4.5-5.5) and completely dissolve at pH > 6. To determine which Glu residue is responsible for this reversibility, aggregation of single, double, and quadruple Ala and Gln mutants were examined by intrinsic Trp fluorescence, circular dichroism spectroscopy, and transmission electron microscopy. Charge neutralization of E404, E422, E425, or E430, which are located in the putative amyloid-forming region, modulated aggregation kinetics. Remarkably, the removal of a single negative charge at E422, one of 16 carboxylic acids, shifted the pH dependence by a full pH unit. Mutation at E404, E425, or E430 had little to no effect. We suggest that protonation at E422 is essential for initiating amyloid formation and that the other Glu residues play an allosteric role in fibril stability. C1 [McGlinchey, Ryan P.; Jiang, Zhiping; Lee, Jennifer C.] NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Lee, JC (reprint author), NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM leej4@mail.nih.gov FU Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute FX Supported by the Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute. TEM and CD data were collected in the NHLBI EM and Biophysics Core Facilities. NR 22 TC 5 Z9 5 U1 2 U2 17 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1439-4227 EI 1439-7633 J9 CHEMBIOCHEM JI ChemBioChem PD JUL 21 PY 2014 VL 15 IS 11 BP 1569 EP 1572 DI 10.1002/cbic.201402074 PG 4 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA AL9ZT UT WOS:000339502900004 PM 24954152 ER PT J AU Smith, CL Varoqueaux, F Kittelmann, M Azzam, RN Cooper, B Winters, CA Eitel, M Fasshauer, D Reese, TS AF Smith, Carolyn L. Varoqueaux, Frederique Kittelmann, Maike Azzam, Rita N. Cooper, Benjamin Winters, Christine A. Eitel, Michael Fasshauer, Dirk Reese, Thomas S. TI Novel Cell Types, Neurosecretory Cells, and Body Plan of the Early-Diverging Metazoan Trichoplax adhaerens SO CURRENT BIOLOGY LA English DT Article ID RHABDOCALYPTUS-DAWSONI LAMBE; HEXACTINELLID SPONGES; GENOME REVEALS; EVOLUTION; PLACOZOA; GENE; NEUROPEPTIDES; ORGANIZATION; LOCOMOTION; CONDUCTION AB Background: Trichoplax adhaerens is the best-known member of the phylum Placozoa, one of the earliest-diverging metazoan phyla. It is a small disk-shaped animal that glides on surfaces in warm oceans to feed on algae. Prior anatomical studies of Trichoplax revealed that it has a simple three-layered organization with four somatic cell types. Results: We reinvestigate the cellular organization of Trichoplax using advanced freezing and microscopy techniques to identify localize and count cells. Six somatic cell types are deployed in stereotyped positions. A thick ventral plate, comprising the majority of the cells, includes ciliated epithelial cells, newly identified lipophil cells packed with large lipid granules, and gland cells. Lipophils project deep into the interior, where they alternate with regularly spaced fiber cells whose branches contact all other cell types, including cells of the dorsal and ventral epithelium. Crystal cells, each containing a birefringent crystal, are arrayed around the rim. Gland cells express several proteins typical of neurosecretory cells, and a subset of them, around the rim, also expresses an FMRFamide-like neuropeptide. Conclusions: Structural analysis of Trichoplax with significantly improved techniques provides an advance in understanding its cell types and their distributions. We find two previously undetected cell types, lipohil and crystal cells, and an organized body plan in which different cell types are arranged in distinct patterns. The composition of gland cells suggests that they are neurosecretory cells and could control locomotor and feeding behavior. C1 [Smith, Carolyn L.; Azzam, Rita N.; Winters, Christine A.; Reese, Thomas S.] NINDS, NIH, Bethesda, MD 20892 USA. [Varoqueaux, Frederique; Kittelmann, Maike; Cooper, Benjamin] Max Planck Inst Expt Med, Dept Mol Neurobiol, D-37075 Gottingen, Germany. [Varoqueaux, Frederique; Fasshauer, Dirk] Univ Lausanne, Dept Fundamental Neurosci, CH-1005 Lausanne, Switzerland. [Eitel, Michael] TiHo Hannover, Inst Tierokol & Zellbiol, D-30559 Hannover, Germany. RP Smith, CL (reprint author), NINDS, NIH, Bethesda, MD 20892 USA. EM smithca@ninds.nih.gov; dirk.fasshauer@unil.ch RI Fasshauer, Dirk/B-1563-2013; OI Fasshauer, Dirk/0000-0002-1040-4282; Kittelmann, Maike/0000-0002-9710-1136; Eitel, Michael/0000-0002-0531-0732 FU National Institute of Neurological Disorders and Stroke intramural program FX We thank Leo Buss and Bernd Schierwater for providing us with Trichoplax adhaerens and cultivation advice and Joan Barrick, Soe Thein, Vincent Schram, Carolin Wichman, Jan Hegermann, Stefan Eimer, Cordelia Imig, Klaus Hellmann, and Nils Brose for support. Alan Hoofring (NIH Medical Arts) produced the graphics for the graphical abstract and Figure 7. This work was supported by the National Institute of Neurological Disorders and Stroke intramural program. NR 46 TC 33 Z9 33 U1 6 U2 35 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD JUL 21 PY 2014 VL 24 IS 14 BP 1565 EP 1572 DI 10.1016/j.cub.2014.05.046 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AL9MR UT WOS:000339465900017 PM 24954051 ER PT J AU Rahman, M Nirala, NK Singh, A Zhu, LJ Taguchi, K Bamba, T Fukusaki, E Shaw, LM Lambright, DG Acharya, JK Acharya, UR AF Rahman, Motiur Nirala, Niraj K. Singh, Alka Zhu, Lihua Julie Taguchi, Kaori Bamba, Takeshi Fukusaki, Eiichiro Shaw, Leslie M. Lambright, David G. Acharya, Jairaj K. Acharya, Usha R. TI Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase beta and regulates complex V activity SO JOURNAL OF CELL BIOLOGY LA English DT Article ID LYSINE ACETYLATION; MITOCHONDRIAL PROTEINS; CALORIE RESTRICTION; METABOLISM; STRESS; HOMEOSTASIS; ACETYLOME; PATHWAYS; DISEASE; CANCER AB Adenosine triphosphate (ATP) synthase beta, the catalytic subunit of mitochondrial complex V, synthesizes ATP. We show that ATP synthase beta is deacetylated by a human nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylase, sirtuin 3, and its Drosophila melanogaster homologue dsirt2., dsirt2 mutant flies displayed increased acetylation of specific Lys residues in ATP synthase beta and decreased complex V activity. Overexpression of dSirt2 increased complex V activity. Substitution of Lys 259 and Lys 480 with Arg in human ATP synthase beta, mimicking deacetylotion, increased complex V activity, whereas substitution with Gin, mimicking acetylation, decreased activity. Mass spectrometry and proteomic experiments from wild-type and dsirt2 mitochondria identified the Drosophila mitochondrial acetylome and revealed dSirt2 as an important regulator of mitochondria' energy metabolism. Additionally, we unravel a ceramide-NAD(+)-sirtuin axis wherein increased ceramide, a sphingolipid known to induce stress responses, resulted in depletion of NAD(+) and consequent decrease in sirtuin activity. These results provide insight into sirtuin-mediated regulation of complex V and reveal a novel link between ceramide and Drosophila acetylome. C1 [Rahman, Motiur; Nirala, Niraj K.; Singh, Alka; Zhu, Lihua Julie; Acharya, Usha R.] Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. [Rahman, Motiur; Nirala, Niraj K.; Singh, Alka; Zhu, Lihua Julie; Lambright, David G.; Acharya, Usha R.] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. [Zhu, Lihua Julie] Univ Massachusetts, Sch Med, Program Bioinformat & Integrat Biol, Worcester, MA 01605 USA. [Shaw, Leslie M.] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA. [Taguchi, Kaori; Bamba, Takeshi; Fukusaki, Eiichiro] Osaka Univ, Grad Sch Engn, Dept Biotechnol, Osaka 5650871, Japan. [Acharya, Jairaj K.] NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. RP Acharya, UR (reprint author), Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. EM usha.acharya@umassmed.edu FU National Institutes of Health [R01EY016469] FX This research is supported by a National Institutes of Health grant (R01EY016469) to U.R. Acharya. NR 68 TC 26 Z9 26 U1 0 U2 9 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD JUL 21 PY 2014 VL 206 IS 2 BP 289 EP 305 DI 10.1083/jcb.201404118 PG 17 WC Cell Biology SC Cell Biology GA AL9LG UT WOS:000339462000013 PM 25023514 ER PT J AU Makarova, KS Krupovic, M Koonin, EV AF Makarova, Kira S. Krupovic, Mart Koonin, Eugene V. TI Evolution of replicative DNA polymerases in archaea and their contributions to the eukaryotic replication machinery SO FRONTIERS IN MICROBIOLOGY LA English DT Review DE DNA replication; archaea; mobile genetic elements; DNA polymerases; enzyme inactivation ID THERMOCOCCUS-KODAKARENSIS; SULFOLOBUS-SOLFATARICUS; STRUCTURAL INSIGHTS; FAMILY POLYMERASES; HALOPHILIC ARCHAEA; ESCHERICHIA-COLI; PROTEINS; GENOME; VIRUS; PRIMASE AB The elaborate eukaryotic DNA replication machinery evolved from the archaeal ancestors that themselves show considerable complexity. Here we discuss the comparative genomic and phylogenetic analysis of the core replication enzymes, the DNA polymerases, in archaea and their relationships with the eukaryotic polymerases. In archaea, there are three groups of family B DNA polymerases, historically known as PolB1, PolB2 and PolB3. All three groups appear to descend from the last common ancestors of the extant archaea but their subsequent evolutionary trajectories seem to have been widely different. Although PolB3 is present in all archaea, with the exception of Thaumarchaeota, and appears to be directly involved in lagging strand replication, the evolution of this gene does not follow the archaeal phylogeny, conceivably due to multiple horizontal transfers and/or dramatic differences in evolutionary rates. In contrast, PolB1 is missing in Euryarchaeota but otherwise seems to have evolved vertically. The third archaeal group of family B polymerases, PolB2, includes primarily proteins in which the catalytic centers of the polymerase and exonuclease domains are disrupted and accordingly the enzymes appear to be inactivated. The members of the PolB2 group are scattered across archaea and might be involved in repair or regulation of replication along with inactivated members of the RadA family ATPases and an additional, uncharacterized protein that are encoded within the same predicted operon. In addition to the family B polymerases, all archaea, with the exception of the Crenarchaeota, encode enzymes of a distinct family D the origin of which is unclear. We examine multiple considerations that appear compatible with the possibility that family D polymerases are highly derived homologs of family B. The eukaryotic DNA polymerases show a highly complex relationship with their archaeal ancestors including contributions of proteins and domains from both the family B and the family D archaeal polymerases. C1 [Makarova, Kira S.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. [Krupovic, Mart] Inst Pasteur, Unite Biol Molculaire Gene Extremphiles, Paris, France. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bldg 38A Room 5N503,8600 Rockville Pike, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov RI Krupovic, Mart/I-4209-2012 OI Krupovic, Mart/0000-0001-5486-0098 FU US Department of Health and Human Services; European Molecular Biology Organization [ASTF 82-2014] FX Eugene V. Koonin and Kira S. Makarova are supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). Mart Krupovic was partly supported by the European Molecular Biology Organization (ASTF 82-2014). NR 67 TC 14 Z9 15 U1 7 U2 26 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD JUL 21 PY 2014 VL 5 AR 354 DI 10.3389/fmicb.2014.00354 PG 10 WC Microbiology SC Microbiology GA AL6XM UT WOS:000339277000001 PM 25101062 ER PT J AU te Riele, ASJM Tandri, H Bluemke, DA AF te Riele, Anneline S. J. M. Tandri, Harikrishna Bluemke, David A. TI Arrhythmogenic right ventricular cardiomyopathy (ARVC): cardiovascular magnetic resonance update SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Review DE Arrhythmogenic right ventricular cardiomyopathy; Cardiovascular magnetic resonance; Diagnosis; Genetics; Treatment ID TASK-FORCE CRITERIA; STATE FREE PRECESSION; DESMOSOMAL MUTATION CARRIERS; BROADEN DIAGNOSTIC-CRITERIA; AMERICAN-HEART-ASSOCIATION; SINGLE-CENTER EXPERIENCE; FAST GRADIENT-ECHO; DILATED CARDIOMYOPATHY; EPICARDIAL SUBSTRATE; CATHETER ABLATION AB Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is one of the most arrhythmogenic forms of inherited cardiomyopathy and a frequent cause of sudden death in the young. Affected individuals typically present between the second and fourth decade of life with arrhythmias coming from the right ventricle. Pathogenic mutations in genes encoding the cardiac desmosome can be found in approximately 60% of index patients, leading to our current perception of ARVC as a desmosomal disease. Although ARVC is known to preferentially affect the right ventricle, early and/or predominant left ventricular involvement is increasingly recognized. Diagnosis is made by combining multiple sources of diagnostic information as prescribed by the "Task Force" criteria. Recent research suggests that electrical abnormalities precede structural changes in ARVC. Cardiovascular Magnetic Resonance (CMR) is an ideal technique in ARVC workup, as it provides comprehensive information on cardiac morphology, function, and tissue characterization in a single investigation. Prevention of sudden cardiac death using implantable cardioverter-defibrillators is the most important management consideration. This purpose of this paper is to provide an updated review of our understanding of the genetics, diagnosis, current state-of-the-art CMR acquisition and analysis, and management of patients with ARVC. C1 [te Riele, Anneline S. J. M.] Univ Med Ctr Utrecht, Dept Med, Div Cardiol, Utrecht, Netherlands. [te Riele, Anneline S. J. M.; Tandri, Harikrishna] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Bluemke, David A.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. EM david.bluemke@nih.gov OI Bluemke, David/0000-0002-8323-8086 FU Alexandre Suerman Stipend; National Heart, Lung, and Blood Institute [K23HL093350]; Dr. Francis P. Chiaramonte Private Foundation; St. Jude Medical Foundation; Medtronic Inc.; NIH intramural research program; Dr. Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins; Bogle Foundation; Healing Hearts Foundation; Campanella family; Patrick J. Harrison Family; Peter French Memorial Foundation; Wilmerding Endowments FX The authors wish to acknowledge funding from the Alexandre Suerman Stipend (to AT), the National Heart, Lung, and Blood Institute (K23HL093350 to HT), the Dr. Francis P. Chiaramonte Private Foundation, the St. Jude Medical Foundation, Medtronic Inc., and the NIH intramural research program (to DAB). The Johns Hopkins ARVC Program is supported by the Dr. Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins, the Bogle Foundation, the Healing Hearts Foundation, the Campanella family, the Patrick J. Harrison Family, the Peter French Memorial Foundation, and the Wilmerding Endowments. We are grateful to the ARVC patients and families who have made this work possible. NR 126 TC 17 Z9 17 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD JUL 20 PY 2014 VL 16 AR 50 DI 10.1186/s12968-014-0050-8 PG 15 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AM7QF UT WOS:000340061900001 PM 25191878 ER PT J AU Danis, M Abernethy, AP Zafar, SY Samsa, GP Wolf, SP Howie, L Taylor, DH AF Danis, Marion Abernethy, Amy P. Zafar, S. Yousuf Samsa, Gregory P. Wolf, Steven P. Howie, Lynn Taylor, Donald H., Jr. TI A decision exercise to engage cancer patients and families in Deliberation about Medicare Coverage for advanced Cancer Care SO BMC HEALTH SERVICES RESEARCH LA English DT Article DE Medicare; Hospice benefit; Health priorities; Insurance benefits; Public participation ID REFORM AB Background: Concerns about unsustainable costs in the US Medicare program loom as the number of retirees increase and experiences serious and costly illnesses like cancer. Engagement of stakeholders, particularly cancer patients and their families, in prioritizing insured services offers a valuable strategy for informing Medicare coverage policy. We designed and evaluated a decision exercise that allowed cancer patients and family members to choose Medicare benefits for advanced cancer patients. Methods: The decision tool, Choosing Health plans All Together (CHAT) was modified to select services for advanced cancer patients. Patients with a cancer history (N = 246) and their family members (N = 194) from North Carolina participated in 70 CHAT sessions. Variables including participants' socio-demographic characteristics, health status, assessments of the exercise and results of group benefit selections were collected. Routine descriptive statistics summarized participant characteristics and Fisher's exact test compared group differences. Qualitative analysis of group discussions were used to ascertain reasons for or against selecting benefits. Results: Patients and family members (N = 440) participated in 70 CHAT exercises. Many groups opted for such services as palliative care, nursing facilities, and services not currently covered by the Medicare program. In choosing among four levels of cancer treatment coverage, no groups chose basic coverage, 27 groups (39%) selected intermediate coverage, 39 groups (56%) selected high coverage, and 4 groups (6%) chose the most comprehensive cancer coverage. Reasons for or against benefit selection included fairness, necessity, need for prioritizing, personal experience, attention to family needs, holistic health outlook, preference for comfort, freedom of choice, and beliefs about the proper role of government. Participants found the exercise very easy (59%) or fairly easy (39%) to understand and very informative (66%) or fairly informative (31%). The majority agreed that the CHAT exercise led to fair decisions about priorities for coverage by which they could abide. Conclusions: It is possible to involve cancer patients and families in explicit discussions of their priorities for affordable advanced cancer care through the use of decision tools designed for this purpose. A key question is whether such a conversation is possible on a broader, national level. C1 [Danis, Marion] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Taylor, Donald H., Jr.] Duke Univ, Sanford Sch Publ Policy, Durham, NC 27708 USA. [Abernethy, Amy P.; Zafar, S. Yousuf; Samsa, Gregory P.] Duke Clin Res Inst, Ctr Learning Hlth Care, Durham, NC USA. [Wolf, Steven P.; Howie, Lynn] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27708 USA. RP Taylor, DH (reprint author), Duke Univ, Sanford Sch Publ Policy, Box 90253, Durham, NC 27708 USA. EM don.taylor@duke.edu FU Agency for Health Care Research and Quality [RO1 HS018360]; National Institute of Nursing Research [1UC4NR012584]; Health Care Financing and Organization initiative (HCFO); Program of the Robert Wood Johnson Foundation; Department of Bioethics, an intramural program at NIH FX Dr. Taylor had full access to all of the data in the study, takes responsibility for the integrity of the data and the accuracy of the data analysis and has listed everyone who contributed significantly to the work This project was supported in part by grants RO1 HS018360 (Agency for Health Care Research and Quality), 1UC4NR012584 (National Institute of Nursing Research), by a grant from the Health Care Financing and Organization initiative (HCFO), a Program of the Robert Wood Johnson Foundation, and by the Department of Bioethics, an intramural program at NIH. The funding sources had no role in the collection, analysis, data interpretation, or decision to approve publication of the finished manuscript. NR 12 TC 0 Z9 0 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD JUL 19 PY 2014 VL 14 AR 315 DI 10.1186/1472-6963-14-315 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AM0XX UT WOS:000339572100002 PM 25038783 ER PT J AU Raju, TNK AF Raju, Tonse N. K. TI Delayed cord clamping: does gravity matter? SO LANCET LA English DT Editorial Material ID BIRTH; OBSTETRICIANS; MIDWIVES C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Raju, TNK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM rajut@mail.nih.gov NR 11 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUL 19 PY 2014 VL 384 IS 9939 BP 213 EP 214 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AL8JI UT WOS:000339384100006 PM 24746756 ER PT J AU Mendonca, VRR Souza, LCL Garcia, GC Magalhaes, BML Lacerda, MVG Andrade, BB Goncalves, MS Barral-Netto, M AF Mendonca, Vitor R. R. Souza, Ligia C. L. Garcia, Gabriela C. Magalhaes, Belisa M. L. Lacerda, Marcus V. G. Andrade, Bruno B. Goncalves, Marilda S. Barral-Netto, Manoel TI DDX39B (BAT1), TNF and IL6 gene polymorphisms and association with clinical outcomes of patients with Plasmodium vivax malaria SO MALARIA JOURNAL LA English DT Article DE DDX39B (BAT1); Single nucleotide polymorphisms; Immune response; Plasmodium vivax; Malaria ID TUMOR-NECROSIS-FACTOR; MAJOR HISTOCOMPATIBILITY COMPLEX; ALPHA PROMOTER REGION; FALCIPARUM MALARIA; LYMPHOTOXIN-ALPHA; SERUM-LEVELS; CYTOKINE PRODUCTION; BRAZILIAN AMAZON; MALIAN CHILDREN; BURKINA-FASO AB Background: DDX39B (BAT1) encodes an RNA helicase known to regulate expression of TNF and IL-6. Elevated levels of these two cytokines are associated with increased severity of clinical malaria. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) in the DDX39B, TNF and IL6 genes and the clinical outcomes of patients with Plasmodium vivax malaria. Methods: Cross-sectional investigations were carried out in two regions of the Brazilian Amazon where several studies on the pathogenesis of vivax malaria had been performed. Individuals were categorized according to infection status as well as clinical presentation into the following groups: uninfected, asymptomatic infection, mild infection, or complicated infection. Polymorphisms were identified using PCR restriction fragment-length polymorphism analysis and the restriction enzymes NlaIII or NcoI. The plasma levels of cytokines were determined using ELISA. Results: The G allele of DDX39B-22C > G was associated with absent or decreased manifestations of malaria and the C allele was a risk factor for disease complications. Study participants heterozygous for TNF-308 (GA) and DDX39B-348 (CT) had higher TNF levels than wild-type participants. Haplotypes that included DDX39B (-22C > G and -348C > T) and TNF polymorphisms were not directly associated with mild or complicated malaria infections; however, haplotypes AGC, ACC, GGT, AGT and ACT were associated with increased TNF levels. Participants with genotype combinations GC/CC/GG/GG and GG/CT/GG/GG (DDX39B-22/DDX39B-348/TNF-308/IL6-176) had decreased and increased risk of mild malaria, respectively, compared with asymptomatic and uninfected participants. GC/CC/GG/GG was linked to decreased TNF and IL-6 levels. Conclusions: This is the first study to describe patients with DDX39B and IL6 SNPs who had vivax malaria. These findings support the postulation that a set of mutations in immune-related genes is associated with inflammatory mediators and the clinical outcomes of patients with malaria. C1 [Mendonca, Vitor R. R.; Souza, Ligia C. L.; Garcia, Gabriela C.; Goncalves, Marilda S.; Barral-Netto, Manoel] Fundacao Oswaldo Cruz FIOCRUZ, Ctr Pesquisas Goncalo Moniz, Salvador, BA, Brazil. [Mendonca, Vitor R. R.; Souza, Ligia C. L.; Goncalves, Marilda S.; Barral-Netto, Manoel] Univ Fed Bahia, Fac Med, Salvador, BA, Brazil. [Magalhaes, Belisa M. L.; Lacerda, Marcus V. G.] Fundacao Med Trop Dr Heitor Vieira Dourado, Manaus, Amazonas, Brazil. [Andrade, Bruno B.] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Barral-Netto, Manoel] Inst Nacl Ciencia & Tecnol, Inst Invest Imunol, Sao Paulo, Brazil. RP Barral-Netto, M (reprint author), Fundacao Oswaldo Cruz FIOCRUZ, Ctr Pesquisas Goncalo Moniz, Salvador, BA, Brazil. EM mbarral@bahia.fiocruz.br RI Andrade, Bruno/J-9111-2012; Barral Netto, Manoel/B-3904-2009 OI Andrade, Bruno/0000-0001-6833-3811; Barral Netto, Manoel/0000-0002-5823-7903 FU FIOCRUZ; FMT-HVD; CNPq; intramural research programme of the National Institute of Allergy and Infectious Diseases, National Institute of Health FX This work was supported by FIOCRUZ and FMT-HVD. MBN and MSG are senior investigators from CNPq. MVGL is scientific director at FMT-HVD. VRRM, LCLS, GCG, and BMLM are supported by CNPq. The work of BBA is supported by the intramural research programme of the National Institute of Allergy and Infectious Diseases, National Institute of Health. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 8 Z9 8 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD JUL 19 PY 2014 VL 13 AR 278 DI 10.1186/1475-2875-13-278 PG 13 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AM1AE UT WOS:000339578000001 PM 25038626 ER PT J AU Thein, S Pham, A Bayer, KU Tao-Cheng, JH Dosemeci, A AF Thein, Soe Pham, Anna Bayer, K. Ulrich Tao-Cheng, Jung-Hwa Dosemeci, Ayse TI MK regulates the deubiquitinase CYLD at the postsynaptic density SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Ubiquitin; CYLD; Deubiquitinase; IKK; PSD; Postsynaptic density ID HIPPOCAMPAL-NEURONS; CAMKII INHIBITOR; PHOSPHORYLATION; UBIQUITINATION; PROMOTES AB K63-linked polyubiquitination of proteins regulates their trafficking into specific cellular pathways such as endocytosis and autophagy. CYLD, a deubiquitinase specific for K63-linked polyubiquitins, is present in high quantities at the postsynaptic density (PSD). It was previously shown that, under excitatory conditions, CaMKII activates CYLD in a Ca2+-dependent manner. The observation that CYLD can also be phosphorylated in the absence of Ca2+ in isolated PSDs led us to further explore the regulation of CYLD under basal conditions. A possible involvement of the autonomous form of CaMKII and IKK, both kinases known to be localized at the PSD, was examined. A CaMKII inhibitor CN21 had no effect on CYLD phosphorylation in the absence of Ca2+, but two different IKK inhibitors, IKK16 and tatNEMO, inhibited its phosphorylation. Immuno-electron microscopy on hippocampal cultures, using an antibody for CYLD phosphorylated at S-418, revealed that the phosphorylated form of CYLD is present at the PSD under basal conditions. Phosphorylation of CYLD under basal conditions was inhibited by IKK16. NMDA treatment further promoted phosphorylation of CYLD at the PSD, but IKK16 failed to block the NMDA-induced effect. In vitro experiments using purified proteins demonstrated direct phosphorylation and activation of CYLD by the beta catalytic subunit of IKK. Activation of IKK in isolated PSDs also promoted phosphorylation of CYLD and an increase in endogenous deubiquitinase activity for K63-linked polyubiquitins. Altogether, the results suggest that in the absence of excitatory conditions, constitutive IKK activity at the PSD regulates CYLD and maintains basal levels of K63-linkage specific deubiquitination at the synapse. Published by Elsevier Inc. C1 [Thein, Soe; Pham, Anna; Dosemeci, Ayse] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. [Bayer, K. Ulrich] Univ Colorado Denver Sch Med, Dept Pharmacol, Aurora, CO 80045 USA. [Tao-Cheng, Jung-Hwa] NINDS, EM Facil, NIH, Bethesda, MD 20892 USA. RP Dosemeci, A (reprint author), NINDS, Neurobiol Lab, NIH, 49 Convent Dr,Room 3E13, Bethesda, MD 20892 USA. EM dosemeca@mail.nih.gov FU Intramural Research Program of the NINDS, NIH; NIH [R01NS052644] FX We thank Christine A. Winters for hippocampal neuronal cultures, Virginia Crocker and Rita Azzam for EM technical support, Dr. Yan Li for performing and analyzing mass-spectrometry and Dr. Thomas Reese for helpful discussions and a critical reading of the manuscript. This research was supported by the Intramural Research Program of the NINDS, NIH and by NIH grant R01NS052644 (to K.U.B.). NR 21 TC 3 Z9 3 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 18 PY 2014 VL 450 IS 1 BP 550 EP 554 DI 10.1016/j.bbrc.2014.06.019 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AR5RK UT WOS:000343641000090 PM 24928390 ER PT J AU Tao-Cheng, JH Yang, YJ Bayer, KU Reese, TS Dosemeci, A AF Tao-Cheng, Jung-Hwa Yang, Yijung Bayer, K. Ulrich Reese, Thomas S. Dosemeci, Ayse TI NMDA-induced accumulation of Shank at the postsynaptic density is mediated by CaMKII SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE CaMKII; tatCN21; ProSAP; Shank; Homer; PSD ID PROTEINS; INHIBITOR; FAMILY; HOMER; RECEPTORS; CORTACTIN; NEURONS AB Shank is a specialized scaffold protein present in high abundance at the postsynaptic density (PSD). Using pre-embedding immunogold electron microscopy on cultured hippocampal neurons, we had previously demonstrated further accumulation of Shank at the PSD under excitatory conditions. Here, using the same experimental protocol, we demonstrate that a cell permeable CaMKII inhibitor, tatCN21, blocks NMDA-induced accumulation of Shank at the PSD. Furthermore we show that NMDA application changes the distribution pattern of Shank at the PSD, promoting a 7-10 nm shift in the median distance of Shank labels away from the postsynaptic membrane. Inhibition of CaMKII with tatCN21 also blocks this shift in the distribution of Shank. Altogether these results imply that upon activation of NMDA receptors, CaMKII mediates accumulation of Shank, preferentially at the distal regions of the PSD complex extending toward the cytoplasm. Published by Elsevier Inc. C1 [Tao-Cheng, Jung-Hwa] NINDS, EM Facil, NIH, Bethesda, MD 20892 USA. [Yang, Yijung; Reese, Thomas S.; Dosemeci, Ayse] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. [Bayer, K. Ulrich] Univ Colorado Denver, Sch Med, Dept Pharmacol, Aurora, CO USA. RP Dosemeci, A (reprint author), 49 Convent Dr,Room 3A60, Bethesda, MD 20892 USA. EM dosemeca@ninds.nih.gov FU Intramural Research Program of the NINDS, NIH; NIH [R01NS052644] FX We thank Christine A. Winters for hippocampal cultures, Rita Azzam and Virginia Crocker for EM technical assistance. Supported by the Intramural Research Program of the NINDS, NIH, and by NIH grant R01NS052644 (to K.U.B.). NR 26 TC 3 Z9 3 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 18 PY 2014 VL 450 IS 1 BP 808 EP 811 DI 10.1016/j.bbrc.2014.06.049 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AR5RK UT WOS:000343641000133 PM 24952157 ER PT J AU Collins, FS Wilder, EL Zerhouni, E AF Collins, Francis S. Wilder, Elizabeth L. Zerhouni, Elias TI NIH Roadmap/Common Fund at 10 years SO SCIENCE LA English DT Editorial Material ID FUTURE C1 [Collins, Francis S.; Wilder, Elizabeth L.; Zerhouni, Elias] NIH, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM francis.collins@nih.gov NR 10 TC 6 Z9 6 U1 1 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JUL 18 PY 2014 VL 345 IS 6194 BP 274 EP 276 DI 10.1126/science.1255860 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL8PG UT WOS:000339400700032 PM 25035478 ER PT J AU McDannald, MA Esber, GR Wegener, MA Wied, HM Liu, TL Stalnaker, TA Jones, JL Trageser, J Schoenbaum, G AF McDannald, Michael A. Esber, Guillem R. Wegener, Meredyth A. Wied, Heather M. Liu, Tzu-Lan Stalnaker, Thomas A. Jones, Joshua L. Trageser, Jason Schoenbaum, Geoffrey TI Orbitofrontal neurons acquire responses to 'valueless' Pavlovian cues during unblocking SO ELIFE LA English DT Article ID BASOLATERAL AMYGDALA; CORTEX IMPAIR; LESIONS; STIMULUS; REWARD; RATS; REINFORCEMENT; OUTCOMES; CHOICE; ENCODE AB The orbitofrontal cortex (OFC) has been described as signaling outcome expectancies or value. Evidence for the latter comes from the studies showing that neural signals in the OFC correlate with value across features. Yet features can co-vary with value, and individual units may participate in multiple ensembles coding different features. Here we used unblocking to test whether OFC neurons would respond to a predictive cue signaling a 'valueless' change in outcome flavor. Neurons were recorded as the rats learned about cues that signaled either an increase in reward number or a valueless change in flavor. We found that OFC neurons acquired responses to both predictive cues. This activity exceeded that exhibited to a 'blocked' cue and was correlated with activity to the actual outcome. These results show that OFC neurons fire to cues with no value independent of what can be inferred through features of the predicted outcome. C1 [McDannald, Michael A.; Esber, Guillem R.; Stalnaker, Thomas A.; Schoenbaum, Geoffrey] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. [Wegener, Meredyth A.] Univ Pittsburg, Ctr Neurosci, Grad Program, Pittsburg, KS USA. [Wied, Heather M.] Univ Maryland, Sch Med, Program Neurosci, Baltimore, MD 21201 USA. [Liu, Tzu-Lan] Natl Taiwan Univ, Dept Psychol, Taipei 10764, Taiwan. [Jones, Joshua L.; Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Trageser, Jason] Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD USA. [Schoenbaum, Geoffrey] Johns Hopkins Univ, Dept Neurosci, Baltimore, MD USA. RP McDannald, MA (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. EM mcdannal@bc.edu; geoffrey.schoenbaum@nih.gov FU National Institute on Drug Abuse IRP Lab FX National Institute on Drug Abuse IRP Lab Michael A McDannald, Guillem R Esber, Meredyth A Wegener, Heather M Wied, Tzu-Lan Liu, Thomas A Stalnaker, Joshua L Jones, Jason Trageser, Geoffrey Schoenbaum NR 35 TC 19 Z9 19 U1 0 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JUL 18 PY 2014 VL 3 AR e02653 DI 10.7554/eLife.02653 PG 14 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AN9QS UT WOS:000340943300001 PM 25037263 ER PT J AU Bao, WJ Florea, L Wu, NB Wang, Z Banaudha, K Qian, J Houzet, L Kumar, R Kumar, A AF Bao, Wenjie Florea, Liliana Wu, Ningbin Wang, Zhao Banaudha, Krishna Qian, Jason Houzet, Laurent Kumar, Rakesh Kumar, Ajit TI Loss of nuclear PTEN in HCV-infected human hepatocytes SO INFECTIOUS AGENTS AND CANCER LA English DT Article DE HCV infection; Nuclear PTEN restriction ID TENSIN HOMOLOG; ANTIVIRAL IMMUNITY; CHROMOSOME-10 PTEN; VIRUS-REPLICATION; TUMOR SUPPRESSION; MICRORNAS; IMPORT; LOCALIZATION; PHOSPHATASE; EXPRESSION AB Background: Hepatitis C virus (HCV) infection is a major risk factor for chronic hepatitis and hepatocellular carcinoma (HCC); however, the mechanism of HCV-mediated hepatocarcinogenesis is not well understood. Insufficiency of PTEN tumor suppressor is associated with more aggressive cancers, including HCC. We asked whether viral non-coding RNA could initiate oncogenesis in HCV infected human hepatocytes. The results presented herein suggest that loss of nuclear PTEN in HCV-infected human hepatocytes results from depletion of Transportin-2, which is a direct target of viral non-coding RNA, vmr11. Methods: The intracellular distribution of PTEN in HCV-infected cells was monitored by immunostaining and Western blots of nuclear and cytoplasmic proteins. Effects of PTEN depletion were examined by comparing expression arrays of uninfected cells with either HCV-infected or vmr11-transfected cells. Target genes suggested by array analyses were validated by Western blot. The influence of nuclear PTEN deficiency on virus production was determined by quantitative analysis of HCV genomic RNA in culture media of infected hepatocytes. Results: Import of PTEN to the nucleus relies on the interaction of Transportin-2 and PTEN proteins; we show that depletion of Transportin-2 by HCV infection or by the introduction of vmr11 in uninfected cells results in reduced nuclear PTEN. In turn, nuclear PTEN insufficiency correlates with increased virus production and the induction of gamma-H2AX, a marker of DNA double-strand breaks and genomic instability. Conclusion: An HCV-derived small non-coding RNA inhibits Transportin-2 and PTEN translocation to the nucleus, suggesting a direct viral role in hepatic oncogenesis. C1 [Bao, Wenjie; Wu, Ningbin; Wang, Zhao; Banaudha, Krishna; Kumar, Rakesh; Kumar, Ajit] George Washington Univ, Sch Med, Dept Biochem & Mol Med, Washington, DC 20037 USA. [Florea, Liliana] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Houzet, Laurent] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Kumar, A (reprint author), George Washington Univ, Sch Med, Dept Biochem & Mol Med, 2300 Eye St NW, Washington, DC 20037 USA. EM akumar@gwu.edu FU Katzen Cancer Research Funds from the George Washington University; McCormick Genomics Center FX The authors thank Dr. Charles M. Rice (The Rockefeller University) for Huh-7.5 cell line, Drs. Jens Buch and Robert H Purcell (NIH) for the H77 clone. Supported by Katzen Cancer Research Funds from the George Washington University, and the McCormick Genomics Center. NR 41 TC 4 Z9 4 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-9378 J9 INFECT AGENTS CANCER JI Infect. Agents Cancer PD JUL 18 PY 2014 VL 9 AR 23 DI 10.1186/1750-9378-9-23 PG 11 WC Oncology; Immunology SC Oncology; Immunology GA AM2LO UT WOS:000339682400001 PM 25075209 ER PT J AU Anic, GM Weinstein, SJ Mondul, AM Mannisto, S Albanes, D AF Anic, Gabriella M. Weinstein, Stephanie J. Mondul, Alison M. Mannisto, Satu Albanes, Demetrius TI Serum Vitamin D, Vitamin D Binding Protein, and Risk of Colorectal Cancer SO PLOS ONE LA English DT Article ID CIRCULATING 25-HYDROXYVITAMIN D; PROSTATE-CANCER; GC-GLOBULIN; COLON; ASSOCIATION; MEN; SUPPLEMENTATION; REPRODUCIBILITY; RECEPTOR; COHORT AB Background: We previously reported a positive association between serum 25-hydroxyvitamin D (25(OH)D) and colorectal cancer risk. To further elucidate this association, we examined the molar ratio of 25(OH)D to vitamin D binding protein (DBP), the primary 25(OH)D transport protein, and whether DBP modified the association between 25(OH)D and colorectal cancer risk. Methods: In a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, controls were 1: 1 matched to 416 colorectal cancer cases based on age and date of blood collection. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for quartiles of 25(OH)D, DBP, and the molar ratio of 25(OH)D: DBP, a proxy for free, unbound circulating 25(OH)D. Results: Comparing highest to lowest quartiles, DBP was not associated with colorectal cancer risk (OR = 0.91; 95% CI: 0.58, 1.42, p for trend = 0.58); however, a positive risk association was observed for the molar ratio of 25(OH)D: DBP (OR = 1.44; 95% CI: 0.92, 2.26, p for trend = 0.04). In stratified analyses, the positive association between 25(OH)D and colorectal cancer was stronger among men with DBP levels above the median (OR = 1.89; 95% CI: 1.07, 3.36, p for trend = 0.01) than below the median (OR = 1.20; 95% CI: 0.68, 2.12, p for trend = 0.87), although the interaction was not statistically significant (p for interaction = 0.24). Conclusion: Circulating DBP may influence the association between 25(OH)D and colorectal cancer in male smokers, with the suggestion of a stronger positive association in men with higher DBP concentrations. This finding should be examined in other populations, especially those that include women and non-smokers. C1 [Anic, Gabriella M.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Anic, Gabriella M.; Weinstein, Stephanie J.; Mondul, Alison M.; Albanes, Demetrius] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Mannisto, Satu] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Anic, GM (reprint author), NCI, Canc Prevent Fellowship Program, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. EM gabriella.anic@nih.gov RI Albanes, Demetrius/B-9749-2015; OI Mondul, Alison/0000-0002-8843-1416; Mannisto, Satu/0000-0002-8668-3046 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute; US Public Health Service from the Division of Cancer Prevention, National Cancer Institute [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C] FX This work was supported in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute. Additionally, this research was supported by US Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C from the Division of Cancer Prevention, National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 13 Z9 13 U1 2 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 18 PY 2014 VL 9 IS 7 AR e102966 DI 10.1371/journal.pone.0102966 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM1OC UT WOS:000339615200104 PM 25036524 ER PT J AU Huang, JD Amaral, J Lee, JW Rodriguez, IR AF Huang, Jiahn-Dar Amaral, Juan Lee, Jung Wha Rodriguez, Ignacio R. TI 7-Ketocholesterol-Induced Inflammation Signals Mostly through the TLR4 Receptor Both In Vitro and In Vivo SO PLOS ONE LA English DT Article ID NF-KAPPA-B; ACTIVATED PROTEIN-KINASE; LOW-DENSITY-LIPOPROTEIN; SMOOTH-MUSCLE-CELLS; BIOLOGICAL-ACTIVITY; CYTOKINE PRODUCTION; WNT PATHWAY; INHIBITOR; OXYSTEROLS; MECHANISMS AB The cholesterol oxide 7-ketocholesterol (7KCh) has been implicated in numerous age-related diseases such as atherosclerosis, Alzheimer's disease, Parkinson's disease, cancer and age-related macular degeneration. It is formed by the autooxidation of cholesterol and especially cholesterol-fatty acid esters found in lipoprotein deposits. This molecule causes complex and potent inflammatory responses in vitro and in vivo. It is suspected of causing chronic inflammation in tissues exposed to oxidized lipoprotein deposits. In this study we have examined the inflammatory pathways activated by 7KCh both in cultured ARPE19 cells and in vivo using 7KCh-containing implants inserted into the anterior chamber of the rat eye. Our results indicate that 7KCh-induced inflammation is mediated mostly though the TLR4 receptor with some cross-activation of EGFR-related pathways. The majority of the cytokine inductions seem to signal via the TRIF/TRAM side of the TLR4 receptor. The MyD88/TIRAP side only significantly effects IL-1 beta inductions. The 7KCh-induced inflammation also seems to involve a robust ER stress response. However, this response does not seem to involve a calcium efflux-mediated UPR. Instead the ER stress response seems to be mediated by yet identified kinases activated through the TLR4 receptor. Some of the kinases identified are the RSKs which seem to mediate the cytokine inductions and the cell death pathway but do not seem to be involved in the ER stress response. C1 [Huang, Jiahn-Dar; Amaral, Juan; Lee, Jung Wha; Rodriguez, Ignacio R.] NEI, Retinal Cell & Mol Biol Lab, Mech Retinal Dis Sect, NIH, Bethesda, MD 20892 USA. RP Rodriguez, IR (reprint author), NEI, Retinal Cell & Mol Biol Lab, Mech Retinal Dis Sect, NIH, Bethesda, MD 20892 USA. EM rodriguezi@nei.nih.gov FU National Eye Institute Intramural Research Program FX This research was supported by the National Eye Institute Intramural Research Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 6 Z9 6 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 18 PY 2014 VL 9 IS 7 AR e100985 DI 10.1371/journal.pone.0100985 PG 26 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM1OC UT WOS:000339615200011 PM 25036103 ER PT J AU Patel, EU Frank, MA Hsieh, YH Rothman, RE Baker, AEO Kraus, CK Shahan, J Gaydos, CA Kelen, GD Quinn, TC Laeyendecker, O AF Patel, Eshan U. Frank, Melanie A. Hsieh, Yu-Hsiang Rothman, Richard E. Baker, Amy E. O. Kraus, Chadd K. Shahan, Judy Gaydos, Charlotte A. Kelen, Gabor D. Quinn, Thomas C. Laeyendecker, Oliver TI Prevalence and Factors Associated with Herpes Simplex Virus Type 2 Infection in Patients Attending a Baltimore City Emergency Department SO PLOS ONE LA English DT Article ID GENITAL HERPES; UNITED-STATES; INNER-CITY; SEROPREVALENCE; TRENDS; EPIDEMIOLOGY; TRANSMISSION; VALACYCLOVIR; SUPPRESSION; POPULATION AB Objectives: Herpes simplex virus type 2 (HSV-2) is a common sexually transmitted disease, but there is limited data on its epidemiology among urban populations. The urban Emergency Department (ED) is a potential venue for surveillance as it predominantly serves an inner city minority population. We evaluate the seroprevalence and factors associated with HSV-2 infection among patients attending the Johns Hopkins Hospital Adult Emergency Department (JHH ED). Methods: An identity unlinked-serosurvey was conducted between 6/2007 and 9/2007 in the JHH ED; sera were tested by the Focus HerpeSelect ELISA. Prevalence risk ratios (PRR) were used to determine factors associated with HSV-2 infection. Results: Of 3,408 serum samples, 1,853 (54.4%) were seropositive for HSV-2. Females (adjPRR = 1.47, 95% CI 1.38-1.56), non-Hispanic blacks (adjPRR = 2.03, 95% CI 1.82-2.27), single (adjPRR = 1.15, 95% CI 1.07-1.25), divorced (adjPRR = 1.28, 95% CI 1.15-1.41), and unemployed patients (adjPRR = 1.13, 95% CI 1.05-1.21) had significantly higher rates of HSV-2 infection. Though certain zip codes had significantly higher seroprevalence of HSV-2, this effect was completely attenuated when controlling for age and gender. Conclusions: Seroprevalence of HSV-2 in the JHH ED was higher than U. S. national estimates; however, factors associated with HSV-2 infection were similar. The high seroprevalence of HSV-2 in this urban ED highlights the need for targeted testing and treatment. Cross-sectional serosurveys in the urban ED may help to examine the epidemiology of HSV-2. C1 [Patel, Eshan U.; Frank, Melanie A.; Quinn, Thomas C.; Laeyendecker, Oliver] NIAID, Div Intramural Res, NIH, Baltimore, MD 21201 USA. [Hsieh, Yu-Hsiang; Rothman, Richard E.; Baker, Amy E. O.; Kraus, Chadd K.; Shahan, Judy; Gaydos, Charlotte A.; Kelen, Gabor D.; Quinn, Thomas C.; Laeyendecker, Oliver] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. RP Laeyendecker, O (reprint author), NIAID, Div Intramural Res, NIH, Baltimore, MD 21201 USA. EM olaeyen1@jhmi.edu OI Rothman, Richard/0000-0002-1017-9505; Kelen, Gabor/0000-0002-3236-8286; Laeyendecker, Oliver/0000-0002-6429-4760; Patel, Eshan/0000-0003-2174-5004 FU Division of Intramural Research; NIH Award from NIAID [5K01AI100681] FX The work was supported in part by the Division of Intramural Research and Dr. Hsieh is supported in part by an NIH Award, 5K01AI100681 from NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 2 Z9 2 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 18 PY 2014 VL 9 IS 7 AR e102422 DI 10.1371/journal.pone.0102422 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM1OC UT WOS:000339615200058 PM 25036862 ER PT J AU Malley, JD Moore, JH AF Malley, James D. Moore, Jason H. TI First complex, then simple SO BIODATA MINING LA English DT Editorial Material ID PROBABILITY MACHINES C1 [Malley, James D.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. [Moore, Jason H.] Dartmouth Coll, Geisel Sch Med, Dept Genet, Lebanon, NH 03756 USA. [Moore, Jason H.] Dartmouth Coll, Geisel Sch Med, Inst Quantitat Biomed Sci, Lebanon, NH 03756 USA. RP Moore, JH (reprint author), Dartmouth Coll, Geisel Sch Med, Dept Genet, One Med Ctr Dr, Lebanon, NH 03756 USA. EM jason.h.moore@dartmouth.edu NR 3 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-0381 J9 BIODATA MIN JI BioData Min. PD JUL 18 PY 2014 VL 7 AR 13 DI 10.1186/1756-0381-7-13 PG 2 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AM0ZF UT WOS:000339575500001 PM 25076985 ER PT J AU Sommers, JA Banerjee, T Hinds, T Wan, BB Wold, MS Lei, M Brosh, RM AF Sommers, Joshua A. Banerjee, Taraswi Hinds, Twila Wan, Bingbing Wold, Marc S. Lei, Ming Brosh, Robert M., Jr. TI Novel Function of the Fanconi Anemia Group J or RECQ1 Helicase to Disrupt Protein-DNA Complexes in a Replication Protein A-stimulated Manner SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID G-QUADRUPLEX DNA; WERNER-SYNDROME HELICASE; BLOOMS-SYNDROME HELICASE; ESCHERICHIA-COLI; BINDING PROTEIN; HOMOLOGOUS RECOMBINATION; MAMMALIAN TELOMERES; GENOMIC STABILITY; NUCLEOPROTEIN FILAMENTS; SUBSTRATE-SPECIFICITY AB Understanding how cellular machinery deals with chromosomal genome complexity is an important question because protein bound to DNA may affect various cellular processes of nucleic acid metabolism. DNA helicases are at the forefront of such processes, yet there is only limited knowledge how they remodel protein-DNA complexes and how these mechanisms are regulated. We have determined that representative human RecQ and Fe-S cluster DNA helicases are potently blocked by a protein-DNA interaction. The Fanconi anemia group J (FANCJ) helicase partners with the single-stranded DNA-binding protein replication protein A (RPA) to displace BamHI-E111A bound to duplex DNA in a specific manner. Protein displacement was dependent on the ATPase-driven function of the helicase and unique properties of RPA. Further biochemical studies demonstrated that the shelterin proteins TRF1 and TRF2, which preferentially bind the telomeric repeat found at chromosome ends, effectively block FANCJ from unwinding the forked duplex telomeric substrate. RPA, but not the Escherichia coli single-stranded DNA-binding protein or shelterin factor Pot1, stimulated FANCJ ejection of TRF1 from the telomeric DNA substrate. FANCJ was also able to displace TRF2 from the telomeric substrate in an RPA-dependent manner. The stimulation of helicase-catalyzed protein displacement is also observed with the DNA helicase RECQ1, suggesting a conserved functional interaction of RPA-interacting helicases. These findings suggest that partnerships between RPA and interacting human DNA helicases may greatly enhance their ability to dislodge proteins bound to duplex DNA, an activity that is likely to be highly relevant to their biological roles in DNA metabolism. C1 [Sommers, Joshua A.; Banerjee, Taraswi; Hinds, Twila; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Wan, Bingbing; Lei, Ming] Univ Michigan, Sch Med, Dept Biol Chem, Ann Arbor, MI 48109 USA. [Wold, Marc S.] Univ Iowa, Dept Biochem, Carver Coll Med, Iowa City, IA 52242 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov FU National Institutes of Health Intramural Research Program of the NIA; Fanconi Anemia Research Fund FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program of the NIA. This work was also supported by the Fanconi Anemia Research Fund (to R. M. B.). NR 80 TC 13 Z9 14 U1 0 U2 15 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 18 PY 2014 VL 289 IS 29 BP 19928 EP 19941 DI 10.1074/jbc.M113.542456 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AL8NE UT WOS:000339395200011 PM 24895130 ER PT J AU Zhu, BK Ferry, CH Markell, LK Blazanin, N Glick, AB Gonzalez, FJ Peters, JM AF Zhu, Bokai Ferry, Christina H. Markell, Lauren K. Blazanin, Nicholas Glick, Adam B. Gonzalez, Frank J. Peters, Jeffrey M. TI The Nuclear Receptor Peroxisome Proliferator-activated Receptor-beta/delta (PPAR beta/delta) Promotes Oncogene-induced Cellular Senescence through Repression of Endoplasmic Reticulum Stress SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INDUCED SKIN TUMORIGENESIS; LIGAND ACTIVATION; SIGNALING NETWORK; CELLS; CARCINOGENESIS; EXPRESSION; CANCER; DIFFERENTIATION; TRANSCRIPTION; INHIBITION AB Endoplasmic reticulum (ER) stress and ER stress-associated unfolded protein response (UPR) can promote cancer cell survival, but it remains unclear whether they can influence oncogene-induced senescence. The present study examined the role of ER stress in senescence using oncogene-dependent models. Increased ER stress attenuated senescence in part by up-regulating phosphorylated protein kinase B (p-AKT) and decreasing phosphorylated extracellular signal-regulated kinase (p-ERK). A positive feed forward loop between p-AKT, ER stress, and UPR was discovered whereby a transient increase of ER stress caused reduced senescence and promotion of tumorigenesis. Decreased ER stress was further correlated with increased senescence in both mouse and human tumors. Interestingly, H-RAS-expressing Ppar beta/delta null cells and tumors having increased cell proliferation exhibited enhanced ER stress, decreased cellular senescence, and/or enhanced tumorigenicity. Collectively, these results demonstrate a new role for ER stress and UPR that attenuates H-RAS-induced senescence and suggest that PPAR beta/delta can repress this oncogene-induced ER stress to promote senescence in accordance with its role as a tumor modifier that suppresses carcinogenesis. C1 [Zhu, Bokai; Ferry, Christina H.; Markell, Lauren K.; Blazanin, Nicholas; Glick, Adam B.; Peters, Jeffrey M.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Zhu, Bokai; Ferry, Christina H.; Markell, Lauren K.; Blazanin, Nicholas; Glick, Adam B.; Peters, Jeffrey M.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. EM jmp21@psu.edu OI Zhu, Bokai/0000-0003-0827-5757 FU National Institutes of Health [CA124533, CA141029, CA140369, AA018863, CA122109, CA117957, ZIABC005561, ZIABC005562, ZIABC005708] FX This work was supported, in whole or in part, by National Institutes of Health Grants CA124533, CA141029, CA140369, and AA018863 (to J. M. P.), CA122109 and CA117957 (to A. B. G.), and ZIABC005561, ZIABC005562, and ZIABC005708 (NCI Intramural Research Program; to F. J. G.). NR 40 TC 12 Z9 12 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 18 PY 2014 VL 289 IS 29 BP 20102 EP 20119 DI 10.1074/jbc.M114.551069 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AL8NE UT WOS:000339395200024 PM 24898257 ER PT J AU Zhuang, XL Stahl, SJ Watts, NR DiMattia, MA Steven, AC Wingfield, PT AF Zhuang, Xiaolei Stahl, Stephen J. Watts, Norman R. DiMattia, Michael A. Steven, Alasdair C. Wingfield, Paul T. TI A Cell-penetrating Antibody Fragment against HIV-1 Rev Has High Antiviral Activity CHARACTERIZATION OF THE PARATOPE SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ANTI-CD4 MONOCLONAL-ANTIBODY; RESPONSE ELEMENT; NUCLEAR-LOCALIZATION; PROTEIN; PEPTIDE; RNA; BINDING; TAT; RRE; MINIANTIBODY AB The HIV-1 protein Rev oligomerizes on viral transcripts and directs their nuclear export. Previously, a Fab against Rev generated by phage display was used to crystallize and solve the structure of the Rev oligomerization domain. Here we have investigated the capability of this Fab to block Rev oligomerization and inhibit HIV-1 replication. The Fab itself did not have antiviral activity, but when a Tat-derived cell-penetrating peptide was appended, the resulting molecule (FabRev1-Tat) was strongly inhibitory of three different CCR5-tropic HIV-1 isolates (IC50 = 0.09-0.44 mu g/ml), as assessed by suppression of reverse transcriptase activity in infected peripheral blood mononuclear cells, and had low cell toxicity (TC50 > 100 mu g/ml). FabRev1-Tat was taken up by both peripheral blood mononuclear and HEK293T cells, appearing in both the cytoplasm and nucleus, as shown by immunofluorescence confocal laser scanning microscopy. Computational alanine scanning was used to identify key residues in the complementarity-determining regions to guide mutagenesis experiments. Residues in the light chain CDR3 (LCDR3) were assessed to be important. Residues in LCDR3 were mutated, and LCDR3-Tyr(92) was found to be critical for binding to Rev, as judged by surface plasmon resonance and electron microscopy. Peptides corresponding to all six CDR regions were synthesized and tested for Rev binding. None of the linear peptides had significant affinity for Rev, but four of the amide-cyclic forms did. Especially cyclic-LCDR3 (LGGYPAASYRTA) had high affinity for Rev and was able to effectively depolymerize Rev filaments, as shown by both surface plasmon resonance and electron microscopy. C1 NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. [DiMattia, Michael A.; Steven, Alasdair C.] NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. RP Wingfield, PT (reprint author), NIH, Bldg 6B,Rm 1B130, Bethesda, MD 20892 USA. EM pelpw@helix.nih.gov FU Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health [HHSN272200700041C] FX We thank Drs. Marc Nicklaus and Megan Peach (NCI/National Institutes of Health) for performing the computational alanine scanning, and Drs. Steven Turk (NIAID/National Institutes of Health) and Christoph Rader (Scripps) for much appreciated discussions. Drs. Evelyn Ralston and Kristina Zaal (NIAMS/National Institutes of Health) provided advice on the immunofluorescence microscopy. We also thank Joshua Kaufman and Ira Palmer (NIAMS/National Institutes of Health) for expert technical assistance. The anti-HIV testing was conducted by the Southern Research Institute using federal funds from the Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, under contract HHSN272200700041C entitled "Confirmatory In Vitro Evaluations of HIV Therapeutics." NR 41 TC 6 Z9 6 U1 1 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 18 PY 2014 VL 289 IS 29 BP 20222 EP 20233 DI 10.1074/jbc.M114.581090 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AL8NE UT WOS:000339395200035 PM 24878961 ER PT J AU Song, MS Chen, Y Gong, GH Murphy, E Rabinovitch, PS Dorn, GW AF Song, Moshi Chen, Yun Gong, Guohua Murphy, Elizabeth Rabinovitch, Peter S. Dorn, Gerald W., II TI Super-Suppression of Mitochondrial Reactive Oxygen Species Signaling Impairs Compensatory Autophagy in Primary Mitophagic Cardiomyopathy SO CIRCULATION RESEARCH LA English DT Article DE cardiomyopathies; catalase; mitochondria; mitochondrial degradation; mitofusin 1 ID PERMEABILITY TRANSITION; DAMAGED MITOCHONDRIA; CELL-DEATH; OVEREXPRESSION; REVEALS; PARKIN AB Rationale: Mitochondrial reactive oxygen species (ROS) are implicated in aging, chronic degenerative neurological syndromes, and myopathies. On the basis of free radical hypothesis, dietary, pharmacological, and genetic ROS suppression has been tested to minimize tissue damage, with remarkable therapeutic efficacy. The effects of mitochondrial-specific ROS suppression in primary mitophagic dysfunction are unknown. Objective: An in vivo dose-ranging analysis of ROS suppression in an experimental cardiomyopathy provoked by defective mitochondrial clearance. Methods and Results: Mice lacking mitofusin 2 (Mfn2) in hearts have impaired parkin-mediated mitophagy leading to accumulation of damaged ROS-producing organelles and progressive heart failure. As expected, cardiomyocyte-directed expression of mitochondrial-targeted catalase at modest levels normalized mitochondrial ROS production and prevented mitochondrial depolarization, respiratory impairment, and structural degeneration in Mfn2 null hearts. In contrast, catalase expression at higher levels that supersuppressed mitochondrial ROS failed to improve either mitochondrial fitness or cardiomyopathy, revealing that ROS toxicity is not the primary mechanism for cardiac degeneration. Lack of benefit from supersuppressing ROS was associated with failure to invoke secondary autophagic pathways of mitochondrial quality control, revealing a role for ROS signaling in mitochondrial clearance. Mitochondrial permeability transition pore function was normal, and genetic inhibition of mitochondrial permeability transition pore function did not alter mitochondrial or cardiac degeneration, in Mfn2 null hearts. Conclusions: Local mitochondrial ROS (1) contribute to mitochondrial degeneration and (2) activate mitochondrial quality control mechanisms. A therapeutic window for mitochondrial ROS suppression should minimize the former while retaining the latter, which we achieved by expressing lower levels of catalase. C1 [Song, Moshi; Gong, Guohua; Dorn, Gerald W., II] Washington Univ, Ctr Pharmacogen, Dept Internal Med, Sch Med, St Louis, MO 63110 USA. [Murphy, Elizabeth] NHLBI, NIH, Bethesda, MD 20892 USA. [Rabinovitch, Peter S.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. RP Dorn, GW (reprint author), Washington Univ, Ctr Pharmacogen, 660 S Euclid Ave,Campus Box 8220, St Louis, MO 63110 USA. EM gdorn@dom.wustl.edu FU National Institutes of Health [R01 HL059888]; American Heart Association FX This study was supported by R01 HL059888 from the National Institutes of Health (G. W. Dorn) and an American Heart Association predoctoral fellowship award (M. Song). NR 19 TC 49 Z9 49 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD JUL 18 PY 2014 VL 115 IS 3 BP 348 EP + DI 10.1161/CIRCRESAHA.115.304384 PG 11 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AL6VZ UT WOS:000339272700006 PM 24874428 ER PT J AU Ravel, J Blaser, MJ Braun, J Brown, E Bushman, FD Chang, EB Davies, J Dewey, KG Dinan, T Dominguez-Bello, M Erdman, SE Finlay, BB Garrett, WS Huffnagle, GB Huttenhower, C Jansson, J Jeffery, IB Jobin, C Khoruts, A Kong, HH Lampe, JW Ley, RE Littman, DR Mazmanian, SK Mills, DA Neish, AS Petrof, E Relman, DA Rhodes, R Turnbaugh, PJ Young, VB Knight, R White, O AF Ravel, Jacques Blaser, Martin J. Braun, Jonathan Brown, Eric Bushman, Frederic D. Chang, Eugene B. Davies, Julian Dewey, Kathryn G. Dinan, Timothy Dominguez-Bello, Maria Erdman, Susan E. Finlay, B. Brett Garrett, Wendy S. Huffnagle, Gary B. Huttenhower, Curtis Jansson, Janet Jeffery, Ian B. Jobin, Christian Khoruts, Alexander Kong, Heidi H. Lampe, Johanna W. Ley, Ruth E. Littman, Dan R. Mazmanian, Sarkis K. Mills, David A. Neish, Andrew S. Petrof, Elaine Relman, David A. Rhodes, Rosamond Turnbaugh, Peter J. Young, Vincent B. Knight, Rob White, Owen TI Human microbiome science: vision for the future, Bethesda, MD, July 24 to 26, 2013 SO MICROBIOME LA English DT Article ID HUMAN GUT VIROME; DISEASE; INFLAMMATION; METABOLISM; AMERINDIANS; INSIGHTS; PROJECT; NUMBER; OMICS; FLORA AB A conference entitled 'Human microbiome science: Vision for the future' was organized in Bethesda, MD from July 24 to 26, 2013. The event brought together experts in the field of human microbiome research and aimed at providing a comprehensive overview of the state of microbiome research, but more importantly to identify and discuss gaps, challenges and opportunities in this nascent field. This report summarizes the presentations but also describes what is needed for human microbiome research to move forward and deliver medical translational applications. C1 [Ravel, Jacques] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Inst Genome Sci, Baltimore, MD 21201 USA. [Blaser, Martin J.; Dominguez-Bello, Maria] NYU, Langone Med Ctr, Dept Microbiol, Human Microbiome Program, New York, NY 10016 USA. [Braun, Jonathan] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Brown, Eric] Univ British Columbia, Michael Smith Labs, Vancouver, BC V6T 1Z4, Canada. [Brown, Eric] Univ British Columbia, Dept Microbiol & Immunol, Vancouver, BC V6T 1Z4, Canada. [Bushman, Frederic D.; Finlay, B. Brett] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Chang, Eugene B.] Univ Chicago, Knapp Ctr Biomed Discovery, Chicago, IL 60637 USA. [Davies, Julian] Univ British Columbia, Dept Microbiol & Immunol, Life Sci Ctr, Vancouver, BC V6T 1Z3, Canada. [Dewey, Kathryn G.] Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA. [Dinan, Timothy] Cork Univ Hosp, GF Unity, Dept Psychiat, Cork, Wilton, Ireland. [Erdman, Susan E.] MIT, Div Comparat Med, Cambridge, MA 02139 USA. [Garrett, Wendy S.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Huffnagle, Gary B.; Young, Vincent B.] Univ Michigan, Sch Med, Dept Internal Med Infect Dis, Immunol, Ann Arbor, MI 48109 USA. [Huffnagle, Gary B.; Young, Vincent B.] Univ Michigan, Sch Med, Dept Microbiol, Immunol, Ann Arbor, MI 48109 USA. [Huttenhower, Curtis] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Jansson, Janet] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Earth Sci, Berkeley, CA 94720 USA. [Jeffery, Ian B.] Univ Coll, Alimentary Pharmabiot Ctr, Dept Microbiol, Cork, Ireland. [Jobin, Christian] Univ Florida, Coll Med, Dept Infect Dis & Pathol, Gainesville, FL 32611 USA. [Jobin, Christian] Univ Florida, Dept Med, Div Gastroenterol Hepatol & Nutr, Gainesville, FL 32611 USA. [Khoruts, Alexander] Ctr Immunol, Dept Med, Minneapolis, MN 55416 USA. [Kong, Heidi H.] NCI, Ctr Canc Res, NIH, Dermatol Branch, Bethesda, MD 20814 USA. [Lampe, Johanna W.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Canc Prevent Program, Seattle, WA 98109 USA. [Ley, Ruth E.] Cornell Univ, Dept Microbiol, Ithaca, NY 14853 USA. [Littman, Dan R.] Skirball Inst, Dept Pathol, Mol Pathogenesis, New York, NY 10016 USA. [Littman, Dan R.] Skirball Inst, Dept Microbiol, Mol Pathogenesis, New York, NY 10016 USA. [Mazmanian, Sarkis K.] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA. [Mills, David A.] Univ Calif Davis, Dept Food Sci & Technol, Davis, CA 95616 USA. [Mills, David A.] Univ Calif Davis, Dept Viticulture & Enol, Davis, CA 95616 USA. [Neish, Andrew S.] Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. [Petrof, Elaine] Queens Univ, Gastrointestinal Dis Res Unit, Dept Med Infect Dis, Kingston, ON K7L 2V7, Canada. [Petrof, Elaine] Kingston Gen Hosp, Kingston, ON K7L 2V7, Canada. [Relman, David A.] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Relman, David A.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Rhodes, Rosamond] Icahn Sch Med Mt Sinai, Dept Med Educ, New York, NY 10029 USA. [Turnbaugh, Peter J.] Harvard Univ, FAS Ctr Syst Biol, Cambridge, MA 02138 USA. [Knight, Rob] Univ Colorado, Howard Hughes Med Inst, Dept Chem & Biochem, Boulder, CO 80309 USA. [White, Owen] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Inst Genome Sci, Baltimore, MD 21201 USA. RP Ravel, J (reprint author), Univ Maryland, Sch Med, Dept Microbiol & Immunol, Inst Genome Sci, 801 W Baltimore St, Baltimore, MD 21201 USA. EM jravel@som.umaryland.edu RI Ley, Ruth/M-8542-2014; Knight, Rob/D-1299-2010; OI Ley, Ruth/0000-0002-9087-1672; Braun, Jonathan/0000-0003-1646-2974; Turnbaugh, Peter/0000-0002-0888-2875; Ravel, Jacques/0000-0002-0851-2233; Jeffery, Ian/0000-0001-9183-7292 FU National Human Genomics Research Institute, National Institutes of Health [U01HG004866]; Roche; Qiagen; Illumina; Life Technologies; MoBio; Metabolon; BioMed Central journal Microbiome FX The authors would like to thank Lita Proctor (NHGRI/NIH), for conceiving this idea to evaluate the status of microbiome research across the NIH, as well as Christopher Wellington, Nicholas Digiacomo, Sue Dilli, and Michele Giglio for their invaluable contributions to the organization of the scientific program and the logistics of the meeting. The conference was supported in part by grant U01HG004866 from the National Human Genomics Research Institute, National Institutes of Health. The conference organizers are grateful to Roche, Qiagen, Illumina, Life Technologies, MoBio, Metabolon, and the BioMed Central journal Microbiome for their financial support of the meeting. NR 53 TC 7 Z9 7 U1 5 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2049-2618 J9 MICROBIOME JI Microbiome PD JUL 18 PY 2014 VL 2 AR 16 DI 10.1186/2049-2618-2-16 PG 11 WC Microbiology SC Microbiology GA CU0FO UT WOS:000363191700001 ER PT J AU Morton, LM AF Morton, Lindsay M. TI Triple jeopardy for Hodgkin lymphoma survivors? SO BLOOD LA English DT Editorial Material ID CANCER-RISK; RADIOTHERAPY; CHEMOTHERAPY; DISEASE C1 NCI, NIH, Bethesda, MD 20892 USA. RP Morton, LM (reprint author), NCI, NIH, Bethesda, MD 20892 USA. RI Morton, Lindsay/B-5234-2015 OI Morton, Lindsay/0000-0001-9767-2310 NR 10 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 17 PY 2014 VL 124 IS 3 BP 309 EP 310 PG 2 WC Hematology SC Hematology GA AQ2LY UT WOS:000342619000002 PM 25035144 ER PT J AU FitzGerald, DJ AF FitzGerald, David J. TI Targeted diphtheria toxin to treat BPDCN SO BLOOD LA English DT Editorial Material ID LEUKEMIA C1 NIH, Bethesda, MD 20892 USA. RP FitzGerald, DJ (reprint author), NIH, Bethesda, MD 20892 USA. NR 9 TC 3 Z9 3 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 17 PY 2014 VL 124 IS 3 BP 310 EP 312 DI 10.1182/blood-2014-06-578633 PG 5 WC Hematology SC Hematology GA AQ2LY UT WOS:000342619000003 PM 25035145 ER PT J AU Alter, BP AF Alter, Blanche P. TI Pearson syndrome in a Diamond-Blackfan anemia cohort SO BLOOD LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Alter, BP (reprint author), NCI, Bethesda, MD 20892 USA. NR 6 TC 2 Z9 3 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 17 PY 2014 VL 124 IS 3 BP 312 EP 313 DI 10.1182/blood-2014-04-571687 PG 4 WC Hematology SC Hematology GA AQ2LY UT WOS:000342619000004 PM 25035146 ER PT J AU Zhu, SG Phatarpekar, PV Denman, CJ Senyukov, VV Somanchi, SS Nguyen-Jackson, HT Mace, EM Freeman, AF Watowich, SS Orange, JS Holland, SM Lee, DA AF Zhu, Shiguo Phatarpekar, Prasad V. Denman, Cecele J. Senyukov, Vladimir V. Somanchi, Srinivas S. Nguyen-Jackson, Hoainam T. Mace, Emily M. Freeman, Alexandra F. Watowich, Stephanie S. Orange, Jordan S. Holland, Steven M. Lee, Dean A. TI Transcription of the activating receptor NKG2D in natural killer cells is regulated by STAT3 tyrosine phosphorylation SO BLOOD LA English DT Article ID HYPER-IGE SYNDROME; NK CELLS; HERPESVIRUS INFECTIONS; ANTITUMOR-ACTIVITY; IN-VIVO; EXPRESSION; CANCER; INTERLEUKIN-21; IMMUNITY; PATHWAY AB Signal transducer and activator of transcription 3 (STAT3) is considered a negative regulator of inflammation, as inhibition of STAT3 signaling enhances antitumor immunity. However, STAT3 activation is a key oncogenic pathway in natural killer (NK)-lineage large granular lymphomas, and we recently reported enhanced proliferation and function of human NK cells activated with IL-21, which signals primarily through STAT3. These IL-21-expanded NK cells also have increased NKG2D expression, which led us to focus our investigation on whether STAT3 regulates NKG2D. In this study, we show that modulation of STAT3 phosphorylation with cytokines and small-molecule inhibitors correlates with NKG2D expression on human NK cells, leading to altered NK-cell degranulation. Moreover, NKG2D expression on murine NK cells having conditional STAT3 ablation is lower than on NK cells from wildtype mice, and human NK cells carrying dominant-negative STAT3 mutations have decreased baseline NKG2D expression and blunted responses to IL-10 and IL-21. Lastly, we show binding of STAT3 to a predicted STAT3 binding site upstream of the NKG2D gene, which is enhanced by IL-10 and IL-21 and decreased by STAT3 inhibition. Taken together, these data show that NKG2D expression in NK cells is regulated at the transcriptional level by STAT3, resulting in a functional NK cell defect in patients with STAT3 mutations. C1 [Zhu, Shiguo; Phatarpekar, Prasad V.; Denman, Cecele J.; Senyukov, Vladimir V.; Somanchi, Srinivas S.; Lee, Dean A.] Univ Texas MD Anderson Canc Ctr, Div Pediat, Cell Therapy Sect, Houston, TX 77030 USA. [Nguyen-Jackson, Hoainam T.; Watowich, Stephanie S.] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA. [Mace, Emily M.; Orange, Jordan S.] Baylor Coll Med, Dept Pediat, Sect Immunol Allergy & Rheumatol, Houston, TX 77030 USA. [Freeman, Alexandra F.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Lee, DA (reprint author), Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd,Unit 853, Houston, TX 77030 USA. EM dalee@mdanderson.org OI orange, jordan/0000-0001-7117-7725; Lee, Dean/0000-0001-6693-5392; Watowich, Stephanie/0000-0003-1969-659X FU University of Texas MD Anderson Cancer Center Physician Scientist Program; St. Baldrick's Foundation; Farrah Fawcett Foundation; National Cancer Institute Cancer Center Support (Core) Grant [CA 16672]; Mr and Mrs David T. Herr FX This work was supported by funding provided by the University of Texas MD Anderson Cancer Center Physician Scientist Program, the St. Baldrick's Foundation (http://www.stbaldricks.org/), the Farrah Fawcett Foundation, Mr and Mrs David T. Herr, and the National Cancer Institute Cancer Center Support (Core) Grant (CA 16672). NR 44 TC 13 Z9 15 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 17 PY 2014 VL 124 IS 3 BP 403 EP 411 DI 10.1182/blood-2013-05-499707 PG 9 WC Hematology SC Hematology GA AQ2LY UT WOS:000342619000015 PM 24891320 ER PT J AU Gattinoni, L AF Gattinoni, Luca TI Memory T Cells Officially Join the Stem Cell Club SO IMMUNITY LA English DT Editorial Material AB In this issue of Immunity, Graef et al. (2014) demonstrate self-renewal and multipotency of a single CD62L(+) memory T cell across serial adoptive transfers and infection-driven re-expansions, providing evidence of true stemness within the T cell memory compartment. C1 NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gattinoni, L (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM gattinol@mail.nih.gov RI Gattinoni, Luca/A-2281-2008 OI Gattinoni, Luca/0000-0003-2239-3282 NR 10 TC 7 Z9 7 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUL 17 PY 2014 VL 41 IS 1 BP 7 EP 9 DI 10.1016/j.immuni.2014.07.003 PG 4 WC Immunology SC Immunology GA AO6FC UT WOS:000341444200004 PM 25035947 ER PT J AU Murray, PJ Allen, JE Biswas, SK Fisher, EA Gilroy, DW Goerdt, S Gordon, S Hamilton, JA Ivashkiv, LB Lawrence, T Locati, M Mantovani, A Martinez, FO Mege, JL Mosser, DM Natoli, G Saeij, JP Schultze, JL Shirey, KA Sica, A Suttles, J Udalova, I van Ginderachter, JA Vogel, SN Wynn, TA AF Murray, Peter J. Allen, Judith E. Biswas, Subhra K. Fisher, Edward A. Gilroy, Derek W. Goerdt, Sergij Gordon, Siamon Hamilton, John A. Ivashkiv, Lionel B. Lawrence, Toby Locati, Massimo Mantovani, Alberto Martinez, Fernando O. Mege, Jean-Louis Mosser, David M. Natoli, Gioacchino Saeij, Jeroen P. Schultze, Joachim L. Shirey, Kari Ann Sica, Antonio Suttles, Jill Udalova, Irina van Ginderachter, Jo A. Vogel, Stefanie N. Wynn, Thomas A. TI Macrophage Activation and Polarization: Nomenclature and Experimental Guidelines SO IMMUNITY LA English DT Review ID NITRIC-OXIDE PRODUCTION; GENE-EXPRESSION; ALTERNATIVE ACTIVATION; MOUSE MACROPHAGES; ATHEROSCLEROSIS; DIFFERENTIATION; INFLAMMATION; PLASTICITY; DIVERSITY; MECHANISM AB Description of macrophage activation is currently contentious and confusing. Like the biblical Tower of Babel, macrophage activation encompasses a panoply of descriptors used in different ways. The lack of consensus on how to define macrophage activation in experiments in vitro and in vivo impedes progress in multiple ways, including the fact that many researchers still consider there to be only two types of activated macrophages, often termed M1 and M2. Here, we describe a set of standards encompassing three principles-the source of macrophages, definition of the activators, and a consensus collection of markers to describe macrophage activation-with the goal of unifying experimental standards for diverse experimental scenarios. Collectively, we propose a common framework for macrophage-activation nomenclature. C1 [Murray, Peter J.] St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA. [Murray, Peter J.] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA. [Allen, Judith E.] Univ Edinburgh, Sch Biol Sci, Ctr Immun Infect & Evolut, Edinburgh EH9 3JR, Midlothian, Scotland. [Biswas, Subhra K.] ASTAR, Singapore Immunol Network, Singapore 138648, Singapore. [Fisher, Edward A.] NYU, Sch Med, Ctr Prevent Cardiovasc Dis, New York, NY USA. [Gilroy, Derek W.] UCL, Rayne Inst, Div Med, London WC1 6JJ, England. [Goerdt, Sergij] Heidelberg Univ, Univ Med Ctr Mannheim, Dept Dermatol, D-68167 Mannheim, Germany. [Gordon, Siamon] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. [Hamilton, John A.] Univ Melbourne, Dept Med, Parkville, Vic 3050, Australia. [Hamilton, John A.] Royal Melbourne Hosp, Parkville, Vic 3050, Australia. [Ivashkiv, Lionel B.] Cornell Univ, Hosp Special Surg, New York, NY 10021 USA. [Ivashkiv, Lionel B.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Lawrence, Toby] Ctr Immunol Marseille Luminy, F-13009 Marseille, France. [Locati, Massimo; Mantovani, Alberto] Univ Milan, Sch Med, Ist Clin Humanitas, I-20089 Milan, Italy. [Martinez, Fernando O.] Univ Oxford, Botnar Res Ctr, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford OX3 7LD, England. [Mege, Jean-Louis] Aix Marseille Univ, F-13285 Marseille, France. [Mosser, David M.] Univ Maryland, Dept Cell Biol, College Pk, MD 20742 USA. [Natoli, Gioacchino] European Inst Oncol, Dept Expt Oncol, I-20146 Milan, Italy. [Saeij, Jeroen P.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Schultze, Joachim L.] Univ Bonn, LIMES Inst, D-32115 Bonn, Germany. [Shirey, Kari Ann; Vogel, Stefanie N.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Sica, Antonio] Ist Clin Humanitas, I-20089 Milan, Italy. [Sica, Antonio] Univ Piemonte Orientale Amedeo Avogadro, Dept Pharmaceut Sci, I-28100 Novara, Italy. [Suttles, Jill] Univ Louisville, Sch Med, Louisville, KY 40292 USA. [Udalova, Irina] Univ Oxford, Kennedy Inst Rheumatol, Oxford OX3 7FY, England. [van Ginderachter, Jo A.] Vrije Univ Brussel, Cellular & Mol Immunol Lab, B-1050 Brussels, Belgium. [van Ginderachter, Jo A.] VIB, Lab Myeloid Cell Immunol, B-1050 Brussels, Belgium. [Wynn, Thomas A.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Murray, PJ (reprint author), St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA. EM peter.murray@stjude.org RI Schultze, Joachim/D-7794-2011; Mosser, David/I-6697-2016; Allen, Judith/C-9198-2011; MEGE, JEAN-LOUIS/O-6063-2016; Lawrence, Toby/F-4461-2015; OI Fisher, Edward/0000-0001-9802-143X; Schultze, Joachim/0000-0003-2812-9853; Mosser, David/0000-0002-9503-4187; Allen, Judith/0000-0002-3829-066X; Hamilton, John A/0000-0002-9493-9224; Saeij, Jeroen/0000-0003-0289-7109; Locati, Massimo/0000-0003-3077-590X; Mantovani, Alberto/0000-0001-5578-236X FU NIH [AI062921, AI080621, HL084312, AI18797]; Alex's Lemonade Stand Foundation; Hartwell Foundation; Cancer Center Core grant [P30 CA21765]; American Lebanese Syrian Associated Charities; NIH Intramural Program FX This work was supported by NIH grants AI062921 (P.J.M.), AI080621 (J.P.S.), HL084312 (E.A.F.), and AI18797 (K.A.S. and S.N.V.), Alex's Lemonade Stand Foundation (P.J.M.), the Hartwell Foundation (P.J.M.), Cancer Center Core grant P30 CA21765 (P.J.M.), the American Lebanese Syrian Associated Charities (P.J.M.), and the NIH Intramural Program (T.A.W.). NR 45 TC 615 Z9 625 U1 32 U2 214 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUL 17 PY 2014 VL 41 IS 1 BP 14 EP 20 DI 10.1016/j.immuni.2014.06.008 PG 7 WC Immunology SC Immunology GA AO6FC UT WOS:000341444200007 PM 25035950 ER PT J AU van Panhuys, N Klauschen, F Germain, RN AF van Panhuys, Nicholas Klauschen, Frederick Germain, Ronald N. TI T-Cell-Receptor-Dependent Signal Intensity Dominantly Controls CD4(+) T Cell Polarization In Vivo SO IMMUNITY LA English DT Article ID PROTEIN-KINASE-C; DENDRITIC CELLS; LYMPH-NODES; PKC-THETA; DIFFERENTIATION; TRANSCRIPTION; ACTIVATION; ANTIGEN; CYTOKINES; RESPONSES AB Polarization of effector CD4(+) T cells can be influenced by both antigen-specific signals and by pathogen- or adjuvant-induced cytokines, with current models attributing a dominant role to the latter. Here we have examined the relationship between these factors in shaping cell-mediated immunity by using intravital imaging of CD4(+) T cell interactions with dendritic cells (DCs) exposed to polarizing adjuvants. These studies revealed a close correspondence between strength of T cell receptor (TCR)-dependent signaling and T helper 1 (Th1) versus Th2 cell fate, with antigen concentration dominating over adjuvant in controlling T cell polarity. Consistent with this finding, at a fixed antigen concentration, adjuvants inducing Th1 cells operated by affecting DC costimulation that amplified TCR signaling. TCR signal strength controlled downstream cytokine receptor expression, linking the two components in a hierarchical fashion. These data reveal how quantitative integration of antigen display and costimulation regulates downstream checkpoints responsible for cytokine-mediated control of effector differentiation. C1 [van Panhuys, Nicholas; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Klauschen, Frederick] Charite, Inst Pathol, D-10117 Berlin, Germany. RP van Panhuys, N (reprint author), NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. EM vanpanhuysn@niaid.nih.gov; rgermain@niaid.nih.gov RI Klauschen, Frederick/C-5637-2015; van Panhuys, Nicholas/E-1812-2011; OI van Panhuys, Nicholas/0000-0003-2199-852X FU Intramural Research Program of the NIAID, NIH; New Zealand FRST; International Human Frontier Science Program [RGY0077/2011] FX We thank W. E. Paul, J. Zhu, H. Yamane, M. Gerner, R. Gottschalk, Z. Liu, and W. Kastenmueller for their reading and critical discussions of this manuscript. We also thank D. Jankovic for providing reagents. This work was supported by the Intramural Research Program of the NIAID, NIH. N.V.P. was supported by the New Zealand FRST and F.K. was supported by the Grant from the International Human Frontier Science Program (RGY0077/2011). NR 51 TC 49 Z9 49 U1 1 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUL 17 PY 2014 VL 41 IS 1 BP 63 EP 74 DI 10.1016/j.immuni.2014.06.003 PG 12 WC Immunology SC Immunology GA AO6FC UT WOS:000341444200011 PM 24981853 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI Calorie Restriction a Lamarck SO CELL LA English DT Editorial Material ID INHERITANCE; MECHANISMS; ARGONAUTE; EVOLUTION; RNAS; DNA AB Epigenetic inheritance of resistance to exogenous nucleic acids via small interfering (si) RNA is well established in animal models. Rechavi et al. demonstrate epigenetic inheritance of a starvation-induced pattern of gene silencing caused by endogenous siRNAs and resulting in an increased longevity in the third generation progeny. Combined with recent findings in prokaryotes, these results suggest that Lamarckian-type inheritance of acquired traits is a major evolutionary phenomenon. C1 NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov NR 10 TC 6 Z9 6 U1 13 U2 41 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 17 PY 2014 VL 158 IS 2 BP 237 EP 238 DI 10.1016/j.cell.2014.07.004 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9QU UT WOS:000340943600001 PM 25036622 ER PT J AU Levens, D Larson, DR AF Levens, David Larson, Daniel R. TI A New Twist on Transcriptional Bursting SO CELL LA English DT Editorial Material ID EXPRESSION; GENE AB Transcriptional bursting has been observed across species and is one of the primary causes of variable gene expression in cells and tissue. In this issue, Chong et al. describe how DNA topology results in transcriptional bursting in E. coli. C1 [Levens, David; Larson, Daniel R.] NIH, Ctr Canc Res, Bethesda, MD 20814 USA. RP Larson, DR (reprint author), NIH, Ctr Canc Res, Bldg 10, Bethesda, MD 20814 USA. EM dan.larson@nih.gov RI Larson, Daniel/B-9829-2008; Levens, David/C-9216-2009 OI Larson, Daniel/0000-0001-9253-3055; Levens, David/0000-0002-7616-922X NR 10 TC 2 Z9 2 U1 2 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 17 PY 2014 VL 158 IS 2 BP 241 EP 242 DI 10.1016/j.cell.2014.06.042 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9QU UT WOS:000340943600003 PM 25036624 ER PT J AU Hickman, AB Ewis, HE Li, XH Knapp, JA Laver, T Doss, AL Tolun, G Steven, AC Grishaev, A Bax, A Atkinson, PW Craig, NL Dyda, F AF Hickman, Alison B. Ewis, Hosam E. Li, Xianghong Knapp, Joshua A. Laver, Thomas Doss, Anna-Louise Tolun, Goekhan Steven, Alasdair C. Grishaev, Alexander Bax, Ad Atkinson, Peter W. Craig, Nancy L. Dyda, Fred TI Structural Basis of hAT Transposon End Recognition by Hermes, an Octameric DNA Transposase from Musca domestica SO CELL LA English DT Article ID X-RAY-SCATTERING; V(D)J RECOMBINATION; BINDING DOMAIN; SUBTERMINAL SEQUENCES; PUTATIVE TRANSPOSASE; TARGET SITE; AC ELEMENT; IN-VIVO; HOBO; DROSOPHILA AB Hermes is a member of the hAT transposon superfamily that has active representatives, including McClintock's archetypal Ac mobile genetic element, in many eukaryotic species. The crystal structure of the Hermes transposase-DNA complex reveals that Hermes forms an octameric ring organized as a tetramer of dimers. Although isolated dimers are active in vitro for all the chemical steps of transposition, only octamers are active in vivo. The octamer can provide not only multiple specific DNA-binding domains to recognize repeated subterminal sequences within the transposon ends, which are important for activity, but also multiple nonspecific DNA binding surfaces for target capture. The unusual assembly explains the basis of bipartite DNA recognition at hAT transposon ends, provides a rationale for transposon end asymmetry, and suggests how the avidity provided by multiple sites of interaction could allow a transposase to locate its transposon ends amidst a sea of chromosomal DNA. C1 [Hickman, Alison B.; Dyda, Fred] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Ewis, Hosam E.; Li, Xianghong; Craig, Nancy L.] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. [Knapp, Joshua A.; Atkinson, Peter W.] Univ Calif Riverside, Grad Program Biochem & Mol Biol, Riverside, CA 92521 USA. [Laver, Thomas; Atkinson, Peter W.] Univ Calif Riverside, Grad Program Genet Genom & Bioinformat, Riverside, CA 92521 USA. [Doss, Anna-Louise; Atkinson, Peter W.] Univ Calif Riverside, Grad Program Cell Mol & Dev Biol, Riverside, CA 92521 USA. [Atkinson, Peter W.] Univ Calif Riverside, Dept Entomol, Riverside, CA 92521 USA. [Atkinson, Peter W.] Univ Calif Riverside, Inst Integrat Genome Biol, Riverside, CA 92521 USA. [Tolun, Goekhan; Steven, Alasdair C.] NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. [Grishaev, Alexander; Bax, Ad] NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Dyda, F (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM fred.dyda@nih.gov RI TOLUN, Gokhan/D-1971-2012 OI TOLUN, Gokhan/0000-0001-6166-9451 FU NIH Intramural Programs of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); Public Health Service (PHS) award [A1045741]; US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX This work was partially funded by the NIH Intramural Programs of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (F.D. and A.B.) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (A.C.S.). P.W.A. and N.L.C. were funded by Public Health Service (PHS) award A1045741. Crystallographic data were collected at the SER-CAT 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory (ANL). For the SAXS experiments, we gratefully acknowledge use of the shared scattering beamline 12-IDC resource allocated under the PUP-77 agreement between the National Cancer Institute and ANL and thank Soenke Seifert (ANL) for his support. Use of the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract W-31-109-Eng-38. We thank Sriram Subramaniam and members of his laboratory for their preliminary EM efforts. We also thank Nadine Samara for critical reading of the manuscript, Primrose Musingarimi for help with Sf9-expressed Hermes, Robert Hice for assistance with EMSA and insect cell culture experiments, and Susan Chacko of the Helix systems group, CIT, NIH for advice and help with fuzznuc. NR 52 TC 19 Z9 19 U1 0 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 17 PY 2014 VL 158 IS 2 BP 353 EP 367 DI 10.1016/j.cell.2014.05.037 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9QU UT WOS:000340943600015 PM 25036632 ER PT J AU Rodrigo-Brenni, MC Gutierrez, E Hegde, RS AF Rodrigo-Brenni, Monica C. Gutierrez, Erik Hegde, Ramanujan S. TI Cytosolic Quality Control of Mislocalized Proteins Requires RNF126 Recruitment to Bag6 SO MOLECULAR CELL LA English DT Article ID HEAT-SHOCK PROTEINS; E3 UBIQUITIN LIGASE; ENDOPLASMIC-RETICULUM; PRION PROTEIN; CHAPERONE FUNCTIONS; MEMBRANE-PROTEINS; DEGRADATION; RIBOSOME; MUTATION; CHIP AB Approximately 30% of eukaryotic proteins contain hydrophobic signals for localization to the secretory pathway. These proteins can be mislocalized in the cytosol due to mutations in their targeting signals, certain stresses, or intrinsic inefficiencies in their translocation. Mislocalized proteins (MLPs) are protected from aggregation by the Bag6 complex and degraded by a poorly characterized proteasome-dependent pathway. Here, we identify the ubiquitin ligase RNF126 as a key component of the MLP degradation pathway. In vitro reconstitution and fractionation studies reveal that RNF126 is the primary Bag6-dependent ligase. RNF126 is recruited to the N-terminal Ubl domain of Bag6 and preferentially ubiquitinates juxtahydrophobic lysine residues on Bag6-associated clients. Interfering with RNF126 recruitment in vitro prevents ubiquitination, and RNF126 depletion in cells partially stabilizes a Bag6 client. Bag6-dependent ubiquitination can be recapitulated with purified components, paving the way for mechanistic analyses of downstream steps in this cytosolic quality control pathway. C1 [Rodrigo-Brenni, Monica C.; Hegde, Ramanujan S.] MRC Lab Mol Biol, Cambridge CB2 0QH, England. [Gutierrez, Erik] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Hegde, RS (reprint author), MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England. EM rhegde@mrc-lmb.cam.ac.uk OI Hegde, Ramanujan/0000-0001-8338-852X FU Medical Research Council of the UK [MC_UP_A022_1007]; U.S. National Institutes of Health FX We are grateful to T. Hessa for discussions at the early stages of this project; S. Shao for providing the rBag6 complex; and M. Skehel, S.-Y. Peak-Chew, and S. Maslen for mass spectrometry, and Hegde lab members for advice and support. This research was supported by the Medical Research Council of the UK (MC_UP_A022_1007) and the U.S. National Institutes of Health (E.G.). M.C.R.-B. is an Ellison Medical Foundation/AFAR Fellow of the Life Sciences Research Foundation. NR 48 TC 23 Z9 24 U1 2 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD JUL 17 PY 2014 VL 55 IS 2 BP 227 EP 237 DI 10.1016/j.molcel.2014.05.025 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN5OS UT WOS:000340641700008 PM 24981174 ER PT J AU Ding, XC Zhou, N Lin, H Chen, JJ Zhao, CY Zhou, GK Hejtmancik, JF Qi, YH AF Ding, Xuchen Zhou, Nan Lin, Hui Chen, Jianjun Zhao, Chunyuan Zhou, Guangkai Hejtmancik, J. Fielding Qi, Yanhua TI A Novel MIP Gene Mutation Analysis in a Chinese Family Affected with Congenital Progressive Punctate Cataract SO PLOS ONE LA English DT Article ID AUTOSOMAL-DOMINANT CATARACT; MAJOR INTRINSIC PROTEIN; SPLICE-SITE MUTATION; NUCLEAR CATARACT; NONSENSE MUTATION; MISSENSE MUTATION; JUVENILE-ONSET; LENS; LAMELLAR; IDENTIFICATION AB Congenital cataracts are one of the leading causes of visual impairment and blindness in children, and genetic factors play an important role in their development. This study aimed to identify the genetic defects associated with autosomal dominant congenital progressive punctate cataracts in a Chinese family and to explore the potential pathogenesis. Detailed family history and clinical data were recorded, and all the family members' blood samples were collected for DNA extraction. Linkage analysis was performed by microsatellite markers that are associated with punctate cataracts, and logarithm (base 10) of odds (LOD) scores were calculated using the LINKAGE program. Positive two-point LOD scores were obtained at markers D12S1622 (Z(max) = 2.71 at theta = 0.0), D12S1724 (Z(max) = 2.71 at theta = 0.0), and D12S90 (Z(max) = 2.71 at theta = 0.0), which flank the major intrinsic protein of lens fiber (MIP) gene on chromosomal region 12q13. Direct sequencing of the encoding region of the MIP gene revealed a novel mutation (G>D) in exon 4 at nucleotide 644, which caused a substitution of glycine to aspartic acid at codon 215 (p.G215D) for the MIP protein. The mutation cosegregated with all patients with congenital progressive punctate cataracts, but it was absent in the healthy members. Bioinformatics analysis predicted that the mutation affects the function of the MIP protein. The wild type (WT) and G215D mutant of MIP were transfected with green fluorescent protein (GFP) into Hela cells separately, and it was found that the G215D mutant was aberrantly located in the cytoplasm instead of in the plasma membrane. In summary, our study presented genetic and functional evidence linking the new MIP mutation of G215D to autosomal dominant congenital cataracts, which adds to the list of MIP mutations linked to congenital progressive punctate cataracts. C1 [Ding, Xuchen; Zhou, Nan; Lin, Hui; Zhao, Chunyuan; Zhou, Guangkai; Qi, Yanhua] Harbin Med Univ, Affiliated Hosp 2, Dept Ophthalmol, Harbin, Peoples R China. [Chen, Jianjun] Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Dept Ophthalmol, Shanghai 200092, Peoples R China. [Chen, Jianjun] Tongji Univ, Sch Med, Tongji Eye Inst, Shanghai 200092, Peoples R China. [Chen, Jianjun; Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Qi, YH (reprint author), Harbin Med Univ, Affiliated Hosp 2, Dept Ophthalmol, Harbin, Peoples R China. EM qi_yanhua@yahoo.com FU National Natural Science Foundation of China [81341026] FX This work was supported by the National Natural Science Foundation of China [grant number 81341026]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 7 Z9 7 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 17 PY 2014 VL 9 IS 7 AR e102733 DI 10.1371/journal.pone.0102733 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL8VR UT WOS:000339418300085 PM 25033405 ER PT J AU Reinhold, WC Varma, S Sousa, F Sunshine, M Abaan, OD Davis, SR Reinhold, SW Kohn, KW Morris, J Meltzer, PS Doroshow, JH Pommier, Y AF Reinhold, William C. Varma, Sudhir Sousa, Fabricio Sunshine, Margot Abaan, Ogan D. Davis, Sean R. Reinhold, Spencer W. Kohn, Kurt W. Morris, Joel Meltzer, Paul S. Doroshow, James H. Pommier, Yves TI NCI-60 Whole Exome Sequencing and Pharmacological CellMiner Analyses SO PLOS ONE LA English DT Article ID TUMOR-CELL-LINES; ANTICANCER DRUG SCREEN; CANCER-CELLS; KINASE INHIBITOR; GENE-EXPRESSION; PANEL; DNA; SENSITIVITY; IDENTIFICATION; MUTATIONS AB Exome sequencing provides unprecedented insights into cancer biology and pharmacological response. Here we assess these two parameters for the NCI-60, which is among the richest genomic and pharmacological publicly available cancer cell line databases. Homozygous genetic variants that putatively affect protein function were identified in 1,199 genes (approximately 6% of all genes). Variants that are either enriched or depleted compared to non-cancerous genomes, and thus may be influential in cancer progression and differential drug response were identified for 2,546 genes. Potential gene knockouts are made available. Assessment of cell line response to 19,940 compounds, including 110 FDA-approved drugs, reveals approximate to 80-fold range in resistance versus sensitivity response across cell lines. 103,422 gene variants were significantly correlated with at least one compound (at p<0.0002). These include genes of known pharmacological importance such as IGF1R, BRAF, RAD52, MTOR, STAT2 and TSC2 as well as a large number of candidate genes such as NOM1, TLL2, and XDH. We introduce two new web-based CellMiner applications that enable exploration of variant-to-compound relationships for a broad range of researchers, especially those without bioinformatics support. The first tool, "Genetic variant versus drug visualization'', provides a visualization of significant correlations between drug activity-gene variant combinations. Examples are given for the known vemurafenib-BRAF, and novel ifosfamide-RAD52 pairings. The second, "Genetic variant summation'' allows an assessment of cumulative genetic variations for up to 150 combined genes together; and is designed to identify the variant burden for molecular pathways or functional grouping of genes. An example of its use is provided for the EGFR-ERBB2 pathway gene variant data and the identification of correlated EGFR, ERBB2, MTOR, BRAF, MEK and ERK inhibitors. The new tools are implemented as an updated web-based CellMiner version, for which the present publication serves as a compendium. C1 [Reinhold, William C.; Varma, Sudhir; Sousa, Fabricio; Sunshine, Margot; Reinhold, Spencer W.; Kohn, Kurt W.; Morris, Joel; Doroshow, James H.; Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Varma, Sudhir] HiThru Analyt LLC, Laurel, MD USA. [Sousa, Fabricio] Univ Fed Mato Grosso do Sul, Ctr Estudos Celulas Tronco Terapia Celular & Gene, Programa Posgrad Farm, Campo Grande, MS, Brazil. [Sunshine, Margot] SRA Int, Fairfax, VA USA. [Abaan, Ogan D.; Davis, Sean R.; Meltzer, Paul S.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD USA. RP Reinhold, WC (reprint author), NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM wcr@mail.nih.gov; pommier@nih.gov RI Varma, Sudhir/N-8763-2014; Sousa, Fabricio/O-8878-2015; OI Varma, Sudhir/0000-0002-4096-4782; Sousa, Fabricio/0000-0003-0444-754X; Davis, Sean/0000-0002-8991-6458; Sousa, Filipe/0000-0003-4681-8951 FU Center for Cancer Research, Intramural Program of the National Cancer Institute [Z01 BC 006150] FX Our studies are supported by the Center for Cancer Research, Intramural Program of the National Cancer Institute (Z01 BC 006150). The funders had no role had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 10 Z9 10 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 17 PY 2014 VL 9 IS 7 AR e101670 DI 10.1371/journal.pone.0101670 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL8VR UT WOS:000339418300023 PM 25032700 ER PT J AU Lhoumaud, P Hennion, M Gamot, A Cuddapah, S Queille, S Liang, J Micas, G Morillon, P Urbach, S Bouchez, O Severac, D Emberly, E Zhao, K Cuvier, O AF Lhoumaud, Priscillia Hennion, Magali Gamot, Adrien Cuddapah, Suresh Queille, Sophie Liang, Jun Micas, Gael Morillon, Pauline Urbach, Serge Bouchez, Olivier Severac, Dany Emberly, Eldon Zhao, Keji Cuvier, Olivier TI Insulators recruit histone methyltransferase dMes4 to regulate chromatin of flanking genes SO EMBO JOURNAL LA English DT Article DE chromatin barrier; higher-order chromatin organization; nucleosome positioning; physical borders; RNA splicing ID RNA-POLYMERASE-II; PROTEIN-BINDING SITES; DROSOPHILA GENOME; BOUNDARY-ELEMENT; TOPOISOMERASE-II; DNA-REPLICATION; ORGANIZATION; METHYLATION; TRANSCRIPTION; EXPRESSION AB Chromosomal domains in Drosophila are marked by the insulator-binding proteins (IBPs) dCTCF/Beaf32 and cofactors that participate in regulating long-range interactions. Chromosomal borders are further enriched in specific histone modifications, yet the role of histone modifiers and nucleosome dynamics in this context remains largely unknown. Here, we show that IBP depletion impairs nucleosome dynamics specifically at the promoters and coding sequence of genes flanked by IBP binding sites. Biochemical purification identifies the H3K36 histone methyltransferase NSD/dMes-4 as a novel IBP cofactor, which specifically co-regulates the chromatin accessibility of hundreds of genes flanked by dCTCF/Beaf32. NSD/dMes-4 presets chromatin before the recruitment of transcriptional activators including DREF that triggers Set2/Hypb-dependent H3K36 trimethylation, nucleosome positioning, and RNA splicing. Our results unveil a model for how IBPs regulate nucleosome dynamics and gene expression through NSD/dMes-4, which may regulate H3K27me3 spreading. Our data uncover how IBPs dynamically regulate chromatin organization depending on distinct cofactors. C1 [Lhoumaud, Priscillia; Hennion, Magali; Gamot, Adrien; Queille, Sophie; Liang, Jun; Micas, Gael; Morillon, Pauline; Cuvier, Olivier] Univ Toulouse UPS, CNRS, LBME, Toulouse, France. [Cuddapah, Suresh; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Urbach, Serge] Inst Genom Fonct, Mass Spectrometry Facil, Montpellier, France. [Bouchez, Olivier] INRA, Lab Genet Cellulaire, UMR444, Toulouse, France. [Bouchez, Olivier] INRA, GeT PlaGe, Toulouse, France. [Severac, Dany] MGX Montpellier GenomiX, Inst Genom Fonct, Montpellier, France. [Emberly, Eldon] Simon Fraser Univ, Dept Phys, Burnaby, BC V5A 1S6, Canada. RP Cuvier, O (reprint author), Univ Toulouse UPS, CNRS, LBME, Toulouse, France. EM cuvier@ibcg.biotoul.fr FU NSERC; Canadian Institute For Advanced Research (CIFAR); University of Toulouse; Division of Intramural Research Program of the National Heart, Lung and Blood Institute, NIH; La Ligue Nationale Contre le Cancer (LNCC); Region Midi-Pyrnes; Cancer Research funding of the ARC; ATIP-AVENIR program of the CNRS; ANR "INSULa" FX We thank Artem Barski and Kairong Cui for performing the Hi-Seq sequencing of MNase data, S. Gadat and G. Fichant for suggestion regarding statistical analyses, L. Lacroix and additional OC's laboratory members for critical reading of the manuscript, C. Carles for help with the web server, P. Martin for technical help. E. E.'s laboratory was supported by NSERC and the Canadian Institute For Advanced Research (CIFAR) and by the University of Toulouse (while in O.C.'s laboratory). K.Z.'s laboratory was supported by the Division of Intramural Research Program of the National Heart, Lung and Blood Institute, NIH. P. L. and M. H. were supported by a fellowship from La Ligue Nationale Contre le Cancer (LNCC). O.C.'s laboratory was supported by grants from the Region Midi-Pyrnes, the Cancer Research funding of the ARC, the ATIP-AVENIR program of the CNRS and Inserm joint program and the ANR "INSULa". NR 61 TC 7 Z9 7 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD JUL 17 PY 2014 VL 33 IS 14 BP 1599 EP 1613 DI 10.15252/embj.201385965 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AL8LO UT WOS:000339390500010 PM 24916307 ER PT J AU Malley, JD Moore, JH AF Malley, James D. Moore, Jason H. TI Innovation is often unnerving: the door into summer SO BIODATA MINING LA English DT Editorial Material C1 [Malley, James D.] Natl Inst Hlth, Ctr Informat Technol, Bethesda, MD USA. [Moore, Jason H.] Dartmouth Coll, Geisel Sch Med, Dept Genet, Lebanon, NH 03756 USA. [Moore, Jason H.] Dartmouth Coll, Geisel Sch Med, Inst Quantitat Biomed, Lebanon, NH 03756 USA. RP Moore, JH (reprint author), Dartmouth Coll, Geisel Sch Med, Dept Genet, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM jason.h.moore@dartmouth.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-0381 J9 BIODATA MIN JI BioData Min. PD JUL 17 PY 2014 VL 7 AR 12 DI 10.1186/1756-0381-7-12 PG 2 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AL7CD UT WOS:000339289700001 PM 25057294 ER PT J AU Anderson, TJ Boden, WE Desvigne-Nickens, P Fleg, JL Kashyap, ML McBride, R Probstfield, JL AF Anderson, Todd J. Boden, William E. Desvigne-Nickens, Patrice Fleg, Jerome L. Kashyap, Moti L. McBride, Ruth Probstfield, Jeffrey L. CA AIM-HIGH Investigators TI Safety Profile of Extended-Release Niacin in the AIM-HIGH Trial SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Anderson, Todd J.] Libin Cardiovasc Inst, Calgary, AB, Canada. [Boden, William E.] Albany Stratton Vet Affairs VA Med Ctr, Albany, NY USA. [Desvigne-Nickens, Patrice; Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. [Kashyap, Moti L.] VA Long Beach Healthcare Syst, Long Beach, CA USA. [McBride, Ruth] Axio Res, Seattle, WA USA. [Probstfield, Jeffrey L.] Univ Washington, Seattle, WA 98195 USA. RP Anderson, TJ (reprint author), Libin Cardiovasc Inst, Calgary, AB, Canada. EM ruthm@axioresearch.com FU Intramural NIH HHS [Z99 HL999999]; NHLBI NIH HHS [U01 HL081649] NR 5 TC 30 Z9 30 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 17 PY 2014 VL 371 IS 3 BP 288 EP 290 DI 10.1056/NEJMc1311039 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AL3BK UT WOS:000338999800029 PM 25014706 ER PT J AU Gallat, FX Matsugaki, N Coussens, NP Yagi, KJ Boudes, M Higashi, T Tsuji, D Tatano, Y Suzuki, M Mizohata, E Tono, K Joti, Y Kameshima, T Park, J Song, CY Hatsui, T Yabashi, M Nango, E Itoh, K Coulibaly, F Tobe, S Ramaswamy, S Stay, B Iwata, S Chavas, LMG AF Gallat, Francois-Xavier Matsugaki, Naohiro Coussens, Nathan P. Yagi, Koichiro J. Boudes, Marion Higashi, Tetsuya Tsuji, Daisuke Tatano, Yutaka Suzuki, Mamoru Mizohata, Eiichi Tono, Kensuke Joti, Yasumasa Kameshima, Takashi Park, Jaehyun Song, Changyong Hatsui, Takaki Yabashi, Makina Nango, Eriko Itoh, Kohji Coulibaly, Fasseli Tobe, Stephen Ramaswamy, S. Stay, Barbara Iwata, So Chavas, Leonard M. G. TI In vivo crystallography at X-ray free-electron lasers: the next generation of structural biology? SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE serial femtosecond crystallography; in vivo crystallography; X-ray free-electron laser ID POLYHEDRA; CRYSTALS AB The serendipitous discovery of the spontaneous growth of protein crystals inside cells has opened the field of crystallography to chemically unmodified samples directly available from their natural environment. On the one hand, through in vivo crystallography, protocols for protein crystal preparation can be highly simplified, although the technique suffers from difficulties in sampling, particularly in the extraction of the crystals from the cells partly due to their small sizes. On the other hand, the extremely intense X-ray pulses emerging from X-ray free-electron laser (XFEL) sources, along with the appearance of serial femtosecond crystallography (SFX) is a milestone for radiation damage-free protein structural studies but requires micrometre-size crystals. The combination of SFX with in vivo crystallography has the potential to boost the applicability of these techniques, eventually bringing the field to the point where in vitro sample manipulations will no longer be required, and direct imaging of the crystals from within the cells will be achievable. To fully appreciate the diverse aspects of sample characterization, handling and analysis, SFX experiments at the Japanese SPring-8 angstrom compact free-electron laser were scheduled on various types of in vivo grown crystals. The first experiments have demonstrated the feasibility of the approach and suggest that future in vivo crystallography applications at XFELs will be another alternative to nano-crystallography. C1 [Gallat, Francois-Xavier; Matsugaki, Naohiro] High Energy Accelerator Res Org, Photon Factory, Tsukuba, Ibaraki 3050801, Japan. [Coussens, Nathan P.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Yagi, Koichiro J.; Tobe, Stephen] Univ Toronto, Dept Cell & Syst Biol, Toronto, ON M5S 3G5, Canada. [Boudes, Marion; Coulibaly, Fasseli] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. [Higashi, Tetsuya; Tsuji, Daisuke; Itoh, Kohji] Univ Tokushima, Dept Med Biotechnol, Tokushima 7708505, Japan. [Tatano, Yutaka] Shimane Univ, Sch Med, Dept Microbiol & Immunol, Izumo, Shimane 6938501, Japan. [Suzuki, Mamoru] Osaka Univ, Inst Prot Res, Suita, Osaka 5650871, Japan. [Mizohata, Eiichi] Osaka Univ, Grad Sch Engn, Div Appl Chem, Suita, Osaka 5650871, Japan. [Tono, Kensuke; Joti, Yasumasa; Kameshima, Takashi] Japan Synchrotron Radiat Res Inst, Sayo, Hyogo 6795198, Japan. [Park, Jaehyun; Song, Changyong; Hatsui, Takaki; Yabashi, Makina; Nango, Eriko] RIKEN SPring 8 Ctr, Sayo, Hyogo 6795148, Japan. [Ramaswamy, S.] Inst Stem Cell Biol & Regenerat Med, Bangalore 560065, Karnataka, India. [Stay, Barbara] Univ Iowa, Dept Biol, Iowa City, IA 52242 USA. [Chavas, Leonard M. G.] Ctr Free Electron Laser Sci, D-22607 Hamburg, Germany. RP Iwata, S (reprint author), RIKEN SPring 8 Ctr, Kouto 1-1-1, Sayo, Hyogo 6795148, Japan. EM s.iwata@mfour.med.kyoto-u.ac.jp; leonard.chavas@desy.de RI Hatsui, Takaki/J-4429-2014; Yabashi, Makina/A-2832-2015; Suzuki, Mamoru/G-6576-2016; OI Hatsui, Takaki/0000-0001-8144-3484; Yabashi, Makina/0000-0002-2472-1684; Suzuki, Mamoru/0000-0001-7071-5093; Subramanian, Ramaswamy/0000-0002-6709-190X FU X-ray Free-Electron Laser Priority Strategy Program (MEXT, Japan); ARC Future Fellowship FX This work was supported by the X-ray Free-Electron Laser Priority Strategy Program (MEXT, Japan). F.C. is supported by an ARC Future Fellowship. NR 16 TC 12 Z9 13 U1 3 U2 29 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD JUL 17 PY 2014 VL 369 IS 1647 AR 20130497 DI 10.1098/rstb.2013.0497 PG 4 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AJ0SZ UT WOS:000337367600021 PM 24914164 ER PT J AU Kumar, A Harrelson, T Lewis, NE Gallagher, EJ LeRoith, D Shiloach, J Betenbaugh, MJ AF Kumar, Amit Harrelson, Thomas Lewis, Nathan E. Gallagher, Emily J. LeRoith, Derek Shiloach, Joseph Betenbaugh, Michael J. TI Multi-Tissue Computational Modeling Analyzes Pathophysiology of Type 2 Diabetes in MKR Mice SO PLOS ONE LA English DT Article ID PROTEIN REFERENCE DATABASE; SUBUNIT-RELATED PROTEIN; HUMAN SKELETAL-MUSCLE; HUMAN METABOLIC NETWORK; FATTY-ACID-METABOLISM; INSULIN-RESISTANCE; MOLECULAR-CLONING; MENDELIAN-INHERITANCE; PANCREATIC-ISLET; SYSTEMS BIOLOGY AB Computational models using metabolic reconstructions for in silico simulation of metabolic disorders such as type 2 diabetes mellitus (T2DM) can provide a better understanding of disease pathophysiology and avoid high experimentation costs. There is a limited amount of computational work, using metabolic reconstructions, performed in this field for the better understanding of T2DM. In this study, a new algorithm for generating tissue-specific metabolic models is presented, along with the resulting multi-confidence level (MCL) multi-tissue model. The effect of T2DM on liver, muscle, and fat in MKR mice was first studied by microarray analysis and subsequently the changes in gene expression of frank T2DM MKR mice versus healthy mice were applied to the multi-tissue model to test the effect. Using the first multi-tissue genome-scale model of all metabolic pathways in T2DM, we found out that branched-chain amino acids' degradation and fatty acids oxidation pathway is downregulated in T2DM MKR mice. Microarray data showed low expression of genes in MKR mice versus healthy mice in the degradation of branched-chain amino acids and fatty-acid oxidation pathways. In addition, the flux balance analysis using the MCL multi-tissue model showed that the degradation pathways of branched-chain amino acid and fatty acid oxidation were significantly downregulated in MKR mice versus healthy mice. Validation of the model was performed using data derived from the literature regarding T2DM. Microarray data was used in conjunction with the model to predict fluxes of various other metabolic pathways in the T2DM mouse model and alterations in a number of pathways were detected. The Type 2 Diabetes MCL multi-tissue model may explain the high level of branched-chain amino acids and free fatty acids in plasma of Type 2 Diabetic subjects from a metabolic fluxes perspective. C1 [Kumar, Amit; Harrelson, Thomas; Betenbaugh, Michael J.] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. [Kumar, Amit; Shiloach, Joseph] NIDDK, Biotechnol Core Lab, Biotechnol Core Lab, Bethesda, MD 20892 USA. [Lewis, Nathan E.] Brigham Young Univ, Dept Biol, Provo, UT 84602 USA. [Gallagher, Emily J.; LeRoith, Derek] Icahn Sch Med Mt Sinai, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA. [Gallagher, Emily J.; LeRoith, Derek] Icahn Sch Med Mt Sinai, Metab Inst, New York, NY 10029 USA. RP Betenbaugh, MJ (reprint author), Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. EM beten@jhu.edu OI Harrelson, Thomas/0000-0002-8689-4273; Lewis, Nathan/0000-0001-7700-3654 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX Funding for the study was provided by the Intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 111 TC 3 Z9 4 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 16 PY 2014 VL 9 IS 7 AR e102319 DI 10.1371/journal.pone.0102319 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO4KM UT WOS:000341306600062 PM 25029527 ER PT J AU Tajuddin, N Moon, KH Marshall, SA Nixon, K Neafsey, EJ Kim, HY Collins, MA AF Tajuddin, Nuzhath Moon, Kwan-Hoon Marshall, S. Alex Nixon, Kimberly Neafsey, Edward J. Kim, Hee-Yong Collins, Michael A. TI Neuroinflammation and Neurodegeneration in Adult Rat Brain from Binge Ethanol Exposure: Abrogation by Docosahexaenoic Acid SO PLOS ONE LA English DT Article ID ALCOHOL-INDUCED NEURODEGENERATION; INDEPENDENT PHOSPHOLIPASE A(2); SLICE CULTURES; AQUAPORIN-4 EXPRESSION; NERVOUS-SYSTEM; NEURONAL DEGENERATION; COGNITIVE IMPAIRMENT; NEUROBLASTOMA-CELLS; IN-VIVO; ACTIVATION AB Evidence that brain edema and aquaporin-4 (AQP4) water channels have roles in experimental binge ethanol-induced neurodegeneration has stimulated interest in swelling/edema-linked neuroinflammatory pathways leading to oxidative stress. We report here that neurotoxic binge ethanol exposure produces comparable significant effects in vivo and in vitro on adult rat brain levels of AQP4 as well as neuroinflammation-linked enzymes: key phospholipase A2 (PLA2) family members and poly (ADP-ribose) polymerase-1 (PARP-1). In adult male rats, repetitive ethanol intoxication (3 gavages/d for 4 d, similar to 9 g/kg/d, achieving blood ethanol levels similar to 375 mg/dl; "Majchrowicz" model) significantly increased AQP4, Ca+2-dependent PLA2 GIVA (cPLA2), phospho-cPLA2 GIVA (p-cPLA2), secretory PLA2 GIIA (sPLA2) and PARP-1 in regions incurring extensive neurodegeneration in this model-hippocampus, entorhinal cortex, and olfactory bulb-but not in two regions typically lacking neurodamage, frontal cortex and cerebellum. Also, ethanol reduced hippocampal Ca+2-independent PLA2 GVIA (iPLA2) levels and increased brain "oxidative stress footprints" (4-hydroxynonenal-adducted proteins). For in vitro studies, organotypic cultures of rat hippocampal-entorhinocortical slices of adult age (similar to 60 d) were ethanol-binged (100 mM or,450 mg/dl) for 4 d, which augments AQP4 and causes neurodegeneration (Collins et al. 2013). Reproducing the in vivo results, cPLA2, p-cPLA2, sPLA2 and PARP-1 were significantly elevated while iPLA2 was decreased. Furthermore, supplementation with docosahexaenoic acid (DHA; 22:6n-3), known to quell AQP4 and neurodegeneration in ethanol-treated slices, blocked PARP-1 and PLA2 changes while counteracting endogenous DHA reduction and increases in oxidative stress footprints (3-nitrotyrosinated proteins). Notably, the PARP-1 inhibitor PJ-34 suppressed binge ethanol-dependent neurodegeneration, indicating PARP upstream involvement. The results with corresponding models support involvement of AQP4- and PLA2-associated neuroinflammatory pro-oxidative pathways in the neurodamage, with potential regulation by PARP-1 as well. Furthermore, DHA emerges as an effective inhibitor of these binge ethanol-dependent neuroinflammatory pathways as well as associated neurodegeneration in adult-age brain. C1 [Tajuddin, Nuzhath; Moon, Kwan-Hoon; Neafsey, Edward J.; Collins, Michael A.] Loyola Univ Chicago, Stritch Sch Med, Dept Mol Pharmacol & Therapeut, Maywood, IL 60660 USA. [Marshall, S. Alex; Nixon, Kimberly] Univ Kentucky, Dept Pharmaceut Sci, Lexington, KY USA. [Kim, Hee-Yong] NIAAA, Lab Mol Signaling, NIH, Bethesda, MD USA. RP Collins, MA (reprint author), Loyola Univ Chicago, Stritch Sch Med, Dept Mol Pharmacol & Therapeut, Maywood, IL 60660 USA. EM mcollin@luc.edu RI Nixon, Kimberly/A-1217-2015 FU NIH [U01 AA018279, R01 AA0016959, T32 DA016176] FX Supported by NIH U01 AA018279 (MAC), R01 AA0016959 (KN), and T32 DA016176 (SAM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 99 TC 11 Z9 11 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 16 PY 2014 VL 9 IS 7 AR e101223 DI 10.1371/journal.pone.0101223 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO4KM UT WOS:000341306600012 PM 25029343 ER PT J AU Underhill, SM Wheeler, DS Li, MH Watts, SD Ingram, SL Amara, SG AF Underhill, Suzanne M. Wheeler, David S. Li, Minghua Watts, Spencer D. Ingram, Susan L. Amara, Susan G. TI Amphetamine Modulates Excitatory Neurotransmission through Endocytosis of the Glutamate Transporter EAAT3 in Dopamine Neurons SO NEURON LA English DT Article ID VENTRAL TEGMENTAL AREA; NUCLEUS-ACCUMBENS; EXTRACELLULAR GLUTAMATE; LOCOMOTOR SENSITIZATION; PREFRONTAL CORTEX; AWAKE RAT; COCAINE; TRAFFICKING; ACTIVATION; WITHDRAWAL AB Amphetamines modify the brain and alter behavior through mechanisms generally attributed to their ability to regulate extracellular dopamine concentrations. However, the actions of amphetamine are also linked to adaptations in glutamatergic signaling. We report here that when amphetamine enters dopamine neurons through the dopamine transporter, it stimulates endocytosis of an excitatory amino acid transporter, EAAT3, in dopamine neurons. Consistent with this decrease in surface EAAT3, amphetamine potentiates excitatory synaptic responses in dopamine neurons. We also show that the process of internalization is dynamin-and Rho-mediated and requires a unique sequence in the cytosolic C terminus of EAAT3. Introduction of a peptide based on this motif into dopamine neurons blocks the effects of amphetamine on EAAT3 internalization and its action on excitatory responses. These data indicate that the internalization of EAAT3 triggered by amphetamine increases glutamatergic signaling and thus contributes to the effects of amphetamine on neurotransmission. C1 [Underhill, Suzanne M.; Amara, Susan G.] NIMH, Lab Mol & Cellular Neurobiol, NIH, Bethesda, MD 20892 USA. [Wheeler, David S.] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15260 USA. [Li, Minghua; Ingram, Susan L.] Oregon Hlth & Sci Univ, Dept Neurol Surg, Portland, OR 97239 USA. [Watts, Spencer D.; Amara, Susan G.] Univ Pittsburgh, Dept Neurobiol, Pittsburgh, PA 15260 USA. RP Underhill, SM (reprint author), NIMH, Lab Mol & Cellular Neurobiol, NIH, Bethesda, MD 20892 USA. EM smunderhill@yahoo.com FU NIH [MH080726, DA024041]; NIMH Department of Intramural Research FX This work was supported by NIH grants MH080726 (S. M. U. and S. G. A.) and DA024041 (S. L. I.) and by the NIMH Department of Intramural Research (S.M.U. and S.G.A.). NR 50 TC 14 Z9 14 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JUL 16 PY 2014 VL 83 IS 2 BP 404 EP 416 DI 10.1016/j.neuron.2014.05.043 PG 13 WC Neurosciences SC Neurosciences & Neurology GA AN3HU UT WOS:000340478700015 PM 25033183 ER PT J AU Lee, AM Hoy, JL Bonci, A Wilbrecht, L Stryker, MP Niell, CM AF Lee, A. Moses Hoy, Jennifer L. Bonci, Antonello Wilbrecht, Linda Stryker, Michael P. Niell, Cristopher M. TI Identification of a Brainstem Circuit Regulating Visual Cortical State in Parallel with Locomotion SO NEURON LA English DT Article ID MESOPONTINE CHOLINERGIC NUCLEI; LATERAL GENICULATE-NUCLEUS; GAMMA OSCILLATIONS; BASAL FOREBRAIN; ELECTRICAL MICROSTIMULATION; RECEPTIVE-FIELDS; BEHAVIORAL STATE; FRONTAL-CORTEX; THETA RHYTHM; NEURONS AB Sensory processing is dependent upon behavioral state. In mice, locomotion is accompanied by changes in cortical state and enhanced visual responses. Although recent studies have begun to elucidate intrinsic cortical mechanisms underlying this effect, the neural circuits that initially couple locomotion to cortical processing are unknown. The mesencephalic locomotor region (MLR) has been shown to be capable of initiating running and is associated with the ascending reticular activating system. Here, we find that optogenetic stimulation of the MLR in awake, head-fixed mice can induce both locomotion and increases in the gain of cortical responses. MLR stimulation below the threshold for overt movement similarly changed cortical processing, revealing that MLR's effects on cortex are dissociable from locomotion. Likewise, stimulation of MLR projections to the basal forebrain also enhanced cortical responses, suggesting a pathway linking the MLR to cortex. These studies demonstrate that the MLR regulates cortical state in parallel with locomotion. C1 [Lee, A. Moses; Hoy, Jennifer L.; Niell, Cristopher M.] Univ Oregon, Inst Neurosci, Eugene, OR 97403 USA. [Lee, A. Moses; Hoy, Jennifer L.; Niell, Cristopher M.] Univ Oregon, Dept Biol, Eugene, OR 97403 USA. [Lee, A. Moses] Univ Calif San Francisco, Med Scientist Training Program, Neurosci Grad Program, San Francisco, CA 94158 USA. [Bonci, Antonello] NIDA, Intramural Program, Baltimore, MD 21224 USA. [Bonci, Antonello] Johns Hopkins Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21287 USA. [Wilbrecht, Linda] Univ Calif Berkeley, Dept Psychol, Berkeley, CA 94720 USA. [Wilbrecht, Linda] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. [Wilbrecht, Linda] Ernest Gallo Clin & Res Ctr, Emeryville, CA 94608 USA. [Lee, A. Moses; Stryker, Michael P.; Niell, Cristopher M.] Univ Calif San Francisco, Dept Physiol, Ctr Integrat Neurosci, San Francisco, CA 94158 USA. RP Niell, CM (reprint author), Univ Oregon, Inst Neurosci, Eugene, OR 97403 USA. EM cniell@uoregon.edu OI Stryker, Michael/0000-0003-1546-5831 FU NIH [1R01EY023337, 1R01EY02874, 1RC2NS069350, 1R01MH087542]; State of California FX This work was supported by NIH Grants 1R01EY023337 (to C.M.N.), 1R01EY02874 (to M. P. S.), and 1RC2NS069350 and 1R01MH087542 (to L. W.), and the State of California. We thank Dr. Loren Frank, Dr. Denise Piscopo, and Dr. Michael Wehr for comments on the manuscript, and members of the L. W., M. P. S., A. B., and C.M.N. labs for insightful discussions. NR 58 TC 39 Z9 39 U1 2 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JUL 16 PY 2014 VL 83 IS 2 BP 455 EP 466 DI 10.1016/j.neuron.2014.06.031 PG 12 WC Neurosciences SC Neurosciences & Neurology GA AN3HU UT WOS:000340478700019 PM 25033185 ER PT J AU Ortiz, E Oparil, S James, PA AF Ortiz, Eduardo Oparil, Suzanne James, Paul A. TI Untitled Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID ISOLATED SYSTOLIC HYPERTENSION; ANTIHYPERTENSIVE DRUG-TREATMENT; OLDER PERSONS; PREVENTION; TRIAL C1 [Oparil, Suzanne] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [James, Paul A.] Univ Iowa, Iowa City, IA USA. [Ortiz, Eduardo] NHLBI, Bethesda, MD 20892 USA. RP James, PA (reprint author), Univ Iowa, 200 Hawkins Dr, Iowa City, IA 52242 USA. EM paul-james@uiowa.edu NR 6 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 16 PY 2014 VL 312 IS 3 BP 295 EP 296 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AL2FC UT WOS:000338940300032 PM 25027150 ER PT J AU Mastwal, S Ye, YZ Ren, M Jimenez, DV Martinowich, K Gerfen, CR Wang, KH AF Mastwal, Surjeet Ye, Yizhou Ren, Ming Jimenez, Dennisse V. Martinowich, Keri Gerfen, Charles R. Wang, Kuan Hong TI Phasic Dopamine Neuron Activity Elicits Unique Mesofrontal Plasticity in Adolescence SO JOURNAL OF NEUROSCIENCE LA English DT Article DE adolescence; dopamine; frontal cortex; in vivo imaging; optogenetics; phasic activity ID VENTRAL TEGMENTAL AREA; RECEPTOR-DEFICIENT MICE; POST-PUBERTAL EMERGENCE; PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS; STRUCTURAL PLASTICITY; 2-PHOTON EXCITATION; LONG-TERM; IN-VIVO; BRAIN AB The mesofrontal dopaminergic circuit, which connects the midbrain motivation center to the cortical executive center, is engaged in control of motivated behaviors. In addition, deficiencies in this circuit are associated with adolescent-onset psychiatric disorders in humans. Developmental studies suggest that the mesofrontal circuit exhibits a protracted maturation through adolescence. However, whether the structure and function of this circuit are modifiable by activity in dopaminergic neurons during adolescence remains unknown. Using optogenetic stimulation and in vivo two-photon imaging in adolescent mice, we found that phasic, but not tonic, dopamine neuron activity induces the formation of mesofrontal axonal boutons. In contrast, in adult mice, the effect of phasic activity diminishes. Furthermore, our results showed that dopaminergic and glutamatergic transmission regulate this axonal plasticity in adolescence and inhibition of dopamine D2-type receptors restores this plasticity in adulthood. Finally, we found that phasic activation of dopamine neurons also induces greater changes in mesofrontal circuit activity and psychomotor response in adolescent mice than in adult mice. Together, our findings demonstrate that the structure and function of the mesofrontal circuit are modifiable by phasic activity in dopaminergic neurons during adolescence and suggest that the greater plasticity in adolescence may facilitate activity-dependent strengthening of dopaminergic input and improvement in behavioral control. C1 [Mastwal, Surjeet; Ye, Yizhou; Ren, Ming; Wang, Kuan Hong] NIMH, Unit Neural Circuits & Adapt Behav, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Gerfen, Charles R.] NIMH, Lab Syst Neurosci, NIH, Bethesda, MD 20892 USA. [Jimenez, Dennisse V.; Martinowich, Keri] Johns Hopkins Univ, Sch Med, Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Martinowich, Keri] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Martinowich, Keri] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Wang, KH (reprint author), NIMH, Unit Neural Circuits & Adapt Behav, Genes Cognit & Psychosis Program, NIH, 35 Convent Dr,Room 2D913, Bethesda, MD 20892 USA. EM wkuan@mail.nih.gov RI Wang, Kuan Hong/J-1150-2016; Martinowich, Keri/F-9841-2012; OI Wang, Kuan Hong/0000-0002-2249-5417; Martinowich, Keri/0000-0002-5237-0789 FU National Institutes of Health-National Institute of Mental Health Intramural Research Programs; Genes Cognition and Psychosis Program; NARSAD young investigator awards FX This work was supported by National Institutes of Health-National Institute of Mental Health Intramural Research Programs (S. M., Y.Y., M. R., C. R. G., K. W.), Genes Cognition and Psychosis Program (K. W.), and NARSAD young investigator awards (S. M., M. R.). We thank T. R. Insel, D. R. Weinberger, R. Costa, and W. Chen for discussions and critical reading of the manuscript; K. Deisseroth for ChR2 plasmid; R. Costa and Z. He for technical advice; and A. Levin and K. Louhiranta for technical assistance. NR 70 TC 12 Z9 13 U1 0 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 16 PY 2014 VL 34 IS 29 BP 9484 EP 9496 DI 10.1523/JNEUROSCI.1114-14.2014 PG 13 WC Neurosciences SC Neurosciences & Neurology GA AL5LS UT WOS:000339175800003 PM 25031392 ER PT J AU Averbeck, BB Lehman, J Jacobson, M Haber, SN AF Averbeck, Bruno B. Lehman, Julia Jacobson, Moriah Haber, Suzanne N. TI Estimates of Projection Overlap and Zones of Convergence within Frontal-Striatal Circuits SO JOURNAL OF NEUROSCIENCE LA English DT Article ID BASAL GANGLIA; RHESUS-MONKEY; PREFRONTAL CORTEX; ORBITOFRONTAL CORTEX; COGNITIVE DEFICITS; NEURONAL-ACTIVITY; CEREBRAL-CORTEX; CONNECTIONS; REWARD; BRAIN AB Frontal-striatal circuits underlie important decision processes, and pathology in these circuits is implicated in many psychiatric disorders. Studies have shown a topographic organization of cortical projections into the striatum. However, work has also shown that there is considerable overlap in the striatal projection zones of nearby cortical regions. To characterize this in detail, we quantified the complete striatal projection zones from 34 cortical injection locations in rhesus monkeys. We first fit a statistical model that showed that the projection zone of a cortical injection site could be predicted with considerable accuracy using a cross-validated model estimated on only the other injection sites. We then examined the fraction of overlap in striatal projection zones as a function of distance between cortical injection sites, and found that there was a highly regular relationship. Specifically, nearby cortical locations had as much as 80% overlap, and the amount of overlap decayed exponentially as a function of distance between the cortical injection sites. Finally, we found that some portions of the striatum received inputs from all the prefrontal regions, making these striatal zones candidates as information-processing hubs. Thus, the striatum is a site of convergence that allows integration of information spread across diverse prefrontal cortical areas. C1 [Averbeck, Bruno B.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Lehman, Julia; Jacobson, Moriah; Haber, Suzanne N.] Univ Rochester, Sch Med & Dent, Dept Pharmacol & Physiol, Rochester, NY 14642 USA. RP Averbeck, BB (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 49,Room 1B80,49 Convent Dr,MSC 4415, Bethesda, MD 20892 USA. EM bruno.averbeck@nih.gov FU National Institute of Mental Health [MH 045573, MH 086404] FX This work was supported in part by the Intramural Research Program of the National Institute of Mental Health (B. B. A.); and National Institute of Mental Health Grants MH 045573 and MH 086404 (S.N.H.). NR 56 TC 25 Z9 25 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 16 PY 2014 VL 34 IS 29 BP 9497 EP 9505 DI 10.1523/JNEUROSCI.5806-12.2014 PG 9 WC Neurosciences SC Neurosciences & Neurology GA AL5LS UT WOS:000339175800004 PM 25031393 ER PT J AU Leylek, RA Blankenship-Paris, TL Boyle, MC AF Leylek, Rebecca A. Blankenship-Paris, Terry L. Boyle, Michael C. TI Pathology in Practice SO JAVMA-JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Boyle, Michael C.] NIEHS, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. [Leylek, Rebecca A.; Blankenship-Paris, Terry L.] NIEHS, Comparat Med Branch, Res Triangle Pk, NC 27709 USA. RP Boyle, MC (reprint author), Amgen Inc, 1 Amgen Ctr Dr, Thousand Oaks, CA 91320 USA. EM mboyle@amgen.com NR 13 TC 0 Z9 0 U1 0 U2 1 PU AMER VETERINARY MEDICAL ASSOC PI SCHAUMBURG PA 1931 N MEACHAM RD SUITE 100, SCHAUMBURG, IL 60173-4360 USA SN 0003-1488 EI 1943-569X J9 JAVMA-J AM VET MED A JI JAVMA-J. Am. Vet. Med. Assoc. PD JUL 15 PY 2014 VL 245 IS 2 BP 191 EP 193 PG 3 WC Veterinary Sciences SC Veterinary Sciences GA CA6CU UT WOS:000348996900032 PM 24984129 ER PT J AU Tran, E Rosenberg, SA AF Tran, Eric Rosenberg, Steven A. TI T-cell therapy against cancer mutations SO ONCOTARGET LA English DT Editorial Material ID TUMOR-REGRESSION; MELANOMA; PATIENT C1 [Tran, Eric] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Tran, E (reprint author), NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM eric.tran@nih.gov NR 7 TC 4 Z9 6 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUL 15 PY 2014 VL 5 IS 13 BP 4579 EP 4580 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ0EG UT WOS:000347918500001 PM 25046408 ER PT J AU Dongworth, RK Campbell-Washburn, AE Roberts, T Yellon, DM Lythgoe, MF Hausenloy, DJ AF Dongworth, R. K. Campbell-Washburn, A. E. Roberts, T. Yellon, D. M. Lythgoe, M. F. Hausenloy, D. J. TI T2-mapping cardiac MRI for in vivo quantification of myocardial area-at-risk SO CARDIOVASCULAR RESEARCH LA English DT Meeting Abstract CT 3rd Congress of the ESC-Council-on-Basic-Cardiovascular-Science on Frontiers in Cardio Vascular Biology CY JUL 04-06, 2014 CL Barcelona, SPAIN SP ESC Council Basic Cardiovascular Science C1 [Dongworth, R. K.; Yellon, D. M.; Hausenloy, D. J.] UCL, Hatter Cardiovasc Inst, London, England. [Campbell-Washburn, A. E.] NHLBI, NIH, Div Intramural Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 EI 1755-3245 J9 CARDIOVASC RES JI Cardiovasc. Res. PD JUL 15 PY 2014 VL 103 SU 1 MA P645 DI 10.1093/cvr/cvu098.71 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AR6ZQ UT WOS:000343730100505 ER PT J AU Steuer, E Schaefer, ML Belluscio, L AF Steuer, Elizabeth Schaefer, Michele L. Belluscio, Leonardo TI Using the Olfactory System as an In Vivo Model To Study Traumatic Brain Injury and Repair SO JOURNAL OF NEUROTRAUMA LA English DT Article DE apoptosis; APP; biomarker; circuit repair; mouse model; olfactory system; p75(NTR); regeneration; traumatic brain injury ID AMYLOID PRECURSOR PROTEIN; FIBRILLARY ACIDIC PROTEIN; HEAD-INJURY; S-NITROSOGLUTATHIONE; SYNAPTIC PLASTICITY; SUBVENTRICULAR ZONE; FUNCTIONAL RECOVERY; CORTICAL CONTUSION; VOLUNTARY EXERCISE; CEREBRAL-ISCHEMIA AB Loss of olfactory function is an early indicator of traumatic brain injury (TBI). The regenerative capacity and well-defined neural maps of the mammalian olfactory system enable investigations into the degeneration and recovery of neural circuits after injury. Here, we introduce a unique olfactory-based model of TBI that reproduces many hallmarks associated with human brain trauma. We performed a unilateral penetrating impact to the mouse olfactory bulb and observed a significant loss of olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) ipsilateral to the injury, but not contralateral. By comparison, we detected the injury markers p75(NTR), beta-APP, and activated caspase-3 in both the ipsi- and contralateral OE. In the olfactory bulb (OB), we observed a graded cell loss, with ipsilateral showing a greater reduction than contralateral and both significantly less than sham. Similar to OE, injury markers in the OB were primarily detected on the ipsilateral side, but also observed contralaterally. Behavioral experiments measured 4 days after impact also demonstrated loss of olfactory function, yet following a 30-day recovery period, we observed a significant improvement in olfactory function and partial recovery of olfactory circuitry, despite the persistence of TBI markers. Interestingly, by using the M71-IRES-tauLacZ reporter line to track OSN organization, we further determined that inducing neural activity during the recovery period with intense odor conditioning did not enhance the recovery process. Together, these data establish the mouse olfactory system as a new model to study TBI, serving as a platform to understand neural disruption and the potential for circuit restoration. C1 [Steuer, Elizabeth; Schaefer, Michele L.; Belluscio, Leonardo] NINDS, Dev Neural Plast Sect, NIH, Bethesda, MD 20892 USA. [Steuer, Elizabeth; Schaefer, Michele L.; Belluscio, Leonardo] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. RP Belluscio, L (reprint author), NINDS, Dev Neural Plast Sect, Porter Neurosci Res Ctr, Bldg 35,Room 3E-410,35 Convent Dr,MSC 3703, Bethesda, MD 20892 USA. EM belluscl@ninds.nih.gov FU Center for Neuroscience and Regenerative Medicine (HJF) [60855-CNRM]; National Institute of Neurological Disorders and Stroke Intramural Research Program [ZIANS003116-02] FX This work was supported by the Center for Neuroscience and Regenerative Medicine (HJF# 60855-CNRM) and the National Institute of Neurological Disorders and Stroke Intramural Research Program (ZIANS003116-02). NR 89 TC 1 Z9 1 U1 1 U2 9 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL 15 PY 2014 VL 31 IS 14 BP 1277 EP 1291 DI 10.1089/neu.2013.3296 PG 15 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AN4CA UT WOS:000340534000005 PM 24694002 ER PT J AU Menendez, D Anderson, CW AF Menendez, Daniel Anderson, Carl W. TI p53 vs. ISG15: Stop, you're killing me SO CELL CYCLE LA English DT Editorial Material C1 [Menendez, Daniel; Anderson, Carl W.] NIEHS, Chromosome Stabil Sect, Lab Mol Genet, Res Triangle Pk, NC 27709 USA. [Anderson, Carl W.] Brookhaven Natl Lab, Biosci Dept, Upton, NY 11973 USA. RP Menendez, D (reprint author), NIEHS, Chromosome Stabil Sect, Lab Mol Genet, POB 12233, Res Triangle Pk, NC 27709 USA. EM cwa@bnl.gov NR 7 TC 2 Z9 2 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD JUL 15 PY 2014 VL 13 IS 14 BP 2160 EP 2161 DI 10.4161/cc.29466 PG 2 WC Cell Biology SC Cell Biology GA AN0JZ UT WOS:000340272100006 PM 24911913 ER PT J AU Chen, YW Fiscella, KA Bacharach, SZ Calu, DJ AF Chen, Yu-Wei Fiscella, Kimberly A. Bacharach, Samuel Z. Calu, Donna J. TI Effect of Cafeteria Diet History on Cue-, Pellet-Priming-, and Stress-Induced Reinstatement of Food Seeking in Female Rats SO PLOS ONE LA English DT Article ID SUCCESSIVE NEGATIVE CONTRAST; ANXIOGENIC DRUG YOHIMBINE; DOPAMINE D2 RECEPTORS; COCAINE-SEEKING; HEROIN-SEEKING; WEIGHT-LOSS; EATING BEHAVIOR; RELAPSE MODEL; OBESE RATS; DARK SIDE AB Background: Relapse to unhealthy eating habits is a major problem in human dietary treatment. The individuals most commonly seeking dietary treatment are overweight or obese women, yet the commonly used rat reinstatement model to study relapse to palatable food seeking during dieting primarily uses normal-weight male rats. To increase the clinical relevance of the relapse to palatable food seeking model, here we pre-expose female rats to a calorically-dense cafeteria diet in the home-cage to make them overweight prior to examining the effect of this diet history on cue-, pellet-priming-and footshock-induced reinstatement of food seeking. Methods: Post-natal day 32 female Long-Evans rats had seven weeks of home-cage access to either chow only or daily or intermittent cafeteria diet alongside chow. Next, they were trained to self-administer normally preferred 45 mg food pellets accompanied by a tone-light cue. After extinction, all rats were tested for reinstatement induced by discrete cue, pellet-priming, and intermittent footshock under extinction conditions. Results: Access to daily cafeteria diet and to a lesser degree access to intermittent cafeteria diet decreased food pellet self-administration compared to chow-only. Prior history of these cafeteria diets also reduced extinction responding, cue-and pellet-priming-induced reinstatement. In contrast, modest stress-induced reinstatement was only observed in rats with a history of daily cafeteria diet. Conclusion: A history of cafeteria diet does not increase the propensity for cue-and pellet-priming-induced relapse in the rat reinstatement model but does appear to make rats more susceptible to footshock stress-induced reinstatement. C1 [Chen, Yu-Wei; Fiscella, Kimberly A.; Bacharach, Samuel Z.; Calu, Donna J.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Calu, DJ (reprint author), NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM donna.calu@nih.gov OI Calu, Donna/0000-0003-2377-9494 FU Intramural Research Program of the National Institute on Drug Abuse FX The work was supported by the Intramural Research Program of the National Institute on Drug Abuse. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 73 TC 2 Z9 2 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 15 PY 2014 VL 9 IS 7 AR e102213 DI 10.1371/journal.pone.0102213 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM6RN UT WOS:000339992400051 PM 25025329 ER PT J AU Khoury, MJ AF Khoury, Muin J. TI A Primer Series on -Omic Technologies for the Practice of Epidemiology SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material C1 [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA 30333 USA. [Khoury, Muin J.] NCI, Epidemiol & Genom Res Program, Bethesda, MD 20892 USA. RP Khoury, MJ (reprint author), Ctr Dis Control & Prevent, Off Publ Hlth Genom, 1600 Clifton Rd,Mail Stop E61, Atlanta, GA 30333 USA. EM muk1@cdc.gov FU Intramural CDC HHS [CC999999] NR 5 TC 5 Z9 5 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 15 PY 2014 VL 180 IS 2 BP 127 EP 128 DI 10.1093/aje/kwu141 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AM4FM UT WOS:000339808700001 PM 24966223 ER PT J AU Freedman, LS Commins, JM Moler, JE Arab, L Baer, DJ Kipnis, V Midthune, D Moshfegh, AJ Neuhouser, ML Prentice, RL Schatzkin, A Spiegelman, D Subar, AF Tinker, LF Willett, W AF Freedman, Laurence S. Commins, John M. Moler, James E. Arab, Lenore Baer, David J. Kipnis, Victor Midthune, Douglas Moshfegh, Alanna J. Neuhouser, Marian L. Prentice, Ross L. Schatzkin, Arthur Spiegelman, Donna Subar, Amy F. Tinker, Lesley F. Willett, Walter TI Pooled Results From 5 Validation Studies of Dietary Self-Report Instruments Using Recovery Biomarkers for Energy and Protein Intake SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE 24-hour recall; attenuation factors; calibration equations; dietary measurement error; food frequency questionnaire; under-reporting ID FOOD FREQUENCY QUESTIONNAIRE; FAILURE TIME REGRESSION; MEASUREMENT ERROR; CALIBRATION; CANCER; RISK; REPRODUCIBILITY; EPIDEMIOLOGY; RELIABILITY; COLLECTION AB We pooled data from 5 large validation studies of dietary self-report instruments that used recovery biomarkers as references to clarify the measurement properties of food frequency questionnaires (FFQs) and 24-hour recalls. The studies were conducted in widely differing US adult populations from 1999 to 2009. We report on total energy, protein, and protein density intakes. Results were similar across sexes, but there was heterogeneity across studies. Using a FFQ, the average correlation coefficients for reported versus true intakes for energy, protein, and protein density were 0.21, 0.29, and 0.41, respectively. Using a single 24-hour recall, the coefficients were 0.26, 0.40, and 0.36, respectively, for the same nutrients and rose to 0.31, 0.49, and 0.46 when three 24-hour recalls were averaged. The average rate of under-reporting of energy intake was 28% with a FFQ and 15% with a single 24-hour recall, but the percentages were lower for protein. Personal characteristics related to under-reporting were body mass index, educational level, and age. Calibration equations for true intake that included personal characteristics provided improved prediction. This project establishes that FFQs have stronger correlations with truth for protein density than for absolute protein intake, that the use of multiple 24-hour recalls substantially increases the correlations when compared with a single 24-hour recall, and that body mass index strongly predicts under-reporting of energy and protein intakes. C1 [Freedman, Laurence S.; Commins, John M.; Moler, James E.] Informat Management Syst Inc, Rockville, MD USA. [Freedman, Laurence S.] Gertner Inst Epidemiol & Hlth Policy Res, Biostat Unit, Tel Hashomer, Israel. [Arab, Lenore] Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med, Los Angeles, CA 90095 USA. [Baer, David J.; Moshfegh, Alanna J.] ARS, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD USA. [Kipnis, Victor; Midthune, Douglas] NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Neuhouser, Marian L.; Prentice, Ross L.; Tinker, Lesley F.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Schatzkin, Arthur] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Spiegelman, Donna; Willett, Walter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Spiegelman, Donna; Willett, Walter] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Spiegelman, Donna] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Subar, Amy F.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Willett, Walter] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Willett, Walter] Harvard Univ, Sch Med, Boston, MA USA. RP Freedman, LS (reprint author), Chaim Sheba Med Ctr, Gertner Inst Epidemiol & Hlth Policy Res, Biostat Unit, IL-52621 Tel Hashomer, Israel. EM lsf@actcom.co.il OI Moler, James/0000-0001-8738-6898 FU National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [HHSN268201100046C, HHSN2682011 00001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C] FX The Women's Health Initiative program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN2682011 00001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. NR 38 TC 65 Z9 66 U1 4 U2 21 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 15 PY 2014 VL 180 IS 2 BP 172 EP 188 DI 10.1093/aje/kwu116 PG 17 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AM4FM UT WOS:000339808700006 PM 24918187 ER PT J AU Burnett-Hartman, AN Newcomb, PA Hutter, CM Peters, U Passarelli, MN Schwartz, MR Upton, MP Zhu, LC Potter, JD Makar, KW AF Burnett-Hartman, Andrea N. Newcomb, Polly A. Hutter, Carolyn M. Peters, Ulrike Passarelli, Michael N. Schwartz, Malaika R. Upton, Melissa P. Zhu, Lee-Ching Potter, John D. Makar, Karen W. TI Variation in the Association Between Colorectal Cancer Susceptibility Loci and Colorectal Polyps by Polyp Type SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE adenoma; colorectal cancer; colorectal polyps; genome-wide association studies; serrated polyps; single-nucleotide polymorphisms ID GENOME-WIDE ASSOCIATION; SERRATED POLYPS; HYPERPLASTIC POLYPS; ADENOMATOUS POLYPS; CIGARETTE-SMOKING; RISK-FACTORS; POLYMORPHISMS; METAANALYSIS; COLON; 8Q24 AB We conducted a case-control study of the association between subsets of colorectal polyps, including adenomas and serrated polyps, and single-nucleotide polymorphisms (SNPs) related to colorectal cancer through prior genome-wide association studies (GWAS). Participants were enrollees in the Group Health Cooperative (Seattle, Washington) aged 24-79 years who received a colonoscopy from 1998 to 2007, donated a buccal or blood sample, and completed a structured questionnaire. We performed genotyping of 13 colorectal cancer susceptibility SNPs. Polytomous logistic regression models were used to estimate odds ratios and 95% confidence intervals for associations between polyps and the colorectal cancer risk allele for each SNP under a log-additive model. Analyses included 781 controls, 489 cases with adenoma, 401 cases with serrated polyps, and 188 cases with both polyp types. The following SNPs were associated with advanced adenomas: rs10936599, rs10795668, rs16892766, and rs9929218 (P < 0.05). For nonadvanced adenomas and for serrated polyps overall, only rs961253 was statistically significant (P < 0.05). These associations were in the same directions as those in prior colorectal cancer GWAS. No SNP was significantly associated with hyperplastic polyps, and only rs6983267 was significantly associated with sessile serrated polyps, but this association was opposite of that found in colorectal cancer GWAS. Our results suggest that the association between colorectal cancer susceptibility SNPs and colorectal polyps varies by polyp type. C1 [Burnett-Hartman, Andrea N.; Newcomb, Polly A.; Peters, Ulrike; Passarelli, Michael N.; Potter, John D.; Makar, Karen W.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98109 USA. [Burnett-Hartman, Andrea N.; Newcomb, Polly A.; Peters, Ulrike; Passarelli, Michael N.; Schwartz, Malaika R.; Potter, John D.; Makar, Karen W.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Hutter, Carolyn M.] NHGRI, NIH, Bethesda, MD 20892 USA. [Upton, Melissa P.] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA. [Zhu, Lee-Ching] Grp Hlth Cooperat Puget Sound, Seattle, WA USA. RP Burnett-Hartman, AN (reprint author), Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1100 Fairview Ave North,M4-B402, Seattle, WA 98109 USA. EM aburnett@fhcrc.org OI Potter, John/0000-0001-5439-1500 FU National Cancer Institute [P01 CA074184, R01 CA097325, R03 CA153323, K05 CA152715, T32 CA009168]; National Center for Advancing Translational Sciences at the National Institutes of Health [KL2 TR000421] FX This work was supported by the National Cancer Institute (grant P01 CA074184 to J.D.P. and P.A.N., grants R01 CA097325, R03 CA153323, and K05 CA152715 to P.A.N., and grant T32 CA009168 to M.N.P.) and the National Center for Advancing Translational Sciences at the National Institutes of Health (grant KL2 TR000421 to A.N.B.-H.). NR 42 TC 4 Z9 4 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 15 PY 2014 VL 180 IS 2 BP 223 EP 232 DI 10.1093/aje/kwu114 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AM4FM UT WOS:000339808700012 PM 24875374 ER PT J AU Zannad, F Stough, WG Pina, IL Mehran, R Abraham, WT Anker, SD De Ferrari, GM Farb, A Geller, NL Kieval, RS Linde, C Redberg, RF Stein, K Vincent, A Woehrle, H Pocock, SJ AF Zannad, Faiez Stough, Wendy Gattis Pina, Ileana L. Mehran, Roxana Abraham, William T. Anker, Stefan D. De Ferrari, Gaetano M. Farb, Andrew Geller, Nancy L. Kieval, Robert S. Linde, Cecilia Redberg, Rita F. Stein, Kenneth Vincent, Alphons Woehrle, Holger Pocock, Stuart J. TI Current challenges for clinical trials of cardiovascular medical devices SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Review DE Cardiovascular devices; Device approval; Clinical trial; Research design ID CARDIAC RESYNCHRONIZATION THERAPY; LEFT-VENTRICULAR DYSFUNCTION; HEART-FAILURE; RANDOMIZED-TRIALS; EUROPEAN-SOCIETY; PREMARKET APPROVAL; CONTINUOUS-FLOW; ASSIST DEVICE; SURVEILLANCE; SAFETY AB Several features of cardiovascular devices raise considerations for clinical trial conduct. Prospective, randomized, controlled trials remain the highest quality evidence for safety and effectiveness assessments, but, for instance, blinding may be challenging. In order to avoid bias and not confound data interpretation, the use of objective endpoints and blinding patients, study staff, core labs, and clinical endpoint committees to treatment assignment are helpful approaches. Anticipation of potential bias should be considered and planned for prospectively in a cardiovascular device trial. Prospective, single-arm studies (often referred to as registry studies) can provide additional data in some cases. They are subject to selection bias even when carefully designed; thus, they are generally not acceptable as the sole basis for pre-market approval of high risk cardiovascular devices. However, they complement the evidence base and fill the gaps unanswered by randomized trials. Registry studies present device safety and effectiveness in day-to-day clinical practice settings and detect rare adverse events in the post-market period. No single research design will be appropriate for every cardiovascular device or target patient population. The type of trial, appropriate control group, and optimal length of follow-up will depend on the specific device, its potential clinical benefits, the target patient population and the existence (or lack) of effective therapies, and its anticipated risks. Continued efforts on the part of investigators, the device industry, and government regulators are needed to reach the optimal approach for evaluating the safety and performance of innovative devices for the treatment of cardiovascular disease. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Zannad, Faiez] Univ Lorraine, Dept Cardiol, Nancy, France. [Stough, Wendy Gattis] Campbell Univ, Coll Pharm & Hlth Sci, Buies Creek, NC 27506 USA. [Pina, Ileana L.] Montefiore Med Ctr, Dept Med, Div Cardiol, Bronx, NY 10467 USA. [Mehran, Roxana] Cardiovasc Res Fdn, New York, NY USA. [Mehran, Roxana] Mt Sinai Med Ctr, New York, NY 10029 USA. [Abraham, William T.] Ohio State Univ, Div Cardiovasc Med, Columbus, OH 43210 USA. [Anker, Stefan D.] Charite, Dept Cardiol, Berlin, Germany. [De Ferrari, Gaetano M.] IRCCS Policlin San Matteo, Dept Cardiol, Pavia, Italy. [Farb, Andrew] US FDA, Silver Spring, MD USA. [Geller, Nancy L.] Natl Heart Lung & Blood Inst, Bethesda, MD USA. [Kieval, Robert S.] CVRx Inc, Minneapolis, MN USA. [Linde, Cecilia] Karolinska Univ Hosp, Karolinska Inst, Dept Cardiol, Stockholm, Sweden. [Redberg, Rita F.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Stein, Kenneth] Boston Sci Corp, St Paul, MN USA. [Vincent, Alphons] Medtronic, Tolochenaz, Switzerland. [Woehrle, Holger] ResMed Sci Ctr, Martinsried, Germany. [Woehrle, Holger] Sleep & Ventilat Ctr Blaubeuren, Lung Ctr, Ulm, Germany. [Pocock, Stuart J.] London Sch Hyg & Trop Med, Dept Med Stat, London WC1, England. RP Zannad, F (reprint author), Univ Lorraine Coordinateur Sci, CHU, F-54500 Vandoeuvre Les Nancy, France. EM f.zannad@chu-nancy.fr RI De Ferrari, Gaetano/K-5188-2016; Stough, Wendy/R-4287-2016; OI De Ferrari, Gaetano/0000-0003-4940-0876; Stough, Wendy/0000-0001-8290-1205; LInde, Cecilia/0000-0002-9039-6023 NR 50 TC 9 Z9 9 U1 4 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD JUL 15 PY 2014 VL 175 IS 1 BP 30 EP 37 DI 10.1016/j.ijcard.2014.05.021 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM3ZG UT WOS:000339790700013 PM 24861254 ER PT J AU Lansdorp-Vogelaar, I Gulati, R Mariotto, AB Schechter, CB de Carvalho, TM Knudsen, AB van Ravesteyn, NT Heijnsdijk, EAM Pabiniak, C van Ballegooijen, M Rutter, CM Kuntz, KM Feuer, EJ Etzioni, R de Koning, HJ Zauber, AG Mandelblatt, JS AF Lansdorp-Vogelaar, Iris Gulati, Roman Mariotto, Angela B. Schechter, Clyde B. de Carvalho, Tiago M. Knudsen, Amy B. van Ravesteyn, Nicolien T. Heijnsdijk, Eveline A. M. Pabiniak, Chester van Ballegooijen, Marjolein Rutter, Carolyn M. Kuntz, Karen M. Feuer, Eric J. Etzioni, Ruth de Koning, Harry J. Zauber, Ann G. Mandelblatt, Jeanne S. TI Personalizing Age of Cancer Screening Cessation Based on Comorbid Conditions: Model Estimates of Harms and Benefits SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID SERVICES TASK-FORCE; COLORECTAL-CANCER; PROSTATE-CANCER; LIFE-STYLE; RECOMMENDATION STATEMENT; POTENTIAL BENEFITS; COST-EFFECTIVENESS; DECISION-ANALYSIS; ELDERLY-PATIENTS; BREAST AB Background: Harms and benefits of cancer screening depend on age and comorbid conditions, but reliable estimates are lacking. Objective: To estimate the harms and benefits of cancer screening by age and comorbid conditions to inform decisions about screening cessation. Design: Collaborative modeling with 7 cancer simulation models and common data on average and comorbid condition level-specific life expectancy. Setting: U. S. population. Patients: U. S. cohorts aged 66 to 90 years in 2010 with average health or 1 of 4 comorbid condition levels: none, mild, moderate, or severe. Intervention: Mammography, prostate-specific antigen testing, or fecal immunochemical testing. Measurements: Lifetime cancer deaths prevented and life-years gained (benefits); false-positive test results and overdiagnosed cancer cases (harms). For each comorbid condition level, the age at which harms and benefits of screening were similar to that for persons with average health having screening at age 74 years. Results: Screening 1000 women with average life expectancy at age 74 years for breast cancer resulted in 79 to 96 (range across models) false-positive results, 0.5 to 0.8 overdiagnosed cancer cases, and 0.7 to 0.9 prevented cancer deaths. Although absolute numbers of harms and benefits differed across cancer sites, the ages at which to cease screening were consistent across models and cancer sites. For persons with no, mild, moderate, and severe comorbid conditions, screening until ages 76, 74, 72, and 66 years, respectively, resulted in harms and benefits similar to average-health persons. Limitation: Comorbid conditions influenced only life expectancy. Conclusion: Comorbid conditions are an important determinant of harms and benefits of screening. Estimates of screening benefits and harms by comorbid condition can inform discussions between providers and patients about personalizing screening cessation decisions. C1 Erasmus Univ, Med Ctr, NL-3000 CA Rotterdam, Netherlands. Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. Grp Hlth Res Inst, Seattle, WA 98101 USA. NCI, Bethesda, MD 20892 USA. Yeshiva Univ, Albert Einstein Coll Med, Bronx, NY USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Minnesota, Minneapolis, MN 55455 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. Georgetown Univ, Washington, DC 20007 USA. RP Lansdorp-Vogelaar, I (reprint author), Erasmus Univ, Med Ctr, Dept Publ Hlth, POB 2040, NL-3000 CA Rotterdam, Netherlands. EM i.vogelaar@erasmusmc.nl FU National Cancer Institute at the National Institutes of Health; Centers for Disease Control and Prevention [U01CA097426, U01CA115953, U01CA152959, U01CA157224, U01CA088283, U01CA152958]; National Cancer Institute at the National Institutes of Health [KO5CA96940, P01CA154292, U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040, HHSN261201100031C]; Dutch Cancer Society [94-869, 98-1657, 2002-277, 2006-3518]; Netherlands Organisation for Health Research and Development [002822820, 22000106, 50-50110-98-311] FX By the National Cancer Institute at the National Institutes of Health and the Centers for Disease Control and Prevention (grants U01CA097426, U01CA115953, U01CA152959, U01CA157224, U01CA088283, and U01CA152958) and in part by the National Cancer Institute at the National Institutes of Health (grants KO5CA96940 to Dr. Mandelblatt and P01CA154292 to Drs. Mandelblatt, Schechter, van Ravesteyn, Heijnsdijk, and de Koning), the Dutch Cancer Society (grants 94-869, 98-1657, 2002-277, and 2006-3518 to Drs. Heijnsdijk and de Koning), and the Netherlands Organisation for Health Research and Development (grants 002822820, 22000106, and 50-50110-98-311 to Drs. Heijnsdijk and de Koning). Breast Cancer Surveillance Consortium data collection and sharing used in some variables for modeling breast cancer screening was supported by the National Cancer Institute at the National Institutes of Health (grants U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040, and HHSN261201100031C). NR 51 TC 28 Z9 28 U1 0 U2 9 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 15 PY 2014 VL 161 IS 2 BP 104 EP + DI 10.7326/M13-2867 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AM3PJ UT WOS:000339764600019 PM 25023249 ER PT J AU Fleurence, RL Forsythe, LP Lauer, M Rotter, J Ioannidis, JPA Beal, A Frank, L Selby, JV AF Fleurence, Rachael L. Forsythe, Laura P. Lauer, Michael Rotter, Jason Ioannidis, John P. A. Beal, Anne Frank, Lori Selby, Joseph V. TI Engaging Patients and Stakeholders in Research Proposal Review: The Patient-Centered Outcomes Research Institute SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID BREAST-CANCER RESEARCH AB The inaugural round of merit review for the Patient-Centered Outcomes Research Institute (PCORI) in November 2012 included patients and other stakeholders, as well as scientists. This article examines relationships among scores of the 3 reviewer types, changes in scoring after in-person discussion, and the effect of inclusion of patient and stakeholder reviewers on the review process. In the first phase, 363 scientists scored 480 applications. In the second phase, 59 scientists, 21 patients, and 31 stakeholders provided a "prediscussion" score and a final "postdiscussion" score after an in-person meeting for applications. Bland-Altman plots were used to characterize levels of agreement among and within reviewer types before and after discussion. Before discussion, there was little agreement among average scores given by the 4 lead scientific reviewers and patient and stakeholder reviewers. After discussion, the 4 primary reviewers showed mild convergence in their scores, and the 21-member panel came to a much stronger agreement. Of the 25 awards with the best (and lowest) scores after phase 2, only 13 had ranked in the top 25 after the phase 1 review by scientists. Five percent of the 480 proposals submitted were funded. The authors conclude that patient and stakeholder reviewers brought different perspectives to the review process but that in-person discussion led to closer agreement among reviewer types. It is not yet known whether these conclusions are generalizable to future rounds of peer review. Future work would benefit from additional data collection for evaluation purposes and from long-term evaluation of the effect on the funded research. C1 [Fleurence, Rachael L.] Patient Ctr Outcomes Res Inst, Washington, DC 20036 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. RP Fleurence, RL (reprint author), Patient Ctr Outcomes Res Inst, 1828 L St,Suite 900, Washington, DC 20036 USA. EM rfleurence@pcori.org NR 13 TC 8 Z9 8 U1 1 U2 7 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 15 PY 2014 VL 161 IS 2 BP 122 EP + DI 10.7326/M13-2412 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AM3PJ UT WOS:000339764600021 PM 25023251 ER PT J AU Lee, O Page, K Ivancic, D Helenowski, I Parini, V Sullivan, ME Margenthaler, JA Chatterton, RT Jovanovic, B Dunn, BK Heckman-Stoddard, BM Foster, K Muzzio, M Shklovskaya, J Skripkauskas, S Kulesza, P Green, D Hansen, NM Bethke, KP Jeruss, JS Bergan, R Khan, SA AF Lee, Oukseub Page, Katherine Ivancic, David Helenowski, Irene Parini, Vamsi Sullivan, Megan E. Margenthaler, Julie A. Chatterton, Robert T., Jr. Jovanovic, Borko Dunn, Barbara K. Heckman-Stoddard, Brandy M. Foster, Kathleen Muzzio, Miguel Shklovskaya, Julia Skripkauskas, Silvia Kulesza, Piotr Green, David Hansen, Nora M. Bethke, Kevin P. Jeruss, Jacqueline S. Bergan, Raymond Khan, Seema A. TI A Randomized Phase II Presurgical Trial of Transdermal 4-Hydroxytamoxifen Gel versus Oral Tamoxifen in Women with Ductal Carcinoma In Situ of the Breast SO CLINICAL CANCER RESEARCH LA English DT Article ID SURGICAL ADJUVANT BREAST; ESTROGEN-RECEPTOR-ALPHA; SENTINEL LYMPH-NODE; BOWEL PROJECT P-1; CANCER PREVENTION; PROGESTERONE-RECEPTORS; METABOLIC-ACTIVATION; GENE-EXPRESSION; OUTCOMES; CELLS AB Purpose: Local transdermal therapy to the breast may achieve effective target-organ drug delivery, while diminishing systemic effects. We conducted a randomized, double-blind, placebo-controlled phase II trial comparing transdermal 4-hydroxytamoxifen gel (4-OHT) to oral tamoxifen (oral-T) in women with ductal carcinoma in situ (DCIS). Methods: Twenty-seven pre- and postmenopausal women were randomized to 4-OHT (4 mg/day) or oral-T (20 mg/day) for 6 to 10 weeks before surgery. Plasma, nipple aspirate fluid, and breast adipose tissue concentrations of tamoxifen and its major metabolites were determined by liquid chromatography/tandem mass spectrometry. The primary endpoint was Ki67 labeling in DCIS lesions, measured by immunohistochemistry. In plasma, insulin-like growth factor-1 (IGFI), sex hormone-binding globulin (SHBG), and coagulation protein concentrations were determined. Results: Posttherapy Ki67 decreased by 3.4% in the 4-OHT and 5.1% in the oral-T group (P <= 0.03 in both, between-group P = 0.99). Mean plasma 4-OHT was 0.2 and 1.1 ng/mL in 4-OHT and oral groups, respectively (P = 0.0003), whereas mean breast adipose tissue concentrations of 4-OHT were 5.8 ng/g in the 4-OHT group and 5.4 ng/g in the oral group (P = 0.88). There were significant increases in plasma SHBG, factor VIII, and von Willebrand factor and a significant decrease in plasma IGFI with oral-T, but not with 4-OHT. The incidence of hot flashes was similar in both groups. Conclusions: The antiproliferative effect of 4-OHT gel applied to breast skin was similar to that of oral-T, but effects on endocrine and coagulation parameters were reduced. These findings support the further evaluation of local transdermal therapy for DCIS and breast cancer prevention. (C)2014 AACR. C1 [Lee, Oukseub; Ivancic, David; Hansen, Nora M.; Bethke, Kevin P.; Jeruss, Jacqueline S.] Northwestern Univ, Dept Surg, Chicago, IL 60611 USA. [Helenowski, Irene; Jovanovic, Borko] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Parini, Vamsi; Sullivan, Megan E.; Kulesza, Piotr] Northwestern Univ, Dept Pathol, Chicago, IL 60611 USA. [Chatterton, Robert T., Jr.] Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Green, David; Bergan, Raymond] Northwestern Univ, Dept Med, Div Hematol Oncol, Chicago, IL 60611 USA. [Page, Katherine; Shklovskaya, Julia; Skripkauskas, Silvia; Hansen, Nora M.; Bethke, Kevin P.; Jeruss, Jacqueline S.; Bergan, Raymond; Khan, Seema A.] Northwestern Univ, Robert H Lurie Canc Ctr, Chicago, IL 60611 USA. [Muzzio, Miguel] IIT, Res Inst, Chicago, IL 60616 USA. [Dunn, Barbara K.; Heckman-Stoddard, Brandy M.; Foster, Kathleen] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Margenthaler, Julie A.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. RP Khan, SA (reprint author), Northwestern Univ, Feinberg Sch Med, 303 E Super St Lurie 4-111, Chicago, IL 60611 USA. EM skhan@nmh.org RI Parimi, Vamsi/P-5675-2014 FU NIH [N01-CN-35157]; BHR Pharma, LLC FX This work was supported by the NIH (contract No. N01-CN-35157) and BHR Pharma, LLC. NR 48 TC 12 Z9 12 U1 1 U2 12 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2014 VL 20 IS 14 BP 3672 EP 3682 DI 10.1158/1078-0432.CCR-13-3045 PG 11 WC Oncology SC Oncology GA AM1MX UT WOS:000339611500008 PM 25028506 ER PT J AU Bradford, D Raghuram, V Wilson, JLL Chou, CL Hoffert, JD Knepper, MA Pisitkun, T AF Bradford, Davis Raghuram, Viswanathan Wilson, Justin L. L. Chou, Chung-Lin Hoffert, Jason D. Knepper, Mark A. Pisitkun, Trairak TI Use of LC-MS/MS and Bayes' theorem to identify protein kinases that phosphorylate aquaporin-2 at Ser(256) SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE Bayes' theorem; vasopressin; inner medullary collecting duct; aquaporin-2; urea channel UT-A ID COLLECTING DUCT CELLS; WATER CHANNEL AQUAPORIN-2; MASS-SPECTROMETRY; PROSTATE-CANCER; RAT-KIDNEY; QUANTITATIVE PHOSPHOPROTEOMICS; ENDOPLASMIC-RETICULUM; INTRACELLULAR CA2+; RENAL-CELLS; VASOPRESSIN AB In the renal collecting duct, binding of AVP to the V-2 receptor triggers signaling changes that regulate osmotic water transport. Short-term regulation of water transport is dependent on vasopressin-induced phosphorylation of aquaporin-2 (AQP2) at Ser(256). The protein kinase that phosphorylates this site is not known. We use Bayes' theorem to rank all 521 rat protein kinases with regard to the likelihood of a role in Ser(256) phosphorylation on the basis of prior data and new experimental data. First, prior probabilities were estimated from previous transcriptomic and proteomic profiling data, kinase substrate specificity data, and evidence for kinase regulation by vasopressin. This ranking was updated using new experimental data describing the effects of several small-molecule kinase inhibitors with known inhibitory spectra (H-89, KN-62, KN-93, and GSK-650394) on AQP2 phosphorylation at Ser(256) in inner medullary collecting duct suspensions. The top-ranked kinase was Ca2+/calmodulin-dependent protein kinase II (CAMK2), followed by protein kinase A (PKA) and protein kinase B (AKT). Liquid chromatography-tandem mass spectrometry (LC-MS/MS)based in vitro phosphorylation studies compared the ability of three highly ranked kinases to phosphorylate AQP2 and other inner medullary collecting duct proteins, PKA, CAMK2, and serum/glucocorticoid-regulated kinase (SGK). All three proved capable of phosphorylating AQP2 at Ser(256), although CAMK2 and PKA were more potent than SGK. The in vitro phosphorylation experiments also identified candidate protein kinases for several additional phosphoproteins with likely roles in collecting duct regulation, including Nedd4-2, Map4k4, and 3-phosphoinositide-dependent protein kinase 1. We conclude that Bayes' theorem is an effective means of integrating data from multiple data sets in physiology. C1 [Bradford, Davis; Raghuram, Viswanathan; Wilson, Justin L. L.; Chou, Chung-Lin; Hoffert, Jason D.; Knepper, Mark A.; Pisitkun, Trairak] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NIH, Bldg 10,Rm 6N307,10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. EM knepperm@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute [ZO1-HL-001285]; CU Research Cluster: Ratchadapisek Sompoch Endowment Fund, Chulalongkorn University FX The study was carried out in the intramural program of the National Heart, Lung, and Blood Institute (Project ZO1-HL-001285, M. A. Knepper).; Present address of T. Pisitkun: Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. T. Pisitkun is currently supported by CU Research Cluster: 2014 Ratchadapisek Sompoch Endowment Fund, Chulalongkorn University. NR 69 TC 12 Z9 12 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 EI 1522-1563 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD JUL 15 PY 2014 VL 307 IS 2 BP C123 EP C139 DI 10.1152/ajpcell.00377.2012 PG 17 WC Cell Biology; Physiology SC Cell Biology; Physiology GA AL5KZ UT WOS:000339173800002 PM 24598363 ER PT J AU Vergara, A Benkstein, KD Montgomery, CB Semancik, S AF Vergara, Alexander Benkstein, Kurt D. Montgomery, Christopher B. Semancik, Steve TI Demonstration of Fast and Accurate Discrimination and Quantification of Chemically Similar Species Utilizing a Single Cross-Selective Chemiresistor SO ANALYTICAL CHEMISTRY LA English DT Article ID GAS SENSORS; TEMPERATURE MODULATION; TRANSIENT-RESPONSE; ELECTRONIC-NOSE; IDENTIFICATION; OPTIMIZATION; OLFACTION; MIXTURE; SURFACE; MODE AB Performance characteristics of gas-phase microsensors will determine the ultimate utility of these devices for a wide range of chemical monitoring applications. Commonly employed chemiresistor elements are quite sensitive to selected analytes, and relatively new methods have increased the selectivity to specific compounds, even in the presence of interfering species. Here, we have focused on determining whether purposefully driven temperature modulation can produce faster sensor-response characteristics, which could enable measurements for a broader range of applications involving dynamic compositional analysis. We investigated the response speed of a single chemiresitive In2O3 microhotplate sensor to four analytes (methanol, ethanol, acetone, 2-butanone) by systematically varying the oscillating frequency (semicycle periods of 20-120 ms) of a bilevel temperature cycle applied to the sensing element. It was determined that the fastest response (approximate to 9 s), as indicated by a 98% signal-change metric, occurred for a period of 30 ms and that responses under such modulation were dramatically faster than for isothermal operation of the same device (>300 s). Rapid modulation between 150 and 450 degrees C exerts kinetic control over transient processes, including adsorption, desorption, diffusion, and reaction phenomena, which are important for charge transfer occurring in transduction processes and the observed response times. We also demonstrate that the fastest operation is accompanied by excellent discrimination within a challenging 16-category recognition problem (consisting of the four analytes at four separate concentrations). This critical finding demonstrates that both speed and high discriminatory capabilities can be realized through temperature modulation. C1 [Vergara, Alexander; Benkstein, Kurt D.; Montgomery, Christopher B.; Semancik, Steve] NIST, Biomol Measurement Div, Mat Measurement Lab, Gaithersburg, MD 20899 USA. [Vergara, Alexander] NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Semancik, S (reprint author), NIST, Biomol Measurement Div, Mat Measurement Lab, Gaithersburg, MD 20899 USA. EM stephen.semancik@nist.gov FU National Research Council NIH-NIST; NIST; National Institute for Biomedical Imaging and Bioengineering of the NIH; Office of Naval Research FX This research was performed while A.V. held a National Research Council NIH-NIST Postdoctoral Associateship Award with funding provided by NIST and the Intramural Program of the National Institute for Biomedical Imaging and Bioengineering of the NIH. We also acknowledge partial funding of this work by the Office of Naval Research. We thank Dr. P. Rogers for the precursor sensing materials and programming of the sensor control/data acquisition software. NR 39 TC 4 Z9 4 U1 5 U2 29 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD JUL 15 PY 2014 VL 86 IS 14 BP 6753 EP 6757 DI 10.1021/ac501490k PG 5 WC Chemistry, Analytical SC Chemistry GA AL6FG UT WOS:000339227400004 PM 24931319 ER PT J AU Das, A AF Das, Arupratan TI A Critical Pull to Polarize the Cell SO BIOPHYSICAL JOURNAL LA English DT News Item ID ARP2/3 COMPLEX; MIGRATION; MOVEMENT; PROTEINS; RIGIDITY; FORCE C1 NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Das, A (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM arupratan.das@nih.gov FU Intramural NIH HHS NR 11 TC 0 Z9 0 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD JUL 15 PY 2014 VL 107 IS 2 BP 285 EP 286 DI 10.1016/j.bpj.2014.06.008 PG 2 WC Biophysics SC Biophysics GA AL5BM UT WOS:000339148500003 PM 25028869 ER PT J AU Tollanes, MC Wilcox, AJ Lie, RT Moster, D AF Tollanes, Mette C. Wilcox, Allen J. Lie, Rolv T. Moster, Dag TI Familial risk of cerebral palsy: population based cohort study SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID GESTATIONAL-AGE; NORWAY; BIRTHS; ASSOCIATIONS; SURVEILLANCE; AGGREGATION; PREVALENCE; RECURRENCE; DISEASE AB Objective To investigate risks of recurrence of cerebral palsy in family members with various degrees of relatedness to elucidate patterns of hereditability. Design Population based cohort study. Setting Data from the Medical Birth Registry of Norway, linked to the Norwegian social insurance scheme to identify cases of cerebral palsy and to databases of Statistics Norway to identify relatives. Participants 2 036 741 Norwegians born during 1967-2002, 3649 of whom had a diagnosis of cerebral palsy; 22 558 pairs of twins, 1 851 144 pairs of first degree relatives, 1 699 856 pairs of second degree relatives, and 5 165 968 pairs of third degree relatives were identified. Main outcome measure Cerebral palsy. Results If one twin had cerebral palsy, the relative risk of recurrence of cerebral palsy was 15.6 (95% confidence interval 9.8 to 25) in the other twin. In families with an affected singleton child, risk was increased 9.2 (6.4 to 13)-fold in a subsequent full sibling and 3.0 (1.1 to 8.6)-fold in a half sibling. Affected parents were also at increased risk of having an affected child (6.5 (1.6 to 26)-fold). No evidence was found of differential transmission through mothers or fathers, although the study had limited power to detect such differences. For people with an affected first cousin, only weak evidence existed for an increased risk (1.5 (0.9 to 2.7)-fold). Risks in siblings or cousins were independent of sex of the index case. After exclusion of preterm births (an important risk factor for cerebral palsy), familial risks remained and were often stronger. Conclusions People born into families in which someone already has cerebral palsy are themselves at elevated risk, depending on their degree of relatedness. Elevated risk may extend even to third degree relatives (first cousins). The patterns of risk suggest multifactorial inheritance, in which multiple genes interact with each other and with environmental factors. These data offer additional evidence that the underlying causes of cerebral palsy extend beyond the clinical management of delivery. C1 [Tollanes, Mette C.; Lie, Rolv T.; Moster, Dag] Univ Bergen, Dept Global Publ Hlth & Primary Care, N-5020 Bergen, Norway. [Wilcox, Allen J.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Lie, Rolv T.; Moster, Dag] Natl Inst Publ Hlth, Med Birth Registry Norway, Bergen, Norway. [Moster, Dag] Haukeland Hosp, Dept Pediat, N-5021 Bergen, Norway. RP Tollanes, MC (reprint author), Univ Bergen, Dept Global Publ Hlth & Primary Care, PB 7804, N-5020 Bergen, Norway. EM mette.tollanes@igs.uib.no OI Wilcox, Allen/0000-0002-3376-1311 FU University of Bergen; Western Norway Regional Health Authority; National Institute of Environmental Health Sciences, National Institutes of Health FX The study has been supported by grants from the University of Bergen and the Western Norway Regional Health Authority and by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. The authors' institutions had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. NR 30 TC 13 Z9 13 U1 2 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD JUL 15 PY 2014 VL 349 AR g4294 DI 10.1136/bmj.g4294 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AL7OZ UT WOS:000339325400002 PM 25028249 ER PT J AU Hong, DS Garrido-Laguna, I Ekmekcioglu, S Falchook, GS Naing, A Wheler, JJ Fu, SQ Moulder, SL Piha-Paul, S Tsimberidou, AM Wen, YJ Culotta, KS Anderes, K Davis, DW Liu, W George, GC Camacho, LH Ivy, SP Kurzrock, R AF Hong, David S. Garrido-Laguna, Ignacio Ekmekcioglu, Suhendan Falchook, Gerald S. Naing, Aung Wheler, Jennifer J. Fu, Siqing Moulder, Stacy L. Piha-Paul, Sarina Tsimberidou, Apostolia M. Wen, YueJin Culotta, Kirk S. Anderes, Kenna Davis, Darren W. Liu, Wen George, Goldy C. Camacho, Luis H. Ivy, Susan Percy Kurzrock, Razelle TI Dual Inhibition of the Vascular Endothelial Growth Factor Pathway SO CANCER LA English DT Article DE angiogenesis; phase 1; bevacizumab; cediranib ID METASTATIC COLORECTAL-CANCER; CIRCULATING TUMOR-CELLS; TYROSINE KINASE INHIBITOR; NITRIC-OXIDE SYNTHASE; BREAST-CANCER; SOLID TUMORS; BEVACIZUMAB; CARCINOMA; METAANALYSIS; MELANOMA AB BACKGROUND: The current study was conducted to evaluate the safety and biological activity of dual inhibition of the vascular endothelial growth factor (VEGF) pathway with combined bevacizumab and cediranib (a VEGF receptor tyrosine kinase inhibitor). METHODS: This was a 313 dose escalation study in patients with advanced solid tumors. Cediranib was given orally daily for 21 days and bevacizumab intravenously every 2 weeks. Pharmacokinetics and correlates (nitric oxide synthase, nitrate oxide, and circulating tumor cells) were assessed. RESULTS: Fifty-one patients were treated. Dose-limiting toxicities (DLTs) (grade 3-4; graded according to the National Cancer Institute Common Terminology Criteria of Adverse Events [version 3.0]) observed included 1 patient with chest pain, 1 patient with fatigue, 2 patients with thrombocytopenia, 3 patients with hypertension (1 with intracranial hemorrhage), and 1 patient with grade 5 hemoptysis. Moreover, 2 patients presented with grade 3 intracranial bleeding beyond the DLT window. Dose level 2 (cediranib at a dose of 20 mg/day and bevacizumab at a dose of 5 mg/kg every 2 weeks) was selected as the recommended phase 2 dose (RP2D); 17 patients were treated at dose level 2 with 1 DLT and no intracranial bleeding or severe hypertension reported. Pharmacokinetics of cediranib at dose level 3 demonstrated a 46% to 77% increase in area under the curve (0-24 hours) on cycle 1 day 1 compared with historical controls. Four patients attained partial remissions: inflammatory breast cancer (-54%), basal cell carcinoma (-33%), alveolar soft part sarcoma (-33%), and synovial sarcoma (-32%). Patients with a lower circulating tumor cell count (<30) at the predose period had a longer time to tumor progression (P=.024, log-rank test). CONCLUSIONS: Cediranib at a dose of 20 mg/day and bevacizumab at a dose of 5 mg/kg every 2 weeks was found to be the RP2D. Activity in several tumor types was noted. Central nervous system bleeding and severe hypertension were observed at doses above the RP2D. (C) 2014 American Cancer Society. C1 [Hong, David S.; Garrido-Laguna, Ignacio; Falchook, Gerald S.; Wheler, Jennifer J.; Fu, Siqing; Moulder, Stacy L.; Piha-Paul, Sarina; Tsimberidou, Apostolia M.; Wen, YueJin; George, Goldy C.; Camacho, Luis H.; Kurzrock, Razelle] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Phase Program 1, Houston, TX 77030 USA. [Ekmekcioglu, Suhendan] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA. [Culotta, Kirk S.] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. [Anderes, Kenna; Davis, Darren W.; Liu, Wen] Apocell Mol Profiling & Diagnost, Houston, TX USA. [Ivy, Susan Percy] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Kurzrock, Razelle] Univ Calif San Diego, Moores Canc Ctr, Div Hematol & Oncol, San Diego, CA 92103 USA. RP Hong, DS (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Phase Clin Trials Program 1, Unit 455,1515 Holcombe Blvd, Houston, TX 77030 USA. EM dshong@mdanderson.org FU National Institutes of Health (NIH) Clinical and Translational Science Award [UL1 RR024148]; NIH Cancer Center Support Grant (CCSG) award [CA016672]; NIH [5 UO1 CA062461]; The University of Texas MD Anderson; Commonwealth Foundation for Cancer Research FX Supported by the National Institutes of Health (NIH) Clinical and Translational Science Award UL1 RR024148, NIH Cancer Center Support Grant (CCSG) award CA016672 to The University of Texas MD Anderson Cancer Center, NIH grant award 5 UO1 CA062461 (to Dr. Kurzrock), and by Goodwin funds from The University of Texas MD Anderson. Circulating tumor cell analysis performed by Apocell Molecular Profiling and Diagnostics was supported by the Commonwealth Foundation for Cancer Research. NR 45 TC 11 Z9 11 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUL 15 PY 2014 VL 120 IS 14 BP 2164 EP 2173 DI 10.1002/cncr.28701 PG 10 WC Oncology SC Oncology GA AL3FD UT WOS:000339010800016 PM 24752867 ER PT J AU Gopinathan, L Tan, SLW Padmakumar, VC Coppola, V Tessarollo, L Kaldis, P AF Gopinathan, Lakshmi Tan, Shawn Lu Wen Padmakumar, V. C. Coppola, Vincenzo Tessarollo, Lino Kaldis, Philipp TI Loss of Cdk2 and Cyclin A2 Impairs Cell Proliferation and Tumorigenesis SO CANCER RESEARCH LA English DT Article ID EMBRYONIC LETHALITY; IN-VIVO; DNA; CANCER; PHASE; LIVER; PROGNOSIS; MOUSE; MICE; REPLICATION AB Cell-cycle inhibition has yet to offer a generally effective approach to cancer treatment, but a full evaluation of different combinations of cell-cycle inhibitors has not been evaluated. Cyclin A2, a core component of the cell cycle, is often aberrantly expressed in cancer where it may impact cell proliferation. In this study, we investigated the role of cyclin A2 in tumorigenesis using a conditional genetic knockout mouse model. Cyclin A2 deletion in oncogene-transformed mouse embryonic fibroblasts (MEF) suppressed tumor formation in immunocompromised mice. These findings were confirmed in mice with cyclin A2-deficient hepatocytes, where a delay in liver tumor formation was observed. Because cyclin A2 acts in complex with Cdk2 in the cell cycle, we explored a hypothesized role for Cdk2 dysregulation in this effect through conditional deletions of both genes. In oncogenetransformed MEFs lacking both genes, tumor formation was strongly suppressed in a manner associated with decreased proliferation, premature senescence, and error-prone recovery from serum deprivation after immortalization. Whereas loss of cyclin A2 led to a compensatory increase in Cdk1 activity, this did not occur with loss of both Cdk2 and cyclin A2. Our work offers a rationale to explore combinations of Cdk1 and Cdk2 inhibitors as a general approach in cancer therapy. (C) 2014 AACR. C1 [Gopinathan, Lakshmi; Tan, Shawn Lu Wen; Kaldis, Philipp] ASTAR, IMCB, Singapore, Singapore. [Kaldis, Philipp] NUS, Dept Biochem, Singapore, Singapore. [Padmakumar, V. C.; Coppola, Vincenzo; Tessarollo, Lino] NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. RP Kaldis, P (reprint author), IMCB, 61 Biopolis Dr,Proteos 3-09, Singapore 138673, Singapore. EM kaldis@imcb.a-star.edu.sg RI ASTAR, IMCB/E-2320-2012 FU Biomedical Research Council of A*STAR (Agency for Science, Technology and Research); Intramural Research Program of the NIH FX This work was primarily funded by the Biomedical Research Council of A*STAR (Agency for Science, Technology and Research) and partly by the Intramural Research Program of the NIH. NR 35 TC 15 Z9 15 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2014 VL 74 IS 14 BP 3870 EP 3879 DI 10.1158/0008-5472.CAN-13-3440 PG 10 WC Oncology SC Oncology GA AL1GY UT WOS:000338875000021 PM 24802190 ER PT J AU Bosquet, JG Marchion, DC Chon, H Lancaster, JM Chanock, S AF Bosquet, Jesus Gonzalez Marchion, Douglas C. Chon, HyeSook Lancaster, Johnathan M. Chanock, Stephen TI Analysis of Chemotherapeutic Response in Ovarian Cancers Using Publicly Available High-Throughput Data SO CANCER RESEARCH LA English DT Article ID GENE-EXPRESSION REGULATION; PALLIATIVE-CHEMOTHERAPY; PATIENT SURVIVAL; CELL-LINES; CISPLATIN; DNA; SENSITIVITY; RESISTANCE; SIGNATURES; TRANSFAC AB A third of patients with epithelial ovarian cancer (OVCA) will not respond to standard treatment. The determination of a robust signature that predicts chemoresponse could lead to the identification of molecular markers for response as well as possible clinical implementation in the future to identify patients at risk of failing therapy. This pilot study was designed to identify biologic processes affecting candidate pathways associated with chemoresponse and to create a robust gene signature for follow-up studies. After identifying common pathways associated with chemoresponse in serous OVCA in three independent gene-expression experiments, we assessed the biologic processes associated with them using The Cancer Genome Atlas (TCGA) dataset for serous OVCA. We identified differential copy-number alterations (CNA), mutations, DNA methylation, and miRNA expression between patients that responded to standard treatment and those who did not or recurred prematurely. We correlated these significant parameters with gene expression to create a signature of 422 genes associated with chemoresponse. A consensus clustering of this signature identified two differentiated clusters with unique molecular patterns: cluster 1 was significant for cellular signaling and immune response (mainly cell-mediated); and cluster 2 was significant for pathways involving DNA-damage repair and replication, cell cycle, and apoptosis. Validation through consensus clustering was performed in five independent OVCA gene-expression experiments. Genes were located in the same cluster with consistent agreement in all five studies (kappa coefficient >= 0.6 in 4). Integrating high-throughput biologic data have created a robust molecular signature that predicts chemoresponse in OVCA. (C) 2014 AACR. C1 [Bosquet, Jesus Gonzalez] Univ Iowa Hosp & Clin, Dept Obstet & Gynecol, Div Gynecol Oncol, Iowa City, IA 52242 USA. [Marchion, Douglas C.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Womens Oncol,Expt Therapeut Program,Dept Onc, Tampa, FL 33612 USA. [Chon, HyeSook; Lancaster, Johnathan M.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Womens Oncol,Dept Oncol Sci, Tampa, FL 33612 USA. [Chanock, Stephen] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Bosquet, JG (reprint author), Univ Iowa Hosp & Clin, Dept Obstet & Gynecol, Div Gynecol Oncol, 200 Hawkins Dr, Iowa City, IA 52242 USA. EM jesus-gonzalezbosquet@uiowa.edu FU U.S. Army Medical Research and Materiel Command; "National Functional Genomics Center" at the H. Lee Moffitt Cancer Center and Research Institute [W81XWH-08-2-0101]; University of South Florida; "St. Louis Ovarian Cancer Awareness Research Grant" from Foundation for Women's Cancer FX The research was supported in part by the U.S. Army Medical Research and Materiel Command, in support of the proposal, "National Functional Genomics Center" (award number: W81XWH-08-2-0101) at the H. Lee Moffitt Cancer Center and Research Institute, University of South Florida (Tampa, FL); and by the "St. Louis Ovarian Cancer Awareness Research Grant" from the 2012-2013 Foundation for Women's Cancer grants. NR 53 TC 9 Z9 9 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2014 VL 74 IS 14 BP 3902 EP 3912 DI 10.1158/0008-5472.CAN-14-0186 PG 11 WC Oncology SC Oncology GA AL1GY UT WOS:000338875000024 PM 24848511 ER PT J AU Hall, MD Telma, KA Chang, KE Lee, TD Madigan, JP Lloyd, JR Goldlust, IS Hoeschele, JD Gottesman, MM AF Hall, Matthew D. Telma, Katherine A. Chang, Ki-Eun Lee, Tobie D. Madigan, James P. Lloyd, John R. Goldlust, Ian S. Hoeschele, James D. Gottesman, Michael M. TI Say No to DMSO: Dimethylsulfoxide Inactivates Cisplatin, Carboplatin, and Other Platinum Complexes SO CANCER RESEARCH LA English DT Article ID DIMETHYL-SULFOXIDE; INFUSION SOLUTIONS; DEFENSE-MECHANISM; ANTICANCER DRUGS; BINDING-PROTEINS; CANCER-CELLS; DNA; RESISTANCE; ACCUMULATION; CHEMOTHERAPY AB The platinumdrugs cisplatin, carboplatin, and oxaliplatin are highly utilized in the clinic and as a consequence are extensively studied in the laboratory setting. In this study, we examined the literature and found a significant number of studies (11%-34%) in prominent cancer journals utilizing cisplatin dissolved in DMSO. However, dissolving cisplatin in DMSO for laboratory-based studies results in ligand displacement and changes to the structure of the complex. We examined the effect of DMSO on platinum complexes, including cisplatin, carboplatin, and oxaliplatin, finding that DMSO reacted with the complexes, inhibited their cytotoxicity and their ability to initiate cell death. These results render a substantial portion of the literature on cisplatin uninterpretable. Raising awareness of this significant issue in the cancer biology community is critical, and we make recommendations on appropriate solvation of platinum drugs for research. (C) 2014 AACR. C1 [Hall, Matthew D.; Telma, Katherine A.; Chang, Ki-Eun; Lee, Tobie D.; Madigan, James P.; Gottesman, Michael M.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lloyd, John R.] NIDDK, Adv Mass Spectrometry Facil, NIH, Bethesda, MD USA. [Goldlust, Ian S.] NIH, Div Preclin Innovat, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Hoeschele, James D.] Eastern Michigan Univ, Dept Chem, Ypsilanti, MI 48197 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, 37 Convent Dr,Rm 2108, Bethesda, MD 20892 USA. EM gottesmm@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute; NIH FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute. K.-E. Chang is an NIH Medical Research Scholars Program scholar, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc, The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities, Inc., Mr. and Mrs. Joel S. Marcus, and the Howard Hughes Medical Institute, as well as other private donors. NR 50 TC 40 Z9 40 U1 2 U2 29 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2014 VL 74 IS 14 BP 3913 EP 3922 DI 10.1158/0008-5472.CAN-14-0247 PG 10 WC Oncology SC Oncology GA AL1GY UT WOS:000338875000025 PM 24812268 ER PT J AU Dracup, K Moser, DK Pelter, MM Nesbitt, TS Southard, J Paul, SM Robinson, S Cooper, LS AF Dracup, Kathleen Moser, Debra K. Pelter, Michele M. Nesbitt, Thomas S. Southard, Jeffrey Paul, Steven M. Robinson, Susan Cooper, Lawton S. TI Randomized, Controlled Trial to Improve Self-Care in Patients With Heart Failure Living in Rural Areas SO CIRCULATION LA English DT Article DE clinical trials as topic; heart failure; patient education as topic ID DISEASE MANAGEMENT PROGRAMS; HEALTH-CARE; MEDICARE BENEFICIARIES; HOSPITALIZED-PATIENTS; URBAN; MORTALITY; LITERACY; PATTERNS; INTERVENTION; METAANALYSIS AB Background-Patients with heart failure (HF) who live in rural areas have less access to cardiac services than patients in urban areas. We conducted a randomized, clinical trial to determine the impact of an educational intervention on the composite end point of HF rehospitalization and cardiac death in this population. Methods and Results-Patients (n=602; age, 66 +/- 13 years; 41% female; 51% with systolic HF) were randomized to 1 of 3 groups: control (usual care), Fluid Watchers LITE, or Fluid Watchers PLUS. Both intervention groups included a face-to-face education session delivered by a nurse focusing on self-care. The LITE group received 2 follow-up phone calls, whereas the PLUS group received biweekly calls (mean, 5.3 +/- 3.6; range, 1-19) until the nurse judged the patient to be adequately trained. Over 2 years of follow-up, 35% of patients (n=211) experienced cardiac death or hospitalization for HF, with no difference among the 3 groups in the proportion who experienced the combined clinical outcome (P=0.06). Although patients in the LITE group had reduced cardiac mortality compared with patients in the control group over the 2 years of follow-up (7.5% and 17.7%, respectively; P=0.003), there was no significant difference in cardiac mortality between patients in the PLUS group and the control group. Conclusions-A face-to-face education intervention did not significantly decrease the combined end point of cardiac death or hospitalization for HF. Increasing the number of contacts between the patient and nurse did not significantly improve outcome. C1 [Dracup, Kathleen; Paul, Steven M.; Robinson, Susan] Univ Calif San Francisco, Sch Nursing, San Francisco, CA 94143 USA. [Moser, Debra K.] Univ Kentucky, Coll Nursing, Lexington, KY 40506 USA. [Pelter, Michele M.] Univ Nevada, Reno, NV 89557 USA. [Nesbitt, Thomas S.; Southard, Jeffrey] Univ Calif Davis, Sch Med, Davis, CA 95616 USA. [Cooper, Lawton S.] NHLBI, Bethesda, MD 20892 USA. RP Dracup, K (reprint author), Univ Calif San Francisco, Sch Nursing, 2 Koret Way,N611E, San Francisco, CA 94143 USA. EM kathy.dracup@nursing.ucsf.edu FU National Heart, Lung, and Blood Institute; National Institute of Nursing Research [5R01HL83176-5] FX This study was funded by the National Heart, Lung, and Blood Institute and the National Institute of Nursing Research (5R01HL83176-5). NR 39 TC 14 Z9 14 U1 1 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUL 15 PY 2014 VL 130 IS 3 BP 256 EP 264 DI 10.1161/CIRCULATIONAHA.113.003542 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AL8MB UT WOS:000339392000011 PM 24815499 ER PT J AU Abraham, J Nunez-Alvarez, Y Hettmer, S Carrio, E Chen, HIH Nishijo, K Huang, ET Prajapati, SI Walker, RL Davis, S Rebeles, J Wiebush, H McCleish, AT Hampton, ST Bjornson, CRR Brack, AS Wagers, AJ Rando, TA Capecchi, MR Marini, FC Ehler, BR Zarzabal, LA Goros, MW Michalek, JE Meltzer, PS Langenau, DM LeGallo, RD Mansoor, A Chen, Y Suelves, M Rubin, BP Keller, C AF Abraham, Jinu Nunez-Alvarez, Yaiza Hettmer, Simone Carrio, Elvira Chen, Hung-I Harry Nishijo, Koichi Huang, Elaine T. Prajapati, Suresh I. Walker, Robert L. Davis, Sean Rebeles, Jennifer Wiebush, Hunter McCleish, Amanda T. Hampton, Sheila T. Bjornson, Christopher R. R. Brack, Andrew S. Wagers, Amy J. Rando, Thomas A. Capecchi, Mario R. Marini, Frank C. Ehler, Benjamin R. Zarzabal, Lee Ann Goros, Martin W. Michalek, Joel E. Meltzer, Paul S. Langenau, David M. LeGallo, Robin D. Mansoor, Atiya Chen, Yidong Suelves, Monica Rubin, Brian P. Keller, Charles TI Lineage of origin in rhabdomyosarcoma informs pharmacological response SO GENES & DEVELOPMENT LA English DT Article DE alveolar rhabdomyosarcoma; Pax3:Foxo1; sarcoma; satellite cell; myoblast; histone ID CHILDRENS ONCOLOGY GROUP; ALVEOLAR RHABDOMYOSARCOMA; EMBRYONAL RHABDOMYOSARCOMA; SATELLITE CELLS; MOUSE MODEL; STEM-CELLS; MUSCLE DIFFERENTIATION; EXPRESSION SIGNATURE; PAX7 EXPRESSION; BREAST-CANCER AB Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1. C1 [Abraham, Jinu; Huang, Elaine T.; Keller, Charles] Oregon Hlth & Sci Univ, Pape Family Pediat Res Inst, Pediat Canc Biol Program, Dept Pediat, Portland, OR 97239 USA. [Nunez-Alvarez, Yaiza; Carrio, Elvira; Suelves, Monica] Germans I Trias Pujol Hlth Sci Res Inst IGTP, IMPPC, Badalona 08916, Spain. [Hettmer, Simone; Wagers, Amy J.] Harvard Univ, Howard Hughes Med Inst, Harvard Stem Cell Inst, Joslin Diabet Ctr,Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Hettmer, Simone] Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Chen, Hung-I Harry; Nishijo, Koichi; Prajapati, Suresh I.; Rebeles, Jennifer; Wiebush, Hunter; McCleish, Amanda T.; Hampton, Sheila T.; Chen, Yidong] Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA. [Walker, Robert L.; Davis, Sean; Meltzer, Paul S.] Natl Canc Inst, Oncogen Sect, Pediat Oncol Branch, Adv Technol Ctr, Gaithersburg, MD 20877 USA. [Bjornson, Christopher R. R.; Brack, Andrew S.] Stanford Univ, Dept Neurol, Dept Neurol Sci, Glenn Labs Biol Aging, Palo Alto, CA 94304 USA. [Capecchi, Mario R.] Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA. [Marini, Frank C.] Wake Forest Univ, Bowman Gray Sch Med, Inst Regenerat Med, Winston Salem, NC 27157 USA. [Ehler, Benjamin R.; Zarzabal, Lee Ann; Goros, Martin W.; Michalek, Joel E.; Chen, Yidong] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Langenau, David M.] Massachusetts Gen Hosp, Ctr Canc Res, Dept Pathol, Charlestown, MA 02129 USA. [LeGallo, Robin D.] Univ Virginia, Dept Pathol, Charlottesville, VA 22903 USA. [Mansoor, Atiya] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97239 USA. [Rubin, Brian P.] Cleveland Clin Fdn, Lerner Res Inst, Taussig Canc Ctr, Dept Anat Pathol,Dept Mol Genet, Cleveland, OH 44195 USA. RP Keller, C (reprint author), Oregon Hlth & Sci Univ, Pape Family Pediat Res Inst, Pediat Canc Biol Program, Dept Pediat, Portland, OR 97239 USA. EM keller@ohsu.edu RI Marini, Frank/L-8018-2016; OI Davis, Sean/0000-0002-8991-6458 FU Scott Carter Foundation; Ministerio de Ciencia e Innovacion (MICINN) [SAF2009-08128/SAF2012-37427]; National Cancer Institute [5R01CA133229, 1R01CA154923, R01 AR062185]; National Institute of General Medical Sciences (NIGMS) MARC-U*STAR [GM 07717]; NIGMS MBRS-RISE [GM 60655]; Eunice Kennedy Shriver National Institute of Child Health (NICHD) FX We thank Rishi Rikhi and Noah Berlow for assistance with data analysis. This work was sponsored by training awards to K.N. and J.A. from the Scott Carter Foundation; support from Ministerio de Ciencia e Innovacion (MICINN) (SAF2009-08128/SAF2012-37427) to M.S.; and National Cancer Institute awards 5R01CA133229 to C.K., 1R01CA154923 to D. M. L., and R01 AR062185 to T. A. R. Y.N.-A. is a FPU fellow (Ministerio de Educacion, Cultura y Deporte), E. C. is a FPI fellow (MICINN), and A. T. M. was supported by National Institute of General Medical Sciences (NIGMS) MARC-U*STAR GM 07717 and NIGMS MBRS-RISE GM 60655. The Developmental Studies Hybridoma Bank was developed under the auspices of the Eunice Kennedy Shriver National Institute of Child Health (NICHD) and is maintained by the University of Iowa, Iowa City, IA. NR 60 TC 20 Z9 21 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD JUL 15 PY 2014 VL 28 IS 14 BP 1578 EP 1591 DI 10.1101/gad.238733.114 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA AL5IC UT WOS:000339166100007 PM 25030697 ER PT J AU Guo, MS Updegrove, TB Gogol, EB Shabalina, SA Gross, CA Storz, G AF Guo, Monica S. Updegrove, Taylor B. Gogol, Emily B. Shabalina, Svetlana A. Gross, Carol A. Storz, Gisela TI MicL, a new sigma(E)-dependent sRNA, combats envelope stress by repressing synthesis of Lpp, the major outer membrane lipoprotein SO GENES & DEVELOPMENT LA English DT Article DE sRNA; Hfq; cutC; copper; outer membrane homeostasis; sigma(E) ID SMALL REGULATORY RNA; ESCHERICHIA-COLI; MESSENGER-RNA; CELL-ENVELOPE; DEPENDENT REGULATION; MUREIN-LIPOPROTEIN; PEPTIDE SIGNALS; DOWN-REGULATION; NONCODING RNAS; ANTISENSE RNA AB In enteric bacteria, the transcription factor sigma(E) maintains membrane homeostasis by inducing synthesis of proteins involved in membrane repair and two small regulatory RNAs (sRNAs) that down-regulate synthesis of abundant membrane porins. Here, we describe the discovery of a third sigma(E)-dependent sRNA, MicL (mRNA-interfering complementary RNA regulator of Lpp), transcribed from a promoter located within the coding sequence of the cutC gene. MicL is synthesized as a 308-nucleotide (nt) primary transcript that is processed to an 80-nt form. Both forms possess features typical of Hfq-binding sRNAs but surprisingly target only a single mRNA, which encodes the outer membrane lipoprotein Lpp, the most abundant protein of the cell. We show that the copper sensitivity phenotype previously ascribed to inactivation of the cutC gene is actually derived from the loss of MicL and elevated Lpp levels. This observation raises the possibility that other phenotypes currently attributed to protein defects are due to deficiencies in unappreciated regulatory RNAs. We also report that sigma(E) activity is sensitive to Lpp abundance and that MicL and Lpp comprise a new sigma(E) regulatory loop that opposes membrane stress. Together MicA, RybB, and MicL allow sigma(E) to repress the synthesis of all abundant outer membrane proteins in response to stress. C1 [Guo, Monica S.; Gogol, Emily B.; Gross, Carol A.] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94158 USA. [Updegrove, Taylor B.; Storz, Gisela] Eunice Kennedy Shriver Natl Inst Hlth, Cell Biol & Metab Program, Bethesda, MD 20892 USA. [Shabalina, Svetlana A.] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Gross, CA (reprint author), Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94158 USA. EM cgrossucsf@gmail.com; storzg@mail.nih.gov FU National Institute of General Medical Science [GM036278]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [ZIA HD001608-23]; Intramural Research Program of National Library of Medicine FX We thank A. Zhang for assistance with the tiling array analysis, S. Gottesman for plasmids and strains, T. Silhavy for sharing Lpp antiserum, and G.-W. Li and D. Burkhardt for helpful discussions. Work in the Gross laboratory was supported by National Institute of General Medical Science (GM036278), and work in the Storz laboratory was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (ZIA HD001608-23). This work was also supported by the Intramural Research Program of the National Library of Medicine. NR 79 TC 51 Z9 51 U1 1 U2 16 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD JUL 15 PY 2014 VL 28 IS 14 BP 1620 EP 1634 DI 10.1101/gad.243485.114 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA AL5IC UT WOS:000339166100010 PM 25030700 ER PT J AU Prince, AL Watkin, LB Yin, CC Selin, LK Kang, J Schwartzberg, PL Berg, LJ AF Prince, Amanda L. Watkin, Levi B. Yin, Catherine C. Selin, Liisa K. Kang, Joonsoo Schwartzberg, Pamela L. Berg, Leslie J. TI Innate PLZF(+)CD4(+) alpha beta T Cells Develop and Expand in the Absence of Itk SO JOURNAL OF IMMUNOLOGY LA English DT Article ID THYMOCYTE-THYMOCYTE INTERACTION; TEC KINASE ITK; GAMMA-DELTA; NATURAL-KILLER; NKT CELLS; CYTOKINE PRODUCTION; POSITIVE SELECTION; SIGNALING PATHWAY; TCR REPERTOIRE; IN-VIVO AB T cell development in the thymus produces multiple lineages of cells, including innate T cells. Studies in mice harboring alterations in TCR signaling proteins or transcriptional regulators have revealed an expanded population of CD4(+) innate T cells in the thymus that produce IL-4 and express the transcription factor promyelocytic leukemia zinc finger (PLZF). In these mice, IL-4 produced by the CD4(+)PLZF(+) T cell population leads to the conversion of conventional CD8(+) thymocytes into innate CD8(+) T cells resembling memory T cells expressing eomesodermin. The expression of PLZF, the signature invariant NKT cell transcription factor, in these innate CD4(+) T cells suggests that they might be a subset of alpha beta or gamma delta TCR+ NKT cells or mucosal-associated invariant T (MAIT) cells. To address these possibilities, we characterized the CD4(+)PLZF(+) innate T cells in itk(-/-) mice. We show that itk(-/-) innate PLZF(+)CD4(+) T cells are not CD1d-dependent NKT cells, MR1-dependent MAIT cells, or gamma delta T cells. Furthermore, although the itk(-/-) innate PLZF(+)CD4(+) T cells express alpha beta TCRs, neither beta(2)-microglobulin-dependent MHC class I nor any MHC class II molecules are required for their development. In contrast to invariant NKT cells and MAIT cells, this population has a highly diverse TCR alpha-chain repertoire. Analysis of peripheral tissues indicates that itk(-/-) innate PLZF(+)CD4(+) T cells preferentially home to spleen and mesenteric lymph nodes owing to increased expression of gut-homing receptors, and that their expansion is regulated by commensal gut flora. These data support the conclusion that itk(-/-) innate PLZF(+)CD4(+) T cells are a novel subset of innate T cells. C1 [Prince, Amanda L.; Watkin, Levi B.; Yin, Catherine C.; Selin, Liisa K.; Kang, Joonsoo; Berg, Leslie J.] Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01655 USA. [Schwartzberg, Pamela L.] NHGRI, NIH, Bethesda, MD 20814 USA. RP Berg, LJ (reprint author), Univ Massachusetts, Sch Med, Albert Sherman Ctr, Dept Pathol, 9-1049,368 Plantat St, Worcester, MA 01655 USA. EM Leslie.Berg@umassmed.edu FU National Institutes of Health [AI084987] FX This work was supported by National Institutes of Health Grant AI084987 (to L.J.B.). NR 57 TC 7 Z9 7 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2014 VL 193 IS 2 BP 673 EP 687 DI 10.4049/jimmunol.1302058 PG 15 WC Immunology SC Immunology GA AL2LY UT WOS:000338958300025 PM 24928994 ER PT J AU Prince, AL Kraus, Z Carty, SA Ng, C Yin, CC Jordan, MS Schwartzberg, PL Berg, LJ AF Prince, Amanda L. Kraus, Zachary Carty, Shannon A. Ng, Caleb Yin, Catherine C. Jordan, Martha S. Schwartzberg, Pamela L. Berg, Leslie J. TI Development of Innate CD4(+) and CD8(+) T Cells in Itk-Deficient Mice Is Regulated by Distinct Pathways SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TEC KINASE ITK; THYMOCYTE-THYMOCYTE INTERACTION; GAMMA-DELTA; CYTOKINE PRODUCTION; IN-VIVO; POSITIVE SELECTION; SIGNALING PATHWAY; IGE PRODUCTION; NKT CELLS; MATURATION AB T cell development in the thymus produces multiple lineages of cells, including innate T cells such as gamma delta TCR+ cells, invariant NKT cells, mucosal-associated invariant T cells, and H2-M3-specific cells. Although innate cells are generally a minor subset of thymocytes, in several strains of mice harboring mutations in T cell signaling proteins or transcriptional regulators, conventional CD8(+) T cells develop as innate cells with characteristics of memory T cells. Thus, in Itk-deficient mice, mature CD4(-)CD8(+) (CD8 single-positive [SP]) thymocytes express high levels of the transcription factor eomesodermin (Eomes) and are dependent on IL-4 being produced in the thymic environment by a poorly characterized subset of CD4(+) thymocytes expressing the transcriptional regulator promyelocytic leukemia zinc finger. In this study, we show that a sizeable proportion of mature CD4(+)CD8(-) (CD4SP) thymocytes in itk(-/-) mice also develop as innate Eomes-expressing T cells. These cells are dependent on MHC class II and IL-4 signaling for their development, indicating that they are conventional CD4(+) T cells that have been converted to an innate phenotype. Surprisingly, neither CD4SP nor CD8SP innate Eomes(+) thymocytes in itk(-/-) or SLP-76(Y145F) mice are dependent on gamma delta T cells for their development. Instead, we find that the predominant population of Eomes(+) innate itk(-/-) CD4SP thymocytes is largely absent in mice lacking CD1d-specific invariant NKT cells, with no effect on innate itk(-/-) CD8SP thymocytes. In contrast, both subsets of innate Eomes(+)itk(-/-) T cells require the presence of a novel promyelocytic leukemia zinc finger-expressing, SLAM family receptor adapter protein-dependent thymocyte population that is essential for the conversion of conventional CD4(+) and CD8(+) T cells into innate T cells with a memory phenotype. C1 [Prince, Amanda L.; Yin, Catherine C.; Berg, Leslie J.] Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01655 USA. [Kraus, Zachary; Schwartzberg, Pamela L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Carty, Shannon A.; Ng, Caleb; Jordan, Martha S.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Berg, LJ (reprint author), Univ Massachusetts, Sch Med, Albert Sherman Ctr, Dept Pathol, 9-1049,368 Plantat St, Worcester, MA 01655 USA. EM Leslie.Berg@umassmed.edu FU National Institutes of Health [AI084987, 5K08 AI101008] FX This work was supported by National Institutes of Health Grants AI084987 (to L.J.B.) and 5K08 AI101008 (to S.A.C.). NR 40 TC 8 Z9 8 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2014 VL 193 IS 2 BP 688 EP 699 DI 10.4049/jimmunol.1302059 PG 12 WC Immunology SC Immunology GA AL2LY UT WOS:000338958300026 PM 24943215 ER PT J AU Allam, A Swiecki, M Vermi, W Ashwell, JD Colonna, M AF Allam, Atef Swiecki, Melissa Vermi, William Ashwell, Jonathan D. Colonna, Marco TI Dual Function of CD70 in Viral Infection: Modulator of Early Cytokine Responses and Activator of Adaptive Responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID REGULATORY T-CELLS; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; NATURAL-KILLER-CELLS; DENDRITIC CELLS; NK-CELLS; IN-VIVO; CYTOMEGALOVIRUS-INFECTION; CD27-CD70 INTERACTIONS; CD27; IMMUNITY AB The role of the TNF family member CD70 in adaptive T cell responses has been intensively studied, but its function in innate responses is still under investigation. In this study, we show that CD70 inhibits the early innate response to murine CMV (MCMV) but is essential for the optimal generation of virus-specific CD8 T cells. CD70(-/-) mice reacted to MCMV infection with a robust type I IFN and proinflammatory cytokine response. This response was sufficient for initial control of MCMV, although at later time points, CD70(-/-) mice became more susceptible to MCMV infection. The heightened cytokine response during the early phase of MCMV infection in CD70(-/-) mice was paralleled by a reduction in regulatory T cells (Treg). Treg from naive CD70(-/-) mice were not as efficient at suppressing T cell proliferation compared with Treg from naive wild-type mice, and depletion of Treg during MCMV infection in Foxp3-diphtheria toxin receptor mice or in wild-type mice recapitulated the phenotype observed in CD70(-/-) mice. Our study demonstrates that although CD70 is required for the activation of the antiviral adaptive response, it has a regulatory role in early cytokine responses to viruses such as MCMV, possibly through maintenance of Treg survival and function. C1 [Allam, Atef; Swiecki, Melissa; Vermi, William; Colonna, Marco] Washington Univ, Dept Pathol & Immunol, Sch Med, St Louis, MO 63110 USA. [Vermi, William] Univ Brescia, Dept Pathol, I-25123 Brescia, Italy. [Ashwell, Jonathan D.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Colonna, M (reprint author), Washington Univ, BJC Inst Hlth, Sch Med, 425 South Euclid Ave,Campus Box 8118, St Louis, MO 63110 USA. EM mcolonna@pathology.wustl.edu OI Colonna, Marco/0000-0001-5222-4987 FU National Cancer Institute [5-T32CA09547]; National Institute of Diabetes and Digestive and Kidney Diseases [K01DK095972]; National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health [P30AR048335] FX A.A. was supported by Training Grant 5-T32CA09547 from the National Cancer Institute. M.S. was supported by Grant K01DK095972 from the National Institute of Diabetes and Digestive and Kidney Diseases. Research reported in this study was also supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the National Institutes of Health, under Award P30AR048335. NR 44 TC 5 Z9 5 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2014 VL 193 IS 2 BP 871 EP 878 DI 10.4049/jimmunol.1302429 PG 8 WC Immunology SC Immunology GA AL2LY UT WOS:000338958300043 PM 24913981 ER PT J AU Srinivasan, P Ekanem, E Diouf, A Tonkin, ML Miura, K Boulanger, MJ Long, CA Narum, DL Miller, LH AF Srinivasan, Prakash Ekanem, Emmanuel Diouf, Ababacar Tonkin, Michelle L. Miura, Kazutoyo Boulanger, Martin J. Long, Carole A. Narum, David L. Miller, Louis H. TI Immunization with a functional protein complex required for erythrocyte invasion protects against lethal malaria SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID APICAL MEMBRANE ANTIGEN-1; BLOOD-STAGE MALARIA; ALLELE-SPECIFIC EFFICACY; WEB SERVER; VACCINE; AMA1; PARASITES; ANTIBODY; INFECTION; PEPTIDE AB An essential step in the invasion of red blood cells (RBCs) by Plasmodium falciparum (Pf) merozoites is the binding of rhoptry neck protein 2 (RON2) to the hydrophobic groove of apical membrane antigen 1 (AMA1), triggering junction formation between the apical end of the merozoite and the RBC surface to initiate invasion. Vaccination with AMA1 provided protection against homologous parasites in one of two phase 2 clinical trials; however, despite its ability to induce high-titer invasion-blocking antibodies in a controlled human challenge trial, the vaccine conferred little protection even against the homologous parasite. Here we provide evidence that immunization with an AMA1-RON2 peptide complex, but not with AMA1 alone, provided complete protection against a lethal Plasmodium yoelii challenge in mice. Significantly, IgG from mice immunized with the complex transferred protection. Furthermore, IgG from PfAMA1-RON2-immunized animals showed enhanced invasion inhibition compared with IgG elicited by AMA1 alone. Interestingly, this qualitative increase in inhibitory activity appears to be related, at least in part, to a switch in the proportion of IgG specific for certain loop regions in AMA1 surrounding the binding site of RON2. Antibodies induced by the complex were not sufficient to block the FVO strain heterologous parasite, however, reinforcing the need to include multiallele AMA1 to cover polymorphisms. Our results suggest that AMA1 subunit vaccines may be highly effective when presented to the immune system as an invasion complex with RON2. C1 [Srinivasan, Prakash; Diouf, Ababacar; Miura, Kazutoyo; Long, Carole A.; Miller, Louis H.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Ekanem, Emmanuel; Narum, David L.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. [Tonkin, Michelle L.; Boulanger, Martin J.] Univ Victoria, Dept Biochem & Microbiol, Victoria, BC V8W 3P6, Canada. RP Srinivasan, P (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM srinivasanp@niaid.nih.gov; lmiller@niaid.nih.gov FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Canadian Institutes for Health Research [MOP82915] FX We thank Dr. Susan Pierce for a critical reading of the manuscript, Dr. Patrick Duffy for valuable suggestions, and Dr. Nicholas MacDonald, Dr. Harold Obiakor, Raul Herrera, and Karine Reiter from the Process Development Unit for their excellent technical assistance. These studies were supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health and by the Canadian Institutes for Health Research [Research Grant MOP82915 (to M.J.B.)]. NR 36 TC 28 Z9 28 U1 1 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 15 PY 2014 VL 111 IS 28 BP 10311 EP 10316 DI 10.1073/pnas.1409928111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL2WG UT WOS:000338985700065 PM 24958881 ER PT J AU Rao, P Korin, Y Warshaw, B Sarwal, M Tsai, E Ettenger, R Grimm, P Ikle, D Sledge, T Kirk, A Reed, E AF Rao, P. Korin, Y. Warshaw, B. Sarwal, M. Tsai, E. Ettenger, R. Grimm, P. Ikle, D. Sledge, T. Kirk, A. Reed, E. TI HLA and MICA Alloantibody Profi ling in Pediatric Renal Transplant Recipients: Report From The Clinical Trials in Organ Transplantation in Children (CTOTC-02) SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Rao, P.; Korin, Y.; Tsai, E.; Ettenger, R.; Reed, E.] Univ Calif Los Angeles, Los Angeles, CA USA. [Warshaw, B.; Kirk, A.] Emory Univ, Atlanta, GA 30322 USA. [Sarwal, M.] CPMC Res Inst, San Francisco, CA USA. [Grimm, P.] Stanford Univ, Palo Alto, CA 94304 USA. [Ikle, D.] Rho, Chapel Hill, NC USA. [Sledge, T.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA 2197 BP 12 EP 13 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104600035 ER PT J AU Singh, A Corcoran, P Thomas, M Lewis, B Ayares, D Reimann, K Horvath, K Mohiuddin, M AF Singh, A. Corcoran, P. Thomas, M. Lewis, B. Ayares, D. Reimann, K. Horvath, K. Mohiuddin, M. TI Costimulation Blockade With Anti CD40 Antibody Maintains CD4+and Treg Cell Numbers in Pig To Baboon Cardiac Transplantation Model SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Singh, A.; Corcoran, P.; Horvath, K.; Mohiuddin, M.] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Thomas, M.; Lewis, B.] NIH, Bethesda, MD 20892 USA. [Ayares, D.] Revivicor Inc, Blacksburgh, VA USA. [Reimann, K.] Mass Biol, Bethesda, MD USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA 1424 BP 30 EP 30 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104600097 ER PT J AU Wood, S Feng, J He, S Marquez, V Bishop, D Zhang, Y AF Wood, S. Feng, J. He, S. Marquez, V. Bishop, D. Zhang, Y. TI Inhibition of Histone Methylation Induces Long-Term Survival of Vascularized Cardiac Allografts and Preserves the Third-Party T Cell Immunity SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Wood, S.; Feng, J.; Bishop, D.] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA. [He, S.; Zhang, Y.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Marquez, V.] NIH, Biol Chem Lab, Ctr Canc Res, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA 2109 BP 35 EP 35 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104600114 ER PT J AU Randhawa, P Pastrana, D Zeng, G Berger, M Hariharan, S Ron, S Buck, C AF Randhawa, P. Pastrana, D. Zeng, G. Berger, M. Hariharan, S. Ron, S. Buck, C. TI Neutralizing Antibodies For Polyomavirus BK (BKV) in Intravenous Immunoglobulins: Pre-Clinical Studies SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Randhawa, P.; Zeng, G.; Hariharan, S.; Ron, S.] Univ Pittsburgh, Pittsburgh, PA USA. [Pastrana, D.; Buck, C.] NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. [Berger, M.] CSL Behring, Immunol R&D, King Of Prussia, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA 727 BP 85 EP 85 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104600263 ER PT J AU Nickerson, P Wiebe, C Formica, R Tinckam, K Poggio, E Bunnapradist, S Gibson, I Rush, D Samaniego, M Gaber, O Ilke, D Bridges, N Fairchild, R Hricik, D Heeger, P AF Nickerson, P. Wiebe, C. Formica, R. Tinckam, K. Poggio, E. Bunnapradist, S. Gibson, I. Rush, D. Samaniego, M. Gaber, O. Ilke, D. Bridges, N. Fairchild, R. Hricik, D. Heeger, P. TI Epitope Mismatch Predicts De Novo DSA After CNI Withdrawal in Low-Risk Kidney Transplant Recipients SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Nickerson, P.; Wiebe, C.; Gibson, I.; Rush, D.] UM, Winnipeg, MB, Canada. [Formica, R.] Yale Univ, New Haven, CT USA. [Tinckam, K.] UHN, Toronto, ON, Canada. [Poggio, E.; Fairchild, R.] Cleveland Clin, Cleveland, OH USA. [Bunnapradist, S.] Univ Calif Los Angeles, Los Angeles, CA USA. [Samaniego, M.] UoM, Ann Arbor, MI USA. [Gaber, O.] MTC, Houston, TX USA. [Ilke, D.] Rho, Chapel Hill, NC USA. [Bridges, N.] NIH, Bethesda, MD 20892 USA. [Hricik, D.] UHCMC, Cleveland, OH USA. [Heeger, P.] MSSM, New York, NY USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA 2888 BP 137 EP 137 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104600423 ER PT J AU Olthoff, K Chang, B Christie, J Levitsky, J Emond, J Bridges, N Sledge, T Shaked, A AF Olthoff, K. Chang, B. Christie, J. Levitsky, J. Emond, J. Bridges, N. Sledge, T. Shaked, A. TI Immediate Post-Reperfusion PBL Activation Associated With Liver Early Allograft Dysfunction (EAD) SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Olthoff, K.; Chang, B.; Christie, J.; Shaked, A.] Univ Penn, Philadelphia, PA 19104 USA. [Levitsky, J.] Northwestern Univ, Chicago, IL 60611 USA. [Emond, J.] Columbia Univ, New York, NY USA. [Bridges, N.; Sledge, T.] NIDDK, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA 1332 BP 224 EP 224 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104601189 ER PT J AU Formica, R Nickerson, P Poggio, E Tinckam, K Rush, D Gibson, I Fairchild, R Bridges, N Ikle, D Samaniego, M Graber, O Bunnapradist, S Armstrong, B Heeger, P Hricik, D AF Formica, R. Nickerson, P. Poggio, E. Tinckam, K. Rush, D. Gibson, I. Fairchild, R. Bridges, N. Ikle, D. Samaniego, M. Graber, O. Bunnapradist, S. Armstrong, B. Heeger, P. Hricik, D. TI Immune Monitoring and Tacrolimus (Tac) Withdrawal in Low Risk Recipients of Kidney Transplants - Results of CTOT09 SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Formica, R.] Yale, New Haven, CT USA. [Nickerson, P.; Rush, D.; Gibson, I.] UM, Winnipeg, MB, Canada. [Poggio, E.; Fairchild, R.] Cleveland Clin, Cleveland, OH USA. [Tinckam, K.] UHN, Toronto, ON, Canada. [Bridges, N.] NIH, Bethesda, MD 20892 USA. [Ikle, D.; Armstrong, B.] Rho, Chapel Hill, NC USA. [Samaniego, M.] UoM, Ann Arbor, MI USA. [Graber, O.] MTC, Houston, TX USA. [Bunnapradist, S.] Univ Calif Los Angeles, Los Angeles, CA USA. MSSM, New York, NY USA. [Heeger, P.] UHCMC, Cleveland, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA 1436 BP 225 EP 225 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104601195 ER PT J AU Shaked, A Feng, S Punch, J Reyes, J Klintmalm, G Zimmerman, M DesMarais, M Kopetskie, H Priore, A Bridges, N Sayre, P AF Shaked, A. Feng, S. Punch, J. Reyes, J. Klintmalm, G. Zimmerman, M. DesMarais, M. Kopetskie, H. Priore, A. Bridges, N. Sayre, P. TI Feasibility and Benefit of Minimization and Withdrawal of Immunosuppression (IS) Early After Liver Transplantation in HCV Positive Recipients. SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Shaked, A.] Univ Penn, Philadelphia, PA 19104 USA. [Feng, S.; DesMarais, M.; Sayre, P.] UCSF, San Francisco, CA USA. [Punch, J.] Univ Michigan, Ann Arbor, MI 48109 USA. Univ Washington, Seattle, WA 98195 USA. [Reyes, J.] Northwestern, Chicago, IL USA. [Klintmalm, G.] Baylor, Dallas, TX USA. [Zimmerman, M.] Univ Colorado, Denver, CO 80202 USA. [Kopetskie, H.] RhoFed, Chapel Hill, NC USA. [Priore, A.; Bridges, N.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA 2959 BP 230 EP 231 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104601213 ER PT J AU Arron, S Yankis, E Raymond, A McCulloch, C Engels, E AF Arron, S. Yankis, E. Raymond, A. McCulloch, C. Engels, E. TI Increased Mortality in Transplant Recipients With a History of Pretransplant Melanoma. SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Arron, S.; Raymond, A.; McCulloch, C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Yankis, E.; Engels, E.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA A529 BP 240 EP 240 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104601244 ER PT J AU Kalil, R Lynch, C Engels, E AF Kalil, R. Lynch, C. Engels, E. TI Risk of Cancer in Kidney Retransplants Compared To Primary Kidney Transplants in The Transplant Cancer Match Study SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Kalil, R.; Lynch, C.] Univ Iowa, Iowa City, IA USA. [Engels, E.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA A528 BP 240 EP 240 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104601243 ER PT J AU Yanik, E Snyder, J Clarke, C Engels, E AF Yanik, E. Snyder, J. Clarke, C. Engels, E. TI Cancer Risk Patterns Among End Stage Renal Disease Patients During Intervals of Kidney Transplant Function and Non-Function. SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Yanik, E.] NCI, Rockville, MD USA. [Snyder, J.] Univ Minnesota, Minneapolis, MN USA. [Clarke, C.] Canc Prevent Inst Calif, Fremont, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA A532 BP 241 EP 242 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104601247 ER PT J AU Yanik, E Gustafson, S Kasiske, B Israni, A Snyder, J Engels, E Segev, D AF Yanik, E. Gustafson, S. Kasiske, B. Israni, A. Snyder, J. Engels, E. Segev, D. TI Sirolimus Use and Cancer Incidence Among US Kidney Transplant Recipients SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Yanik, E.; Israni, A.; Engels, E.] NCI, Rockville, MD USA. [Gustafson, S.; Kasiske, B.; Israni, A.; Snyder, J.] Sci Registry Transplant Recipients, Minneapolis, MN USA. [Segev, D.] Johns Hopkins Univ, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA A534 BP 242 EP 242 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104601249 ER PT J AU Putheti, P Ding, R Naqvi, R Medeiros, M Sharma, V Kuchibhotla, S LeBeau, P Ikle, D Muthukumar, T Dadhania, D Myers, K Ingelfinger, J McDonald, R Liu, J Spaneas, L Williams, N Bridges, N Harmon, W Suthanthiran, M Strom, T AF Putheti, P. Ding, R. Naqvi, R. Medeiros, M. Sharma, V. Kuchibhotla, S. LeBeau, P. Ikle, D. Muthukumar, T. Dadhania, D. Myers, K. Ingelfinger, J. McDonald, R. Liu, J. Spaneas, L. Williams, N. Bridges, N. Harmon, W. Suthanthiran, M. Strom, T. TI Gene-Expression Profiles of Peripheral Blood Cells and of Allograft Biopsies Are Associated With Acute Rejection in Pediatric Renal Allograft Recipients. SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Putheti, P.; Kuchibhotla, S.; Ingelfinger, J.; Spaneas, L.; Harmon, W.; Strom, T.] HMS, Boston, MA USA. [Ding, R.; Naqvi, R.; Medeiros, M.; Sharma, V.; Muthukumar, T.; Dadhania, D.; Suthanthiran, M.] WCMC, New York, NY USA. [LeBeau, P.; Ikle, D.] Rho, Chapel Hill, NC USA. [Liu, J.] PPD, Morrisville, NC USA. [Williams, N.; Bridges, N.] NIAID, Bethesda, MD 20892 USA. [Myers, K.] CHOP UPenn, Philadelphia, PA USA. [McDonald, R.] Seattle Childrens UW, Seattle, WA USA. RI Medeiros, Mara/B-9230-2015 OI Medeiros, Mara/0000-0002-6848-8933 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA C1528 BP 324 EP 324 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104601560 ER PT J AU Li, Z Xu, X Feng, X Farber, J Young, N Murphy, P AF Li, Z. Xu, X. Feng, X. Farber, J. Young, N. Murphy, P. TI Clodronate-Induced Macrophage Depletion of Mice Receiving Bone Marrow Allotransplantation Enhances Hematopoietic Chimerism and Donor-Specific Skin Allograft Tolerance. SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Li, Z.; Xu, X.; Farber, J.; Murphy, P.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Feng, X.; Young, N.] NIAID, Hematol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA D2770 BP 395 EP 395 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104602254 ER PT J AU Mohiuddin, M Singh, A Corcoran, P Hoyt, R Thomas, M Eckhaus, M Lewis, B Clark, T Phelps, C Ayares, D Reimann, K Horvath, K AF Mohiuddin, M. Singh, A. Corcoran, P. Hoyt, R. Thomas, M. Eckhaus, M. Lewis, B. Clark, T. Phelps, C. Ayares, D. Reimann, K. Horvath, K. TI Long Term GalKO center dot hCD46. hTBM Pig Cardiac Xenograft Survival in Baboon May Be Dependent On Dose and Duration of Anti CD40 (2C10R4) Antibody. SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Mohiuddin, M.; Singh, A.; Corcoran, P.; Horvath, K.] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Hoyt, R.; Thomas, M.; Eckhaus, M.; Lewis, B.; Clark, T.] NIH, Bethesda, MD 20892 USA. [Phelps, C.; Ayares, D.] Revivicor Inc, Blacksburgh, VA USA. [Reimann, K.] Mass Biol, Boston, MA USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA D2844 BP 415 EP 415 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104602328 ER PT J AU Mohiuddin, M Singh, A Corcoran, P Hoyt, R Thomas, M Lewis, B Clark, T Klymiuk, N Wolf, E Reimann, K Ayares, D Horvath, K AF Mohiuddin, M. Singh, A. Corcoran, P. Hoyt, R. Thomas, M. Lewis, B. Clark, T. Klymiuk, N. Wolf, E. Reimann, K. Ayares, D. Horvath, K. TI Normal Histology and Contractility of a Cardiac Xenograft For 450+Days: A Case Report. SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Mohiuddin, M.; Singh, A.; Corcoran, P.; Horvath, K.] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Hoyt, R.; Thomas, M.; Lewis, B.; Clark, T.] NIH, Bethesda, MD 20892 USA. [Ayares, D.] Revivicor Inc, Blacksburg, VA USA. [Reimann, K.] Mass Biol, Boston, MA USA. [Klymiuk, N.; Wolf, E.] LMU, Munich, Germany. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA D2848 BP 416 EP 416 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104602332 ER PT J AU Daly, K Starling, R Armstrong, B Ikle, D Bridges, N Chandraker, A Sayegh, M Stehlik, J Heeger, P Briscoe, D AF Daly, K. Starling, R. Armstrong, B. Ikle, D. Bridges, N. Chandraker, A. Sayegh, M. Stehlik, J. Heeger, P. Briscoe, D. TI Changes in Plasma Levels of VEGF-C and Endothelin-1 During the First Post-Transplant Year Are Predictive of Cardiac Allograft Vasculopathy: Results From the CTOT-05 Study. SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Daly, K.; Briscoe, D.] Boston Childrens Hosp, Boston, MA USA. [Starling, R.] Cleveland Clin, Cleveland, OH 44106 USA. [Armstrong, B.; Ikle, D.] Rho, Chapel Hill, NC USA. [Bridges, N.] NIH, Bethesda, MD 20892 USA. [Chandraker, A.; Sayegh, M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Stehlik, J.] Univ Utah, Salt Lake City, UT USA. [Heeger, P.] Mt Sinai Sch Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA A23 BP 878 EP 878 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104605429 ER PT J AU Hricik, D Augustine, J Poggio, E Fairchild, R Nickerson, P Rush, D Gibson, I Formica, R Goebel, J Newell, K Spain, K Ikle, D Bridges, N Heeger, P AF Hricik, D. Augustine, J. Poggio, E. Fairchild, R. Nickerson, P. Rush, D. Gibson, I. Formica, R. Goebel, J. Newell, K. Spain, K. Ikle, D. Bridges, N. Heeger, P. TI Rabbit ATG Induction Overcomes the Negative Influence of Pretransplant Memory T Cells On Posttransplant GFR: Results From the CTOT01 Kidney Transplant Trial. SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Hricik, D.; Augustine, J.] UH Case Med Ctr, Cleveland, OH USA. [Poggio, E.; Fairchild, R.] Cleveland Clin, Cleveland, OH 44106 USA. [Nickerson, P.; Rush, D.; Gibson, I.] U Manitoba, Winnipeg, MB, Canada. [Formica, R.] Yale U, New Haven, CT USA. [Goebel, J.] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Newell, K.] Emory U, Atlanta, GA USA. [Spain, K.; Ikle, D.] Rho, Chapel Hill, NC USA. [Bridges, N.] NIAID, NIH, Bethesda, MD 20892 USA. [Heeger, P.] Mt Sinai Sch Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA B775 BP 892 EP 893 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104605483 ER PT J AU Chang, B Christie, J Olthoff, K Emond, J Levitsky, J Bridges, N Sledge, T Ikle, D Shaked, A AF Chang, B. Christie, J. Olthoff, K. Emond, J. Levitsky, J. Bridges, N. Sledge, T. Ikle, D. Shaked, A. TI Dynamic Inflammatory Gene Expression Profiles Among Patients With and Without Acute Cellular Rejection (ACR) During the First Post-Transplant Year. SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Chang, B.; Christie, J.; Olthoff, K.; Shaked, A.] Univ Penn, Philadelphia, PA 19104 USA. [Emond, J.] Columbia Univ, New York, NY USA. [Levitsky, J.] Northwestern Univ, Chicago, IL 60611 USA. [Bridges, N.; Sledge, T.] NIDDK, Bethesda, MD 20892 USA. [Ikle, D.] RhoFed, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA D2345 BP 901 EP 902 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104605516 ER PT J AU Shaked, O Chang, B Tobias, J Demetris, A Suthanthiran, M Feng, S Punch, J Reyes, J Levitsky, J Klintmalm, G Zimmerman, M DesMarais, M Kopeskie, H Priore, A Morrison, Y Bridges, N Sayre, P Shaked, A AF Shaked, O. Chang, B. Tobias, J. Demetris, A. Suthanthiran, M. Feng, S. Punch, J. Reyes, J. Levitsky, J. Klintmalm, G. Zimmerman, M. DesMarais, M. Kopeskie, H. Priore, A. Morrison, Y. Bridges, N. Sayre, P. Shaked, A. TI Whole Blood mRNA to Detect Hepatic Inflammation and Fibrosis in Post-Liver Transplant Patients With HCV. SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Shaked, O.; Chang, B.; Tobias, J.; Shaked, A.] UPenn, Philadelphia, PA USA. [Demetris, A.] UPMC, Pittsburgh, PA USA. [Suthanthiran, M.] Cornell, New York, NY USA. [Feng, S.; DesMarais, M.; Sayre, P.] UCSF, San Francisco, CA USA. [Punch, J.] Univ Michigan, Ann Arbor, MI 48109 USA. [Reyes, J.] Univ Wisconsin, Madison, WI 53706 USA. [Levitsky, J.] Northwestern Univ, Chicago, IL 60611 USA. [Klintmalm, G.] Baylor Univ, Dallas, TX USA. [Zimmerman, M.] Univ Colorado, Denver, CO 80202 USA. [Priore, A.; Morrison, Y.; Bridges, N.] NIAID, Bethesda, MD 20892 USA. [Kopeskie, H.] RhoFed, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA D2356 BP 905 EP 905 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104605527 ER PT J AU Chin, MS Hooper, LC Hooks, JJ Detrick, B AF Chin, Marian S. Hooper, Laura C. Hooks, John J. Detrick, Barbara TI Identification of alpha-fodrin as an autoantigen in experimental coronavirus retinopathy (ECOR) SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE Coronavirus; Retinal degeneration; alpha-Fodrin; Autoantibodies; Autoimmunity ID CANCER-ASSOCIATED RETINOPATHY; PIGMENT EPITHELIAL-CELL; AUTOIMMUNE RETINOPATHY; ANTIRETINAL ANTIBODIES; RETINAL DEGENERATION; ALZHEIMERS-DISEASE; BRAIN SPECTRIN; ANTI-RECOVERIN; T-CELLS; IN-VIVO AB The coronavirus, mouse hepatitis virus (MHV), JHM strain induces a biphasic disease in BALB/c mice that consists of an acute retinitis followed by progression to a chronic retinal degeneration with autoimmune reactivity. Retinal degeneration resistant CD-1 mice do not develop either the late phase or autoimmune reactivity. A mouse RPE/choroid DNA expression library was screened using sera from virus infected BALB/c mice. Two clones were identified, villin-2 protein and alpha-fodrin protein. alpha-Fodrin protein was used for further analysis and western blot reactivity was seen only in sera from virus infected BALB/c mice. CD4 T cells were shown to specifically react with MHV antigens and with alpha-fodrin protein. These studies clearly identified both antibody and CD4 T cell reactivities to alpha-fodrin in sera from virus infected, retinal degenerative susceptible BALB/c mice. (C) 2014 Elsevier B.V. All rights reserved. C1 [Chin, Marian S.; Hooper, Laura C.; Hooks, John J.] NEI, Immunol Lab, Immunol & Virol Sect, NIH, Bethesda, MD 20892 USA. [Detrick, Barbara] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. RP Detrick, B (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Immunol Lab, B-125 Meyer,600 N Wolfe St, Baltimore, MD 21205 USA. NR 50 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 EI 1872-8421 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD JUL 15 PY 2014 VL 272 IS 1-2 BP 42 EP 50 DI 10.1016/j.jneuroim.2014.05.002 PG 9 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA AK7MX UT WOS:000338613500006 PM 24864013 ER PT J AU Jiao, S Peters, U Berndt, S Brenner, H Butterbach, K Caan, BJ Carlson, CS Chan, AT Chang-Claude, J Chanock, S Curtis, KR Duggan, D Gong, J Harrison, TA Hayes, RB Henderson, BE Hoffmeister, M Kolonel, LN Le Marchand, L Potter, JD Rudolph, A Schoen, RE Seminara, D Slattery, ML White, E Hsu, L AF Jiao, Shuo Peters, Ulrike Berndt, Sonja Brenner, Hermann Butterbach, Katja Caan, Bette J. Carlson, Christopher S. Chan, Andrew T. Chang-Claude, Jenny Chanock, Stephen Curtis, Keith R. Duggan, David Gong, Jian Harrison, Tabitha A. Hayes, Richard B. Henderson, Brian E. Hoffmeister, Michael Kolonel, Laurence N. Le Marchand, Loic Potter, John D. Rudolph, Anja Schoen, Robert E. Seminara, Daniela Slattery, Martha L. White, Emily Hsu, Li TI Estimating the heritability of colorectal cancer SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; COLON-CANCER; COMMON SNPS; PANCREATIC-CANCER; HUMAN HEIGHT; RISK LOCI; DISEASE; DESIGN; HEALTH AB A sizable fraction of colorectal cancer (CRC) is expected to be explained by heritable factors, with heritability estimates ranging from 12 to 35% twin and family studies. Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) associated with CRC risk. Although it has been shown that these CRC susceptibility SNPs only explain a small proportion of the genetic risk, it is not clear how much of the heritability these SNPs explain and how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we estimated the heritability of CRC under different scenarios using Genome-Wide Complex Trait Analysis in the Genetics and Epidemiology of Colorectal Cancer Consortium including 8025 cases and 10 814 controls. We estimated that the heritability explained by known common CRC SNPs identified in GWAS was 0.65% (95% CI:0.3-1%; P = 1.11 x 10-16), whereas the heritability explained by all common SNPs was at least 7.42% (95% CI: 4.71-10.12%; P = 8.13 x 10(-8)), suggesting that many common variants associated with CRC risk remain to be detected. Comparing the heritability explained by the common variants with that from twin and family studies, a fraction of the heritability may be explained by other genetic variants, such as rare variants. In addition, our analysis showed that the gene x smoking interaction explained a significant proportion of the CRC variance (P = 1.26 x 10(-2)). In summary, our results suggest that known CRC SNPs only explain a small proportion of the heritability and more common SNPs have yet to be identified. C1 [Jiao, Shuo; Peters, Ulrike; Carlson, Christopher S.; Curtis, Keith R.; Gong, Jian; Harrison, Tabitha A.; Potter, John D.; White, Emily; Hsu, Li] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Berndt, Sonja; Chanock, Stephen] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Caan, Bette J.; Rudolph, Anja; Seminara, Daniela] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Chan, Andrew T.] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Chan, Andrew T.] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Chang-Claude, Jenny] Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94611 USA. [Duggan, David] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Carlson, Christopher S.; Potter, John D.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Carlson, Christopher S.; Hayes, Richard B.; Potter, John D.] Harvard Univ, Sch Med, Boston, MA USA. [Hayes, Richard B.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Henderson, Brian E.] Translat Genom Res Inst, Phoenix, AZ USA. [Kolonel, Laurence N.] NYU, Sch Med, Div Epidemiol, New York, NY USA. Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Potter, John D.] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [Brenner, Hermann; Butterbach, Katja; Hoffmeister, Michael; Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA USA. [Slattery, Martha L.] Univ Utah, Hlth Sci Ctr, Dept Internal Med, Salt Lake City, UT USA. RP Hsu, L (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,M2-B500, Seattle, WA 98109 USA. EM lih@fhcrc.org RI Hoffmeister, Michael/B-5745-2012; Brenner, Hermann/B-4627-2017; OI Hoffmeister, Michael/0000-0002-8307-3197; Brenner, Hermann/0000-0002-6129-1572; Potter, John/0000-0001-5439-1500; Hayes, Richard/0000-0002-0918-661X FU GECCO: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services [U01 CA137088, R01 CA059045, U01 CA164930]; COLO2&3: National Institutes of Health [R01 CA60987]; DACHS: German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; DALS: National Institutes of Health [R01 CA48998]; National Institutes of Health [P01 CA 055075, UM1 CA167552, R01 137178, CA42182, R01 CA137178, P01 CA 087969, P50 CA 127003]; MEC: National Institutes of Health [R37 CA54281, P01 CA033619, R01 CA63464]; PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; National Institutes of Health (NIH); Genes, Environment and Health Initiative (GEI) [Z01 CP 010200]; NIH [U01 HG004446]; NIH GEI [U01 HG 004438]; National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268 201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN27 1201100004C] FX The work was supported by: GECCO: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088; R01 CA059045; U01 CA164930). COLO2&3: National Institutes of Health (R01 CA60987). DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS: National Institutes of Health (R01 CA48998 to M. L. S.); HPFS is supported by the National Institutes of Health (P01 CA 055075, UM1 CA167552, R01 137178 and P50 CA 127003), NHS by the National Institutes of Health (R01 CA137178, P01 CA 087969 and P50 CA 127003) and PHS by the National Institutes of Health (CA42182). MEC: National Institutes of Health (R37 CA54281, P01 CA033619 and R01 CA63464). PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Additionally, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS (50), Colon CGEMS pancreatic cancer scan (PanScan) (51,52) and the Lung Cancer and Smoking study. The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207v.1p1 and phs000206.v3.p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093 v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446 and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. VITAL: National Institutes of Health (K05 CA154337). WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268 201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN27 1201100004C. NR 52 TC 20 Z9 20 U1 3 U2 17 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUL 15 PY 2014 VL 23 IS 14 BP 3898 EP 3905 DI 10.1093/hmg/ddu087 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AK7TJ UT WOS:000338630300025 PM 24562164 ER PT J AU Klug, YA Ashkenazi, A Viard, M Porat, Z Blumenthal, R Shai, Y AF Klug, Yoel A. Ashkenazi, Avraham Viard, Mathias Porat, Ziv Blumenthal, Robert Shai, Yechiel TI Early and late HIV-1 membrane fusion events are impaired by sphinganine lipidated peptides that target the fusion site SO BIOCHEMICAL JOURNAL LA English DT Article DE biophysics; HIV; HIV entry inhibitor; membrane fusion; membrane protein; protein folding ID HUMAN-IMMUNODEFICIENCY-VIRUS; ENVELOPE GLYCOPROTEIN; MEDIATED FUSION; GP41; CELL; CHOLESTEROL; TYPE-1; RAFTS; PROTEIN; DIHYDROSPHINGOMYELIN AB Lipid-conjugated peptides have advanced. the understanding of membrane protein functions and the roles of lipids in the membrane milieu. These lipopeptides modulate various biological systems such as viral fusion. A single function has been suggested for the lipid, binding to the membrane and thus elevating the local concentration of the peptide at the target site. In the present paper, we challenged this argument by exploring in-depth the antiviral mechanism of lipopeptides, which comprise sphinganine, the lipid backbone of DHSM (dihydrosphingomyelin), and an HIV-1 envelope-derived peptide. Surprisingly, we discovered a partnership between the lipid and the peptide that impaired early membrane fusion events by reducing CD4 receptor lateral diffusion and HIV-1 fusion peptide-mediated lipid mixing. Moreover, only the joint function of sphinganine and its conjugate peptide disrupted HIV-1 fusion protein assembly and folding at the later fusion steps. Via imaging techniques we revealed for the first time the direct localization of these lipopeptides to the virus- cell and cell-cell contact sites. Overall, the findings of the present study may suggest lipid-protein interactions in various biological systems and may help uncover a role for elevated DHSM in HIV-1 and its target cell membranes. C1 [Klug, Yoel A.; Ashkenazi, Avraham; Shai, Yechiel] Weizmann Inst Sci, Dept Biol Chem, IL-7610001 Rehovot, Israel. [Viard, Mathias; Blumenthal, Robert] NCI, Sect Membrane Struct & Funct, Basic Res Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Viard, Mathias] NCI, Basic Sci Program, Ctr Canc Res, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Porat, Ziv] Weizmann Inst Sci, Flow Cytometry Unit, Dept Biol Serv, IL-7610001 Rehovot, Israel. RP Shai, Y (reprint author), Weizmann Inst Sci, Dept Biol Chem, IL-7610001 Rehovot, Israel. EM Yechiel.Shai@weizmann.ac.il OI Porat, Ziv/0000-0003-3059-181X FU Israel Science Foundation [1409/12]; National Institutes of Health from the National Cancer Institute [HHSN261200800001E]; National Institutes of Health Intramural Research Program of the National Cancer Institute; Center for Cancer Research; National Institutes of Health Intramural AIDS Targeted Antiviral Program (IATAP); NIAID Intramural Biodefense Research Program FX This work was supported by the Israel Science Foundation (project number 1409/12) and, in part, by National Institutes of Health Contract HHSN261200800001E from the National Cancer Institute, the National Institutes of Health Intramural Research Program of the National Cancer Institute, the Center for Cancer Research, and grants from the National Institutes of Health Intramural AIDS Targeted Antiviral Program (IATAP) and the NIAID Intramural Biodefense Research Program. NR 45 TC 7 Z9 7 U1 0 U2 13 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD JUL 15 PY 2014 VL 461 BP 213 EP 222 DI 10.1042/BJ20140189 PN 2 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AK5TN UT WOS:000338489400005 PM 24766462 ER PT J AU Chen, G Henter, ID Manji, HK AF Chen, Guang Henter, Ioline D. Manji, Husseini K. TI Looking Ahead: Electroretinographic Anomalies, Glycogen Synthase Kinase-3, and Biomarkers for Neuropsychiatric Disorders SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID PATHWAYS; WNT C1 [Chen, Guang] Johnson & Johnson, Janssen Pharmaceut Res & Dev, San Diego, CA USA. [Henter, Ioline D.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Manji, Husseini K.] Johnson & Johnson, Janssen Pharmaceut Res & Dev, Titusville, NJ 08560 USA. RP Manji, HK (reprint author), Johnson & Johnson, Janssen Pharmaceut Res & Dev, 1125 Trenton Harbourton Rd,E32000, Titusville, NJ 08560 USA. EM hmanji@its.jnj.com RI Chen, Guang/A-2570-2017 FU Intramural NIH HHS [Z99 MH999999] NR 10 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 15 PY 2014 VL 76 IS 2 BP 86 EP 88 DI 10.1016/j.biopsych.2014.05.005 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AK5FU UT WOS:000338450900001 PM 24948381 ER PT J AU Zhang, X Raghavan, S Ihnat, M Thorpe, JE Disch, BC Bastian, A Bailey-Downs, LC Dybdal-Hargreaves, NF Rohena, CC Hamel, E Mooberry, SL Gangjee, A AF Zhang, Xin Raghavan, Sudhir Ihnat, Michael Thorpe, Jessica E. Disch, Bryan C. Bastian, Anja Bailey-Downs, Lora C. Dybdal-Hargreaves, Nicholas F. Rohena, Cristina C. Hamel, Ernest Mooberry, Susan L. Gangjee, Aleem TI The design and discovery of water soluble 4-substituted-2, 6-dimethylfuro[2,3-d]pyrimidines as multitargeted receptor tyrosine kinase inhibitors and microtubule targeting antitumor agents SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Tyrosine kinase inhibitors; Single agent combination chemotherapy; Anticancer agents; Microtubule targeting agents ID STABILIZING AGENTS; BETA-TUBULIN; BINDING-SITE; IN-VITRO; CANCER; ANGIOGENESIS; COMBINATION; CHEMOTHERAPY; CHLORIDE; DRUGS AB The design, synthesis and biological evaluations of fourteen 4-substituted 2,6-dimethylfuro[2,3-d]pyrimidines are reported. Four compounds (11-13, 15) inhibit vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFR-beta), and target tubulin leading to cytotoxicity. Compound 11 has nanomolar potency, comparable to sunitinib and semaxinib, against tumor cell lines overexpressing VEGFR-2 and PDGFR-beta. Further, 11 binds at the colchicine site on tubulin, depolymerizes cellular microtubules and inhibits purified tubulin assembly and overcomes both beta III-tubulin and P-glycoprotein-mediated drug resistance, and initiates mitotic arrest leading to apoptosis. In vivo, its HCl salt, 21, reduced tumor size and vascularity in xenograft and allograft murine models and was superior to docetaxel and sunitinib, without overt toxicity. Thus 21 affords potential combination chemotherapy in a single agent. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Zhang, Xin; Raghavan, Sudhir; Gangjee, Aleem] Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, Pittsburgh, PA 15282 USA. [Ihnat, Michael; Thorpe, Jessica E.; Disch, Bryan C.; Bastian, Anja; Bailey-Downs, Lora C.] Univ Oklahoma, Hlth Sci Ctr, Coll Pharm, Oklahoma City, OK 73117 USA. [Dybdal-Hargreaves, Nicholas F.; Rohena, Cristina C.; Mooberry, Susan L.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, Dept Pharmacol, San Antonio, TX 78229 USA. [Hamel, Ernest] NIH, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. RP Gangjee, A (reprint author), Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, 600 Forbes Ave, Pittsburgh, PA 15282 USA. EM gangjee@duq.edu RI Raghavan, Sudhir/C-8871-2011; OI Raghavan, Sudhir/0000-0001-5449-362X; Dybdal-Hargreaves, Nicholas/0000-0002-5847-5231 FU National Cancer Institute [CA142868]; Duquesne University Adrian Van Kaam Chair in Scholarly Excellence; CTRC Cancer Center [P30 CA054174]; NSF [NMR: CHE 0614785]; COSTAR [DE014318] FX The support of the National Cancer Institute for performing the in vitro antitumor evaluation in their 60 tumor preclinical screening program is gratefully acknowledged. Grant support from the National Cancer Institute, CA142868 (A.G., S.L.M.) is acknowledged as is support by the Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (A.G.), the CTRC Cancer Center Support Grant, P30 CA054174 and an NSF equipment Grant for NMR instrumentation (NMR: CHE 0614785), COSTAR grant DE014318 (NF, DH). NR 34 TC 13 Z9 13 U1 2 U2 21 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JUL 15 PY 2014 VL 22 IS 14 BP 3753 EP 3772 DI 10.1016/j.bmc.2014.04.049 PG 20 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA AJ8XJ UT WOS:000337991100019 PM 24890652 ER PT J AU Wang, HN Fang, ZZ Zheng, Y Zhou, K Hu, CY Krausz, KW Sun, DQ Idle, JR Gonzalez, FJ AF Wang, Haina Fang, Zhong-Ze Zheng, Yang Zhou, Kun Hu, Changyan Krausz, Kristopher W. Sun, Dequn Idle, Jeffrey R. Gonzalez, Frank J. TI Metabolic profiling of praziquantel enantiomers SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Cytochromes P450; Enantioselective metabolism; In silica metabolomics; Praziquantel ID SCHISTOSOMA-MANSONI; HEALTHY-VOLUNTEERS; ACYL GLUCURONIDE; DRUG-RESISTANCE; EFFICACY; STEREOSELECTIVITY; PHARMACOKINETICS; FLURBIPROFEN; DISPOSITION; INHIBITION AB Praziquantel (PZQ), prescribed as a racemic mixture, is the most readily available drug to treat schistosomiasis. In the present study, ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) based metabolomics was employed to decipher the metabolic pathways and enantioselective metabolic differences of PZQ. Many phase I and four new phase II metabolites were found in urine and feces samples of mice 24 h after dosing, indicating that the major metabolic reactions encompassed oxidation, dehydrogenation, and glucuronidation. Differences in the formation of all these metabolites were observed between (R)-PZQ and (S)-PZQ In an in vitro phase I incubation system, the major involvement of CYP3A, CYP2C9, and CYP2C19 in the metabolism of PZQ and CYP3A, CYP2C9, and CYP2C19 exhibited different catalytic activity toward the PZQ enantiomers. Apparent K-m and V-max differences were observed in the catalytic formation of three mono-oxidized metabolites by CYP2C9 and CYP3A4 further supporting the metabolic differences for PZQ enantiomers. Molecular docking showed that chirality resulted in differences in substrate location and conformation, which likely accounts for the metabolic differences. In conclusion, in silico, in vitro, and in vivo methods revealed the enantioselective metabolic profile of praziquantel. Published by Elsevier Inc. C1 [Wang, Haina] Shandong Univ, Coll Pharmaceut Sci, Jinan 250012, Peoples R China. [Wang, Haina; Fang, Zhong-Ze; Krausz, Kristopher W.; Idle, Jeffrey R.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Fang, Zhong-Ze; Zhou, Kun] Chinese Acad Sci, Dalian Inst Chem Phys, Joint Ctr Translat Med, Dalian 116023, Peoples R China. [Fang, Zhong-Ze; Zhou, Kun] Liaoning Med Univ, Affiliated Hosp 1, Dalian 116023, Peoples R China. [Zheng, Yang; Hu, Changyan; Sun, Dequn] Shandong Univ Weihai, Marine Coll, Weihai 264209, Peoples R China. [Zhou, Kun] Liaoning Univ Tradit Chinese Med, Coll Pharm, Dept Basic Chem, Dalian 116600, Peoples R China. [Idle, Jeffrey R.] Univ Bern, Dept Clin Res, CH-3010 Bern, Switzerland. RP Sun, DQ (reprint author), 180 Wenhua West Rd, Weihai 264209, Peoples R China. EM dequn.sun@sdu.edu.cn; gonzalef@mail.nih.gov OI Idle, Jeff/0000-0002-6143-1520 FU National Natural Science Foundation of China [81102504, 81202586]; National High-Tech Program of China (863 Project) [2012AA020306]; Shandong Natural Science Foundation of China [BS2013YY054, ZR2010HL023]; Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health [1ZIABC005562-24] FX This study was funded by the National Natural Science Foundation of China (No. 81102504 and 81202586), the National High-Tech Program of China (863 Project No. 2012AA020306), Shandong Natural Science Foundation of China (No. BS2013YY054 and ZR2010HL023), and the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (1ZIABC005562-24). NR 40 TC 14 Z9 14 U1 3 U2 39 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 EI 1873-2968 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD JUL 15 PY 2014 VL 90 IS 2 BP 166 EP 178 DI 10.1016/j.bcp.2014.05.001 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AJ6EE UT WOS:000337781700008 PM 24821110 ER PT J AU Hopping, G Kellock, J Barnwal, RP Law, P Bryers, J Varani, G Caughey, B Daggett, V AF Hopping, Gene Kellock, Jackson Barnwal, Ravi Pratap Law, Peter Bryers, James Varani, Gabriele Caughey, Byron Daggett, Valerie TI Designed alpha-sheet peptides inhibit amyloid formation by targeting toxic oligomers SO ELIFE LA English DT Article AB Previous studies suggest that the toxic soluble-oligomeric form of different amyloid proteins share a common backbone conformation, but the amorphous nature of this oligomer prevents its structural characterization by experiment. Based on molecular dynamics simulations we proposed that toxic intermediates of different amyloid proteins adopt a common, nonstandard secondary structure, called alpha-sheet. Here we report the experimental characterization of peptides designed to be complementary to the alpha-sheet conformation observed in the simulations. We demonstrate inhibition of aggregation in two different amyloid systems, beta-amyloid peptide (A beta) and transthyretin, by these designed alpha-sheet peptides. When immobilized the alpha-sheet designs preferentially bind species from solutions enriched in the toxic conformer compared with non-aggregated, nontoxic species or mature fibrils. The designs display characteristic spectroscopic signatures distinguishing them from conventional secondary structures, supporting alpha-sheet as a structure involved in the toxic oligomer stage of amyloid formation and paving the way for novel therapeutics and diagnostics. C1 [Hopping, Gene; Kellock, Jackson; Law, Peter; Bryers, James; Daggett, Valerie] Univ Washington, Dept Bioengn, Seattle, WA 98195 USA. [Barnwal, Ravi Pratap; Varani, Gabriele] Univ Washington, Dept Chem, Seattle, WA 98195 USA. [Caughey, Byron] NIAID, Lab Persistent Viral Dis, Rocky Mt Labs, NIH, Hamilton, NY USA. RP Daggett, V (reprint author), Univ Washington, Dept Bioengn, Seattle, WA 98195 USA. EM daggett@u.washington.edu FU National Institutes of Health [GM-095808, GM-064440, AI-074661]; National Science Foundation [CBET-0966977]; Wallace H Coulter Foundation; Coins for Alzheimer's Research Trust; National Institutes of Health Intramural Research Program FX National Institutes of Health GM-095808 Valerie Daggett; National Science Foundation CBET-0966977 Valerie Daggett; Wallace H Coulter Foundation Valerie Daggett; Coins for Alzheimer's Research Trust Valerie Daggett; National Institutes of Health GM-064440 Gabriele Varani; National Institutes of Health AI-074661 James Bryers; National Institutes of Health Intramural Research Program Byron Caughey; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 47 TC 17 Z9 17 U1 1 U2 7 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JUL 15 PY 2014 VL 3 AR e01681 DI 10.7554/eLife.01681 PG 14 WC Biology SC Life Sciences & Biomedicine - Other Topics GA V43LS UT WOS:000209683500001 PM 25027691 ER PT J AU Ciuciu, P Abry, P He, BYJ AF Ciuciu, Philippe Abry, Patrice He, Biyu J. TI Interplay between functional connectivity and scale-free dynamics in intrinsic fMRI networks SO NEUROIMAGE LA English DT Article DE Scale-free dynamics; Cross-temporal dynamics; fMRI; Intrinsic brain activity; Task modulation ID SPONTANEOUS BRAIN ACTIVITY; RESTING HUMAN BRAIN; TIME-SERIES; LOW-FREQUENCY; DEFAULT MODE; MULTIFRACTAL ANALYSIS; WAVELET ANALYSIS; CEREBRAL-CORTEX; MOTOR CORTEX; STATE AB Studies employing functional connectivity-type analyses have established that spontaneous fluctuations in functional magnetic resonance imaging (fMRI) signals are organized within large-scale brain networks. Meanwhile, fMRI signals have been shown to exhibit 1/f-type power spectra - a hallmark of scale-free dynamics. We studied the interplay between functional connectivity and scale-free dynamics in fMRI signals, utilizing the fractal connectivity framework - a multivariate extension of the univariate fractional Gaussian noise model, which relies on a wavelet formulation for robust parameter estimation. We applied this framework to fMRI data acquired from healthy young adults at rest and while performing a visual detection task. First, we found that scale-invariance existed beyond univariate dynamics, being present also in bivariate cross-temporal dynamics. Second, we observed that frequencies within the scale-free range do not contribute evenly to inter-regional connectivity, with a systematically stronger contribution of the lowest frequencies, both at rest and during task. Third, in addition to a decrease of the Hurst exponent and inter-regional correlations, task performance modified cross-temporal dynamics, inducing a larger contribution of the highest frequencies within the scale-free range to global correlation. Lastly, we found that across individuals, a weaker task modulation of the frequency contribution to inter-regional connectivity was associated with better task performance manifesting as shorter and less variable reaction times. These findings bring together two related fields that have hitherto been studied separately - resting-state networks and scale-free dynamics, and show that scale-free dynamics of human brain activity manifest in cross-regional interactions as well. (C) 2014 Elsevier Inc. All rights reserved. C1 [Ciuciu, Philippe] CEA, NeuroSpin Ctr, INRIA, Parietal Team, F-91191 Gif Sur Yvette, France. [Abry, Patrice] ENS Lyon, CNRS, UMR 5672, Dept Phys, F-69007 Lyon, France. [He, Biyu J.] NINDS, NIH, Bethesda, MD 20892 USA. RP Ciuciu, P (reprint author), CEA, NeuroSpin Ctr, INRIA, Parietal Team, Bat 145, F-91191 Gif Sur Yvette, France. EM philippe.ciuciu@cea.fr OI Abry, Patrice/0000-0002-7096-8290; He, Biyu/0000-0003-1549-1351 FU ANR Schubert [ANR-0909-JCJC-071]; ANR Amatis [ANR-11-BS01-0011]; Intramural Research Program of the National Institutes of Health/National Institute of Neurological Disorders and Stroke FX This work was supported by an ANR Schubert ANR-0909-JCJC-071 to P.C, an ANR Amatis ANR-11-BS01-0011 to P.A. B.J.H is supported by the Intramural Research Program of the National Institutes of Health/National Institute of Neurological Disorders and Stroke NR 93 TC 18 Z9 18 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JUL 15 PY 2014 VL 95 BP 248 EP 263 DI 10.1016/j.neuroimage.2014.03.047 PG 16 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AI9QN UT WOS:000337267900023 PM 24675649 ER PT J AU Patel, AX Kundu, P Rubinov, M Jones, PS Vertes, PE Ersche, KD Suckling, J Bullmore, ET AF Patel, Ameera X. Kundu, Prantik Rubinov, Mikail Jones, P. Simon Vertes, Petra E. Ersche, Karen D. Suckling, John Bullmore, Edward T. TI A wavelet method for modeling and despiking motion artifacts from resting-state fMRI time series SO NEUROIMAGE LA English DT Article DE fMRI; Resting-state; Connectivity; Motion; Artifact; Spike; Wavelet; Despike; Non-stationary ID FUNCTIONAL CONNECTIVITY MRI; STIMULUS-CORRELATED MOTION; SUBJECT MOTION; BOLD SIGNALS; HEAD MOTION; BRAIN; NETWORKS; IMPACT; EPI AB The impact of in-scanner head movement on functional magnetic resonance imaging (fMRI) signals has long been established as undesirable. These effects have been traditionally corrected by methods such as linear regression of head movement parameters. However, a number of recent independent studies have demonstrated that these techniques are insufficient to remove motion confounds, and that even small movements can spuriously bias estimates of functional connectivity. Here we propose a new data-driven, spatially-adaptive, wavelet-based method for identifying, modeling, and removing non-stationary events in fMRI time series, caused by head movement, without the need for data scrubbing. This method involves the addition of just one extra step, the Wavelet Despike, in standard pre-processing pipelines. With this method, we demonstrate robust removal of a range of different motion artifacts and motion-related biases including distance-dependent connectivity artifacts, at a group and single-subject level, using a range of previously published and new diagnostic measures. The Wavelet Despike is able to accommodate the substantial spatial and temporal heterogeneity of motion artifacts and can consequently remove a range of high and low frequency artifacts from fMRI time series, that may be linearly or non-linearly related to physical movements. Our methods are demonstrated by the analysis of three cohorts of resting-state fMRI data, including two high-motion datasets: a previously published dataset on children (N = 22) and a new dataset on adults with stimulant drug dependence (N = 40). We conclude that there is a real risk of motion-related bias in connectivity analysis of fMRI data, but that this risk is generally manageable, by effective time series denoising strategies designed to attenuate synchronized signal transients induced by abrupt head movements. (C) 2014 Published by Elsevier Inc. C1 [Patel, Ameera X.; Kundu, Prantik; Rubinov, Mikail; Jones, P. Simon; Vertes, Petra E.; Ersche, Karen D.; Suckling, John; Bullmore, Edward T.] Univ Cambridge, Dept Psychiat, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England. [Kundu, Prantik] NIH, Bethesda, MD 20892 USA. [Rubinov, Mikail] Univ Cambridge, Churchill Coll, Cambridge CB2 3EB, England. RP Patel, AX (reprint author), Univ Cambridge, Brain Mapping Unit, Behav & Clin Neurosci Inst, Sir William Hardy Bldg,Downing Site, Cambridge CB2 3EB, England. EM ap531@cam.ac.uk OI Kundu, Prantik/0000-0001-9367-3068; Vertes, Petra E./0000-0002-0992-3210; Bullmore, Edward/0000-0002-8955-8283 FU Wellcome Trust Translational Medicine and Therapeutics Programme [085686/Z/08/C]; University of Cambridge MB/PhD Programme; NIH-Cambridge PhD Programme; UK Medical Research Council [G0701497]; NARSAD Young Investigator [19490]; Isaac Newton Trust [13.07q]; Core Award from the Medical Research Council [G1000183]; Wellcome Trust [093875/Z/ 10/Z] FX This work was supported by the Wellcome Trust Translational Medicine and Therapeutics Programme (085686/Z/08/C, award to AXP) and the University of Cambridge MB/PhD Programme (AXP). PK was supported by the NIH-Cambridge PhD Programme. The data for cohorts 2 and 3, KDE, and PSJ were supported by the UK Medical Research Council (G0701497). MR was supported by the NARSAD Young Investigator (19490) and Isaac Newton Trust (13.07q) grants. The Behavioral and Clinical Neuroscience Institute is funded by a Core Award from the Medical Research Council (G1000183) and the Wellcome Trust (093875/Z/ 10/Z). We also thank Jonathan Power, Sophie Achard and Ted Satterthwaite for their helpful correspondence, and Ted Satterthwaite for his code implementing spike regression. NR 32 TC 52 Z9 52 U1 6 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JUL 15 PY 2014 VL 95 BP 287 EP 304 DI 10.1016/j.neuroimage.2014.03.012 PG 18 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AI9QN UT WOS:000337267900026 PM 24657353 ER PT J AU Webber, C Gospodarowicz, M Sobin, LH Wittekind, C Greene, FL Mason, MD Compton, C Brierley, J Groome, PA AF Webber, Colleen Gospodarowicz, Mary Sobin, Leslie H. Wittekind, Christian Greene, Frederick L. Mason, Malcolm D. Compton, Carolyn Brierley, James Groome, Patti A. TI Improving the TNM classification: Findings from a 10-year continuous literature review SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE neoplasm staging; TNM classification; evidence-based practice; international cooperation; prognosis ID FORTHCOMING 7TH EDITION; CANCER STAGING PROJECT; LUNG-CANCER; CONSENSUS METHODS; MALIGNANT-TUMORS; PROPOSALS; GROUPINGS; REVISION; SYSTEM; CARE AB The Union for International Cancer Control's (UICC) TNM classification is a globally accepted system to describe the anatomic extent of malignant tumors. Since its development seventy years ago, the TNM classification has undergone significant revisions to reflect the current understanding of extent of disease and its role in prognosis. To ensure that revisions are evidence-based, the UICC implemented a process for continuous improvement of the TNM classification that included a formalized system for submitting proposals for revisions directly to the UICC and an annual review of the scientific literature on staging that assessed, criticized or made suggestions for changes. The process involves review of the proposals and literature by a group of international, multidisciplinary Expert Panels. The process has been in place for 10 years and informed the development of the 7th edition of the TNM classification published in 2009. The purpose of this article is to provide a description of the annual literature review process, including the search strategy, article selection process and the roles and requirements of the Expert Panels in the review of the literature. Since 2002, 147 Expert Panel members in 11 cancer sites have reviewed over 770 articles. The results of the annual literature reviews, Expert Panel feedback and documentation and dissemination of results are described. What's new? The Union for International Cancer Control's TNM classification undergoes periodic revisions to incorporate current knowledge of anatomic extent of disease and its relationship with patient management and prognosis. This article describes the results of an annual literature review process that was implemented in 2002 to inform revisions to the classification. Since that time, more than 770 articles have been reviewed, with the number of articles reviewed increasing over time, reflecting growing research interest in cancer staging and new developments in cancer diagnosis. The report suggests that the literature review process has enhanced recent changes to the TNM classification. C1 [Webber, Colleen; Groome, Patti A.] Queens Univ, Div Canc Care & Epidemiol, Queens Canc Res Inst, Kingston, ON, Canada. [Webber, Colleen; Groome, Patti A.] Queens Univ, Dept Publ Hlth Sci, Kingston, ON, Canada. [Gospodarowicz, Mary; Brierley, James] Princess Margaret Canc Ctr, Radiat Med Program, Toronto, ON, Canada. [Sobin, Leslie H.] NCI, Canc Human Biobank, Frederick Natl Lab Canc Res, Rockville, MD USA. [Wittekind, Christian] Univ Leipzig, Inst Pathol, D-04109 Leipzig, Germany. [Greene, Frederick L.] Univ N Carolina, Sch Med, Charlotte, NC 28223 USA. [Mason, Malcolm D.] Cardiff Univ, Sch Med, Cardiff CF10 3AX, S Glam, Wales. [Compton, Carolyn] Amer Joint Comm Canc, Chicago, IL USA. [Compton, Carolyn] Arizona State Univ, Coll Hlth Solut, Sch Sci Healthcare Delivery, Phoenix, AZ USA. RP Groome, PA (reprint author), Queens Canc Res Inst, Div Canc Care & Epidemiol, 10 Stuart St,2nd Level, Kingston, ON K7L 3N6, Canada. EM groomep@queensu.ca FU Union for International Cancer Control (UICC) from the Centers for Disease Control and Prevention (CDC), U.S. Dept. Health and Human Services FX Grant sponsor: Union for International Cancer Control (UICC) from the Centers for Disease Control and Prevention (CDC), U.S. Dept. Health and Human Services NR 17 TC 26 Z9 27 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JUL 15 PY 2014 VL 135 IS 2 BP 371 EP 378 DI 10.1002/ijc.28683 PG 8 WC Oncology SC Oncology GA AG5LL UT WOS:000335460400015 PM 24921087 ER PT J AU Arem, H Moore, SC Park, Y Ballard-Barbash, R Hollenbeck, A Leitzmann, M Matthews, CE AF Arem, Hannah Moore, Steve C. Park, Yikyung Ballard-Barbash, Rachel Hollenbeck, Albert Leitzmann, Michael Matthews, Charles E. TI Physical activity and cancer- specific mortality in the NIH- AARP Diet and Health Study cohort SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE physical activity; cancer; mortality ID RENAL-CELL CANCER; BODY-MASS INDEX; NATIONAL INSTITUTES; SEDENTARY BEHAVIOR; LIFE-STYLE; ALL-CAUSE; RISK; SURVIVORS; WOMEN; ADIPOSITY AB Higher physical activity levels have been associated with a lower risk of developing various cancers and all-cancer mortality, but the impact of pre-diagnosis physical activity on cancer-specific death has not been fully characterized. In the prospective National Institutes of Health-AARP Diet and Health Study with 293,511 men and women, we studied prediagnosis moderate to vigorous intensity leisure time physical activity (MVPA) in the past 10 years and cancer-specific mortality. Over a median 12.1 years, we observed 15,001 cancer deaths. Using Cox proportional hazards regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for MVPA with cancer mortality overall and by 20 specific cancer sites, adjusting for relevant risk factors. Compared to participants reporting never/rare MVPA, those reporting >7 hr/week MVPA had a lower risk of total cancer mortality (HR=0.89, 95% CI 0.84-0.94; p-trend <0.001). When analyzed by cancer site-specific deaths, comparing those reporting >7 hr/week of MVPA to those reporting never/rare MVPA, we observed a lower risk of death from colon (HR=0.70; 95% CI 0.57-0.85; p-trend <0.001), liver (0.71; 0.52-0.98; p-trend=0.012) and lung cancer (0.84; 0.77-0.92; p-trend <0.001) and a significant p-trend for non-Hodgkins lymphoma (0.80; 0.62-1.04; p-trend=0.017). An unexpected increased mortality p-trend with increasing MVPA was observed for death from kidney cancer (1.42; 0.98-2.03; p-trend=0.016). Our findings suggest that higher prediagnosis leisure time physical activity is associated with lower risk of overall cancer mortality and mortality from multiple cancer sites. Future studies should confirm observed associations and further explore timing of physical activity and underlying biological mechanisms. What's new? Despite evidence that physical activity reduces risk of multiple chronic diseases, including cancer, as much as one-third of the U.S. population is inactive. In this study, the authors explored associations between pre-diagnosis physical activity and cancer mortality. They found that higher pre-diagnosis leisure-time physical activity is associated with a decreased risk of overall cancer mortality, and particularly mortality from cancers of the colon, liver, lung, and non-Hodgkin's lymphoma. C1 [Arem, Hannah; Moore, Steve C.; Park, Yikyung; Matthews, Charles E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ballard-Barbash, Rachel] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Hollenbeck, Albert] AARP, Washington, DC USA. [Leitzmann, Michael] Univ Regensburg, Dept Epidemiol & Prevent Med, D-93053 Regensburg, Germany. RP Arem, H (reprint author), 9609 Med Ctr Dr,Rm 6E324, Bethesda, MD 20892 USA. EM Aremhe2@mail.nih.gov RI matthews, Charles/E-8073-2015; Moore, Steven/D-8760-2016; OI matthews, Charles/0000-0001-8037-3103; Moore, Steven/0000-0002-8169-1661; Park, Yikyung/0000-0002-6281-489X FU NIH, National Cancer Institute (Intramural Research Program) FX Grant sponsor: NIH, National Cancer Institute (Intramural Research Program) NR 35 TC 15 Z9 15 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JUL 15 PY 2014 VL 135 IS 2 BP 423 EP 431 DI 10.1002/ijc.28659 PG 9 WC Oncology SC Oncology GA AG5LL UT WOS:000335460400020 PM 24311115 ER PT J AU Brand, JS Rovers, MM Yeap, BB Schneider, HJ Tuomainen, TP Haring, R Corona, G Onat, A Maggio, M Bouchard, C Tong, PCY Chen, RYT Akishita, M Gietema, JA Gannage-Yared, MH Unden, AL Hautanen, A Goncharov, NP Kumanov, P Chubb, SAP Almeida, OP Wittchen, HU Klotsche, J Wallaschofski, H Volzke, H Kauhanen, J Salonen, JT Ferrucci, L van der Schouw, YT AF Brand, Judith S. Rovers, Maroeska M. Yeap, Bu B. Schneider, Harald J. Tuomainen, Tomi-Pekka Haring, Robin Corona, Giovanni Onat, Altan Maggio, Marcello Bouchard, Claude Tong, Peter C. Y. Chen, Richard Y. T. Akishita, Masahiro Gietema, Jourik A. Gannage-Yared, Marie-Helene Unden, Anna-Lena Hautanen, Aarno Goncharov, Nicolai P. Kumanov, Philip Chubb, S. A. Paul Almeida, Osvaldo P. Wittchen, Hans-Ulrich Klotsche, Jens Wallaschofski, Henri Voelzke, Henry Kauhanen, Jussi Salonen, Jukka T. Ferrucci, Luigi van der Schouw, Yvonne T. TI Testosterone, Sex Hormone-Binding Globulin and the Metabolic Syndrome in Men: An Individual Participant Data Meta-Analysis of Observational Studies SO PLOS ONE LA English DT Article ID CARDIOVASCULAR RISK-FACTORS; MIDDLE-AGED MEN; INSULIN-RESISTANCE; MASS-SPECTROMETRY; ANDROGEN DEFICIENCY; SERUM TESTOSTERONE; OLDER MEN; OBESE MEN; NONOBESE MEN; PRIMARY-CARE AB Background: Low total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations have been associated with the metabolic syndrome (MetS) in men, but the reported strength of association varies considerably. Objectives: We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components. Data sources: Two previously published meta-analyses including an updated systematic search in PubMed and EMBASE. Study Eligibility Criteria: Cross-sectional or prospective observational studies with data on TT and/or SHBG concentrations in combination with MetS in men. Methods: We conducted an individual participant data meta-analysis of 20 observational studies. Mixed effects models were used to assess cross-sectional and prospective associations of TT, SHBG and free testosterone (FT) with MetS and its individual components. Multivariable adjusted odds ratios (ORs) and hazard ratios (HRs) were calculated and effect modification by age and BMI was studied. Results: Men with low concentrations of TT, SHBG or FT were more likely to have prevalent MetS (ORs per quartile decrease were 1.69 (95% CI 1.60-1.77), 1.73 (95% CI 1.62-1.85) and 1.46 (95% CI 1.36-1.57) for TT, SHBG and FT, respectively) and incident MetS (HRs per quartile decrease were 1.25 (95% CI 1.16-1.36), 1.44 (95% 1.30-1.60) and 1.14 (95% 1.01-1.28) for TT, SHBG and FT, respectively). Overall, the magnitude of associations was largest in non-overweight men and varied across individual components: stronger associations were observed with hypertriglyceridemia, abdominal obesity and hyperglycaemia and associations were weakest for hypertension. Conclusions: Associations of testosterone and SHBG with MetS vary according to BMI and individual MetS components. These findings provide further insights into the pathophysiological mechanisms linking low testosterone and SHBG concentrations to cardiometabolic risk. C1 [Brand, Judith S.; Rovers, Maroeska M.; van der Schouw, Yvonne T.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Rovers, Maroeska M.] Radboud Univ Nijmegen, Med Ctr, Dept EBH Room, NL-6525 ED Nijmegen, Netherlands. [Rovers, Maroeska M.] Radboud Univ Nijmegen, Med Ctr, Dept Operating Room, NL-6525 ED Nijmegen, Netherlands. [Yeap, Bu B.; Chubb, S. A. Paul] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Schneider, Harald J.] Univ Munich, Med Klin Innenstadt, D-80539 Munich, Germany. [Tuomainen, Tomi-Pekka; Kauhanen, Jussi] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. [Haring, Robin; Wallaschofski, Henri] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Corona, Giovanni] Univ Florence, Dept Clin Physiopathol, Androl & Sexual Med Unit, Florence, Italy. [Onat, Altan] Istanbul Univ, Dept Cardiol, Istanbul, Turkey. [Maggio, Marcello] Univ Parma, Dept Internal Med & Biomed Sci, I-43100 Parma, Italy. [Bouchard, Claude] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Tong, Peter C. Y.] Chinese Univ Hong Kong, Dept Med & Therapeut, Shatin, Hong Kong, Peoples R China. [Chen, Richard Y. T.] Changing Gen Hosp, Dept Endocrinol, Singapore, Singapore. [Akishita, Masahiro] Univ Tokyo, Grad Sch Med, Dept Geriatr Med, Tokyo, Japan. [Gietema, Jourik A.] Univ Groningen, Univ Med Ctr Groningen, Dept Med Oncol, Groningen, Netherlands. [Gannage-Yared, Marie-Helene] St Joseph Univ, Dept Endocrinol, Beirut, Lebanon. [Unden, Anna-Lena] Ctr Family & Community Med, Stockholm, Sweden. [Hautanen, Aarno] Univ Helsinki, Dept Clin Chem, SF-00100 Helsinki, Finland. [Goncharov, Nicolai P.] Endocrinol Res Ctr, Moscow, Russia. [Kumanov, Philip] Med Univ Sofia, Clin Ctr Endocrinol & Gerontol, Sofia, Bulgaria. [Almeida, Osvaldo P.] Univ Western Australia, Sch Psychiat & Clin Neurosci, Perth, WA 6009, Australia. [Wittchen, Hans-Ulrich; Klotsche, Jens] Univ Dresden, Ctr Clin Epidemiol & Longitudinal Studies, Inst Clin Psychol, Dresden, Germany. [Voelzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Salonen, Jukka T.] MAS Metab Analyt Serv Oy, Helsinki, Finland. [Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. RP van der Schouw, YT (reprint author), Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. EM y.t.vanderschouw@umcutrecht.nl RI Almeida, Osvaldo/A-4925-2008; Rovers, Maroeska/F-2969-2014; Bouchard, Claude/A-7637-2009; OI Rovers, Maroeska/0000-0002-3095-170X; Wittchen, Hans-Ulrich/0000-0002-6311-7711 NR 57 TC 34 Z9 34 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 14 PY 2014 VL 9 IS 7 AR e100409 DI 10.1371/journal.pone.0100409 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM1PC UT WOS:000339618600006 PM 25019163 ER PT J AU Young, RM Staudt, LM AF Young, Ryan M. Staudt, Louis M. TI lbrutinib Treatment of CLL: The Cancer Fights Back SO CANCER CELL LA English DT Editorial Material ID CHRONIC LYMPHOCYTIC-LEUKEMIA; B-CELL LYMPHOMA; RESISTANCE; IBRUTINIB; MUTATION C1 [Young, Ryan M.; Staudt, Louis M.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Staudt, LM (reprint author), NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov FU Intramural NIH HHS [ZIA BC011010-06] NR 11 TC 10 Z9 10 U1 0 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD JUL 14 PY 2014 VL 26 IS 1 BP 11 EP 13 DI 10.1016/j.ccr.2014.06.023 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AL7HQ UT WOS:000339305200006 PM 25026208 ER PT J AU Liu, XX AF Liu, Xunxian TI Overstimulation can create health problems due to increases in PI3K/Akt/GSK3 insensitivity and GSK3 activity SO SPRINGERPLUS LA English DT Article DE Aging; AMD; Complement; Death hormones; Insensitivity; IL17/IL17RC; PI3K/Akt/GSK3/GSK3 substrates; Signaling; VEGF ID GLYCOGEN-SYNTHASE KINASE-3; MACULAR DEGENERATION; BETA-CATENIN; WNT PATHWAY; AGE; PHOSPHORYLATION; CELLS; EXPRESSION; DISEASE; INFLAMMATION AB Aging is linked to decrease of the body cell use of growth hormone (GH) and thyroxine, whereas the decrease is via "death hormones" inhibition? This study proposes different viewpoints. Since interleukin 17 receptor C (IL17RC) is highly expressed in tissues from age-related macular degeneration (AMD) patients, IL17RC signaling pathways are explored to evaluate Wnts/vascular endothelial growth factor (VEGF) expression and complement activity, which are pathological factors in AMD. IL17RC overexpression or VEGF treatment was performed in two cell lines for up to two-day. Real-time Quantitative PCR, confocal microscopy, immune-blot, MTT assay, etc. measured downstream effects. IL17RC overexpression increases Wnts and VEGF that forms complexes with Wnt-signaling components. VEGF or the Wnt-signaling components interacting with C3 suggests alternative complement pathway activation. Moreover, IL17RC-overexpressed cells or VEGF-treated cells for two-day, which is overstimulation, increase PI3K/Akt/GSK3 insensitivity and GSK3 activity, and decrease growth/survival. High GSK3 activity associates with many chronic diseases including type II Diabetes. This study shows high GSK3 activity can result from PI3K/Akt overstimulation. Type II Diabetes shows insulin resistance that the body cells decrease insulin use. Possessing little sensitive PI3K/Akt for receptor activation, cells after overstimulation, although live, hardly respond to PI3K/Akt activators including GH, thyroxine and insulin. These results suggest an alternative explanation of the body cells declining hormone use since various kinds of cell signaling-induced overstimulation events almost always linked to PI3K/Akt, increase with age. Playing pathological roles in senescence and diseases, overstimulation eventually generates health problems. C1 NIH, Intramural Res Program, Natl Ctr Complementary & Alternat Med, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Liu, XX (reprint author), NIH, Intramural Res Program, Natl Ctr Complementary & Alternat Med, US Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 USA. EM xunxianl@mail.nih.gov FU NCCAM, National Institutes of Health, US Department of Health and Human Services FX This research was supported by intramural research program in NCCAM, National Institutes of Health, US Department of Health and Human Services. The author thanks Drs. Julia T Arnold, Hui Chen and Min Chen for their constructive critiques of the manuscript. NR 43 TC 3 Z9 4 U1 0 U2 2 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 2193-1801 J9 SPRINGERPLUS JI SpringerPlus PD JUL 14 PY 2014 VL 3 AR 356 DI 10.1186/2193-1801-3-356 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CO3KC UT WOS:000359055100002 PM 25089247 ER PT J AU Sen, SK Boelte, KC Barb, JJ Joehanes, R Zhao, XQ Cheng, Q Adams, L Teer, JK Accame, DS Chowdhury, S Singh, LN Kavousi, M Peyser, PA Quigley, L Priel, DL Lau, K Kuhns, DB Yoshimura, T Johnson, AD Hwang, SJ Chen, MY Arai, AE Green, ED Mullikin, JC Kolodgie, FD O'Donnell, CJ Virmani, R Munson, PJ McVicar, DW Biesecker, LG AF Sen, Shurjo K. Boelte, Kimberly C. Barb, Jennifer J. Joehanes, Roby Zhao, XiaoQing Cheng, Qi Adams, Lila Teer, Jamie K. Accame, David S. Chowdhury, Soma Singh, Larry N. Kavousi, Maryam Peyser, Patricia A. Quigley, Laura Priel, Debra Long Lau, Karen Kuhns, Douglas B. Yoshimura, Teizo Johnson, Andrew D. Hwang, Shih-Jen Chen, Marcus Y. Arai, Andrew E. Green, Eric D. Mullikin, James C. Kolodgie, Frank D. O'Donnell, Christopher J. Virmani, Renu Munson, Peter J. McVicar, Daniel W. Biesecker, Leslie G. CA NISC Comparative Sequencing Progra CHARGE Consortium TI Integrative DNA, RNA, and Protein Evidence Connects TREML4 to Coronary Artery Calcification SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; HEART-DISEASE; GENE-EXPRESSION; WHOLE-BLOOD; CELLS; INFLAMMATION; RISK; ATHEROSCLEROSIS; MYELOPEROXIDASE; MECHANISMS AB Coronary artery calcification (CAC) is a heritable and definitive morphologic marker of atherosclerosis that strongly predicts risk for future cardiovascular events. To search for genes involved in CAC, we used an integrative transcriptomic, genomic, and protein expression strategy by using next-generation DNA sequencing in the discovery phase with follow-up studies using traditional molecular biology and histopathology techniques. RNA sequencing of peripheral blood from a discovery set of CAC cases and controls was used to identify dysregulated genes, which were validated by ClinSeq and Framingham Heart Study data. Only a single gene, TREML4, was upregulated in CAC cases in both studies. Further examination showed that rs2803496 was a TREML4 cis-eQTL and that the minor allele at this locus conferred up to a 6.5-fold increased relative risk of CAC. We characterized human TREML4 and demonstrated by immunohistochemical techniques that it is localized in macrophages surrounding the necrotic core of coronary plaques complicated by calcification (but not in arteries with less advanced disease). Finally, we determined by von Kossa staining that TREML4 colocalizes with areas of microcalcification within coronary plaques. Overall, we present integrative RNA, DNA, and protein evidence implicating TREML4 in coronary artery calcification. Our findings connect mulfimodal genomics data with a commonly used clinical marker of cardiovascular disease. C1 [Sen, Shurjo K.; Accame, David S.; Singh, Larry N.; Green, Eric D.; Mullikin, James C.; Biesecker, Leslie G.; NISC Comparative Sequencing Progra] NHGRI, NIH, Bethesda, MD 20892 USA. [Boelte, Kimberly C.; Quigley, Laura; Yoshimura, Teizo; McVicar, Daniel W.] NCI, NTH, Frederick, MD 21702 USA. [Barb, Jennifer J.; Joehanes, Roby; Munson, Peter J.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. [Zhao, XiaoQing; Cheng, Qi; Adams, Lila; Kolodgie, Frank D.; Virmani, Renu] CVPath Inst, Gaithersburg, MD 20878 USA. [Teer, Jamie K.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Chowdhury, Soma] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Kavousi, Maryam] Erasmus Univ, Med Ctr, Netherlands Genom Initiat Sponsored Netherlands C, NL-3000 CA Rotterdam, Netherlands. [Kavousi, Maryam] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Peyser, Patricia A.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48104 USA. [Priel, Debra Long; Lau, Karen; Kuhns, Douglas B.] SAIC Frederick Inc, Appl Dev Res Directorate, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Johnson, Andrew D.; Hwang, Shih-Jen; O'Donnell, Christopher J.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Johnson, Andrew D.; Hwang, Shih-Jen; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Chen, Marcus Y.; Arai, Andrew E.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM lesb@mail.nih.gov RI McVicar, Daniel/G-1970-2015; Johnson, Andrew/G-6520-2013 FU NHGRI; NCI; NHLBI; NIH [NO1-HC-25195]; National Cancer Institute, NIH [HHSN261200800001E] FX The authors thank Marjorie Lindhurst, Jennifer Johnston, David Ng, Steve Gonsalves, and the ClinSeq support and nursing staff for their help with the clinical aspects of this study; Yusuf Demirkale for help with statistical analyses; and Danielle Fink, Laura Coffin, and Dara Riva for their help with the neutrophil studies. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was funded by the NHGRI, NCI, and NHLBI Intramural Research Programs. The National Heart, Lung, and Blood Institute's (NHLBI's) FHS is supported by NIH Grant NO1-HC-25195. This project has also been funded in part with federal funds from the National Cancer Institute, NIH, under Contract No. HHSN261200800001E. L.G.B. is an uncompensated advisor to the Illumina Corporation and receives royalties from the Genentech Corporation. NR 50 TC 3 Z9 3 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 13 PY 2014 VL 95 IS 1 BP 66 EP 76 DI 10.1016/j.ajhg.2014.06.003 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA AL1RP UT WOS:000338904100005 PM 24975946 ER PT J AU Simino, J Shi, G Bis, JC Chasman, DI Ehret, GB Gu, XJ Guo, XQ Hwang, SJ Sijbrands, E Smith, AV Verwoert, GC Bragg-Gresham, JL Cadby, G Chen, P Cheng, CY Corre, TG de Boer, RA Goel, A Johnson, T Khor, CC Lluis-Ganella, C Luan, J Lyytikainen, LP Nolte, IM Sim, XL Sober, S van der Most, PJ Verweij, N Zhao, JH Amin, N Boerwinkle, E Bouchard, C Dehghan, A Eiriksdottir, G Elosua, R Franco, OH Gieger, C Harris, TB Hercberg, S Hofman, A James, AL Johnson, AD Kahonen, M Khaw, KT Kutalik, Z Larson, MG Launer, LJ Li, G Liu, JJ Liu, K Morrison, AC Navis, G Ong, RTH Papanicolau, GJ Penninx, BW Psaty, BM Raffel, LJ Raitakari, OT Rice, K Rivadeneira, F Rose, LM Sanna, S Scott, RA Siscovick, DS Stolk, RP Uitterlinden, AG Vaidya, D van der Klauw, MM Vasan, RS Vithana, EN Volker, U Volzke, H Watkins, H Young, TL Aung, T Bochud, M Farrall, M Hartman, CA Laan, M Lakatta, EG Lehtimaki, T Loos, RJF Lucas, G Meneton, P Palmer, LJ Rettig, R Snieder, H Tai, ES Teo, YY van der Harst, P Wareham, NJ Wijmenga, C Wong, TY Fornage, M Gudnason, V Levy, D Palmas, W Ridker, PM Rotter, JI van Duijn, CM Witteman, JCM Chakravarti, A Rao, DC AF Simino, Jeannette Shi, Gang Bis, Joshua C. Chasman, Daniel I. Ehret, Georg B. Gu, Xiangjun Guo, Xiuqing Hwang, Shih-Jen Sijbrands, Eric Smith, Albert V. Verwoert, Germaine C. Bragg-Gresham, Jennifer L. Cadby, Gemma Chen, Peng Cheng, Ching-Yu Corre, Tanguy de Boer, Rudolf A. Goel, Anuj Johnson, Toby Khor, Chiea-Chuen Lluis-Ganella, Carla Luan, Jian'an Lyytikainen, Leo-Pekka Nolte, Ilja M. Sim, Xueling Sober, Siim van der Most, Peter J. Verweij, Niek Zhao, Jing Hua Amin, Najaf Boerwinkle, Eric Bouchard, Claude Dehghan, Abbas Eiriksdottir, Gudny Elosua, Roberto Franco, Oscar H. Gieger, Christian Harris, Tamara B. Hercberg, Serge Hofman, Albert James, Alan L. Johnson, Andrew D. Kahonen, Mika Khaw, Kay-Tee Kutalik, Zoltan Larson, Martin G. Launer, Lenore J. Li, Guo Liu, Jianjun Liu, Kiang Morrison, Alanna C. Navis, Gerjan Ong, Rick Twee-Hee Papanicolau, George J. Penninx, Brenda W. Psaty, Bruce M. Raffel, Leslie J. Raitakari, Olli T. Rice, Kenneth Rivadeneira, Fernando Rose, Lynda M. Sanna, Serena Scott, Robert A. Siscovick, David S. Stolk, Ronald P. Uitterlinden, Andre G. Vaidya, Dhananjay van der Klauw, Melanie M. Vasan, Ramachandran S. Vithana, Eranga Nishanthie Voelker, Uwe Voelzke, Henry Watkins, Hugh Young, Terri L. Aung, Tin Bochud, Murielle Farrall, Martin Hartman, Catharina A. Laan, Maris Lakatta, Edward G. Lehtimaki, Terho Loos, Ruth J. F. Lucas, Gavin Meneton, Pierre Palmer, Lyle J. Rettig, Rainer Snieder, Harold Tai, E. Shyong Teo, Yik-Ying van der Harst, Pim Wareham, Nicholas J. Wijmenga, Cisca Wong, Tien Yin Fornage, Myriam Gudnason, Vilmundur Levy, Daniel Palmas, Walter Ridker, Paul M. Rotter, Jerome I. van Duijn, Cornelia M. Witteman, Jacqueline C. M. Chakravarti, Aravinda Rao, Dabeeru C. CA LifeLines Cohort Study TI Gene-Age Interactions in Blood Pressure Regulation: A Large-Scale Investigation with the CHARGE, Global BPgen, and ICBP Consortia SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; ENVIRONMENT INTERACTIONS; SUSCEPTIBILITY LOCI; CARDIOVASCULAR-DISEASE; CROHNS-DISEASE; HYPERTENSION; POPULATION; METAANALYSIS; VARIANTS; WOMEN AB Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p <= 5 x 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 x 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations. C1 [Simino, Jeannette; Shi, Gang; Rao, Dabeeru C.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Bis, Joshua C.; Li, Guo; Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Chasman, Daniel I.; Rose, Lynda M.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Chasman, Daniel I.; Ridker, Paul M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Ehret, Georg B.; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, Ctr Complex Dis Genom, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Ehret, Georg B.] Univ Hosp Geneva, Dept Specialties Internal Med, CH-1211 Geneva, Switzerland. [Gu, Xiangjun; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Res Ctr Human Genet, Houston, TX 77030 USA. [Guo, Xiuqing; Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90502 USA. [Guo, Xiuqing; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA. [Hwang, Shih-Jen; Johnson, Andrew D.; Larson, Martin G.; Vasan, Ramachandran S.; Levy, Daniel] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. [Hwang, Shih-Jen; Levy, Daniel] NHLBI, Ctr Populat Studies, Framingham, MA 01702 USA. [Sijbrands, Eric; Verwoert, Germaine C.; Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus Univ, Med Ctr, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands. [Smith, Albert V.; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Verwoert, Germaine C.; Amin, Najaf; Dehghan, Abbas; Franco, Oscar H.; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands. [Bragg-Gresham, Jennifer L.; Sim, Xueling] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Cadby, Gemma] Univ Western Australia, Ctr Genet Origins Hlth & Dis, Nedlands, WA 6009, Australia. [Cadby, Gemma; Palmer, Lyle J.] Ontario Inst Canc Res, Genet Epidemiol & Biostat Platform, Toronto, ON M5G 0A3, Canada. [Cadby, Gemma; Palmer, Lyle J.] Samuel Lunenfeld Res Inst, Toronto, ON M5T 3L9, Canada. [Chen, Peng; Cheng, Ching-Yu; Khor, Chiea-Chuen; Liu, Jianjun; Ong, Rick Twee-Hee; Tai, E. Shyong; Teo, Yik-Ying] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117597, Singapore. [Chen, Peng; Cheng, Ching-Yu; Khor, Chiea-Chuen; Liu, Jianjun; Ong, Rick Twee-Hee; Tai, E. Shyong; Teo, Yik-Ying] Natl Univ Hlth Syst, Saw Swee Hock Sch Publ Hlth, Singapore 117597, Singapore. [Cheng, Ching-Yu; Khor, Chiea-Chuen; Vithana, Eranga Nishanthie; Aung, Tin; Wong, Tien Yin] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore 119228, Singapore. [Cheng, Ching-Yu; Khor, Chiea-Chuen; Vithana, Eranga Nishanthie; Aung, Tin; Wong, Tien Yin] Natl Univ Hlth Syst, Dept Ophthalmol, Singapore 119228, Singapore. [Cheng, Ching-Yu; Vithana, Eranga Nishanthie; Aung, Tin; Wong, Tien Yin] Singapore Eye Res Inst, Singapore 168751, Singapore. [Cheng, Ching-Yu] Duke NUS Grad Med Sch, Off Clin Sci, Ctr Quantitat Med, Singapore 169857, Singapore. [Corre, Tanguy; Kutalik, Zoltan] Univ Lausanne, Dept Med Genet, CH-1005 Lausanne, Switzerland. [Corre, Tanguy; Kutalik, Zoltan] Swiss Inst Bioinforrnat, CH-1015 Lausanne, Switzerland. [de Boer, Rudolf A.; Verweij, Niek; van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands. [Goel, Anuj; Watkins, Hugh; Farrall, Martin] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Goel, Anuj; Watkins, Hugh; Farrall, Martin] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford OX3 9DU, England. [Johnson, Toby] Queen Mary Univ London, Barts & London Sch Med & Dent, London EC1M 6BQ, England. [Khor, Chiea-Chuen; Liu, Jianjun] Genome Inst Singapore, Div Human Genet, Singapore 138672, Singapore. [Khor, Chiea-Chuen] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Paediat, Singapore 119228, Singapore. [Khor, Chiea-Chuen] Natl Univ Hlth Syst, Dept Paediat, Singapore 119074, Singapore. [Lluis-Ganella, Carla; Elosua, Roberto; Lucas, Gavin] IMIM Hosp Mar Med Res Inst, Barcelona 08003, Spain. [Luan, Jian'an; Zhao, Jing Hua; Scott, Robert A.; Loos, Ruth J. F.; Wareham, Nicholas J.] Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere 30101, Finland. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, Tampere 33101, Finland. [Nolte, Ilja M.; van der Most, Peter J.; Stolk, Ronald P.; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands. [Sim, Xueling] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 119260, Singapore. [Sober, Siim; Laan, Maris] Univ Tartu, Inst Mol & Cell Biol, Human Mol Genet Grp, EE-51010 Tartu, Estonia. [Boerwinkle, Eric; Morrison, Alanna C.; Fornage, Myriam] Univ Texas Houston, Hlth Sci Ctr, Human Genet Ctr, Houston, TX 77225 USA. [Bouchard, Claude] Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70808 USA. [Elosua, Roberto] Epidemio1 & Publ Hlth Network CIBERESP, Barcelona 08036, Spain. [Gieger, Christian] Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Genet Epidemiol, D-85764 Neuherberg, Germany. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Hercberg, Serge] Univ Paris 13, Inst Natl Rech Agronom, U1125, Inst Natl Sante & Rech Med,U557, F-93000 Bobigny, France. [James, Alan L.] Sir Charles Gairdner Hosp, Dept Pulm Physiol & Sleep Med, Nedlands, WA 6009, Australia. [James, Alan L.] Univ Western Australia, Sch Med & Pharmacol, Nedlands, WA 6009, Australia. [Johnson, Andrew D.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, NIH, Bethesda, MD 20892 USA. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland. [Kahonen, Mika] Univ Tampere, Sch Med, Dept Clin Physiol, Tampere 33521, Finland. [Khaw, Kay-Tee] Univ Cambridge, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Cambridge CB2 2SR, England. [Larson, Martin G.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Liu, Kiang] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Navis, Gerjan] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, NL-9700 RB Groningen, Netherlands. [Papanicolau, George J.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Penninx, Brenda W.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, EMGO Inst, NL-1081 BT Amsterdam, Netherlands. [Penninx, Brenda W.] Leiden Univ, Med Ctr, Dept Psychiat, NL-2333 ZD Leiden, Netherlands. [Penninx, Brenda W.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9700 RB Groningen, Netherlands. [Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Raffel, Leslie J.] Pacif Theatres, Cedars Sinai Med Ctr, Med Genet Inst, Los Angeles, CA 90048 USA. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20521, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku 20521, Finland. [Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Sanna, Serena] CNR, Ist Ric Genet & Biomed, I-09042 Monserrato, Italy. [Uitterlinden, Andre G.; van Duijn, Cornelia M.] Netherlands Ctr Hlth Aging, Netherland Genom Inititiat, NL-2509 The Hague, Netherlands. [Vaidya, Dhananjay] Johns Hopkins Univ, Dept Med, Baltimore, MD 21202 USA. [van der Klauw, Melanie M.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, NL-9700 RB Groningen, Netherlands. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Div Epidemiol & Cardiol, Boston, MA 02118 USA. [Vithana, Eranga Nishanthie] Duke NUS Grad Med Sch, Neurosci & Behav Disorders NBD Program, Singapore 169857, Singapore. [Voelker, Uwe] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, D-17487 Greifswald, Germany. [Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, D-17487 Greifswald, Germany. [Young, Terri L.] Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. [Young, Terri L.] Duke Natl Univ Singapore, Div Neurosci, Singapore 169857, Singapore. [Bochud, Murielle] Univ Lausanne Hosp, Inst Social & Prevent Med, CH-1010 Lausanne, Switzerland. [Hartman, Catharina A.] Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Pathol Emot, NL-9700 RB Groningen, Netherlands. [Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, NIH, Bethesda, MD 21224 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Meneton, Pierre] Ctr Rech Cordeliers, Inst Natl Sante & Rech Med, U872, F-75006 Paris, France. [Rettig, Rainer] Ernst Moritz Arndt Univ Greifswald, Inst Physiol, D-17495 Karlsburg, Germany. [Tai, E. Shyong] Natl Univ Singapore, Dept Med, Natl Univ Hlth Syst, Singapore 119228, Singapore. [Tai, E. Shyong] Natl Univ Singapore, Yong Loo Lin Sch Med, Singapore 119228, Singapore. [Tai, E. Shyong] Duke Natl Univ Singapore, Grad Sch Med, Singapore 169857, Singapore. [Teo, Yik-Ying] Natl Univ Singapore, Life Sci Inst, Singapore 117456, Singapore. [Teo, Yik-Ying] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117543, Singapore. [Teo, Yik-Ying] ASTAR, Genome Inst Singapore, Singapore 138672, Singapore. [van der Harst, Pim; Wijmenga, Cisca] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. [van der Harst, Pim] Durrer Ctr Cardiogenet Res, NL-3501 DG Utrecht, Netherlands. [Levy, Daniel] Boston Univ, Sch Med, Boston, MA 02118 USA. [Palmas, Walter] Columbia Univ, Dept Med, New York, NY 10032 USA. [van Duijn, Cornelia M.] Ctr Med Syst Biol, Netherland Genom Initiat, NL-2300 RC Leiden, Netherlands. [Rao, Dabeeru C.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Rao, Dabeeru C.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Rao, Dabeeru C.] Washington Univ, Sch Med, Dept Math, St Louis, MO 63110 USA. RP Simino, J (reprint author), Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. EM jeannette@wubios.wustl.edu; aravinda@jhmi.edu RI Ormel, Johan/C-6094-2013; Wijmenga, Cisca/D-2173-2009; Verweij, Niek/A-4499-2017; Lluis-Ganella, Carla/G-5998-2012; Lyytikainen, Leo-Pekka/C-8544-2016; Shi, Gang/D-3301-2016; Bouchard, Claude/A-7637-2009; Smith, Albert/K-5150-2015; Bochud, Murielle/A-3981-2010; Johnson, Andrew/G-6520-2013; Palmer, Lyle/K-3196-2014; EHRET, Georg/A-9532-2009; Laan, Maris/A-4100-2011; Chen, Peng/E-5546-2015; Colaus, PsyColaus/K-6607-2013; Gudnason, Vilmundur/K-6885-2015; Rivadeneira, Fernando/O-5385-2015 OI Tai, E Shyong/0000-0003-2929-8966; Dehghan, Abbas/0000-0001-6403-016X; Johnson, Toby/0000-0002-5998-3270; Ramachandran, Vasan/0000-0001-7357-5970; Gieger, Christian/0000-0001-6986-9554; Verweij, Niek/0000-0002-4303-7685; Wolffenbuttel, Bruce H.R./0000-0001-9262-6921; Watkins, Hugh/0000-0002-5287-9016; Stolk, Ronald/0000-0002-0518-1205; Khor, Chiea Chuen/0000-0002-1128-4729; Vaidya, Dhananjay/0000-0002-7164-1601; Franke, Lude/0000-0002-5159-8802; Lluis-Ganella, Carla/0000-0001-7609-5497; ELOSUA, ROBERTO/0000-0001-8235-0095; Sijbrands, Eric/0000-0001-8857-7389; sanna, serena/0000-0002-3768-1749; Wijmenga, Cisca/0000-0002-5635-1614; Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Smith, Albert/0000-0003-1942-5845; Bochud, Murielle/0000-0002-5727-0218; Palmer, Lyle/0000-0002-1628-3055; EHRET, Georg/0000-0002-5730-0675; Laan, Maris/0000-0002-8519-243X; Chen, Peng/0000-0002-1422-4641; Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441 FU Medtronic; Amgen FX B.M.P. served on a data and safety monitoring board for a clinical trial (Zoll LifeCor) and a steering committee for the Yale Open Data Access Project funded by Medtronic. P.M.R. received a grant from Amgen (>$10,000) for genotyping the WGHS. A.C. is on the Science Advisory Board of Affymetrix and Biogen Idec. NR 56 TC 22 Z9 22 U1 3 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 13 PY 2014 VL 95 IS 1 BP 24 EP 38 DI 10.1016/j.ajhg.2014.05.010 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA AL1RP UT WOS:000338904100002 PM 24954895 ER PT J AU Ganesh, SK Chasman, DI Larson, MG Guo, X Verwoert, G Bis, JC Gu, XJ Smith, AV Yang, ML Zhang, Y Ehret, G Rose, LM Hwang, SJ Papanicolau, GJ Sijbrands, EJ Rice, K Eiriksdottir, G Pihur, V Ridker, PM Vasan, RS Newton-Cheh, C Raffel, LJ Amin, N Rotter, JI Liu, K Launer, LJ Xu, M Caulfield, M Morrison, AC Johnson, AD Vaidya, D Dehghan, A Li, G Bouchard, C Harris, TB Zhang, H Boerwinkle, E Siscovick, DS Gao, W Uitterlinden, AG Rivadeneira, F Hofman, A Willer, CJ Franco, OH Huo, Y Witteman, JCM Munroe, PB Gudnason, V Palmas, W van Duijn, C Fornage, M Levy, D Psaty, BM Chakravarti, A AF Ganesh, Santhi K. Chasman, Daniel I. Larson, Martin G. Guo, Xiuqing Verwoert, Germain Bis, Joshua C. Gu, Xiangjun Smith, Albert V. Yang, Min-Lee Zhang, Yan Ehret, Georg Rose, Lynda M. Hwang, Shih-Jen Papanicolau, George J. Sijbrands, Eric J. Rice, Kenneth Eiriksdottir, Gudny Pihur, Vasyl Ridker, Paul M. Vasan, Ramachandran S. Newton-Cheh, Christopher Raffel, Leslie J. Amin, Najaf Rotter, Jerome I. Liu, Kiang Launer, Lenore J. Xu, Ming Caulfield, Mark Morrison, Alanna C. Johnson, Andrew D. Vaidya, Dhananjay Dehghan, Abbas Li, Guo Bouchard, Claude Harris, Tamara B. Zhang, He Boerwinkle, Eric Siscovick, David S. Gao, Wei Uitterlinden, Andre G. Rivadeneira, Fernando Hofman, Albert Willer, Cristen J. Franco, Oscar H. Huo, Yong Witteman, Jacqueline C. M. Munroe, Patricia B. Gudnason, Vilmundur Palmas, Walter van Duijn, Cornelia Fornage, Myriam Levy, Daniel Psaty, Bruce M. Chakravarti, Aravinda CA Global Blood Pressure Genetics Con TI Effects of Long-Term Averaging of Quantitative Blood Pressure Traits on the Detection of Genetic Associations SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; HUMAN PREFRONTAL CORTEX; GROWTH-FACTOR-I; CARDIOVASCULAR-DISEASE; MEASUREMENT ERROR; CANDIDATE GENES; WHOLE-BLOOD; HUMAN BRAIN; EXPRESSION; LOCI AB Blood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations. We studied systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) averaged over multiple years in 46,629 individuals of European ancestry. We identified 39 trait-variant associations across 19 independent loci (p < 5 x 10(-8)); five associations (in four loci) uniquely identified by our LTA analyses included those of SBP and MAP at 2p23 (rs1275988, near KCNK3), DBP at 2q11.2 (rs7599598, in FER1L5), and PP at 6p21 (rs10948071, near CRIP3) and 7p13 (rs2949837, near IGEBP3). Replication analyses conducted in cohorts with single-visit BP data showed positive replication of associations and a nominal association (p <0.05). We estimated a 20% gain in statistical power with long-term average (LTA) as compared to single-visit BP association studies. Using LTA analysis, we identified genetic loci influencing BP. LTA might be one way of increasing the power of genetic associations for continuous traits in extant samples for other phenotypes that are measured serially over time. C1 [Ganesh, Santhi K.; Yang, Min-Lee; Zhang, He; Willer, Cristen J.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Ganesh, Santhi K.; Yang, Min-Lee; Zhang, He; Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Chasman, Daniel I.; Rose, Lynda M.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Chasman, Daniel I.; Ridker, Paul M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Larson, Martin G.; Hwang, Shih-Jen; Vasan, Ramachandran S.; Johnson, Andrew D.; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Larson, Martin G.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Guo, Xiuqing; Rotter, Jerome I.] Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA. [Guo, Xiuqing; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA. [Verwoert, Germain; Amin, Najaf; Dehghan, Abbas; Uitterlinden, Andre G.; Rivadeneira, Fernando; Hofman, Albert; Franco, Oscar H.; Witteman, Jacqueline C. M.; van Duijn, Cornelia] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 Rotterdam, Netherlands. [Verwoert, Germain; Sijbrands, Eric J.; Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus Univ, Med Ctr, Dept Internal Med, NL-3015 Rotterdam, Netherlands. [Bis, Joshua C.; Li, Guo; Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Gu, Xiangjun; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Res Ctr Human Genet, Brown Fdn Inst Mol Med, Houston, TX 77030 USA. [Smith, Albert V.; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Zhang, Yan; Huo, Yong] Peking Univ, Dept Cardiol, Hosp 1, Beijing 100034, Peoples R China. [Ehret, Georg; Pihur, Vasyl; Chakravarti, Aravinda] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Sch Med, Baltimore, MD 21205 USA. [Ehret, Georg] Univ Hosp Geneva, Dept Specialties Internal Med, CH-1211 Geneva, Switzerland. [Hwang, Shih-Jen; Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Papanicolau, George J.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Div Epidemiol, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Div Cardiol, Dept Med, Boston, MA 02118 USA. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Raffel, Leslie J.] Cedars Sinai Med Ctr, Med Genet Res Inst, Los Angeles, CA 90048 USA. [Liu, Kiang] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Xu, Ming; Gao, Wei] Peking Univ, Hosp 3, Dept Cardiol, Beijing 100191, Peoples R China. [Caulfield, Mark; Munroe, Patricia B.] Queen Mary Univ London, Clin Pharmacol & Genome Ctr, William Harvey Res Inst, Barts & London Sch Med & Dent, London EC1M 6BQ, England. [Caulfield, Mark; Munroe, Patricia B.] Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, London EC1M 6BQ, England. [Morrison, Alanna C.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Johnson, Andrew D.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Bethesda, MD 20892 USA. [Vaidya, Dhananjay] Johns Hopkins Univ, Dept Med, Baltimore, MD 21287 USA. [Bouchard, Claude] Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70808 USA. [Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA. [Uitterlinden, Andre G.; van Duijn, Cornelia] Netherlands Genom Initiat, Netherlands Consortium Healthy Aging, NL-2593 The Hague, Netherlands. [Palmas, Walter] Columbia Univ, Dept Med, New York, NY 10032 USA. [van Duijn, Cornelia] Netherlands Genom Initiat, Ctr Med Syst Biol, NL-2593 The Hague, Netherlands. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Sch Publ Hlth, Houston, TX 77030 USA. [Levy, Daniel] Boston Univ, Sch Med, Boston, MA 02118 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Group Hlth Res Inst, Seattle, WA 98101 USA. RP Ganesh, SK (reprint author), Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. EM sganesh@umich.edu; aravinda@jhmi.edu RI Newhouse, Stephen/C-9330-2011; Johnson, Andrew/G-6520-2013; Beckmann, Jacques S /A-9772-2008; Bouchard, Claude/A-7637-2009; Smith, Albert/K-5150-2015; Matullo, Giuseppe/K-6383-2016; Deloukas, Panos/B-2922-2013; EHRET, Georg/A-9532-2009; Bochud, Murielle/A-3981-2010; Laan, Maris/A-4100-2011; Colaus, PsyColaus/K-6607-2013; Onland-Moret, N. Charlotte/G-9185-2011; Gudnason, Vilmundur/K-6885-2015; Pfeufer, Arne/B-6634-2013; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015 OI Forouhi, Nita/0000-0002-5041-248X; Vaidya, Dhananjay/0000-0002-7164-1601; Dehghan, Abbas/0000-0001-6403-016X; Wain, Louise/0000-0003-4951-1867; Newhouse, Stephen/0000-0002-1843-9842; Beckmann, Jacques S /0000-0002-9741-1900; Org, Elin/0000-0003-1451-9375; Sijbrands, Eric/0000-0001-8857-7389; Ramachandran, Vasan/0000-0001-7357-5970; Luben, Robert/0000-0002-5088-6343; Zeggini, Eleftheria/0000-0003-4238-659X; Sacerdote, Carlotta/0000-0002-8008-5096; Smith, Albert/0000-0003-1942-5845; Deloukas, Panos/0000-0001-9251-070X; EHRET, Georg/0000-0002-5730-0675; Bochud, Murielle/0000-0002-5727-0218; Laan, Maris/0000-0002-8519-243X; Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441 FU Cancer Research UK [14136]; Medical Research Council [G1000143, G0401527, G9521010, MR/K006584/1]; NCATS NIH HHS [UL1 TR000124]; NHLBI NIH HHS [R01 HL105756]; NIDDK NIH HHS [P30 DK063491] NR 91 TC 18 Z9 18 U1 3 U2 27 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 13 PY 2014 VL 95 IS 1 BP 49 EP 65 DI 10.1016/j.ajhg.2014.06.002 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA AL1RP UT WOS:000338904100004 PM 24975945 ER PT J AU Cortazar, P Zhang, LJ Untch, M Mehta, K Costantino, JP Wolmark, N Bonnefoi, H Cameron, D Gianni, L Valagussa, P Swain, SM Prowell, T Loibl, S Wickerham, DL Bogaerts, J Baselga, J Perou, C Blumenthal, G Blohmer, J Mamounas, EP Bergh, J Semiglazov, V Justice, R Eidtmann, H Paik, S Piccart, M Sridhara, R Fasching, PA Slaets, L Tang, SH Gerber, B Geyer, CE Pazdur, R Ditsch, N Rastogi, P Eiermann, W von Minckwitz, G AF Cortazar, Patricia Zhang, Lijun Untch, Michael Mehta, Keyur Costantino, Joseph P. Wolmark, Norman Bonnefoi, Herve Cameron, David Gianni, Luca Valagussa, Pinuccia Swain, Sandra M. Prowell, Tatiana Loibl, Sibylle Wickerham, D. Lawrence Bogaerts, Jan Baselga, Jose Perou, Charles Blumenthal, Gideon Blohmer, Jens Mamounas, Eleftherios P. Bergh, Jonas Semiglazov, Vladimir Justice, Robert Eidtmann, Holger Paik, Soonmyung Piccart, Martine Sridhara, Rajeshwari Fasching, Peter A. Slaets, Leen Tang, Shenghui Gerber, Bernd Geyer, Charles E., Jr. Pazdur, Richard Ditsch, Nina Rastogi, Priya Eiermann, Wolfgang von Minckwitz, Gunter TI Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis SO LANCET LA English DT Article ID DOSE-INTENSIFIED CHEMOTHERAPY; SURGICAL ADJUVANT BREAST; III RANDOMIZED GEPARTRIO; PRIMARY SYSTEMIC THERAPY; NEOADJUVANT CHEMOTHERAPY; PREOPERATIVE CHEMOTHERAPY; DARBEPOETIN ALPHA; PREPARE TRIAL; CYCLOPHOSPHAMIDE; DOXORUBICIN AB Background Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS. Methods We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response-ypT0 ypN0, ypT0/is ypN0, and ypT0/is-for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS. Findings We obtained data from 12 identified international trials and 11955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0.44, 95% CI 0.39-0.51; ypT0/is ypN0: 0.48, 0.43-0.54) and OS (0.36, 0.30-0.44; 0.36, 0.31-0.42) than was tumour eradication from the breast alone(ypT0/is; EFS: HR 0.60, 95% CI 0.55-0.66; OS 0.51, 0.45-0.58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0.24, 95% CI 0.18-0.33; OS: 0.16, 0.11-0.25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0.15, 0.09-0.27; OS: 0.08, 0.03, 0. 22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R-2=0.03, 95% CI 0.00-0.25) and OS (R-2=0.24,0.00-0.70). Interpretation Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS. Funding US Food and Drug Administration. C1 [Cortazar, Patricia; Zhang, Lijun; Prowell, Tatiana; Blumenthal, Gideon; Justice, Robert; Sridhara, Rajeshwari; Tang, Shenghui; Pazdur, Richard] US FDA, Silver Spring, MD USA. [Untch, Michael] HELIOS Klin, Berlin, Germany. [Mehta, Keyur; Loibl, Sibylle; von Minckwitz, Gunter] German Breast Grp, Neu Isenburg, Germany. [Costantino, Joseph P.; Wolmark, Norman; Wickerham, D. Lawrence; Paik, Soonmyung; Rastogi, Priya] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. [Bonnefoi, Herve] Inst Bergonie INSERM U916, Bordeaux, France. [Bonnefoi, Herve] Univ Bordeaux Segalen, Bordeaux, France. [Cameron, David] Univ Edinburgh, Edinburgh Canc Res Ctr, Edinburgh EH8 9YL, Midlothian, Scotland. [Cameron, David] NHS Lothian, Edinburgh, Midlothian, Scotland. [Gianni, Luca] Ist Sci San Raffaele, I-20132 Milan, Italy. [Valagussa, Pinuccia] Fdn Michelangelo, Milan, Italy. [Swain, Sandra M.] Medstar Washington Hosp Ctr, Washington, DC USA. [Bogaerts, Jan; Slaets, Leen] EORTC Headquarters, Brussels, Belgium. [Baselga, Jose] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Perou, Charles] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Blohmer, Jens] St Gertrauden Hosp, Berlin, Germany. [Mamounas, Eleftherios P.] MD Anderson Canc Ctr Orlando, Orlando, FL USA. [Bergh, Jonas] KarolinskaInst, Stockholm, Sweden. [Bergh, Jonas] Univ Hosp, Stockholm, Sweden. [Semiglazov, Vladimir] NN Petrov Oncol Res Inst, St Petersburg, Russia. [Eidtmann, Holger] Univ Womens Hosp, Kiel, Germany. [Piccart, Martine] Inst Jules Bordet, B-1000 Brussels, Belgium. [Fasching, Peter A.] Univ Klinikums, Frauenklin, Erlangen, Germany. [Gerber, Bernd] Univ Frauenklin, Rostock, Germany. [Geyer, Charles E., Jr.] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA. [Ditsch, Nina; Eiermann, Wolfgang] Hosp Ludwig Maximilian Univ Munich, Munich, Germany. RP Cortazar, P (reprint author), 10903 New Hampshire Ave,Bldg 22,Room 2333, Silver Spring, MD 20993 USA. EM patricia.cortazar@fda.hhs.gov OI Semiglazov, Vladimir/0000-0003-0077-9619; Perou, Charles/0000-0001-9827-2247; Swain, Sandra/0000-0002-1320-3830 FU US Food and Drug Administration; CTNeoBC pooled analysis FX This project was partly funded by the US Food and Drug Administration. We thank Janet Woodcock, who provided financial support for the CTNeoBC pooled analysis; all the patients, Breast Cancer Cooperative Groups, investigators, pathologists, and statisticians who participated in the neoadjuvant trials; and Jo Anne Zujewski for her help. NR 28 TC 426 Z9 451 U1 5 U2 56 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUL 12 PY 2014 VL 384 IS 9938 BP 164 EP 172 DI 10.1016/S0140-6736(13)62422-8 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AL1YC UT WOS:000338921500035 PM 24529560 ER PT J AU Murphy, E Pan, X Nguyen, T Liu, J Holmstrom, KM Finkel, T AF Murphy, Elizabeth Pan, Xin Tiffany Nguyen Liu, Jie Holmstroem, Kira M. Finkel, Toren TI Unresolved questions from the analysis of mice lacking MCU expression SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Editorial Material ID MITOCHONDRIAL PERMEABILITY TRANSITION; ISCHEMIA-REPERFUSION; CELL-DEATH; INJURY; GENE AB Entry of mitochondrial calcium is believed to play an essential role in regulating bioenergetics and initiating cell death pathways. We have recently described a mouse model lacking MCU expression. Surprisingly, these mice are viable and the cells and tissues from these animals do not exhibit any marked protection from cell death. Here, we discuss our findings as well as potential explanations for some of the more unexpected results. Published by Elsevier Inc. C1 [Murphy, Elizabeth; Tiffany Nguyen] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Pan, Xin; Liu, Jie; Holmstroem, Kira M.; Finkel, Toren] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Murphy, E (reprint author), NHLBI, Cardiac Physiol Sect, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM murphy1@mail.nih.gov; finkelt@nih.gov OI Holmstrom, Kira/0000-0001-6434-7909 FU Intramural NIH HHS [Z99 HL999999, ZIA HL002066-06] NR 13 TC 21 Z9 21 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 11 PY 2014 VL 449 IS 4 BP 384 EP 385 DI 10.1016/j.bbrc.2014.04.144 PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AR5NO UT WOS:000343631400006 PM 24792186 ER PT J AU Malley, JD Fine, A AF Malley, James D. Fine, Arthur TI A simplified basis for Bell-Kochen-Specker theorems SO PHYSICS LETTERS A LA English DT Article DE Hidden variables; No-go; Bell-Kochen-Specker theorem ID HIDDEN VARIABLES; QUANTUM MECHANICS; OBSERVABLES AB We show that a reduced form of the structural requirements for deterministic hidden variables used in Bell-Kochen-Specker theorems is already sufficient for the no-go results. Those requirements are captured by the following principle: an observable takes a spectral value x if and only if the spectral projector associated with x takes the value 1. We show that the "only if" part of this condition suffices. The proof identifies an important structural feature behind the no-go results; namely, if at least one projector is assigned the value 1 in any resolution of the identity, then at most one is. Published by Elsevier B.V. C1 [Malley, James D.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. [Fine, Arthur] Univ Washington, Seattle, WA 98195 USA. RP Malley, JD (reprint author), NIH, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. FU NIH Intramural Research Program FX J.D.M. acknowledges support from the NIH Intramural Research Program. J.D.M. and A.F. want to thank Maximilian Schlosshauer for his careful reading of the manuscript and for identifying important links to the applied literature. NR 17 TC 0 Z9 0 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0375-9601 EI 1873-2429 J9 PHYS LETT A JI Phys. Lett. A PD JUL 11 PY 2014 VL 378 IS 35 BP 2611 EP 2613 DI 10.1016/j.physleta.2014.07.022 PG 3 WC Physics, Multidisciplinary SC Physics GA AO4YN UT WOS:000341347400004 PM 25197159 ER PT J AU Malhotra, A Kobes, S Bogardus, C Knowler, WC Baier, LJ Hanson, RL AF Malhotra, Alka Kobes, Sayuko Bogardus, Clifton Knowler, William C. Baier, Leslie J. Hanson, Robert L. TI Assessing Accuracy of Genotype Imputation in American Indians SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; ALZHEIMER-DISEASE; HUMAN-POPULATIONS; POWER AB Background: Genotype imputation is commonly used in genetic association studies to test untyped variants using information on linkage disequilibrium (LD) with typed markers. Imputing genotypes requires a suitable reference population in which the LD pattern is known, most often one selected from HapMap. However, some populations, such as American Indians, are not represented in HapMap. In the present study, we assessed accuracy of imputation using HapMap reference populations in a genome-wide association study in Pima Indians. Results: Data from six randomly selected chromosomes were used. Genotypes in the study population were masked (either 1% or 20% of SNPs available for a given chromosome). The masked genotypes were then imputed using the software Markov Chain Haplotyping Algorithm. Using four HapMap reference populations, average genotype error rates ranged from 7.86% for Mexican Americans to 22.30% for Yoruba. In contrast, use of the original Pima Indian data as a reference resulted in an average error rate of 1.73%. Conclusions: Our results suggest that the use of HapMap reference populations results in substantial inaccuracy in the imputation of genotypes in American Indians. A possible solution would be to densely genotype or sequence a reference American Indian population. C1 [Malhotra, Alka; Kobes, Sayuko; Bogardus, Clifton; Knowler, William C.; Baier, Leslie J.; Hanson, Robert L.] NIDDK, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ 85014 USA. RP Malhotra, A (reprint author), NIDDK, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ 85014 USA. EM alka@niddk.nih.gov RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU National Institute of Diabetes and Digestive and Kidney Diseases; American Diabetes Association FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and a mentor grant from the American Diabetes Association (Clifton Bogardus). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 19 TC 0 Z9 0 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 11 PY 2014 VL 9 IS 7 AR e102544 DI 10.1371/journal.pone.0102544 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL8HH UT WOS:000339378400103 PM 25014012 ER PT J AU Chang, FMJ Coyne, HJ Cubillas, C Vinuesa, P Fang, XY Ma, Z Ma, DJ Helmann, JD Garcia-de los Santos, A Wang, YX Dann, CE Giedroc, DP AF Chang, Feng-Ming James Coyne, H. Jerome Cubillas, Ciro Vinuesa, Pablo Fang, Xianyang Ma, Zhen Ma, Dejian Helmann, John D. Garcia-de los Santos, Alejandro Wang, Yun-Xing Dann, Charles E., III Giedroc, David P. TI Cu(I)-mediated Allosteric Switching in a Copper-sensing Operon Repressor (CsoR) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SMALL-ANGLE SCATTERING; ESCHERICHIA-COLI RCNR; MYCOBACTERIUM-TUBERCULOSIS; BACILLUS-SUBTILIS; LISTERIA-MONOCYTOGENES; STREPTOMYCES-LIVIDANS; STAPHYLOCOCCUS-AUREUS; PROTEIN; HOMEOSTASIS; RESISTANCE AB The copper-sensing operon repressor (CsoR) is representative of a major Cu(I)-sensing family of bacterial metalloregulatory proteins that has evolved to prevent cytoplasmic copper toxicity. It is unknown how Cu(I) binding to tetrameric CsoRs mediates transcriptional derepression of copper resistance genes. A phylogenetic analysis of 227 DUF156 protein members, including biochemically or structurally characterized CsoR/RcnR repressors, reveals that Geobacillus thermodenitrificans (Gt) CsoR characterized here is representative of CsoRs from pathogenic bacilli Listeria monocytogenes and Bacillus anthracis. The 2.56 structure of Cu(I)-bound Gt CsoR reveals that Cu(I) binding induces a kink in the alpha 2-helix between two conserved copper-ligating residues and folds an N-terminal tail (residues 12-19) over the Cu(I) binding site. NMR studies of Gt CsoR reveal that this tail is flexible in the apo-state with these dynamics quenched upon Cu(I) binding. Small angle x-ray scattering experiments on an N-terminally truncated Gt CsoR (Delta 2-10) reveal that the Cu(I)-bound tetramer is hydrodynamically more compact than is the apo-state. The implications of these findings for the allosteric mechanisms of other CsoR/RcnR repressors are discussed. C1 [Chang, Feng-Ming James; Coyne, H. Jerome; Ma, Dejian; Dann, Charles E., III; Giedroc, David P.] Indiana Univ, Dept Chem, Bloomington, IN 47405 USA. [Cubillas, Ciro; Vinuesa, Pablo; Garcia-de los Santos, Alejandro] Univ Nacl Autonoma Mexico, Programa Ingn Genom, Ctr Ciencias Genom, Cuernavaca 04510, Morelos, Mexico. [Fang, Xianyang; Wang, Yun-Xing] NCI, Struct Biophys Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Ma, Zhen; Helmann, John D.] Cornell Univ, Dept Microbiol, Ithaca, NY 14853 USA. RP Giedroc, DP (reprint author), Indiana Univ, Dept Chem, Bloomington, IN 47405 USA. EM giedroc@indiana.edu FU National Institutes of Health [GM042569]; Consejo Nacional de Ciencia y Tecnologia (Mexico) [CVU 269108]; Ciencia Basica Grant [179133]; Universidad Nacional Autonoma de Mexico/PAPIIT (Programa de Apoyo a Projectos de Investigacion e Innovacion Tecnologica) [IN201112]; Lilly Endowment, Inc.; United States Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357, 22978] FX This work was supported, in whole or in part, by National Institutes of Health Grant GM042569 (to D. P. G.). This work was also supported by Consejo Nacional de Ciencia y Tecnologia (Mexico) Ph.D. Scholarship CVU 269108 (to C. C.), Ciencia Basica Grant 179133 (to P. V.), and Universidad Nacional Autonoma de Mexico/PAPIIT (Programa de Apoyo a Projectos de Investigacion e Innovacion Tecnologica) Grant IN201112 (to A. G. S.). The NMR instrumentation at Indiana University was supported by the Indiana METACyt Initiative of Indiana University, funded in part through a major grant from the Lilly Endowment, Inc. Use of the Advanced Photon Source was supported by the United States Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract DE-AC02-06CH11357 and under Partner User Proposal 22978. NR 55 TC 18 Z9 18 U1 2 U2 16 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 11 PY 2014 VL 289 IS 27 BP 19204 EP 19217 DI 10.1074/jbc.M114.556704 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AL3WV UT WOS:000339062900048 PM 24831014 ER PT J AU Goldgof, M Xiao, CY Chanturiya, T Jou, W Gavrilova, O Reitman, ML AF Goldgof, Margalit Xiao, Cuiying Chanturiya, Tatyana Jou, William Gavrilova, Oksana Reitman, Marc L. TI The Chemical Uncoupler 2,4-Dinitrophenol (DNP) Protects against Diet-induced Obesity and Improves Energy Homeostasis in Mice at Thermoneutrality SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BROWN ADIPOSE-TISSUE; ENVIRONMENTAL TEMPERATURES; THERMOGENESIS; COLD; EXPENDITURE; METABOLISM; BALANCE; DINITROPHENOL; GENE; ANIMALS AB The chemical uncoupler 2,4-dinitrophenol (DNP) was an effective and widely used weight loss drug in the early 1930s. However, the physiology of DNP has not been studied in detail because toxicity, including hyperthermia and death, reduced interest in the clinical use of chemical uncouplers. To investigate DNP action, mice fed a high fat diet and housed at 30 degrees C (to minimize facultative thermogenesis) were treated with 800 mg/liter DNP in drinking water. DNP treatment increased energy expenditure by similar to 17%, but did not change food intake. DNP-treated mice weighed 26% less than controls after 2 months of treatment due to decreased fat mass, without a change in lean mass. DNP improved glucose tolerance and reduced hepatic steatosis without observed toxicity. DNP treatment also reduced circulating T3 and T4 levels, Ucp1 expression, and brown adipose tissue activity, demonstrating that DNP-mediated heat generation substituted for brown adipose tissue thermogenesis. At 22 degrees C, a typical vivarium temperature that is below thermoneutrality, DNP treatment had no effect on body weight, adiposity, or glucose homeostasis. Thus, environmental temperature should be considered when assessing an anti-obesity drug in mice, particularly agents acting on energy expenditure. Furthermore, the beneficial effects of DNP suggest that chemical uncouplers deserve further investigation for the treatment of obesity and its comorbidities. C1 [Goldgof, Margalit; Xiao, Cuiying; Reitman, Marc L.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Chanturiya, Tatyana; Jou, William; Gavrilova, Oksana] NIDDK, Mouse Metab Core, NIH, Bethesda, MD 20892 USA. RP Reitman, ML (reprint author), Bldg 10-CRC,Rm 5-5940,10 Ctr Dr, Bethesda, MD 20892 USA. EM marc.reitman@nih.gov RI Reitman, Marc/B-4448-2013 OI Reitman, Marc/0000-0002-0426-9475 FU National Institutes of Health, NIDDK, Intramural Research Program [DK075062, DK075063] FX This work was supported, in whole or in part, by National Institutes of Health, NIDDK, Intramural Research Program Grants DK075062 and DK075063. NR 51 TC 19 Z9 20 U1 5 U2 32 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 11 PY 2014 VL 289 IS 28 BP 19341 EP 19350 DI 10.1074/jbc.M114.568204 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AL7PL UT WOS:000339326800011 PM 24872412 ER PT J AU Woo, AYH Jozwiak, K Toll, L Tanga, MJ Kozocas, JA Jimenez, L Huang, Y Song, Y Plazinska, A Pajak, K Paul, RK Bernier, M Wainer, IW Xiao, RP AF Woo, Anthony Yiu-Ho Jozwiak, Krzysztof Toll, Lawrence Tanga, Mary J. Kozocas, Joseph A. Jimenez, Lucita Huang, Ying Song, Ying Plazinska, Anita Pajak, Karolina Paul, Rajib K. Bernier, Michel Wainer, Irving W. Xiao, Rui-Ping TI Tyrosine 308 Is Necessary for Ligand-directed G(s) Protein-biased Signaling of beta(2)-Adrenoceptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MOLECULAR-FIELD ANALYSIS; FUNCTIONAL SELECTIVITY; COUPLED RECEPTOR; CARDIAC MYOCYTES; KINASE-A; FENOTEROL DERIVATIVES; DRUG DISCOVERY; PHOSPHORYLATION; BINDING; G(I) AB Interaction of a given G protein-coupled receptor to multiple different G proteins is a widespread phenomenon. For instance, beta(2)-adrenoceptor (beta(2)-AR) couples dually to G(s) and G(i) proteins. Previous studies have shown that cAMP-dependent protein kinase (PKA)-mediated phosphorylation of beta(2)-AR causes a switch in receptor coupling from G(s) to G(i). More recent studies have demonstrated that phosphorylation of beta(2)-AR byGproteincoupled receptor kinases, particularly GRK2, markedly enhances the G(i) coupling. Wehave previously shown that although most beta(2)-AR agonists cause both G(s) and G(i) activation, (R,R')fenoterol preferentially activates beta(2)-AR-G(s) signaling. However, the structural basis for this functional selectivity remains elusive. Here, using docking simulation and site-directed mutagenesis, we defined Tyr-308 as the key amino acid residue on beta(2)-AR essential for G(s)-biased signaling. Following stimulation with a beta(2)-AR-G(s)-biased agonist (R,R')-4'-aminofenoterol, the G(i) disruptor pertussis toxin produced no effects on the receptor-mediated ERK phosphorylation in HEK293 cells nor on the contractile response in cardiomyocytes expressing the wild-type beta(2)-AR. Interestingly, Y308F substitution on beta(2)-AR enabled (R,R')-4'-aminofenoterol to activate G(i) and to produce these responses in a pertussis toxin-sensitive manner without altering beta(2)-AR phosphorylation by PKA or G protein-coupled receptor kinases. These results indicate that, in addition to the phosphorylation status, the intrinsic structural feature of beta(2)-AR plays a crucial role in the receptor coupling selectivity to G proteins. We conclude that specific interactions between the ligand and the Tyr-308 residue of beta(2)-AR stabilize receptor conformations favoring the receptor-G(s) protein coupling and subsequently result in G(s)-biased agonism. C1 [Woo, Anthony Yiu-Ho; Huang, Ying; Song, Ying] Peking Univ, Shenzhen Grad Sch, Sch Chem Biol & Biotechnol, Key Lab Chem Genom, Shenzhen 518055, Peoples R China. [Woo, Anthony Yiu-Ho; Huang, Ying; Song, Ying; Xiao, Rui-Ping] Peking Univ, Inst Mol Med, Ctr Life Sci, Beijing 100871, Peoples R China. [Woo, Anthony Yiu-Ho] NIA, Lab Cardiovasc Sci, NIH, Baltimore, MD 21224 USA. [Paul, Rajib K.; Bernier, Michel; Wainer, Irving W.] NIA, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. [Jozwiak, Krzysztof; Plazinska, Anita; Pajak, Karolina] Med Univ Lublin, Dept Chem, Lublin, Poland. [Toll, Lawrence] Torrey Pines Inst Mol Studies, Port St Lucie, FL 34987 USA. [Tanga, Mary J.; Kozocas, Joseph A.; Jimenez, Lucita] SRI Int, Menlo Pk, CA 94025 USA. RP Woo, AYH (reprint author), Peking Univ, Shenzhen Grad Sch, Sch Chem Biol & Biotechnol, Shenzhen 518055, Peoples R China. EM yiuhowoo@pkusz.edu.cn; xiaor@pku.edu.cn RI Woo, Anthony/D-4305-2014; OI Woo, Anthony/0000-0003-0662-698X; Bernier, Michel/0000-0002-5948-368X FU National Institutes of Health Intramural Research Program from NIA; National Institutes of Health from NIA [N01-AG31009]; National Basic Research Program of China [2012CB518000]; National Science Foundation of China [31221002]; National Major Scientific Research Program of China [2012CB910402]; National Scientific Technology Major Project of China [2013ZX09507001]; Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University; Foundation for Polish Science [TEAM 2009-4/5] FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program from NIA (to A. Y. H. W., R. K. P., M. B., and I. W. W.) and by National Institutes of Health Grant N01-AG31009 from NIA. This work was also supported by National Basic Research Program of China Grant 2012CB518000 and National Science Foundation of China Project 31221002 (to R. P. X.), National Major Scientific Research Program of China Grant 2012CB910402, National Scientific Technology Major Project of China Grant 2013ZX09507001 (to A. Y. H. W.), Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, and Foundation for Polish Science Grant TEAM 2009-4/5 Programs (to K. J.). NR 48 TC 9 Z9 12 U1 1 U2 18 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 11 PY 2014 VL 289 IS 28 BP 19351 EP 19363 DI 10.1074/jbc.M114.558882 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AL7PL UT WOS:000339326800012 PM 24831005 ER PT J AU Karabasheva, D Cole, NB Donaldson, JG AF Karabasheva, Darya Cole, Nelson B. Donaldson, Julie G. TI Roles for Trafficking and O-Linked Glycosylation in the Turnover of Model Cell Surface Proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SOLUBLE INTERLEUKIN-2 RECEPTOR; ANCHORED MEMBRANE-PROTEIN; ALPHA-CONVERTING ENZYME; DI-LEUCINE MOTIF; ENDOCYTIC PATHWAY; PLASMA-MEMBRANE; TRANSFERRIN RECEPTOR; TARGETING SIGNAL; CYTOPLASMIC TAIL; FUSION PROTEINS AB Proteins targeted to the plasma membrane (PM) of cells are degraded at different rates. Sorting motifs contained within the cytoplasmic domains of transmembrane proteins, post-translational modifications (e. g. ubiquitination), and assembly into multiprotein or protein-lipid complexes all may affect the efficiency of endocytosis and recycling and influence the delivery to degradative compartments. Using the SNAP-tag labeling system, we examined the turnover of a model PM protein, the alpha chain of the interleukin-2 receptor (Tac). The surface lifetimes of SNAP-Tac fusions were influenced by their mode of entry into cells (clathrin-dependent versus clathrin-independent), their orientation in the PM (transmembrane versus glycosylphosphatidylinositol-anchored), and ubiquitination in their cytosolic domains. In addition, shedding of SNAP-Tac into the medium was greatly influenced by its O-linked glycosylation status. For a number of PM proteins, delivery to lysosomes and ectodomain shedding represent distinct parallel mechanisms to determine protein half-life. C1 [Karabasheva, Darya; Cole, Nelson B.; Donaldson, Julie G.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Cole, NB (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM ncole@mail.nih.gov FU National Institutes of Health from the Intramural Research Program in the NHLBI [HL006060] FX This work was supported, in whole or in part, by National Institutes of Health Grant HL006060 from the Intramural Research Program in the NHLBI. NR 64 TC 3 Z9 4 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 11 PY 2014 VL 289 IS 28 BP 19477 EP 19490 DI 10.1074/jbc.M114.564666 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AL7PL UT WOS:000339326800023 PM 24891503 ER PT J AU Maldarelli, F Wu, X Su, L Simonetti, FR Shao, W Hill, S Spindler, J Ferris, AL Mellors, JW Kearney, MF Coffin, JM Hughes, SH AF Maldarelli, F. Wu, X. Su, L. Simonetti, F. R. Shao, W. Hill, S. Spindler, J. Ferris, A. L. Mellors, J. W. Kearney, M. F. Coffin, J. M. Hughes, S. H. TI Specific HIV integration sites are linked to clonal expansion and persistence of infected cells SO SCIENCE LA English DT Article ID CD4(+) T-CELLS; ANTIRETROVIRAL THERAPY; RESERVOIR; GENES; CURE; IDENTIFICATION; LYMPHOMAS; DYNAMICS; DNA AB The persistence of HIV-infected cells in individuals on suppressive combination antiretroviral therapy (cART) presents a major barrier for curing HIV infections. HIV integrates its DNA into many sites in the host genome; we identified 2410 integration sites in peripheral blood lymphocytes of five infected individuals on cART. About 40% of the integrations were in clonally expanded cells. Approximately 50% of the infected cells in one patient were from a single clone, and some clones persisted for many years. There were multiple independent integrations in several genes, including MKL2 and BACH2; many of these integrations were in clonally expanded cells. Our findings show that HIV integration sites can play a critical role in expansion and persistence of HIV-infected cells. C1 [Maldarelli, F.; Simonetti, F. R.; Hill, S.; Spindler, J.; Ferris, A. L.; Kearney, M. F.; Hughes, S. H.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Wu, X.; Su, L.; Shao, W.] Leidos Biomed Res, Frederick, MD 21702 USA. [Simonetti, F. R.] Univ Milan, Dept Biomed & Clin Sci L Sacco, I-20122 Milan, Italy. [Mellors, J. W.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA. [Coffin, J. M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM hughesst@mail.nih.gov FU Federal funds from the National Cancer Institute, an NIH; National Cancer Institute [HSSN261200800001E, 25XS119]; American Cancer Society; F. M. Kirby Foundation FX The authors are indebted to the study participants and to the clinical staff of the National Institute of Allergy and Infectious Diseases/Critical Care Medicine Department clinic who cared for them. We thank C. Lane, H. Malech, H. Imamichi, S. Matsushita, and L. Frenkel for stimulating discussions. We are grateful to J. Meyer and A. Kane for help with the figures and T. Burdette for help in preparing the manuscript. The data presented in this work is tabulated in the main paper and in the supplementary materials. The integration sites are compiled in table S3; the data can also be accessed using the National Center for Biotechnology Information accession no. PRJNA241020. Funding for this research was provided with Federal funds from the National Cancer Institute, an NIH Bench to Bedside award (F. M.), and by funds from the National Cancer Institute under contract HSSN261200800001E (X. W. and L. S.). J. M. C. was supported by a Research Professorship from the American Cancer Society with additional support from the F. M. Kirby Foundation and by funding from the National Cancer Institute (Leidos contract 25XS119). J. W. M. was supported by funding from the National Cancer Institute (Leidos contract 25XS119). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. NR 29 TC 131 Z9 132 U1 4 U2 32 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JUL 11 PY 2014 VL 345 IS 6193 BP 179 EP 183 DI 10.1126/science.1254194 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL8SS UT WOS:000339409900044 PM 24968937 ER PT J AU Huang, RL Sakamuru, S Martin, MT Reif, DM Judson, RS Houck, KA Casey, W Hsieh, JH Shockley, KR Ceger, P Fostel, J Witt, KL Tong, WD Rotroff, DM Zhao, TG Shinn, P Simeonov, A Dix, DJ Austin, CP Kavlock, RJ Tice, RR Xia, MH AF Huang, Ruili Sakamuru, Srilatha Martin, Matt T. Reif, David M. Judson, Richard S. Houck, Keith A. Casey, Warren Hsieh, Jui-Hua Shockley, Keith R. Ceger, Patricia Fostel, Jennifer Witt, Kristine L. Tong, Weida Rotroff, Daniel M. Zhao, Tongan Shinn, Paul Simeonov, Anton Dix, David J. Austin, Christopher P. Kavlock, Robert J. Tice, Raymond R. Xia, Menghang TI Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway SO SCIENTIFIC REPORTS LA English DT Article ID BREAST-CANCER CELLS; IN-VITRO ASSAYS; PYRETHROID INSECTICIDES; ANTIESTROGENIC ACTIVITY; ANDROGENIC ACTIVITY; IONIC LIQUIDS; HUMAN HEALTH; CHEMICALS; PHYTOESTROGENS; MECHANISMS AB The U.S. Tox21 program has screened a library of approximately 10,000 (10K) environmental chemicals and drugs in three independent runs for estrogen receptor alpha (ER alpha) agonist and antagonist activity using two types of ER reporter gene cell lines, one with an endogenous full length ER alpha (ER-luc; BG1 cell line) and the other with a transfected partial receptor consisting of the ligand binding domain (ER-bla; ER alpha beta-lactamase cell line), in a quantitative high-throughput screening (qHTS) format. The ability of the two assays to correctly identify ER alpha agonists and antagonists was evaluated using a set of 39 reference compounds with known ERa activity. Although both assays demonstrated adequate (i.e. 80%) predictivity, the ER-luc assay was more sensitive and the ER-bla assay more specific. The qHTS assay results were compared with results from previously published ER alpha binding assay data and showed >80% consistency. Actives identified from both the ER-bla and ER-luc assays were analyzed for structure-activity relationships (SARs) revealing known and potentially novel ERa active structure classes. The results demonstrate the feasibility of qHTS to identify environmental chemicals with the potential to interact with the ERa signaling pathway and the two different assay formats improve the confidence in correctly identifying these chemicals. C1 [Huang, Ruili; Sakamuru, Srilatha; Zhao, Tongan; Shinn, Paul; Simeonov, Anton; Austin, Christopher P.; Xia, Menghang] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Martin, Matt T.; Reif, David M.; Judson, Richard S.; Houck, Keith A.; Rotroff, Daniel M.; Dix, David J.; Kavlock, Robert J.] US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Casey, Warren; Hsieh, Jui-Hua; Shockley, Keith R.; Fostel, Jennifer; Witt, Kristine L.; Tice, Raymond R.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Ceger, Patricia] ILS Inc, Res Triangle Pk, NC 27709 USA. [Tong, Weida] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Huang, RL (reprint author), NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. EM huangru@mail.nih.gov OI Judson, Richard/0000-0002-2348-9633; Reif, David/0000-0001-7815-6767 FU Intramural Research Programs of the National Toxicology Program [Y2-ES-7020-01]; National Institute of Environmental Health Sciences; U.S. Environmental Protection Agency [Y3-HG-7026-03]; National Center for Advancing Translational Sciences, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Toxicology Program (Interagency agreement #Y2-ES-7020-01), the National Institute of Environmental Health Sciences, the U.S. Environmental Protection Agency (Interagency Agreement #Y3-HG-7026-03), and the National Center for Advancing Translational Sciences, National Institutes of Health. We would also like to thank Samuel Michael for assisting with the screens, Misha Itkin and Danielle VanLeer for compound management, William Leister for the Tox21 10K library quality control, and Drs. Kevin Crofton, Rusty Thomas and John Bucher for critical review of this manuscript. The views expressed in this article are those of the authors and do not necessarily reflect the statements, opinions, views, conclusions, or policies of the National Institute of Environmental Health Sciences, National Center for Advancing Translational Sciences, National Institutes of Health, U.S. Environmental Protection Agency, or the United States government. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. NR 56 TC 27 Z9 29 U1 3 U2 35 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 11 PY 2014 VL 4 AR 5664 DI 10.1038/srep05664 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL0PJ UT WOS:000338828500005 PM 25012808 ER PT J AU Lee, DW Gardner, R Porter, DL Louis, CU Ahmed, N Jensen, M Grupp, SA Mackall, CL AF Lee, Daniel W. Gardner, Rebecca Porter, David L. Louis, Chrystal U. Ahmed, Nabil Jensen, Michael Grupp, Stephan A. Mackall, Crystal L. TI Current concepts in the diagnosis and management of cytokine release syndrome SO BLOOD LA English DT Review ID MACROPHAGE ACTIVATION SYNDROME; ANTI-INTERLEUKIN-6 RECEPTOR ANTIBODY; CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; C-REACTIVE PROTEIN; T-CELLS; MONOCLONAL-ANTIBODY; RHEUMATOID-ARTHRITIS; CASTLEMAN-DISEASE; RANDOMIZED-TRIAL AB As immune-based therapies for cancer become potent, more effective, and more widely available, optimal management of their unique toxicities becomes increasingly-important. Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that has been observed following administration of natural and bispecific antibodies and, more recently, following adoptive T-cell therapies for cancer. CRS is associated with elevated circulating levels of several cytokines including interleukin (IL)-6 and interferon g, and uncontrolled studies demonstrate that immunosuppression using tocilizumab, an anti-IL-6 receptor antibody, with or without corticosteroids, can reverse the syndrome. However, because early and aggressive immunosuppression could limit the efficacy of the immunotherapy, current approaches seek to limit administration of immunosuppressive therapy to patients at risk for life-threatening consequences of the syndrome. This report presents a novel system to grade the severity of CRS in individual patients and a treatment algorithm for management of CRS based on severity. The goal of our approach is to maximize the chance for therapeutic benefit from the immunotherapy while minimizing the risk for life threatening complications of CRS. C1 [Lee, Daniel W.; Mackall, Crystal L.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Gardner, Rebecca; Jensen, Michael] Seattle Childrens Hosp, Seattle, WA USA. [Porter, David L.; Grupp, Stephan A.] Univ Penn, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Louis, Chrystal U.; Ahmed, Nabil] Texas Childrens Hosp, Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Grupp, Stephan A.] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Mackall, CL (reprint author), NCI, Pediat Oncol Branch, 10 CRC,1W-3750,10 Ctr Dr,MSC 1104, Bethesda, MD 20892 USA. EM mackallc@mail.nih.gov FU National Cancer Institute, National Institutes of Health; St. Baldrick's Foundation; Stand Up To Cancer-St. Baldrick's Pediatric Dream Team Translational Cancer Research Grant FX This work was supported, in part, by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. D.W.L. receives research support from the St. Baldrick's Foundation. Research was also supported by a Stand Up To Cancer-St. Baldrick's Pediatric Dream Team Translational Cancer Research Grant. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. NR 51 TC 154 Z9 159 U1 5 U2 23 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 10 PY 2014 VL 124 IS 2 BP 188 EP 195 DI 10.1182/blood-2014-05-552729 PG 8 WC Hematology SC Hematology GA AQ2LV UT WOS:000342618600011 PM 24876563 ER PT J AU Sharma, K Sharma, NK Anand, A AF Sharma, Kaushal Sharma, Neel Kamal Anand, Akshay TI Why AMD is a disease of ageing and not of development: mechanisms and insights SO FRONTIERS IN AGING NEUROSCIENCE LA English DT Review DE age related macular degeneration; metabolism; 7-ketocholesterol; angiogenic proteins; VEGF; degenerative diseases; complement factors; developmental disorders ID ENDOTHELIAL GROWTH-FACTOR; LOW-DENSITY-LIPOPROTEIN; HUMAN BRUCHS MEMBRANE; E-DEFICIENT MICE; MACULAR DEGENERATION; APOLIPOPROTEIN-E; ALZHEIMERS-DISEASE; CHOROIDAL NEOVASCULARIZATION; CRYSTALLINE CHOLESTEROL; COMPLEMENT ACTIVATION AB Ageing disorders can be defined as the progressive and cumulative outcome of several defective cellular mechanisms as well as metabolic pathways, consequently resulting in degeneration. Environment plays an important role in its pathogenesis. In contrast, developmental disorders arise from inherited mutations and usually the role of environmental factors in development of disease is minimal. Age related macular degeneration (AMD) is one such retinal degenerative disorder which starts with the progression of age. Metabolism plays an important role in initiation of such diseases of ageing. Cholesterol metabolism and their oxidized products like 7-ketocholesterol have been shown to adversely impact retinal pigment epithelium (RPE) cells. These molecules can initiate mitochondrial apoptotic processes and also influence the complements factors and expression of angiogenic proteins like VEGF etc. In this review we highlight why and how AMD is an ageing disorder and not a developmental disease substantiated by disrupted cholesterol metabolism common to several age related diseases. C1 [Sharma, Kaushal; Anand, Akshay] Post Grad Inst Med Educ & Res, Dept Neurol, Neurosci Res Lab, Chandigarh, India. [Sharma, Neel Kamal] NEI, Neurobiol Neurodegenerat & Repair Lab, Bethesda, MD 20892 USA. RP Anand, A (reprint author), Post Grad Inst Med Educ & Res, Dept Neurol, Neurosci Res Lab, Chandigarh, India. EM akshay1anand@rediffmail.com NR 86 TC 14 Z9 14 U1 0 U2 3 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1663-4365 J9 FRONT AGING NEUROSCI JI Front. Aging Neurosci. PD JUL 10 PY 2014 VL 6 AR 151 DI 10.3389/fnagi.2014.00151 PG 11 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA AN8ZT UT WOS:000340895600001 PM 25071560 ER PT J AU Holmes, MV Dale, CE Zuccolo, L Silverwood, RJ Guo, Y Ye, Z Prieto-Merino, D Dehghan, A Trompet, S Wong, A Cavadino, A Drogan, D Padmanabhan, S Li, S Yesupriya, A Leusink, M Sundstrom, J Hubacek, JA Pikhart, H Swerdlow, DI Panayiotou, AG Borinskaya, SA Finan, C Shah, S Kuchenbaecker, KB Shah, T Engmann, J Folkersen, L Eriksson, P Ricceri, F Melander, O Sacerdote, C Gamble, DM Rayaprolu, S Ross, OA McLachlan, S Vikhireva, O Sluijs, I Scott, RA Adamkova, V Flicker, L Van Bockxmeer, FM Power, C Marques-Vidal, P Meade, T Marmot, MG Ferro, JM Paulos-Pinheiro, S Humphries, SE Talmud, PJ Leach, IM Verweij, N Linneberg, A Skaaby, T Doevendans, PA Cramer, MJ Van der Harst, P Klungel, OH Dowling, NF Dominiczak, AF Kumari, M Nicolaides, AN Weikert, C Boeing, H Ebrahim, S Gaunt, TR Price, JF Lannfelt, L Peasey, A Kubinova, R Pajak, A Malyutina, S Voevoda, MI Tamosiunas, A Maitland-van der Zee, AH Norman, PE Hankey, GJ Bergmann, MM Hofman, A Franco, OH Cooper, J Palmen, J Spiering, W de Jong, PA Kuh, D Hardy, R Uitterlinden, AG Ikram, MA Ford, I Hyppoenen, E Almeida, OP Wareham, NJ Khaw, KT Hamsten, A Husemoen, LLN Tjonneland, A Tolstrup, JS Rimm, E Beulens, JWJ Verschuren, WMM Onland-Moret, NC Hofker, MH Wannamethee, SG Whincup, PH Morris, R Vicente, AM Watkins, H Farrall, M Jukema, JW Meschia, J Cupples, LA Sharp, SJ Fornage, M Kooperberg, C LaCroix, AZ Dai, JY Lanktree, MB Siscovick, DS Jorgenson, E Spring, B Coresh, J Li, YR Buxbaum, SG Schreiner, PJ Ellison, RC Tsai, MY Patel, SR Redline, S Johnson, AD Hoogeveen, RC Rotter, JI Boerwinkle, E de Bakker, PIW Kivimaki, M Asselbergs, FW Sattar, N Lawlor, DA Whittaker, J Smith, GD Mukamal, K Psaty, BM Wilson, JG Lange, LA Hamidovic, A Hingorani, AD Nordestgaard, BG Bobak, M Leon, DA Langenberg, C Palmer, TM Reiner, AP Keating, BJ Dudbridge, F Casas, JP AF Holmes, Michael V. Dale, Caroline E. Zuccolo, Luisa Silverwood, Richard J. Guo, Yiran Ye, Zheng Prieto-Merino, David Dehghan, Abbas Trompet, Stella Wong, Andrew Cavadino, Alana Drogan, Dagmar Padmanabhan, Sandosh Li, Shanshan Yesupriya, Ajay Leusink, Maarten Sundstrom, Johan Hubacek, Jaroslav A. Pikhart, Hynek Swerdlow, Daniel I. Panayiotou, Andrie G. Borinskaya, Svetlana A. Finan, Chris Shah, Sonia Kuchenbaecker, Karoline B. Shah, Tina Engmann, Jorgen Folkersen, Lasse Eriksson, Per Ricceri, Fulvio Melander, Olle Sacerdote, Carlotta Gamble, Dale M. Rayaprolu, Sruti Ross, Owen A. McLachlan, Stela Vikhireva, Olga Sluijs, Ivonne Scott, Robert A. Adamkova, Vera Flicker, Leon Van Bockxmeer, Frank M. Power, Christine Marques-Vidal, Pedro Meade, Tom Marmot, Michael G. Ferro, Jose M. Paulos-Pinheiro, Sofia Humphries, Steve E. Talmud, Philippa J. Leach, Irene Mateo Verweij, Niek Linneberg, Allan Skaaby, Tea Doevendans, Pieter A. Cramer, Maarten J. Van der Harst, Pim Klungel, Olaf H. Dowling, Nicole F. Dominiczak, Anna F. Kumari, Meena Nicolaides, Andrew N. Weikert, Cornelia Boeing, Heiner Ebrahim, Shah Gaunt, Tom R. Price, Jackie F. Lannfelt, Lars Peasey, Anne Kubinova, Ruzena Pajak, Andrzej Malyutina, Sofia Voevoda, Mikhail I. Tamosiunas, Abdonas Maitland-van der Zee, Anke H. Norman, Paul E. Hankey, Graeme J. Bergmann, Manuela M. Hofman, Albert Franco, Oscar H. Cooper, Jackie Palmen, Jutta Spiering, Wilko de Jong, Pim A. Kuh, Diana Hardy, Rebecca Uitterlinden, Andre G. Ikram, M. Arfan Ford, Ian Hyppoenen, Elina Almeida, Osvaldo P. Wareham, Nicholas J. Khaw, Kay-Tee Hamsten, Anders Husemoen, Lise Lotte N. Tjonneland, Anne Tolstrup, Janne S. Rimm, Eric Beulens, Joline W. J. Verschuren, W. M. Monique Onland-Moret, N. Charlotte Hofker, Marten H. Wannamethee, S. Goya Whincup, Peter H. Morris, Richard Vicente, Astrid M. Watkins, Hugh Farrall, Martin Jukema, J. Wouter Meschia, James Cupples, L. Adrienne Sharp, Stephen J. Fornage, Myriam Kooperberg, Charles LaCroix, Andrea Z. Dai, James Y. Lanktree, Matthew B. Siscovick, David S. Jorgenson, Eric Spring, Bonnie Coresh, Josef Li, Yun R. Buxbaum, Sarah G. Schreiner, Pamela J. Ellison, R. Curtis Tsai, Michael Y. Patel, Sanjay R. Redline, Susan Johnson, Andrew D. Hoogeveen, Ron C. Rotter, Jerome I. Boerwinkle, Eric de Bakker, Paul I. W. Kivimaki, Mika Asselbergs, Folkert W. Sattar, Naveed Lawlor, Debbie A. Whittaker, John Smith, George Davey Mukamal, Kenneth Psaty, Bruce M. Wilson, James G. Lange, Leslie A. Hamidovic, Ajna Hingorani, Aroon D. Nordestgaard, Borge G. Bobak, Martin Leon, David A. Langenberg, Claudia Palmer, Tom M. Reiner, Alex P. Keating, Brendan J. Dudbridge, Frank Casas, Juan P. CA IMPROVE Study Grp InterAct Consortium TI Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID CORONARY-HEART-DISEASE; RISK-FACTORS; CONSUMPTION; METAANALYSIS; HEALTH; DEHYDROGENASE; DEPENDENCE; MORTALITY; VARIANTS; DESIGN AB Objective To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. Design Mendelian randomisation meta-analysis of 56 epidemiological studies. Participants 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. Main outcome measures Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. Results Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P= 0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). Conclusions Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health. C1 [Holmes, Michael V.; Swerdlow, Daniel I.; Finan, Chris; Shah, Tina; Engmann, Jorgen; Kumari, Meena; Hingorani, Aroon D.; Casas, Juan P.] UCL, Dept Epidemiol & Publ Hlth, Inst Cardiovasc Sci, Genet Epidemiol Grp, London WC1E 6BT, England. [Holmes, Michael V.; Keating, Brendan J.] Univ Penn, Perelman Sch Med, Penn Transplant Inst, Dept Surg, Philadelphia, PA 19104 USA. [Holmes, Michael V.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Dale, Caroline E.; Silverwood, Richard J.; Prieto-Merino, David; Meade, Tom; Ebrahim, Shah; Whittaker, John; Leon, David A.; Dudbridge, Frank; Casas, Juan P.] Univ London London Sch Hyg & Trop Med, Fac Epidemiol & Publ Hlth, London WC1E 7HT, England. [Zuccolo, Luisa; Gaunt, Tom R.; Lawlor, Debbie A.; Smith, George Davey] Univ Bristol, MRC Integrat Epidemiol Unit IEU, Bristol BS8 2BN, Avon, England. [Silverwood, Richard J.] Univ London London Sch Hyg & Trop Med, Ctr Stat Methodol, London WC1E 7HT, England. [Guo, Yiran; Li, Yun R.; Keating, Brendan J.] Childrens Hosp Philadelphia, Abramson Res Ctr, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Guo, Yiran] BGI Shenzhen, Shenzhen 518083, Peoples R China. [Ye, Zheng; Scott, Robert A.; Wareham, Nicholas J.; Sharp, Stephen J.; Langenberg, Claudia] Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England. [Dehghan, Abbas; Hofman, Albert; Uitterlinden, Andre G.; Ikram, M. Arfan] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RA Leiden, Netherlands. [Wong, Andrew; Kuh, Diana; Hardy, Rebecca] UCL, MRC Unit Lifelong Hlth & Ageing, London, England. [Cavadino, Alana; Power, Christine; Hyppoenen, Elina] UCL Inst Child Hlth, Ctr Paediat Epidemiol & Biostat, London, England. [Drogan, Dagmar; Weikert, Cornelia; Boeing, Heiner; Bergmann, Manuela M.] German Inst Human Nutr Potsdam Rehbrucke, D-14558 Nuthetal, Germany. [Padmanabhan, Sandosh; Dominiczak, Anna F.] Univ Glasgow, Coll Med Vet & Life Sci, Inst Cardiovasc & Med Sci, Glasgow G12 8TA, Lanark, Scotland. [Li, Shanshan] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Yesupriya, Ajay; Dowling, Nicole F.] Ctr Dis Control & Prevent, Off Epidemiol Surveillance & Lab Serv, Off Publ Hlth Genom, Atlanta, GA 30333 USA. [Leusink, Maarten; Klungel, Olaf H.; Maitland-van der Zee, Anke H.] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands. [Sundstrom, Johan] Uppsala Univ, Univ Uppsala Hosp, Dept Med Sci, SE-75185 Uppsala, Sweden. [Hubacek, Jaroslav A.] Inst Clin & Expt Med, Ctr Med Expt, Prague 14021 4, Czech Republic. [Pikhart, Hynek; Vikhireva, Olga; Peasey, Anne; Kivimaki, Mika; Bobak, Martin] UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England. [Panayiotou, Andrie G.] Cyprus Univ Technol, Cyprus Int Inst Environm & Publ Hlth Assoc Harvar, CY-3603 Limassol, Cyprus. [Borinskaya, Svetlana A.] Russian Acad Sci, Vavilov Inst Gen Genet, Moscow, Russia. [Shah, Sonia] UCL Genet Inst, Dept Genet Environm & Evolut, London WC1E 6BT, England. [Kuchenbaecker, Karoline B.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Folkersen, Lasse; Eriksson, Per; Hamsten, Anders] Karolinska Inst, Dept Med, Ctr Mol Med, Atherosclerosis Res Unit, Stockholm, Sweden. [Melander, Olle] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Ricceri, Fulvio; Sacerdote, Carlotta] San Giovanni Battista Hosp, Unit Canc Epidemiol, I-10129 Turin, Italy. [Ricceri, Fulvio; Sacerdote, Carlotta] Ctr Canc Prevent CPO Piemonte, I-10129 Turin, Italy. [Gamble, Dale M.; Meschia, James] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Rayaprolu, Sruti; Ross, Owen A.] Mayo Clin Florida, Dept Neurosci, Jacksonville, FL USA. [McLachlan, Stela; Price, Jackie F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Sluijs, Ivonne; Beulens, Joline W. J.; Onland-Moret, N. Charlotte; de Bakker, Paul I. W.] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Adamkova, Vera] Inst Clin & Expt Med, Dept Prevent Cardiol, Prague 14021 4, Czech Republic. 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W.] Univ Med Ctr Utrecht, Ctr Mol Med, Dept Med Genet, Utrecht, Netherlands. [Asselbergs, Folkert W.] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England. [Sattar, Naveed] Univ Glasgow, British Heart Fdn Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Whittaker, John] GlaxoSmithKline, Genet, R&D, Stevenage, Herts, England. [Patel, Sanjay R.; Mukamal, Kenneth] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol & Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Lange, Leslie A.] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC 27514 USA. [Hamidovic, Ajna] Univ New Mexico, Coll Pharm, Albuquerque, NM 87131 USA. [Nordestgaard, Borge G.] Herlev Hosp, Copenhagen Gen Populat Study, Copenhagen, Denmark. [Nordestgaard, Borge G.] Univ Copenhagen, Copenhagen Univ Hosp, Fac Hlth Sci, Copenhagen, Denmark. [Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Copenhagen, Denmark. [Palmer, Tom M.] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England. RP Casas, JP (reprint author), Univ London London Sch Hyg & Trop Med, Fac Epidemiol & Publ Hlth, Keppel St, London WC1E 7HT, England. EM Juan-P.Casas@lshtm.ac.uk RI Johnson, Andrew/G-6520-2013; Padmanabhan, Sandosh/S-3963-2016; Verweij, Niek/A-4499-2017; Silverwood, Richard/A-1249-2014; Amato, Mauro/J-3289-2016; Shah, Sonia/N-7547-2013; Klungel, Olaf/I-9563-2016; Hankey, Graeme /H-4968-2014; Hypponen, Elina/B-2596-2014; Gaunt, Tom/O-3918-2014; de Bakker, Paul/B-8730-2009; Guo, Yiran/H-4120-2011; de Jong, Pim/G-7220-2014; Onland-Moret, N. Charlotte/G-9185-2011; Sundstrom, Johan/A-6286-2009; Dai, Jiyan/I-7098-2013 OI Watkins, Hugh/0000-0002-5287-9016; Marmot, Michael/0000-0002-2431-6419; Lawlor, Debbie A/0000-0002-6793-2262; Prieto-Merino, David/0000-0001-5001-0061; Morris, Richard/0000-0001-7240-4563; Dehghan, Abbas/0000-0001-6403-016X; Linneberg, Allan/0000-0002-0994-0184; Skaaby, Tea/0000-0003-0031-5726; Swerdlow, Daniel/0000-0002-7946-3459; Padmanabhan, Sandosh/0000-0003-3869-5808; Folkersen, Lasse/0000-0003-0708-9530; Humphries, Stephen E/0000-0002-8221-6547; Tolstrup, Janne/0000-0002-9796-3967; Patel, Sanjay/0000-0002-9142-5172; Kumari, Meena/0000-0001-9716-1035; Verweij, Niek/0000-0002-4303-7685; Sacerdote, Carlotta/0000-0002-8008-5096; Lanktree, Matthew/0000-0002-5750-6286; Pikhart, Hynek/0000-0001-5277-4049; Silverwood, Richard/0000-0002-2744-1194; Kivimaki, Mika/0000-0002-4699-5627; Whincup, Peter/0000-0002-5589-4107; Talmud, Philippa/0000-0002-5560-1933; Zuccolo, Luisa/0000-0002-7049-3037; Amato, Mauro/0000-0002-0118-5719; Shah, Sonia/0000-0001-5860-4526; Hankey, Graeme /0000-0002-6044-7328; Hypponen, Elina/0000-0003-3670-9399; Gaunt, Tom/0000-0003-0924-3247; de Bakker, Paul/0000-0001-7735-7858; Guo, Yiran/0000-0002-6549-8589; de Jong, Pim/0000-0003-4840-6854; Sundstrom, Johan/0000-0003-2247-8454; Dai, Jiyan/0000-0002-7720-8032 FU UK Medical Research Council (MRC) population health scientist fellowship [G0802432]; NWO [916.12.154]; EUR Fellowship; Mayo Foundation for Medical Education and Research; Medical Research Council; British Heart Foundation; Economic and Social Research Council; National Heart Lung and Blood Institute [NHLBI: HL36310, HL 114901]; National Institute on Aging [AG13196]; US, NIH; Netherlands Heart Foundation [2001 D 032, 2014T001]; James and Ester King Foundation; Florida State Department of Health; American Heart Association; Myron and Jane Hanley Award in Stroke research; Medical Research Council Professorship; Swedish Heart-Lung Foundation [20041151]; Swedish Research Council [2007-5942, 8691, 0593]; NIH National Heart Lung and Blood Institute [HHSN268200900009C]; MRC [G1000718]; UCL MBPhD; MH CZ - DRO ("Institute for Clinical and Experimental Medicine - IKEM) [IN 00023001]; UK Economic and Social Research Council (NCRM) [ES/I025561/2]; British Heart Foundation [PG/2008/008]; Medical Research Council [MC_UU_12019/1, MRC G0601653, G0000934]; National Institute of Health Research University College London Hospitals Biomedical Research Centre; National Institute on Alcohol Abuse and Alcoholism [NIAAA: AA021223-01]; MD Scientist Fellowship in Genetic Medicine (Northwestern Memorial Foundation); National Research Service Award (NIH/NIDA) [F32DA024920]; NIH [HL075451]; BHF [RG/10/12/28456]; UK Medical Research Council [MC_UU_12013/1, MC_UU_12013/5, 092731]; National Institute on Minority Health and Health Disparities of the National Institutes of Health [P20MD006899]; Wellcome Trust [092731, WT088806, WT087997MA]; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005]; NIH Roadmap for Medical Research; British Heart Foundation (BHF) [PG/09/022, PG/07/131/24254, RG/08/013/25942, RG/98002, RG2008/014, RG/07/005/23633]; UK Department of Health Policy Research Programme (England) [0090049]; National Heart, Lung and Blood Institute; NHLBI [HHSN268200960009C]; National Heart, Lung, and Blood Institute/National Institutes of Health [N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-95095]; National Heart, Lung, and Blood Institute (NHLBI) [HL46380, HHSN268201200036C, HHSN268200800007C, N01 HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC65226, HL080295]; Herlev Hospital; Copenhagen University Hospital; Copenhagen County Research Fund; Danish Medical Research Council; National Institute on Aging (NIA) [AG023629]; Cyprus Cardiovascular Disease Educational and Research Trust (CCDERT); Joint Cyprus Research Promotion Foundation, Ministry of Health; Cyprus Heart Foundation [41/5PE]; Research Promotion Foundation [PENEK 05/04, YGEIA 04/06]; National Institute on Ageing (NIA) [AG1764406S1]; European Union of the European Community [LSHM-CT-2006-037197]; European Commission: Public Health and Consumer Protection Directorate; Dutch Ministry of Public Health, Welfare and Sports; Netherlands Cancer Registry; LK Research Funds; Dutch Prevention Funds; Dutch Zorg Onderzoek Nederland; World Cancer Research Fund (The Netherlands); 'Europe against Cancer' Programme of the European Commission (SANCO); Dutch Ministry of Public Health, Welfare and Sports (VWS); Netherlands Cancer Registry (NKR); Dutch Cancer Society; ZonMW the Netherlands Organisation for Health Research and Development; World Cancer Research Fund (WCRF) (The Netherlands); IOP Genomics grant from Agentschap NL [IGE05012]; Cancer Research UK; Federal Ministry of Science, Germany [01 EA 9401]; European Union [SOC 95201408 05F02]; German Cancer Aid [70-2488-Ha I]; European Community [SOC 98200769 05F02]; Federal Ministry of Education and Research [0312750B]; German Research Federal Ministry (BMBF); Heisenberg-Professorship [SP716/1-1]; German Research Foundation (DFG) [KFO192/1, 218/1]; graduate school of the DFG [GK1208]; Associazione Italiana per le Ricerche sul Cancro, Italy; Compagnia di San Paolo, Turin, Italy; Wellcome Trust 'Determinants of Cardiovascular Diseases in Eastern Europe: A multi-centre cohort study' [064947/Z/01/Z, 081081/Z/06/Z]; MacArthur Foundation 'MacArthur Initiative on Social Upheaval and Health' [712058]; National Institute on Ageing 'Health disparities and aging in societies in transition (the HAPIEE study)' [1R01 AG23522]; Ministry of Health, Czech Republic [00023001]; National Health and Medical Research Council (NHMRC) [279408, 379600, 403963, 513823, 634492]; National Institute of Health, Bethesda; M. D [HL35464, CA55075, CA87969, AA11181, HL34594]; European Commission [QLG1-CT-2002-00896]; Ministero della Salute Ricerca Corrente, Italy; Swedish Heart-Lung Foundation; Foundation for Strategic Research; Stockholm County Council [562183]; Academy of Finland [110413, 12926]; Danish Centre for Evaluation and Health Technology Assessment; Copenhagen County; Danish Heart Foundation; Danish Pharmaceutical Association; Health Insurance Foundation; Augustinus Foundation; Ib Henriksens foundation; Beckett Foundation; Danish Diabetes Association [32]; Health Insurance Foundation [2010 B 131]; ISGS/SWISS: ISGS - National Institute of Neurological Disorders and Stroke (US) [R01 42733]; SWISS - National Institute of Neurological Disorders and Stroke (US) [R01 NS39987]; UK Wellcome Trust [078557]; Swedish Medical Research Council; Swedish Heart and Lung Foundation; Medical Faculty of Lund University, Malmo University Hospital; Albert Pahlsson Research Foundation; Crafoord foundation; Ernhold Lundstroms Research Foundation; Region Skane; Hulda and Conrad Mossfelt Foundation; King Gustaf V and Queen Victoria Foundation; Lennart Hanssons Memorial Fund; Marianne and Marcus Wallenberg Foundation; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development; Juvenile Diabetes Research Foundation International (JDRF); MRC; British Medical Research Council; US National Institutes of Health [NHLBI 33014]; Du Pont Pharma, Wilmington, Delaware; Dutch Kidney Foundation [E033]; Netherlands organisation for health research and development (ZonMw) [90.700.441]; Dutch Inter University Cardiology Institute Netherlands (ICIN); EU FP7 Program [LSHM-CT-2007-037273]; AstraZeneca; Oxford BHF Centre of Research Excellence; Wellcome Trust core award [090532/Z/09/Z]; Swedish Research Council; Knut and Alice Wallenberg Foundation; Torsten and Ragnar Soderberg Foundation; Strategic Cardiovascular Program of Karolinska Institutet; Stockholm County Council; Bristol-Myers Squibb; Interuniversity Cardiology Institute of the Netherlands (ICIN); Netherlands Royal Academy of Arts and Sciences (KNAW); Netherlands Heart Foundation; Center for Medical Systems Biology (CMSB); Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) [050-060-810]; Erasmus Medical Center; Erasmus University Rotterdam; Netherlands Organization for Scientific Research (NWO); Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry of Health Welfare and Sports; European Commission; Municipality of Rotterdam; Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; BBMRI-NL; Dutch government (NWO) [184.021.007]; Bayer Corporation; Veni grant Organization for Scientific Research (NWO) [2001.064]; Netherlands Heart Foundation (NHS); TI Pharma [T6-101]; Netherlands Organisation for Health Research and Development (ZonMW); Dutch Health Care Insurance Board (CVZ); Royal Dutch Pharmacists Association (KNMP); Top Institute Pharma; EU Innovative Medicines Initiative (IMI); EU 7th Framework Program (FP7); Dutch Medicines Evaluation Board; Dutch Ministry of Health and industry (GlaxoSmithKline); Dutch Ministry of Health and industry (Pfizer); National Heart Lung and Blood Institute (NHLBI) [HL36310]; National Heart, Lung, and Blood Institute, National Institutes of Health, U. S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; [R01HL087641]; [R01HL59367]; [R01HL086694]; [U01 DK062418] FX Dr Michael V. Holmes is funded by a UK Medical Research Council (MRC) population health scientist fellowship (G0802432). Dr Abbas Dehghan is supported by NWO grant (veni, 916.12.154) and the EUR Fellowship. Dr James Meschia receives support from a Clinical Investigator grant from the Mayo Foundation for Medical Education and Research. Prof Mika Kivimaki was supported by the Medical Research Council; the British Heart Foundation; the Economic and Social Research Council; the National Heart Lung and Blood Institute (NHLBI: HL36310); and the National Institute on Aging (AG13196), US, NIH. Prof. Dr. J. W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Dr Owen Ross is funded by the James and Ester King Foundation and the Florida State Department of Health, the American Heart Association and the Myron and Jane Hanley Award in Stroke research. Prof Sir Michael Marmot is supported by a Medical Research Council Professorship. Dr Johan Sundstrom is supported by the Swedish Heart-Lung Foundation (grant 20041151), the Swedish Research Council (grant 2007-5942). Dr. Alex Reiner was supported by a contract HHSN268200900009C from the NIH National Heart Lung and Blood Institute. Dr James Y. Dai was supported by a R01 grant from the National Heart Lung and Blood Institute (HL 114901). Prof Hugh Watkins and Prof Martin Farrall are members of the Oxford British Heart Foundation (BHF) Centre of Research Excellence. Dr Daniel Swerdlow was supported by a MRC doctoral training award, and acknowledges support of the UCL MBPhD programme. Prof Frank Dudbridge is supported by a MRC grant (G1000718). Dr Jaroslav Hubacek was supported by MH CZ - DRO ("Institute for Clinical and Experimental Medicine - IKEM, IN 00023001"). Dr Richard Silverwood is supported by the UK Economic and Social Research Council (NCRM Pathways node, ES/I025561/2). Professor Steve E. Humphries is supported by the British Heart Foundation (PG/2008/008). Prof Kuh, Prof Hardy and Dr Wong were supported by the Medical Research Council (MC_UU_12019/1). Dr Folkert W. Asselbergs is supported by National Institute of Health Research University College London Hospitals Biomedical Research Centre and Netherlands Heart Foundation (2014T001). Dr. Jorgenson is supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA: AA021223-01). Ajna Hamidovic was funded by MD Scientist Fellowship in Genetic Medicine (Northwestern Memorial Foundation) and the National Research Service Award F32DA024920 (NIH/NIDA; Ajna Hamidovic). Dr. Spring's work is supported by NIH HL075451. This work was supported in part by BHF Programme Grant RG/10/12/28456. Professors Lawlor and Davey Smith and Dr Zuccolo work in a research unit that receives funding from the UK Medical Research Council (MC_UU_12013/1 and MC_UU_12013/5). Dr. Buxbaum's research is supported in part by P20MD006899 awarded by the National Institute on Minority Health and Health Disparities of the National Institutes of Health. Professors Aroon D. Hingorani and Juan P Casas are supported by the National Institute of Health Research University College London Hospitals Biomedical Research Centre.; ALSPAC: We are extremely grateful to all of the families who took part in this study, the midwives for recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The research leading to the specific results from ALSPAC in this paper received funding from the Wellcome Trust (WT088806 and WT087997MA). The UK Medical Research Council and Wellcome Trust (092731), together with the University of Bristol, provide core support for the ALSPAC study. ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research; BWHHS: The British Women's Heart and Health Study has been supported by funding from the British Heart Foundation (BHF) (grant PG/09/022) and the UK Department of Health Policy Research Programme (England) (grant 0090049). The BWHHS HumanCVD data were funded by the BHF (PG/07/131/24254); We thank all BWHHS participants, the general practitioners and their staff who have supported data collection since the study inception; BRHS: The British Regional Heart Study has been supported by programme grant funding from the British Heart Foundation (RG/08/013/25942); CARe: wishes to acknowledge the support of the National Heart, Lung and Blood Institute and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research (NHLBI contract number HHSN268200960009C); CARDIA: CARDIA is supported by contracts N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050 and N01-HC-95095 from the National Heart, Lung, and Blood Institute/National Institutes of Health; CFS: The Cleveland Family Study (CFS) was supported by grant HL46380 from the National Heart, Lung, and Blood Institute (NHLBI); CGPS: This study was supported by Herlev Hospital, Copenhagen University Hospital, The Copenhagen County Research Fund, and The Danish Medical Research Council; CHS: This research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01 HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC65226, and grant HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.; org; Cyprus: The Cyprus Study has been supported by the Cyprus Cardiovascular Disease Educational and Research Trust (CCDERT) and Joint Cyprus Research Promotion Foundation, Ministry of Health and Cyprus Heart Foundation grant No 41/5PE as well as Research Promotion Foundation grants (PENEK 05/04 and YGEIA 04/06); EAS: The EAS was funded by the British Heart Foundation (Programme Grant RG/98002); ELSA: Samples from the English Longitudinal Study of Ageing (ELSA) DNA Repository (EDNAR), received support under a grant (AG1764406S1) awarded by the National Institute on Ageing (NIA). ELSA was developed by a team of researchers based at the National Centre for Social Research, University College London and the Institute of Fiscal Studies. The data were collected by the National Centre for Social Research.; EPIC InterAct: We thank all EPIC participants and staff for their contribution to the study. We thank staff from the Technical, Field Epidemiology and Data Functional Group Teams of the MRC Epidemiology Unit in Cambridge, UK, for carrying out sample preparation, DNA provision and quality control, genotyping and data-handling work. The InterAct study received funding from the European Union (Integrated Project LSHM-CT-2006-037197 in the Framework Programme 6 of the European Community); EPIC Netherlands: We thank Statistics Netherlands and Netherlands Cancer Registry (NKR) for follow-up data on cancer, cardiovascular disease, vital status and causes of death. Supported by the European Commission: Public Health and Consumer Protection Directorate 1993-2004; Research Directorate-General 2005; Dutch Ministry of Public Health, Welfare and Sports; Netherlands Cancer Registry; LK Research Funds; Dutch Prevention Funds; Dutch Zorg Onderzoek Nederland; and World Cancer Research Fund (The Netherlands) (to the European Prospective Investigation into Cancer and Nutrition-Netherlands study). The EPIC-NL study was funded by 'Europe against Cancer' Programme of the European Commission (SANCO), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch Cancer Society; ZonMW the Netherlands Organisation for Health Research and Development, World Cancer Research Fund (WCRF) (The Netherlands). Genotyping was funded by IOP Genomics grant IGE05012 from Agentschap NL; EPIC Norfolk: We thank all study participants and the general practitioners and the EPIC-Norfolk study team for their helpful input. The EPIC-Norfolk study is supported by programme grants from the Medical Research Council and Cancer Research UK; EPIC Potsdam: The recruitment phase of the EPIC-Potsdam Study was supported by the Federal Ministry of Science, Germany (01 EA 9401), and the European Union (SOC 95201408 05F02). The follow-up was supported by the German Cancer Aid (70-2488-Ha I) and the European Community (SOC 98200769 05F02). The present study was supported by the Federal Ministry of Education and Research (0312750B). Mercodia provided the oxLDL kits free of charge. JS and AFHP were supported by German Research Federal Ministry (BMBF), JS was supported by a Heisenberg-Professorship (SP716/1-1) and clinical research groups of the German Research Foundation (DFG; KFO192/1 and 218/1).; JS, AFHP and MM were also supported by a graduate school of the DFG (GK1208); EPIC Turin: The EPIC Turin study is funded by grants from the Associazione Italiana per le Ricerche sul Cancro, Italy and grants from the Compagnia di San Paolo, Turin, Italy; FHS: The Framingham Heart Study began in 1948 with the recruitment of an original cohort of 5,209 men and women (mean age 44 years; 55 percent women). In 1971 a second generation of study participants was enrolled; this cohort consisted of 5,124 children and spouses of children of the original cohort. The mean age of the offspring cohort was 37 years; 52 percent were women. A third generation cohort of 4,095 children of offspring cohort participants (mean age 40 years; 53 percent women) was enrolled beginning in 2002. At each clinic visit, a medical history was obtained with a focus on cardiovascular content, and participants underwent a physical examination including measurement of height and weight from which BMI was calculated; HAPIEE: This study was supported by Wellcome Trust 'Determinants of Cardiovascular Diseases in Eastern Europe: A multi-centre cohort study' [grants 064947/Z/01/Z; and 081081/Z/06/Z]; the MacArthur Foundation 'MacArthur Initiative on Social Upheaval and Health' [grant 712058]; the National Institute on Ageing 'Health disparities and aging in societies in transition (the HAPIEE study)' [grant 1R01 AG23522]; and a project from the Ministry of Health, Czech Republic, for the development of the research organization No. 00023001 (IKEM, Prague, Czech Republic). We would like to thank researchers, interviewers and participants in Novosibirsk, Krakow, Kaunas, Havriov/Karvina, Jihlava, Usti nad Labem, Liberec, Hradec Kralove, and Kromeriz.; HIMS: National Health and Medical Research Council (NHMRC) project grants 279408, 379600, 403963, 513823 and 634492; HPFS/NHS: We would like to thank Hardeep Ranu and Pati Soule from the DF/HCC Genotyping Core for genotyping and data management. This study was supported by research grants HL35464, CA55075, CA87969, AA11181, and HL34594 from the National Institute of Health, Bethesda; M. D; IMPROVE: This study was supported by the European Commission (Contract number: QLG1-CT-2002-00896), Ministero della Salute Ricerca Corrente, Italy, the Swedish Heart-Lung Foundation, the Swedish Research Council (projects 8691 and 0593), the Foundation for Strategic Research, the Stockholm County Council (project 562183), the Foundation for Strategic Research, the Academy of Finland (Grant #110413) and the British Heart Foundation (RG2008/014). None of the aforementioned funding organizations or sponsors has had a specific role in design or conduct of the study, collection, management, analysis, or interpretation of the data, or preparation, review, or approval of the manuscript; Inter99: The Inter99 study was supported by the Danish Medical Research Council, the Danish Centre for Evaluation and Health Technology Assessment, Copenhagen County, the Danish Heart Foundation, the Danish Pharmaceutical Association, the Health Insurance Foundation, the Augustinus Foundation, the Ib Henriksens foundation and the Beckett Foundation. The present study was further supported by the Danish Diabetes Association (grant No. 32, December 2005) and the Health Insurance Foundation (grant No.; 2010 B 131); ISGS/SWISS: ISGS (Grant Number R01 42733) and SWISS (R01 NS39987) were funded by grants from the National Institute of Neurological Disorders and Stroke (US); Izhevsk: The Izhevsk Family Studies was funded by a UK Wellcome Trust programme grant (078557); MDC: This work was supported by the Swedish Medical Research Council; by the Swedish Heart and Lung Foundation; by the Medical Faculty of Lund University, Malmo University Hospital; by the Albert Pahlsson Research Foundation; by the Crafoord foundation; by the Ernhold Lundstroms Research Foundation, the Region Skane; by the Hulda and Conrad Mossfelt Foundation; by the King Gustaf V and Queen Victoria Foundation; by the Lennart Hanssons Memorial Fund; and by the Marianne and Marcus Wallenberg Foundation. Genotyping was supported by the British Heart Foundation (grant number CH/98001 to A. F. D., RG/07/005/23633 to A. F. D., S. P.); MESA: The Multi-Ethnic Study of Atherosclerosis Study (MESA) is a multicenter prospective cohort study initiated to study the development of subclinical cardiovascular disease. A total of 6814 women and men between the age of 45 and 84 year were recruited for the first examination between 2000 and 2002. Participants were recruited in six US cities (Baltimore, MD; Chicago, IL; Forsyth County, NC; Los Angeles County, CA; Northern Manhattan, NY; and St. Paul, MN). This study was approved by the institutional review boards of each study site, and written informed consent was obtained from all participants. This cohort was genotyped as part of the National Heart Lung and Blood Institute's (NHLBI) Candidate Gene Association Resource (CARe) (Musunuru, K., Lettre, G., Young, T., Farlow, D. N., Pirruccello, J. P., Ejebe, K. G., Keating, B. J., Yang, Q., Chen, M. H., Lapchyk, N. et al. Candidate gene association resource (CARe): design, methods, and proof of concept. Circ. Cardiovasc. Genet, 3, 267-275.); MRC 1958BC: Dr Sue Ring and Dr Wendy McArdle (University of Bristol) and Mr Jon Johnson (Centre for Longitudinal Studies, Institute of Education, London) are thanked for help with data linkage. The study was supported by the Academy of Finland (12926) and the Medical Research Council (MRC G0601653 and SALVE/PrevMedsyn). The Medical Research Council funded the 2002-2004 clinical follow-up of the 1958 birth cohort (grant G0000934). This research used resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development, and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of investigators who contributed to generation of the data is available from the Wellcome Trust Case-Control Consortium website(www.wtccc.org.uk). Funding for the project was provided by the Wellcome Trust under award 076113. Work at the Centre for Paediatric Epidemiology and Biostatistics benefits from funding support from the MRC in its capacity as the MRC Centre of Epidemiology for Child Health. Research at the University College London Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust benefits from R&D funding received from the NHS Executive; MRC NSHD: Supported by Medical Research Council - MC_UU_12019/1.; We are very grateful to the members of this birth cohort for their continuing interest and participation in the study. We would like to acknowledge the Swallow group, UCL, who performed the DNA extractions; NHANES III: The findings and conclusions in this report are those of the author(s) and do not necessarily represent the views of the Centers for Disease Control and Prevention; NORDIL: This work was supported by the British Heart Foundation (grant number CH/98001 to A. F. D., RG/07/005/23633 to A. F. D., S. P.) and a Special Project, for genotyping of the Swedish extremes from the NORDIL and MDC cohorts; and by Pharmacia. We thank Professor Thomas Hedner (Department of Clinical Pharmacology, Sahlgrenska Academy, Gotheburg, Sweden) and Professor Sverre Kjeldsen (Ullevaal University Hospital, University of Oslo, Oslo, Norway), who are investigators of the NORDIL study. Professor Kjeldsen is also an investigator of the ASCOT trial; NPHS II: NPHS-II was supported by the British Medical Research Council, the US National Institutes of Health (grant NHLBI 33014), and Du Pont Pharma, Wilmington, Delaware; Portuguese stroke: Instituto Nacional de Saude Doutor Ricardo Jorge; PREVEND: PREVEND genetics is supported by the Dutch Kidney Foundation (Grant E033), The Netherlands organisation for health research and development (ZonMw grant 90.700.441), and the Dutch Inter University Cardiology Institute Netherlands (ICIN); PROCARDIS: PROCARDIS was supported by the EU FP7 Program (LSHM-CT-2007-037273), AstraZeneca, the British Heart Foundation, the Oxford BHF Centre of Research Excellence, the Wellcome Trust core award (090532/Z/09/Z), the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the Torsten and Ragnar Soderberg Foundation, the Strategic Cardiovascular Program of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council (560283); PROSPER: The PROSPER study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb and by grants from the Interuniversity Cardiology Institute of the Netherlands (ICIN) and the Durrer Center for Cardiogenetic Research both Institutes of the Netherlands Royal Academy of Arts and Sciences (KNAW), the Netherlands Heart Foundation, the Center for Medical Systems Biology (CMSB), a center of excellence approved by the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (NWO), the Netherlands Consortium for Healthy Ageing (NCHA). The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no HEALTH-F2-2009-223004 and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810); Rotterdam: The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research (NWO); the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.; 011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project nr. 050-060-810; SMART: SMART GENETICS was financially supported by BBMRI-NL, a Research Infrastructure financed by the Dutch government (NWO 184.021.007); TPT: TPT was funded by the Medical Research Council, the British Heart Foundation, DuPont Pharma and Bayer Corporation; UCP: The UCP study was funded by Veni grant Organization for Scientific Research (NWO), Grant no. 2001.064 Netherlands Heart Foundation (NHS), and TI Pharma Grant T6-101 Mondriaan. The department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, has received unrestricted research funding from the Netherlands Organisation for Health Research and Development (ZonMW), the Dutch Health Care Insurance Board (CVZ), the Royal Dutch Pharmacists Association (KNMP), the private-public funded Top Institute Pharma (www.tipharma.nl, includes co-funding from universities, government, and industry), the EU Innovative Medicines Initiative (IMI), EU 7th Framework Program (FP7), the Dutch Medicines Evaluation Board, the Dutch Ministry of Health and industry (including GlaxoSmithKline, Pfizer, and others); Whitehall II: The Whitehall II study and Mika Kivimaki were supported by the Medical Research Council; the British Heart Foundation; the Economic and Social Research Council; the National Heart Lung and Blood Institute (NHLBI: HL36310); and the National Institute on Aging (AG13196), US, NIH; WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U. S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. A listing of WHI investigators can be found at https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20 Investigator%20Short%20List.pdf. NR 35 TC 132 Z9 132 U1 9 U2 59 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD JUL 10 PY 2014 VL 349 AR g4164 DI 10.1136/bmj.g4164 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA AL2ZF UT WOS:000338993700001 PM 25011450 ER PT J AU Patel, MR Bhatt, A Steffen, JD Chergui, A Murai, J Pommier, Y Pascal, JM Trombetta, LD Fronczek, FR Talele, TT AF Patel, Maulik R. Bhatt, Aaditya Steffen, Jamin D. Chergui, Adel Murai, Junko Pommier, Yves Pascal, John M. Trombetta, Louis D. Fronczek, Frank R. Talele, Tanaji T. TI Discovery and Structure-Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-carboxamide and 2,3-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives as Poly(ADP-ribose)polymerase-1 Inhibitors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID OXIDATIVE DNA-DAMAGE; PARP INHIBITORS; POLYMERASE INHIBITOR; MUTANT-CELLS; CANCER; POLY(ADP-RIBOSYL)ATION; OPTIMIZATION; THERAPY; ABT-888; DESIGN AB Novel substituted 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide (DHBF-3-one-7-carboxamide) derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). A structure-based design strategy resulted in lead compound 3 (DHBF-7-carboxamide; IC50 = 9.45 mu M). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (36, IC50 = 16.2 mu M). The electrophilic 2-position of this scaffold was accessible for extended modifications. Substituted benzylidene derivatives at the 2-position were found to be the most potent, with 3',4'-dihydroxybenzylidene 58 (IC50 = 0.531 mu M) showing a 30-fold improvement in potency. Various heterocycles attached at the 4'-hydroxyl/4'-amino of the benzylidene moiety resulted in significant improvement in inhibition of PARP-1 activity (e.g., compounds 66-68, 70, 72, and 73; IC50 values from 0.718 to 0.079 mu M). Compound 66 showed selective cytotoxicity in BRCA2-deficient DT40 cells. Crystal structures of three inhibitors (compounds (-)-13c, 59, and 65) bound to a multidomain PARP-1 structure were obtained, providing insights into further development of these inhibitors. C1 [Patel, Maulik R.; Bhatt, Aaditya; Trombetta, Louis D.; Talele, Tanaji T.] St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Queens, NY 11439 USA. [Steffen, Jamin D.; Pascal, John M.] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA. [Chergui, Adel; Murai, Junko; Pommier, Yves] NCI, Dev Therapeut Branch, Mol Pharmacol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Fronczek, Frank R.] Louisiana State Univ, Dept Chem, Baton Rouge, LA 70803 USA. RP Talele, TT (reprint author), St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Queens, NY 11439 USA. EM talelet@stjohns.edu FU Department of Pharmaceutical Sciences of St. John's University; St. John's University [579-1110]; NIH [R01 GM087282]; Ruth L. Kirschstein National Research Service Award; Center for Cancer Research, National Cancer Institute, NIH [Z01 BC006150] FX This research was supported by the Department of Pharmaceutical Sciences of St. John's University and St. John's University Seed Grant 579-1110 to T.T.T. and by funds from the NIH (Grant R01 GM087282) to J.M.P. J.D.S. is supported by a Ruth L. Kirschstein National Research Service Award. Y.P., A.C. and J.M. were supported by the Intramural Program, Center for Cancer Research, National Cancer Institute, NIH (Grant Z01 BC006150). NR 67 TC 11 Z9 11 U1 0 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD JUL 10 PY 2014 VL 57 IS 13 BP 5579 EP 5601 DI 10.1021/jm5002502 PG 23 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AL2TT UT WOS:000338979100007 PM 24922587 ER PT J AU Poliakov, E Koonin, EV Rogozin, IB AF Poliakov, Eugenia Koonin, Eugene V. Rogozin, Igor B. TI Impairment of translation in neurons as a putative causative factor for autism SO BIOLOGY DIRECT LA English DT Article DE Synonymous mutations; Single nucleotide polymorphism; Codon usage; Splicing enhancer; Splicing silencer; mRNA secondary structure; Transcription factor binding; Neurotoxin ID EXONIC SPLICING ENHANCERS; SYNONYMOUS CODON USAGE; HAZARDOUS AIR-POLLUTANTS; RNA SECONDARY STRUCTURE; DE-NOVO MUTATIONS; SPECTRUM DISORDERS; MOLECULAR CHAPERONES; PURIFYING SELECTION; HUNTINGTONS-DISEASE; POSITIVE SELECTION AB Background: A dramatic increase in the prevalence of autism and Autistic Spectrum Disorders (ASD) has been observed over the last two decades in USA, Europe and Asia. Given the accumulating data on the possible role of translation in the etiology of ASD, we analyzed potential effects of rare synonymous substitutions associated with ASD on mRNA stability, splicing enhancers and silencers, and codon usage. Presentation of the hypothesis: We hypothesize that subtle impairment of translation, resulting in dosage imbalance of neuron-specific proteins, contributes to the etiology of ASD synergistically with environmental neurotoxins. Testing the hypothesis: A statistically significant shift from optimal to suboptimal codons caused by rare synonymous substitutions associated with ASD was detected whereas no effect on other analyzed characteristics of transcripts was identified. This result suggests that the impact of rare codons on the translation of genes involved in neuron development, even if slight in magnitude, could contribute to the pathogenesis of ASD in the presence of an aggressive chemical background. This hypothesis could be tested by further analysis of ASD-associated mutations, direct biochemical characterization of their effects, and assessment of in vivo effects on animal models. C1 [Poliakov, Eugenia] NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Koonin, Eugene V.; Rogozin, Igor B.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM koonin@ncbi.nlm.nih.gov; rogozin@ncbi.nlm.nih.gov FU Intramural Research Program of the National Eye Institute; Intramural Research Program of the National Library of Medicine at the National Institutes of Health (US Department Health and Human Services) FX This work was supported by the by the Intramural Research Program of the National Eye Institute and the Intramural Research Program of the National Library of Medicine at the National Institutes of Health (US Department Health and Human Services). NR 124 TC 2 Z9 2 U1 2 U2 20 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD JUL 10 PY 2014 VL 9 AR 16 DI 10.1186/1745-6150-9-16 PG 13 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AL3GX UT WOS:000339016000001 PM 25011470 ER PT J AU Cao, HP Deterding, LJ Blackshear, PJ AF Cao, Heping Deterding, Leesa J. Blackshear, Perry J. TI Identification of a Major Phosphopeptide in Human Tristetraprolin by Phosphopeptide Mapping and Mass Spectrometry SO PLOS ONE LA English DT Article ID NECROSIS-FACTOR-ALPHA; ACTIVATED PROTEIN-KINASE; MESSENGER-RNA STABILITY; MOUSE 3T3-L1 ADIPOCYTES; ZINC-FINGER PROTEINS; RICH ELEMENT; GENE-EXPRESSION; RECOMBINANT TRISTETRAPROLIN; IN-VITRO; TTP AB Tristetraprolin/zinc finger protein 36 (TTP/ZFP36) binds and destabilizes some pro-inflammatory cytokine mRNAs. TTP-deficient mice develop a profound inflammatory syndrome due to excessive production of pro-inflammatory cytokines. TTP expression is induced by various factors including insulin and extracts from cinnamon and green tea. TTP is highly phosphorylated in vivo and is a substrate for several protein kinases. Multiple phosphorylation sites are identified in human TTP, but it is difficult to assign major vs. minor phosphorylation sites. This study aimed to generate additional information on TTP phosphorylation using phosphopeptide mapping and mass spectrometry (MS). Wild-type and site-directed mutant TTP proteins were expressed in transfected human cells followed by in vivo radiolabeling with [P-32]-orthophosphate. Histidine-tagged TTP proteins were purified with Ni-NTA affinity beads and digested with trypsin and lysyl endopeptidase. The digested peptides were separated by C-18 column with high performance liquid chromatography. Wild-type and all mutant TTP proteins were localized in the cytosol, phosphorylated extensively in vivo and capable of binding to ARE-containing RNA probes. Mutant TTP with S-90 and S-93 mutations resulted in the disappearance of a major phosphopeptide peak. Mutant TTP with an S-197 mutation resulted in another major phosphopeptide peak being eluted earlier than the wildtype. Additional mutations at S-186, S-296 and T-271 exhibited little effect on phosphopeptide profiles. MS analysis identified the peptide that was missing in the S-90 and S-93 mutant protein as LGPELSPSPTSPTATSTTPSR (corresponding to amino acid residues 83-103 of human TTP). MS also identified a major phosphopeptide associated with the first zinc-finger region. These analyses suggest that the tryptic peptide containing S-90 and S-93 is a major phosphopeptide in human TTP. C1 [Cao, Heping] ARS, USDA, So Reg Res Ctr, New Orleans, LA 70124 USA. [Deterding, Leesa J.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. RP Cao, HP (reprint author), ARS, USDA, So Reg Res Ctr, New Orleans, LA 70124 USA. EM Heping.Cao@ars.usda.gov FU United States Department of Agriculture-Agriculture Research Service Quality and Utilization of Agricultural Products Research Program 306 [CRIS 6435-41000-102-00D]; Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences FX This work was supported in part by United States Department of Agriculture-Agriculture Research Service Quality and Utilization of Agricultural Products Research Program 306 through CRIS 6435-41000-102-00D and the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 4 Z9 4 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 10 PY 2014 VL 9 IS 7 AR e100977 DI 10.1371/journal.pone.0100977 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK9RG UT WOS:000338763800010 PM 25010646 ER PT J AU Celiku, O Johnson, S Zhao, SP Camphausen, K Shankavaram, U AF Celiku, Orieta Johnson, Seth Zhao, Shuping Camphausen, Kevin Shankavaram, Uma TI Visualizing Molecular Profiles of Glioblastoma with GBM-BioDP SO PLOS ONE LA English DT Article ID CANCER GENOMICS DATA; TEMOZOLOMIDE; EXPRESSION; BROWSER; GENES AB Validation of clinical biomarkers and response to therapy is a challenging topic in cancer research. An important source of information for virtual validation is the datasets generated from multi-center cancer research projects such as The Cancer Genome Atlas project (TCGA). These data enable investigation of genetic and epigenetic changes responsible for cancer onset and progression, response to cancer therapies, and discovery of the molecular profiles of various cancers. However, these analyses often require bulk download of data and substantial bioinformatics expertise, which can be intimidating for investigators. Here, we report on the development of a new resource available to scientists: a data base called Glioblastoma Bio Discovery Portal (GBM-BioDP). GBM-BioDP is a free web-accessible resource that hosts a subset of the glioblastoma TCGA data and enables an intuitive query and interactive display of the resultant data. This resource provides visualization tools for the exploration of gene, miRNA, and protein expression, differential expression within the subtypes of GBM, and potential associations with clinical outcome, which are useful for virtual biological validation. The tool may also enable generation of hypotheses on how therapies impact GBM molecular profiles, which can help in personalization of treatment for optimal outcome. The resource can be accessed freely at http://gbm-biodp.nci.nih.gov (a tutorial is included). C1 [Celiku, Orieta; Johnson, Seth; Zhao, Shuping; Camphausen, Kevin; Shankavaram, Uma] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Shankavaram, U (reprint author), NCI, Radiat Oncol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM uma@mail.nih.gov OI Johnson, Seth/0000-0001-5957-2052 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 14 Z9 14 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 10 PY 2014 VL 9 IS 7 AR e101239 DI 10.1371/journal.pone.0101239 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK9RG UT WOS:000338763800015 PM 25010047 ER PT J AU Coquery, CM Wade, NS Loo, WM Kinchen, JM Cox, KM Jiang, C Tung, KS Erickson, LD AF Coquery, Christine M. Wade, Nekeithia S. Loo, William M. Kinchen, Jason M. Cox, Kelly M. Jiang, Chao Tung, Kenneth S. Erickson, Loren D. TI Neutrophils Contribute to Excess Serum BAFF Levels and Promote CD4(+) T Cell and B Cell Responses in Lupus-Prone Mice SO PLOS ONE LA English DT Article ID SYSTEMIC-LUPUS; INTERFERON-GAMMA; IFN-GAMMA; LYMPHOCYTE STIMULATOR; MURINE LUPUS; DEFICIENT MICE; PLASMA-CELLS; ERYTHEMATOSUS; AUTOIMMUNITY; ACTIVATION AB Despite increased frequencies of neutrophils found in autoimmune diseases such as systemic lupus erythematosus (SLE), how they contribute to disease pathogenesis and the mechanisms that affect the accumulation of neutrophils are poorly understood. The aim of this study was to identify factors in autoantibody-mediated autoimmunity that controls the accumulation of spleen resident neutrophils and to determine whether neutrophils contribute to abnormal B cell responses. Increased levels of the cytokine BAFF have been linked to loss of B cell tolerance in autoimmunity, but the cellular source responsible for excess BAFF is unknown. B cell maturation antigen (BCMA) is a receptor for BAFF and is critical for the survival of bone marrow plasma cells. Paradoxically, BCMA deficiency exacerbates the formation of autoantibody-secreting plasma cells in spleens of lupus-prone mice and the reasons for this effect are not understood. Here we analyzed the phenotype, localization and function of neutrophils in spleens of healthy mice and congenic lupus-prone mice, and compared mice sufficient or deficient in BCMA expression. Neutrophils were found to be significantly increased in frequency and activation status in spleens of lupus-prone mice when BCMA was absent. Furthermore, neutrophils localized within T cell zones and enhanced CD4(+) T cell proliferation and IFN gamma production through the production of BAFF. Reduced BAFF and IFN gamma serum levels, decreased frequencies of IFN gamma-producing T cells, germinal center B cells, and autoantibody production after neutrophil depletion indicated the involvement of neutrophils in these autoimmune traits. Thus, we have identified a novel role for BCMA to control excess BAFF production in murine lupus through restraining the accumulation of BAFF-producing neutrophils. Our data suggests that devising therapeutic strategies to reduce neutrophils in autoimmunity may decrease BAFF levels and ameliorate disease. C1 [Coquery, Christine M.; Kinchen, Jason M.; Cox, Kelly M.; Erickson, Loren D.] Univ Virginia, Dept Microbiol Immunol & Canc Biol, Charlottesville, VA 22903 USA. [Coquery, Christine M.; Wade, Nekeithia S.; Loo, William M.; Kinchen, Jason M.; Cox, Kelly M.; Tung, Kenneth S.; Erickson, Loren D.] Univ Virginia, Beirne B Carter Ctr Immunol Res, Charlottesville, VA USA. [Kinchen, Jason M.] Univ Virginia, Ctr Cell Clearance, Charlottesville, VA USA. [Tung, Kenneth S.] Univ Virginia, Dept Pathol, Charlottesville, VA 22903 USA. [Jiang, Chao] NIH, Div Extramural Res, Bethesda, MD 20892 USA. RP Erickson, LD (reprint author), Univ Virginia, Dept Microbiol Immunol & Canc Biol, Charlottesville, VA 22903 USA. EM lde9w@virginia.edu FU National Institutes of Health [R01 AI 093722, F31 AR 064145, 5T32A1007496-19] FX This work was supported by National Institutes of Health grant R01 AI 093722, F31 AR 064145, and 5T32A1007496-19. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 15 Z9 15 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 10 PY 2014 VL 9 IS 7 AR e102284 DI 10.1371/journal.pone.0102284 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK9RG UT WOS:000338763800088 PM 25010693 ER PT J AU Karayannis, T Au, E Patel, JC Kruglikov, I Markx, S Delorme, R Heron, D Salomon, D Glessner, J Restituito, S Gordon, A Rodriguez-Murillo, L Roy, NC Gogos, JA Rudy, B Rice, ME Karayiorgou, M Hakonarson, H Keren, B Huguet, G Bourgeron, T Hoeffer, C Tsien, RW Peles, E Fishell, G AF Karayannis, T. Au, E. Patel, J. C. Kruglikov, I. Markx, S. Delorme, R. Heron, D. Salomon, D. Glessner, J. Restituito, S. Gordon, A. Rodriguez-Murillo, L. Roy, N. C. Gogos, J. A. Rudy, B. Rice, M. E. Karayiorgou, M. Hakonarson, H. Keren, B. Huguet, G. Bourgeron, T. Hoeffer, C. Tsien, R. W. Peles, E. Fishell, G. TI Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission SO NATURE LA English DT Article ID CORTICAL INTERNEURONS; GABA(A) RECEPTORS; PREPULSE INHIBITION; TOURETTES-SYNDROME; SCHIZOPHRENIA; SYNAPSES; NUMBER; ASSOCIATION; LINKAGE; RELEASE AB Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells(1,2). Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders(3,4). Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism(5,6). Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (gamma-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders. C1 [Karayannis, T.; Au, E.; Kruglikov, I.; Restituito, S.; Roy, N. C.; Rudy, B.; Hoeffer, C.; Tsien, R. W.; Fishell, G.] NYU, Dept Neurosci & Physiol, Neurosci Inst, New York, NY 10016 USA. [Patel, J. C.; Rice, M. E.] NYU, Dept Neurosurg Neurosci & Physiol, Langone Med Ctr, New York, NY 10016 USA. [Markx, S.; Rodriguez-Murillo, L.; Karayiorgou, M.] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Delorme, R.; Hakonarson, H.; Huguet, G.; Bourgeron, T.] Inst Pasteur, Human Genet & Cognit Funct Unit, F-75724 Paris, France. [Delorme, R.; Huguet, G.; Bourgeron, T.] Inst Pasteur, URA Genes Synapses & Cognit 2182, CNRS, F-75724 Paris, France. [Delorme, R.] Hop Robert Debre, AP HP, Dept Child & Adolescent Psychiat, F-75019 Paris, France. [Heron, D.] Grp Hosp Pitie Salpetriere, AP HP, Unite Fonct Genet Med, Dept Genet & Cytogenet,Ctr Reference,CRicm,UMR S9, F-75013 Paris, France. [Salomon, D.; Gordon, A.] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. [Glessner, J.] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Roy, N. C.] Natl Inst Deafness & Other Commun Disorders, Sect Synapt Transmiss, NIH, Bethesda, MD 20892 USA. [Gogos, J. A.] Columbia Univ, Med Ctr, Dept Physiol, New York, NY 10032 USA. [Gogos, J. A.] Columbia Univ, Med Ctr, Dept Cellular Biophys & Neurosci, New York, NY 10032 USA. [Keren, B.] Grp Hosp Pitie Salpetriere, AP HP, Unite Fonct Genet Chromosom, Dept Genet & Cytogenet,CRicm,UMR S975, F-75013 Paris, France. [Huguet, G.; Bourgeron, T.] Univ Paris Diderot, Sorbonne Paris Cite, F-75005 Paris, France. [Bourgeron, T.] FondaMental Fdn, F-94000 Creteil, France. RP Fishell, G (reprint author), NYU, Dept Neurosci & Physiol, Neurosci Inst, New York, NY 10016 USA. EM gordon.fishell@med.nyu.edu RI Karayannis, Theofanis/O-5194-2014; OI Bourgeron, Thomas/0000-0001-8164-9220; Kruglikov, Illya/0000-0002-1575-4636; Patel, Jyoti/0000-0003-0295-6180; Rudy, Bernardo/0000-0001-5748-6900; Rice, Margaret/0000-0003-1793-2798 FU NIH [R01 NS081297, R01 MH071679, R01 NS074972, P01 NS074972, R01 NS036362, R01 DA033811, NS30989, NS50220]; Simons Foundation [94534]; Attilio and Olympia Ricciardi Research Fund; Israel Science Foundation; Patterson Trust; Roche; New York State through its NYSTEM initiative [C024326]; Canadian Institutes of Health Research; NYU COE Addiction Seed Grant; Institut Pasteur; INSERM; AP-HP; University Paris Diderot; Bettencourt-Schueller foundation; Orange foundation; FondaMental foundation; Conny-Maeva foundation; Cognacq-Jay foundation FX The authors are grateful to R. Froemke for critically reading the manuscript, to B. Benedetti, M. McKenzie Chang, L. Cobbs, B. A. Heller, T. Petros and N. Yumoto (all NYU) for help with experiments and analysis and to Charles Nicholson (NYU) for providing specialized software to analyse Vmax. Research in the Fishell laboratory is supported by the NIH (grants R01 NS081297, R01 MH071679, R01 NS074972, P01 NS074972 to B. R. and G. F.) and the Simons Foundation (94534). The Rice laboratory is supported by the NIH (grants R01 NS036362 and R01 DA033811) and the Attilio and Olympia Ricciardi Research Fund. The Rudy laboratory is supported by the NIH (NS30989). The Peles laboratory is supported by the NIH (grant NS50220) and the Israel Science Foundation. T. K. support was provided through postdoctoral fellowships from the Patterson Trust and Roche. E. A. support was provided by New York State through its NYSTEM initiative (C024326) and fellowship from Canadian Institutes of Health Research. J.C.P support was provided by NYU COE Addiction Seed Grant. This work was funded by the Institut Pasteur, INSERM, AP-HP, University Paris Diderot and the Bettencourt-Schueller, Orange, FondaMental, Conny-Maeva, Cognacq-Jay foundations. NR 66 TC 38 Z9 40 U1 3 U2 35 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUL 10 PY 2014 VL 511 IS 7508 BP 236 EP + DI 10.1038/nature13248 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK8AP UT WOS:000338649800047 PM 24870235 ER PT J AU Legro, RS Brzyski, RG Diamond, MP Coutifaris, C Schlaff, WD Casson, P Christman, GM Huang, H Yan, QS Alvero, R Haisenleder, DJ Barnhart, KT Bates, GW Usadi, R Lucidi, S Baker, V Trussell, JC Krawetz, SA Snyder, P Ohl, D Santoro, N Eisenberg, E Zhang, H AF Legro, Richard S. Brzyski, Robert G. Diamond, Michael P. Coutifaris, Christos Schlaff, William D. Casson, Peter Christman, Gregory M. Huang, Hao Yan, Qingshang Alvero, Ruben Haisenleder, Daniel J. Barnhart, Kurt T. Bates, G. Wright Usadi, Rebecca Lucidi, Scott Baker, Valerie Trussell, J. C. Krawetz, Stephen A. Snyder, Peter Ohl, Dana Santoro, Nanette Eisenberg, Esther Zhang, Heping CA NICHD Reproductive Med Network TI Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID AROMATASE INHIBITORS; DOUBLE-BLIND; CLINICAL-TRIAL; LIVE-BIRTH; PHASE-II; WOMEN; ANASTROZOLE; MULTICENTER; PREGNANCY; METFORMIN AB Background Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes. Methods In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1: 1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period. Results Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P = 0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P = 0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups. Conclusions As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. C1 [Legro, Richard S.] Penn State Univ, Dept Obstet & Gynecol, Hershey, PA USA. [Brzyski, Robert G.] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, San Antonio, TX 78229 USA. [Diamond, Michael P.] Georgia Regents Univ, Dept Obstet & Gynecol, Augusta, GA USA. [Diamond, Michael P.; Krawetz, Stephen A.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Coutifaris, Christos; Barnhart, Kurt T.; Snyder, Peter] Univ Penn, Sch Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Schlaff, William D.; Alvero, Ruben; Santoro, Nanette] Univ Colorado, Dept Obstet & Gynecol, Aurora, CO USA. [Casson, Peter] Univ Vermont, Dept Obstet & Gynecol, Burlington, VT 05405 USA. [Christman, Gregory M.; Ohl, Dana] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Huang, Hao; Yan, Qingshang; Zhang, Heping] Yale Univ, Dept Biostat, Sch Publ Hlth, New Haven, CT USA. [Haisenleder, Daniel J.] Univ Virginia, Ctr Res Reprod, Ligand Core Lab, Charlottesville, VA USA. [Bates, G. Wright] Univ Alabama Birmingham, Birmingham, AL USA. [Usadi, Rebecca] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Lucidi, Scott] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Baker, Valerie] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Trussell, J. C.] SUNY Upstate Med Univ, Syracuse, NY USA. [Eisenberg, Esther] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Fertil & Infertil Branch, Rockville, MD USA. RP Legro, RS (reprint author), Penn State Coll Med, MS Hershey Med Ctr, Dept Obstet & Gynecol, 500 Univ Dr,H103, Hershey, PA 17033 USA. EM rsl1@psu.edu OI Diamond, Michael/0000-0001-6353-4489 FU NICHD [U10 HD27049, U10 HD38992, U10HD055925, U10 HD39005, U10 HD38998, U10 HD055936, U10 HD055942, U10 HD055944, U54-HD29834]; National Center for Research Resources; National Center for Advancing Translational Sciences through an NIH [UL1 TR000127]; Ferring Pharmaceuticals; AstraZeneca; Euroscreen; EMD Serono; Bayer FX Supported by grants from the NICHD (U10 HD27049, to Dr. Coutifaris; U10 HD38992, to Dr. Legro; U10HD055925, to Dr. Zhang; U10 HD39005, to Dr. Diamond; U10 HD38998, to Dr. Schlaff; U10 HD055936, to Dr. Christman; U10 HD055942, to Dr. Brzyski; and U10 HD055944, to Dr. Casson; and U54-HD29834, to the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core of the Specialized Cooperative Centers Program in Reproduction and Infertility Research); and by the National Center for Research Resources and the National Center for Advancing Translational Sciences through an NIH grant (UL1 TR000127) to Pennsylvania State University.; Dr. Legro reports receiving consulting fees from Ferring Pharmaceuticals, AstraZeneca, and Euroscreen. Dr. Diamond reports receiving consulting fees from EMD Serono and serving on the board of directors of and owning stock in Advanced Reproductive Care. Dr. Santoro reports receiving grant support from Bayer and holding stock options in MenoGeniX. No other potential conflict of interest relevant to this article was reported. NR 24 TC 78 Z9 83 U1 4 U2 22 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 10 PY 2014 VL 371 IS 2 BP 119 EP 129 DI 10.1056/NEJMoa1313517 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AK7YZ UT WOS:000338645500008 PM 25006718 ER PT J AU Seol, HS Kang, HJ Lee, SI Kim, NE Kim, TI Chun, SM Kim, TW Yu, CS Suh, YA Singh, SR Chang, S Jang, SJ AF Seol, Hyang Sook Kang, Hyo Jeong Lee, Seul-I. Kim, Na Eun Kim, Tae Im Chun, Sung Min Kim, Tae Won Yu, Chang Sik Suh, Young-Ah Singh, Shree Ram Chang, Suhwan Jang, Se Jin TI Development and characterization of a colon PDX model that reproduces drug responsiveness and the mutation profiles of its original tumor (vol 345, pg 56, 2014) SO CANCER LETTERS LA English DT Correction C1 [Seol, Hyang Sook; Lee, Seul-I.; Kim, Na Eun; Kim, Tae Im; Suh, Young-Ah; Chang, Suhwan; Jang, Se Jin] Univ Ulsan, Coll Med, Asan Med Ctr, Asan Inst Life Sci, Seoul, South Korea. [Kang, Hyo Jeong; Chun, Sung Min; Jang, Se Jin] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul, South Korea. [Kim, Tae Won; Yu, Chang Sik] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Radiat Oncol, Seoul, South Korea. [Singh, Shree Ram] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Chang, Suhwan] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Biomed Sci, Seoul, South Korea. RP Chang, S (reprint author), Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul, South Korea. EM singhshr@mail.nih.gov; suhwan.chang@amc.seoul.kr; jangsejin@amc.seoul.kr NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD JUL 10 PY 2014 VL 349 IS 1 BP 96 EP 96 DI 10.1016/j.canlet.2014.02.021 PG 1 WC Oncology SC Oncology GA AI8YW UT WOS:000337213900013 ER PT J AU Winnenburg, R Bodenreider, O AF Winnenburg, Rainer Bodenreider, Olivier TI A framework for assessing the consistency of drug classes across sources SO JOURNAL OF BIOMEDICAL SEMANTICS LA English DT Article DE Drug classes; MeSH; ATC; Instance-based mapping; Lexical mapping AB Background: The objective of this study is to develop a framework for assessing the consistency of drug classes across sources, such as MeSH and ATC. Our framework integrates and contrasts lexical and instance-based ontology alignment techniques. Moreover, we propose metrics for assessing not only equivalence relations, but also inclusion relations among drug classes. Results: We identified 226 equivalence relations between MeSH and ATC classes through the lexical alignment, and 223 through the instance-based alignment, with limited overlap between the two (36). We also identified 6,257 inclusion relations. Discrepancies between lexical and instance-based alignments are illustrated and discussed. Conclusions: Our work is the first attempt to align drug classes with sophisticated instance-based techniques, while also distinguishing between equivalence and inclusion relations. Additionally, it is the first application of aligning drug classes in ATC and MeSH. By providing a detailed account of similarities and differences between drug classes across sources, our framework has the prospect of effectively supporting the creation of a mapping of drug classes between ATC and MeSH by domain experts. C1 [Winnenburg, Rainer; Bodenreider, Olivier] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. RP Bodenreider, O (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. EM obodenreider@mail.nih.gov FU Intramural Research Program of the NIH, National Library of Medicine (NLM); Office of Translational Sciences, Center for Drug Evaluation and Research at the Food and Drug Administration (FDA); NLM [XLM12011 001] FX This work was supported by the Intramural Research Program of the NIH, National Library of Medicine (NLM). This work was also supported by the Office of Translational Sciences, Center for Drug Evaluation and Research at the Food and Drug Administration (FDA) through an interagency agreement with NLM (XLM12011 001). The authors want to thank Fred Sorbello, Ana Szarfman, Rave Harpaz and Anna Ripple for useful discussions. NR 13 TC 1 Z9 1 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2041-1480 J9 J BIOMED SEMANT JI J. Biomed. Semant. PD JUL 9 PY 2014 VL 5 AR 30 DI 10.1186/2041-1480-5-30 PG 14 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AR6RW UT WOS:000343711500001 PM 25101165 ER PT J AU Kim, S Lee, MS Lee, B Gwon, WG Joung, EJ Yoon, NY Kim, HR AF Kim, Sunghee Lee, Min-Sup Lee, Bonggi Gwon, Wi-Gyeong Joung, Eun-Ji Yoon, Na-Young Kim, Hyeung-Rak TI Anti-inflammatory effects of sargachromenol-rich ethanolic extract of Myagropsis myagroides on lipopolysaccharide-stimulated BV-2 cells SO BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE LA English DT Article DE Myagropsis myagroides; Sargachromenol; Pro-inflammatory cytokine; Microglia; Nuclear factor-kappa B; Neuroinflammation ID NF-KAPPA-B; NITRIC-OXIDE SYNTHASE; RAW 264.7 CELLS; MICROGLIAL CELLS; SIGNALING PATHWAYS; P38 MAPK; SARGASSUM-FULVELLUM; INTERFERON-GAMMA; HEXANE FRACTION; ACTIVATION AB Background: Excessive pro-inflammatory cytokine production from activated microglia contributes to neurodegenerative diseases, thus, microglial inactivation may delay the progress of neurodegeneration by attenuating the neuroinflammation. Among 5 selected brown algae, we found the highest antioxidant and anti-neuroinflammatory activities from Myagropsis myagroides ethanolic extract (MME) in lipopolysaccharide (LPS)-stimulated BV-2 cells. Methods: The levels of nitric oxide (NO), prostaglandin E-2 (PGE(2)), and pro-inflammatory cytokines were measured by Griess assay and enzyme linked immunesorbent assay. The levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), mitogen-activated protein kinases (MAPKs), and Akt were measured using Western blot. Nuclear translocation and transcriptional activation of nuclear factor-kappa B (NF-kappa B) were determined by immunefluorescence and reporter gene assay, respectively. Results: MME inhibited the expression of iNOS and COX-2 at mRNA and protein levels, resulting in reduction of NO and PGE(2) production. As a result, pro-inflammatory cytokines were reduced by MME. MME also inhibited the activation and translocation of NF-kappa B by preventing inhibitor kappa B-alpha (I kappa B-alpha) degradation. Moreover, MME inhibited the phosphorylation of extracellular signal regulated kinases (ERKs) and c-Jun N-terminal kinases (JNKs). Main anti-inflammatory compound in MME was identified as sargachromenol by NMR spectroscopy. Conclusions: These results indicate that the anti-inflammatory effect of sargachromenol-rich MME on LPS-stimulated microglia is mainly regulated by the inhibition of I kappa B-alpha/NF-kappa B and ERK/JNK pathways. C1 [Kim, Sunghee; Lee, Min-Sup; Gwon, Wi-Gyeong; Joung, Eun-Ji; Kim, Hyeung-Rak] Pukyong Natl Univ, Dept Food Sci & Nutr, Pusan 608737, South Korea. [Lee, Bonggi] NICHHD, NIH, Bethesda, MD 20892 USA. [Yoon, Na-Young] Natl Fisheries Res & Dev Inst, Food & Safety Res Div, Pusan 619705, South Korea. [Lee, Min-Sup] Pukyong Natl Univ, Inst Fisheries Sci, Pusan 619911, South Korea. RP Kim, HR (reprint author), Pukyong Natl Univ, Dept Food Sci & Nutr, Pusan 608737, South Korea. EM hrkim@pknu.ac.kr FU National Fisheries Research and Development Institute, Republic of Korea [RP-2013-FS-000] FX This work was financially supported by National Fisheries Research and Development Institute, Republic of Korea (RP-2013-FS-000). Authors appreciate the Marine Brown Algae Resources Bank for the deposition and identification of the samples. NR 40 TC 8 Z9 8 U1 1 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6882 J9 BMC COMPLEM ALTERN M JI BMC Complement. Altern. Med. PD JUL 9 PY 2014 VL 14 AR 231 DI 10.1186/1472-6882-14-231 PG 12 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA AM5ST UT WOS:000339921300001 PM 25005778 ER PT J AU Scharpf, RB Mireles, L Yang, Q Kottgen, A Ruczinski, I Susztak, K Halper-Stromberg, E Tin, A Cristiano, S Chakravarti, A Boerwinkle, E Fox, CS Coresh, J Kao, WHL AF Scharpf, Robert B. Mireles, Lynn Yang, Qiong Koettgen, Anna Ruczinski, Ingo Susztak, Katalin Halper-Stromberg, Eitan Tin, Adrienne Cristiano, Stephen Chakravarti, Aravinda Boerwinkle, Eric Fox, Caroline S. Coresh, Josef Kao, Wen Hong Linda TI Copy number polymorphisms near SLC2A9 are associated with serum uric acid concentrations SO BMC GENETICS LA English DT Article DE Copy number polymorphism; Hyperuricemia; Genomewide association study ID GENOME-WIDE ASSOCIATION; HIDDEN MARKOV-MODELS; SNP GENOTYPING DATA; CARDIOVASCULAR-DISEASE; ATHEROSCLEROSIS RISK; URATE CONCENTRATIONS; LOCI; POPULATION; ARRAYS; DISTRIBUTIONS AB Background: Hyperuricemia is associated with multiple diseases, including gout, cardiovascular disease, and renal disease. Serum urate is highly heritable, yet association studies of single nucleotide polymorphisms (SNPs) and serum uric acid explain a small fraction of the heritability. Whether copy number polymorphisms (CNPs) contribute to uric acid levels is unknown. Results: We assessed copy number on a genome-wide scale among 8,411 individuals of European ancestry (EA) who participated in the Atherosclerosis Risk in Communities (ARIC) study. CNPs upstream of the urate transporter SLC2A9 on chromosome 4p16.1 are associated with uric acid (chi(2)(2df) = 3545, p = 3.19 x 10(-23)). Effect sizes, expressed as the percentage change in uric acid per deleted copy, are most pronounced among women ((3.97)4.93(5.87) [(2.5)50(97.5) denoting percentiles], p = 4.57 x 10(-23)) and independent of previously reported SNPs in SLC2A9 as assessed by SNP and CNP regression models and the phasing SNP and CNP haplotypes (chi(2)(2 df) = 3190, p = 7.23 x 10(-08)). Our finding is replicated in the Framingham Heart Study (FHS), where the effect size estimated from 4,089 women is comparable to ARIC in direction and magnitude ((1.41)4.70(7.88), p = 5.46 x 10(-03)). Conclusions: This is the first study to characterize CNPs in ARIC and the first genome-wide analysis of CNPs and uric acid. Our findings suggests a novel, non-coding regulatory mechanism for SLC2A9-mediated modulation of serum uric acid, and detail a bioinformatic approach for assessing the contribution of CNPs to heritable traits in large population-based studies where technical sources of variation are substantial. C1 [Scharpf, Robert B.] Johns Hopkins Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Mireles, Lynn; Koettgen, Anna; Tin, Adrienne; Coresh, Josef; Kao, Wen Hong Linda] Johns Hopkins Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Koettgen, Anna] Univ Hosp Freiburg, Dept Med 4, Freiburg, Germany. [Scharpf, Robert B.; Ruczinski, Ingo] Johns Hopkins Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Susztak, Katalin] Univ Penn, Perelman Sch Med, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA. [Halper-Stromberg, Eitan] Univ Colorado, Computat Biosci Program, Aurora, CO USA. [Cristiano, Stephen] Johns Hopkins Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Chakravarti, Aravinda] Johns Hopkins Sch Med, Dept Med, Baltimore, MD 21205 USA. [Boerwinkle, Eric] Univ Texas Houston, Sch Publ Hlth, Ctr Human Genet, IMM, Houston, TX USA. [Fox, Caroline S.] NHLBI, Lab Metab & Populat Hlth, NIH, Framingham, MA USA. RP Scharpf, RB (reprint author), Johns Hopkins Sch Med, Dept Oncol, 550 N Broadway,Suite 1101, Baltimore, MD 21205 USA. EM rscharpf@jhu.edu FU National Institutes of Health [R01HG005220, R00HG005015, HHSN268200625226C, R01 NS017950-28, R01-HL093328-01]; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278]; National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; [R01HL093328]; [R01HL093029]; [R01NS017950] FX This work was supported by National Institutes of Health grants R01HG005220 and R00HG005015 [R.B.S., L.M., A.C., W.H.L.K.]. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine (Contract No. N01-HC-25195), its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278) and National Institute of Health grants R01 NS017950-28 and R01-HL093328-01. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. Framingham Heart Study investigators were supported in part by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and grant numbers R01HL093328, R01HL093029, R01NS017950 and R01HL093029 [C.F.S. and Q.Y.]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank the staff and participants of the ARIC and FHS studies for their important contributions. We thank Dan Arking for the suggestion of phasing the SNP and CNP haplotypes. NR 59 TC 5 Z9 7 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD JUL 9 PY 2014 VL 15 AR 81 DI 10.1186/1471-2156-15-81 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA AM1DB UT WOS:000339585500001 PM 25007794 ER PT J AU Coady, SA Johnson, NJ Hakes, JK Sorlie, PD AF Coady, Sean A. Johnson, Norman J. Hakes, Jahn K. Sorlie, Paul D. TI Individual education, area income, and mortality and recurrence of myocardial infarction in a Medicare cohort: the National Longitudinal Mortality Study SO BMC PUBLIC HEALTH LA English DT Article DE Myocardial infarction; Epidemiology; Mortality; Socio-economic; Elderly ID NEIGHBORHOOD SOCIOECONOMIC CONTEXT; POSITIVE PREDICTIVE-VALUE; LONG-TERM SURVIVAL; ELDERLY-PATIENTS; HEALTH RESEARCH; CENSUS SAMPLES; HEART-DISEASE; DEATH-INDEX; ASSOCIATION; DIAGNOSIS AB Background: The Medicare program provides universal access to hospital care for the elderly; however, mortality disparities may still persist in this population. The association of individual education and area income with survival and recurrence post Myocardial Infarction (MI) was assessed in a national sample. Methods: Individual level education from the National Longitudinal Mortality Study was linked to Medicare and National Death Index records over the period of 1991-2001 to test the association of individual education and zip code tabulation area median income with survival and recurrence post-MI. Survival was partitioned into 3 periods: in-hospital, discharge to 1 year, and 1 year to 5 years and recurrence was partitioned into two periods: 28 day to 1 year, and 1 year to 5 years. Results: First MIs were found in 8,043 women and 7,929 men. In women and men 66-79 years of age, less than a high school education compared with a college degree or more was associated with 1-5 year mortality in both women (HRR 1.61, 95% confidence interval 1.03-2.50) and men (HRR 1.37, 1.06-1.76). Education was also associated with 1-5 year recurrence in men (HRR 1.68, 1.18-2.41, < High School compared with college degree or more), but not women. Across the spectrum of survival and recurrence periods median zip code level income was inconsistently associated with outcomes. Associations were limited to discharge-1 year survival (RR lowest versus highest quintile 1.31, 95% confidence interval 1.03-1.67) and 28 day-1 year recurrence (RR lowest versus highest quintile 1.72, 95% confidence interval 1.14-2.57) in older men. Conclusions: Despite the Medicare entitlement program, disparities related to individual socioeconomic status remain. Additional research is needed to elucidate the barriers and mechanisms to eliminating health disparities among the elderly. C1 [Coady, Sean A.; Sorlie, Paul D.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20817 USA. [Johnson, Norman J.; Hakes, Jahn K.] US Bur Census, Ctr Adm Records & Res Applicat, Washington, DC 20233 USA. RP Coady, SA (reprint author), NHLBI, Div Cardiovasc Sci, 2 Rockledge Ctr,6701 Rockledge Dr,Rm 10200, Bethesda, MD 20817 USA. EM coadys@nhlbi.nih.gov FU National Heart, Lung and Blood Institute (IAA) [A-HL-12-005-001-01001]; United States Bureau of the Census (IAA) [A-HL-12-005-001-01001] FX Any views expressed on statistical, methodological, technical, or operational issues are those of the authors and not necessarily those of the U.S. Census Bureau. This work was supported by an Interagency Agreement between the National Heart, Lung and Blood Institute and the United States Bureau of the Census (IAA No. A-HL-12-005-001-01001). NR 31 TC 4 Z9 4 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD JUL 9 PY 2014 VL 14 AR 705 DI 10.1186/1471-2458-14-705 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AM1VQ UT WOS:000339636900001 PM 25011538 ER PT J AU Kastrin, A Rindflesch, TC Hristovski, D AF Kastrin, Andrej Rindflesch, Thomas C. Hristovski, Dimitar TI Large-Scale Structure of a Network of Co-Occurring MeSH Terms: Statistical Analysis of Macroscopic Properties SO PLOS ONE LA English DT Article ID LITERATURE-BASED DISCOVERY; COMPLEX NETWORKS; SEMANTIC NETWORKS; SMALL-WORLD; TEXT; GRAPH; KNOWLEDGE; IDENTIFY; PROTEINS; LANGUAGE AB Concept associations can be represented by a network that consists of a set of nodes representing concepts and a set of edges representing their relationships. Complex networks exhibit some common topological features including small diameter, high degree of clustering, power-law degree distribution, and modularity. We investigated the topological properties of a network constructed from co-occurrences between MeSH descriptors in the MEDLINE database. We conducted the analysis on two networks, one constructed from all MeSH descriptors and another using only major descriptors. Network reduction was performed using the Pearson's chi-square test for independence. To characterize topological properties of the network we adopted some specific measures, including diameter, average path length, clustering coefficient, and degree distribution. For the full MeSH network the average path length was 1.95 with a diameter of three edges and clustering coefficient of 0.26. The Kolmogorov-Smirnov test rejects the power law as a plausible model for degree distribution. For the major MeSH network the average path length was 2.63 edges with a diameter of seven edges and clustering coefficient of 0.15. The Kolmogorov-Smirnov test failed to reject the power law as a plausible model. The power-law exponent was 5.07. In both networks it was evident that nodes with a lower degree exhibit higher clustering than those with a higher degree. After simulated attack, where we removed 10% of nodes with the highest degrees, the giant component of each of the two networks contains about 90% of all nodes. Because of small average path length and high degree of clustering the MeSH network is small-world. A power-law distribution is not a plausible model for the degree distribution. The network is highly modular, highly resistant to targeted and random attack and with minimal dissortativity. C1 [Kastrin, Andrej] Fac Informat Studies, Novo Mesto, Slovenia. [Rindflesch, Thomas C.] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD USA. [Hristovski, Dimitar] Univ Ljubljana, Fac Med, Inst Biostat & Med Informat, Ljubljana, Slovenia. RP Kastrin, A (reprint author), Fac Informat Studies, Novo Mesto, Slovenia. EM andrej.kastrin@guest.arnes.si OI Hristovski, Dimitar/0000-0001-6908-0246 FU Slovenian Research Agency [P1-0383]; Intramural Research Program of the U.S. National Institutes of Health, National Library of Medicine FX This work was supported by Slovenian Research Agency grant P1-0383 and by the Intramural Research Program of the U.S. National Institutes of Health, National Library of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 4 Z9 4 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 9 PY 2014 VL 9 IS 7 AR e102188 DI 10.1371/journal.pone.0102188 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL3PK UT WOS:000339040600105 PM 25006672 ER PT J AU Pettigrew, RI AF Pettigrew, Roderic Ivan TI BRAIN Initiative to Transform Human Imaging SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material C1 Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Pettigrew, RI (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. EM rpettigrew@nih.gov FU Intramural NIH HHS [Z99 EB999999] NR 2 TC 1 Z9 1 U1 0 U2 4 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUL 9 PY 2014 VL 6 IS 244 AR 244ed16 DI 10.1126/scitranslmed.3009695 PG 2 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AK8XV UT WOS:000338713000001 PM 25009228 ER PT J AU Miura, K Jongert, E Deng, BB Zhou, LW Lusingu, JP Drakeley, CJ Fay, MP Long, CA Vekemans, J AF Miura, Kazutoyo Jongert, Erik Deng, Bingbing Zhou, Luwen Lusingu, John P. Drakeley, Chris J. Fay, Michael P. Long, Carole A. Vekemans, Johan TI Effect of ingested human antibodies induced by RTS, S/AS01 malaria vaccination in children on Plasmodium falciparum oocyst formation and sporogony in mosquitoes SO MALARIA JOURNAL LA English DT Article DE RTS; S/AS01; Oocyst formation; Sporogony; Standard membrane feeding assay ID MEMBRANE FEEDING ASSAY; CIRCUMSPOROZOITE PROTEIN; ANOPHELES-STEPHENSI; TRANSMISSION; GAMBIAE; LOCALIZATION; SPOROZOITES; RTS,S/AS01E; PARASITES; EFFICACY AB Background: The circumsporozoite protein (CS protein) on the malaria parasites in mosquitoes plays an important role in sporogony in mosquitoes. The RTS, S/AS01 malaria vaccine candidate, which has shown significant efficacy against clinical malaria in a large Phase 3 trial, targets the Plasmodium falciparum CS protein, but the ability of serum from vaccinated individuals to inhibit sporogony in mosquitoes has not been evaluated. Methods: Previously a double-blind, randomized trial of RTS, S/AS01 vaccine, as compared with rabies vaccine, in five-to 17-month old children in Tanzania was conducted. In this study, polyclonal human antibodies were purified from the pools of sera taken one month after the third vaccination. IgGs were purified from four pools of sera from 25 RTS, S/AS01 vaccinated children each, and two pools of sera from 25 children vaccinated with rabies vaccine each. The ability of antibodies to inhibit P. falciparum oocyst formation and/or sporogony in the mosquito host was evaluated by a standard membrane-feeding assay. The test antibodies were fed on day 0 (at the same time as the gametocyte feed), or on days 3 or 6 (serial-feed experiments). The oocyst and sporozoite counts were performed on days 8 and 16, respectively. In addition, two human anti-CS monoclonal antibodies (mAb) and a control mAb were also evaluated. Results: Polyclonal anti-CS IgG preparations from RTS, S-vaccinated children tested at concentrations of 149-210 ELISA units (EU)/ml did not show significant inhibition in oocyst and sporozoite formation when the antibodies were fed with gametocytes at the same time, or later (serial-feed experiments). Similarly, anti-CS mAbs tested at 6,421 or 7,122 EU/ml did not show reduction in oocyst and sporozoite formation. Conclusions: This study does not support the concept that anti-CS antibodies induced by the RTS, S/AS01 vaccines in humans noticeably reduce malaria transmission by blocking P. falciparum sporozoite development or salivary gland invasion in mosquitoes when taken up during feeding. C1 [Miura, Kazutoyo; Deng, Bingbing; Zhou, Luwen; Long, Carole A.] NIAID, NIH, Lab Malaria & Vector Res, Rockville, MD 20852 USA. [Jongert, Erik; Vekemans, Johan] GlaxoSmithKline Vaccines, Wavre, Belgium. [Lusingu, John P.] Natl Inst Med Res, Tanga Ctr, Tanga, Tanzania. [Lusingu, John P.] Univ Copenhagen, Ctr Med Parasitol, Dept Med Microbiol & Immunol, Copenhagen, Denmark. [Drakeley, Chris J.] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London WC1, England. [Fay, Michael P.] NIAID, NIH, Biostat Res Branch, Rockville, MD 20852 USA. RP Miura, K (reprint author), NIAID, NIH, Lab Malaria & Vector Res, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM kmiura@niaid.nih.gov OI Fay, Michael P./0000-0002-8643-9625 FU PATH Malaria Vaccine Initiative; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH FX We are very grateful to the children who participated in the Phase 2 study. We thank Andre Laughinghouse, Kevin Lee, Tovi Lehmann and Robert Gwadz for insectary support, and Ababacar Diouf and Samuel Moretz for helping with the data acquisition. Lorenz von Seidlein was a lead investigator of the Phase 2 study and led the field clinical work. This study was supported in part by the PATH Malaria Vaccine Initiative and also by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. NR 31 TC 2 Z9 2 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD JUL 9 PY 2014 VL 13 AR 263 DI 10.1186/1475-2875-13-263 PG 9 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AL4RJ UT WOS:000339120000001 PM 25007730 ER PT J AU Boheler, KR Bhattacharya, S Kropp, EM Chuppa, S Riordon, DR Bausch-Fluck, D Burridge, PW Wu, JC Wersto, RP Chan, GCF Rao, S Wollscheid, B Gundry, RL AF Boheler, Kenneth R. Bhattacharya, Subarna Kropp, Erin M. Chuppa, Sandra Riordon, Daniel R. Bausch-Fluck, Damaris Burridge, Paul W. Wu, Joseph C. Wersto, Robert P. Chan, Godfrey Chi Fung Rao, Sridhar Wollscheid, Bernd Gundry, Rebekah L. TI A Human Pluripotent Stem Cell Surface N-Glycoproteome Resource Reveals Markers, Extracellular Epitopes, and Drug Targets SO STEM CELL REPORTS LA English DT Article ID EMBRYONIC STEM; MURINE BLASTOCYST; TERATOMA ASSAYS; GROWTH-FACTOR; HUMAN ES; PROTEIN; EXPRESSION; DIFFERENTIATION; GENERATION; REGULATOR AB Detailed knowledge of cell-surface proteins for isolating well-defined populations of human pluripotent stem cells (hPSCs) would significantly enhance their characterization and translational potential. Through a chemoproteomic approach, we developed a cell-surface proteome inventory containing 496 N-linked glycoproteins on human embryonic (hESCs) and induced PSCs (hiPSCs). Against a backdrop of human fibroblasts and 50 other cell types, >100 surface proteins of interest for hPSCs were revealed. The >30 positive and negative markers verified here by orthogonal approaches provide experimental justification for the rational selection of pluripotency and lineage markers, epitopes for cell isolation, and reagents for the characterization of putative hiPSC lines. Comparative differences between the chemoproteomic-defined surfaceome and the transcriptome-predicted surfaceome directly led to the discovery that STF-31, a reported GLUT-1 inhibitor, is toxic to hPSCs and efficient for selective elimination of hPSCs from mixed cultures. C1 [Boheler, Kenneth R.; Chan, Godfrey Chi Fung] Univ Hong Kong, LKS Fac Med, Stem Cell & Regenerat Med Consortium, Hong Kong, Hong Kong, Peoples R China. [Boheler, Kenneth R.; Riordon, Daniel R.; Wersto, Robert P.] NIA, NIH, Baltimore, MD 21224 USA. [Boheler, Kenneth R.] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD 21205 USA. [Bhattacharya, Subarna; Kropp, Erin M.; Chuppa, Sandra; Gundry, Rebekah L.] Med Coll Wisconsin, Dept Biochem, Milwaukee, WI 53226 USA. [Burridge, Paul W.; Wu, Joseph C.] Stanford Univ, Sch Med, Stanford Cardiovasc Inst, Stanford, CA 94305 USA. [Chan, Godfrey Chi Fung] Univ Hong Kong, Dept Pediat & Adolescent Med, Hong Kong, Hong Kong, Peoples R China. [Rao, Sridhar] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Rao, Sridhar] Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, Milwaukee, WI 53226 USA. [Rao, Sridhar] Blood Ctr Wisconsin, Blood Res Inst, Milwaukee, WI 53226 USA. [Bausch-Fluck, Damaris; Wollscheid, Bernd] Swiss Fed Inst Technol, Inst Mol Syst Biol, Dept Biol, CH-8093 Zurich, Switzerland. RP Boheler, KR (reprint author), Univ Hong Kong, LKS Fac Med, Stem Cell & Regenerat Med Consortium, Hong Kong, Hong Kong, Peoples R China. EM bohelerk@hku.hk; rgundry@mcw.edu RI Wollscheid, Bernd/E-8909-2010 OI Wollscheid, Bernd/0000-0002-3923-1610 FU NIH [4R00HL094708-03]; BD Biosciences Research Grant Award; MCW Research Affairs Committee New Faculty Award; Kern foundation (startup funds) at the Medical College of Wisconsin; Intramural Research Program of the NIH/NIA; NIH Induced Pluripotent Stem Cell Center/Center for Regenerative Medicine Research Study Award; Research Grants Council of Hong Kong Theme-based Research Scheme [T13-706/11]; Swiss National Science Foundation [31003A_135805]; American Cancer Society [86-004]; Midwest Athletes against Childhood Cancer; AHA Established Investigator Award; AHA Postdoctoral Fellowship [12POST12050254]; T32 grant from NIGMS [GM080202]; [U01 HL099776] FX This research was supported by NIH 4R00HL094708-03, BD Biosciences Research Grant Award, MCW Research Affairs Committee New Faculty Award, and the Kern foundation (startup funds) at the Medical College of Wisconsin (R. L. G.); the Intramural Research Program of the NIH/NIA, NIH Induced Pluripotent Stem Cell Center/Center for Regenerative Medicine Research Study Award and Research Grants Council of Hong Kong Theme-based Research Scheme T13-706/11 (K. R. B.); the Swiss National Science Foundation (grants 31003A_135805 to B. W.); Institutional Research Grant #86-004 from the American Cancer Society and the Midwest Athletes against Childhood Cancer (S. R.); U01 HL099776 and AHA Established Investigator Award (J.C.W.); AHA Postdoctoral Fellowship 12POST12050254 (P. W. B.); E. M. K. is a member of the MCW-MSTP, which is partially supported by a T32 grant from NIGMS, GM080202. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Hope Campbell at the Flow Cytometry Core of the Blood Research Institute of Wisconsin and Dr. Kate Noon, Michael Pereckas, and Xioagang Wu at the MCW Mass Spectrometry Facility for assistance with data collection. Special thanks to Dr. John Corbett (MCW) for generously providing access to the confocal microscope and the Biotechnology & Bioengineering Center (MCW) for access to the Real-Time PCR System. NR 58 TC 18 Z9 18 U1 1 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD JUL 8 PY 2014 VL 3 IS 1 DI 10.1016/j.stemcr.2014.05.002 PG 19 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AN8VB UT WOS:000340882100018 PM 25068131 ER PT J AU Thalheimer, FB Wingert, S De Giacomo, P Haetscher, N Rehage, M Brill, B Theis, FJ Hennighausen, L Schroeder, T Rieger, MA AF Thalheimer, Frederic B. Wingert, Susanne De Giacomo, Pangrazio Haetscher, Nadine Rehage, Maike Brill, Boris Theis, Fabian J. Hennighausen, Lothar Schroeder, Timm Rieger, Michael A. TI Cytokine-Regulated GADD45G Induces Differentiation and Lineage Selection in Hematopoietic Stem Cells SO STEM CELL REPORTS LA English DT Article ID SELF-RENEWAL; P38 MAPK; STRESS; KINASE; GADD45-GAMMA; ACTIVATION; EXPANSION AB The balance of self-renewal and differentiation in long-term repopulating hematopoietic stem cells (LT-HSC) must be strictly controlled to maintain blood homeostasis and to prevent leukemogenesis. Hematopoietic cytokines can induce differentiation in LT-HSCs; however, the molecular mechanism orchestrating this delicate balance requires further elucidation. We identified the tumor suppressor GADD45G as an instructor of LT-HSC differentiation under the control of differentiation-promoting cytokine receptor signaling. GADD45G immediately induces and accelerates differentiation in LT-HSCs and overrides the self-renewal program by specifically activating MAP3K4-mediated MAPK p38. Conversely, the absence of GADD45G enhances the self-renewal potential of LT-HSCs. Videomicroscopy-based tracking of single LT-HSCs revealed that, once GADD45G is expressed, the development of LT-HSCs into lineage-committed progeny occurred within 36 hr and uncovered a selective lineage choice with a severe reduction in megakaryocytic-erythroid cells. Here, we report an unrecognized role of GADD45G as a central molecular linker of extrinsic cytokine differentiation and lineage choice control in hematopoiesis. C1 [Thalheimer, Frederic B.; Wingert, Susanne; Haetscher, Nadine; Rehage, Maike; Rieger, Michael A.] Goethe Univ Frankfurt, LOEWE Ctr Cell & Gene Therapy, D-60590 Frankfurt, Germany. [Thalheimer, Frederic B.; Wingert, Susanne; Haetscher, Nadine; Rehage, Maike; Rieger, Michael A.] Goethe Univ Frankfurt, Dept Hematol Oncol, D-60590 Frankfurt, Germany. [Thalheimer, Frederic B.; Wingert, Susanne; De Giacomo, Pangrazio; Haetscher, Nadine; Rehage, Maike; Brill, Boris; Rieger, Michael A.] Georg Speyer Haus, D-60596 Frankfurt, Germany. [Theis, Fabian J.] Helmholtz Zentrum Munich, Inst Computat Biol, D-85764 Neuherberg, Germany. [Theis, Fabian J.] Tech Univ Munich, Dept Math, D-85747 Garching, Germany. [Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Schroeder, Timm] Swiss Fed Inst Technol, Dept Biosyst Sci & Engn D BSSE, CH-4058 Basel, Switzerland. [Rieger, Michael A.] German Canc Consortium DKTK, Heidelberg, Germany. [Rieger, Michael A.] German Canc Res Ctr, D-69120 Heidelberg, Germany. RP Rieger, MA (reprint author), Goethe Univ Frankfurt, LOEWE Ctr Cell & Gene Therapy, Theodor Stern Kai 7, D-60590 Frankfurt, Germany. EM m.rieger@em.uni-frankfurt.de RI Schroeder, Timm/F-8448-2010; OI Schroeder, Timm/0000-0001-9320-0252; Theis, Fabian/0000-0002-2419-1943 FU Intramural Research Program of NIDDK/NIH; LOEWE Center for Cell and Gene Therapy [HMWK III L 4-518/17.004] FX We thank C. Jourdan, S. Bothur, T. Merovci, C. Weiser, C. Molenda, K. Pesek, P. Schwab, and A. Eller for excellent technical assistance and J. Lausen and Y. Feuermann for critically reading the manuscript. R. Davis and A. Schambach kindly provided the plasmids Addgene plasmid #13518 and pRRL.PPT.SFFV.IRES.eGFP.wPRE, respectively. Funding was provided by the Intramural Research Program of NIDDK/NIH to L. H. and by the LOEWE Center for Cell and Gene Therapy (HMWK III L 4-518/17.004 [2013]) to M.A.R. NR 28 TC 10 Z9 10 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD JUL 8 PY 2014 VL 3 IS 1 DI 10.1016/j.stemcr.2014.05.010 PG 10 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AN8VB UT WOS:000340882100007 PM 25068120 ER PT J AU Noinaj, N Kuszak, AJ Balusek, C Gumbart, JC Buchanan, SK AF Noinaj, Nicholas Kuszak, Adam J. Balusek, Curtis Gumbart, James C. Buchanan, Susan K. TI Lateral Opening and Exit Pore Formation Are Required for BamA Function SO STRUCTURE LA English DT Article ID BARREL ASSEMBLY MACHINERY; OUTER-MEMBRANE PROTEINS; GRAM-NEGATIVE BACTERIA; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; ESSENTIAL COMPONENT; MOLECULAR-DYNAMICS; COMPLEX; BIOGENESIS AB The outer membrane of Gram-negative bacteria is replete with a host of beta-barrel outer membrane proteins (OMPs). Despite serving a variety of essential functions, including immune response evasion, the exact mechanism of OMP folding and membrane insertion remains largely unclear. The beta-barrel assembly machinery complex is required for OMP biogenesis. Crystal structures and molecular dynamics (MD) simulations of the central and essential component, BamA, suggest a mechanism involving lateral opening of its barrel domain. MD simulations reported here reveal an additional feature of BamA: a substrate exit pore positioned above the lateral opening site. Disulfide crosslinks that prevent lateral opening and exit pore formation result in a loss of BamA function, which can be fully rescued by the reductant tris(2-carboxyethyl) phosphine. These data provide strong evidence that lateral opening and exit pore formation are required for BamA function. C1 [Noinaj, Nicholas; Kuszak, Adam J.; Buchanan, Susan K.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Balusek, Curtis; Gumbart, James C.] Georgia Inst Technol, Sch Phys, Atlanta, GA 30332 USA. RP Buchanan, SK (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM skbuchan@helix.nih.gov FU NIH, National Institute of Diabetes and Digestive and Kidney Diseases; GAANN fellowship; NIH [K22-AI100927, R01-GM67887, RC2GM093307] FX We thank H. Bernstein and R. Ieva for providing JCM-166 cells. N.N., A.K., and S.K.B. are supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. C.B. is funded by a GAANN fellowship in the Molecular Biophysics Training Program at Georgia Tech. J.C.G. is supported by NIH grants K22-AI100927 and R01-GM67887. Anton computer time was provided by the National Resource for Biomedical Supercomputing and the Pittsburgh Supercomputing Center through NIH Grant RC2GM093307, using a machine donated by DE Shaw Research. NR 46 TC 55 Z9 55 U1 1 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD JUL 8 PY 2014 VL 22 IS 7 BP 1055 EP 1062 DI 10.1016/j.str.2014.05.008 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AN3KQ UT WOS:000340487000017 PM 24980798 ER PT J AU Schreiber, JM Lanham, DC Trescher, WH Sparks, SE Wassif, CA Caffo, BS Porter, FD Tierney, E Gropman, AL Ewen, JB AF Schreiber, John M. Lanham, Diane C. Trescher, William H. Sparks, Susan E. Wassif, Christopher A. Caffo, Brian S. Porter, Forbes D. Tierney, Elaine Gropman, Andrea L. Ewen, Joshua B. TI Variations in EEG discharges predict ADHD severity within individual Smith-Lemli-Opitz patients SO NEUROLOGY LA English DT Article ID INTERICTAL EEG; EPILEPSY; CHILDREN; ABNORMALITIES; DIAGNOSIS AB Objective: We sought to examine the prevalence of EEG abnormalities in Smith-Lemli-Opitz syndrome (SLOS) as well as the relationship between interictal epileptiform discharges (IEDs) and within-subject variations in attentional symptom severity. Methods: In the context of a clinical trial for SLOS, we performed cross-sectional and repeated-measure observational studies of the relationship between EEG findings and cognitive/behavioral factors on 23 children (aged 4-17 years). EEGs were reviewed for clinical abnormalities, including IEDs, by readers blinded to participants' behavioral symptoms. Between-group differences in baseline characteristics of participants with and without IEDs were analyzed. Within-subject analyses examined the association between the presence of IEDs and changes in attention-deficit/hyperactivity disorder (ADHD) symptoms. Results: Of 85 EEGs, 43 (51%) were abnormal, predominantly because of IEDs. Only one subject had documented clinical seizures. IEDs clustered in 13 subjects (57%), whereas 9 subjects (39%) had EEGs consistently free of IEDs. While there were no significant group differences in sex, age, intellectual disability, language level, or baseline ADHD symptoms, autistic symptoms tended to be more prevalent in the "IED" group (according to Autism Diagnostic Observation Schedule-2 criteria). Within individuals, the presence of IEDs on a particular EEG predicted, on average, a 27% increase in ADHD symptom severity. Conclusions: Epileptiform discharges are common in SLOS, despite a relatively low prevalence of epilepsy. Fluctuations in the presence of epileptiform discharges within individual children with a developmental disability syndrome may be associated with fluctuations in ADHD symptomatology, even in the absence of clinical seizures. C1 [Schreiber, John M.] NINDS, EEG Sect, NIH, Bethesda, MD 20892 USA. [Sparks, Susan E.; Gropman, Andrea L.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Wassif, Christopher A.] NICHD, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Lanham, Diane C.; Tierney, Elaine] Kennedy Krieger Inst, Dept Child & Adolescent Psychiat, Baltimore, MD USA. [Trescher, William H.; Ewen, Joshua B.] Kennedy Krieger Inst, Dept Neurol & Dev Med, Baltimore, MD 21205 USA. [Trescher, William H.; Ewen, Joshua B.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Tierney, Elaine] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Trescher, William H.; Porter, Forbes D.] Penn State Hershey Childrens Hosp, Dept Pediat Neurol, Hershey, PA USA. [Caffo, Brian S.] Johns Hopkins Univ, Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Gropman, Andrea L.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Gropman, Andrea L.] George Washington Univ Hlth Sci, Washington, DC USA. RP Ewen, JB (reprint author), Kennedy Krieger Inst, Dept Neurol & Dev Med, Baltimore, MD 21205 USA. EM Ewen@kennedykrieger.org OI Ewen, Joshua/0000-0002-9203-9564; Wassif, Christopher/0000-0002-2524-1420 FU Autism Speaks; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Kennedy Krieger/Johns Hopkins NICHD Intellectual and Developmental Disabilities Research Center core grant [P30 HD024061]; National Center for Advancing Translational Sciences (NCATS), a component of the NIH [UL1 TR 000424-06]; NIH Roadmap for Medical Research; Bench to Bedside award from the Office of Rare Diseases; NIH Clinical Center; NICHD; National Institute of Neurological Disorders and Stroke/NIH [K23 NS073626] FX This research was supported by Autism Speaks, the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and by the Kennedy Krieger/Johns Hopkins NICHD Intellectual and Developmental Disabilities Research Center core grant P30 HD024061. This publication was made possible by the Johns Hopkins Institute for Clinical and Translational Research (ICTR), which is funded in part by grant UL1 TR 000424-06 from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH, and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the Johns Hopkins ICTR, NCATS, or NIH. This project was also supported by a Bench to Bedside award to F. D. P. from the Office of Rare Diseases, NIH Clinical Center, and NICHD; and by National Institute of Neurological Disorders and Stroke/NIH grant K23 NS073626 awarded to J.B.E. NR 30 TC 4 Z9 4 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUL 8 PY 2014 VL 83 IS 2 BP 151 EP 159 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA AM8EI UT WOS:000340103400041 PM 24920862 ER PT J AU Babcock, HE Dutta, S Alur, RP Brocker, C Vasiliou, V Vitale, S Abu-Asab, M Brooks, BP AF Babcock, Holly E. Dutta, Sunit Alur, Ramakrishna P. Brocker, Chad Vasiliou, Vasilis Vitale, Susan Abu-Asab, Mones Brooks, Brian P. TI aldh7a1 Regulates Eye and Limb Development in Zebrafish SO PLOS ONE LA English DT Article ID RECESSIVE COLOBOMATOUS MICROPHTHALMIA; PYRIDOXINE-DEPENDENT EPILEPSY; RETINOIC ACID; OCULAR COLOBOMA; FISSURE CLOSURE; EXPRESSION; MUTATIONS; ANOPHTHALMIA; GENES; ANTIQUITIN AB Uveal coloboma is a potentially blinding congenital ocular malformation caused by failure of the optic fissure to close during development. Although mutations in numerous genes have been described, these account for a minority of cases, complicating molecular diagnosis and genetic counseling. Here we describe a key role of aldh7a1 as a gene necessary for normal eye development. We show that morpholino knockdown of aldh7a1 in zebrafish causes uveal coloboma and misregulation of nlz1, another known contributor to the coloboma phenotype, as well as skeletal abnormalities. Knockdown of aldh7a1 leads to reduced cell proliferation in the optic cup of zebrafish, delaying the approximation of the edges of the optic fissure. The aldh7a1 morphant phenotype is partially rescued by co-injection of nlz1 mRNA suggesting that nlz1 is functionally downstream of aldh7a1 in regulating cell proliferation in the optic cup. These results support a role of aldh7a1 in ocular development and skeletal abnormalities in zebrafish. C1 [Babcock, Holly E.; Dutta, Sunit; Alur, Ramakrishna P.; Brooks, Brian P.] NEI, Unit Pediat Dev & Genet Ophthalmol, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Brocker, Chad; Vasiliou, Vasilis] Univ Colorado Denver, Mol Toxicol & Environm Hlth Sci Program, Dept Pharmaceut Sci, Aurora, CO USA. [Vitale, Susan] NEI, Div Biostat & Epidemiol, Clin Trials Branch, NIH, Bethesda, MD 20892 USA. [Abu-Asab, Mones] NEI, Immunopathol Sect, NIH, Bethesda, MD 20892 USA. RP Brooks, BP (reprint author), NEI, Unit Pediat Dev & Genet Ophthalmol, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. EM brooksb@mail.nih.gov FU Intramural Program of the National Eye Institute; National Institutes of Health; US Dpt. Of Health and Human Services FX This work was funded by the Intramural Program of the National Eye Institute, National Institutes of Health, US Dpt. Of Health and Human Services. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 2 Z9 2 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 8 PY 2014 VL 9 IS 7 AR e101782 DI 10.1371/journal.pone.0101782 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL6KZ UT WOS:000339242700064 PM 25004007 ER PT J AU Lynfield, R Davey, R Dwyer, DE Losso, MH Wentworth, D Cozzi-Lepri, A Herman-Lamin, K Cholewinska, G David, D Kuetter, S Ternesgen, Z Uyeki, TM Lane, HC Lundgren, J Neaton, JD AF Lynfield, Ruth Davey, Richard Dwyer, Dominic E. Losso, Marcelo H. Wentworth, Deborah Cozzi-Lepri, Alessandro Herman-Lamin, Kathy Cholewinska, Grazyna David, Daniel Kuetter, Stefan Ternesgen, Zelalem Uyeki, Timothy M. Lane, H. Clifford Lundgren, Jens Neaton, James D. CA INSIGHT Influenza Study Grp TI Outcomes of Influenza A(H1N1)pdm09 Virus Infection: Results from Two International Cohort Studies SO PLOS ONE LA English DT Article ID 2009 H1N1 INFLUENZA; CRITICALLY-ILL PATIENTS; PANDEMIC INFLUENZA; UNITED-STATES; A H1N1; HOSPITALIZED-PATIENTS; ILLNESS; BACTERIAL; ADULTS; RISK AB Background: Data from prospectively planned cohort studies on risk of major clinical outcomes and prognostic factors for patients with influenza A(H1N1)pdm09 virus are limited. In 2009, in order to assess outcomes and evaluate risk factors for progression of illness, two cohort studies were initiated: FLU 002 in outpatients and FLU 003 in hospitalized patients. Methods and Findings: Between October 2009 and December 2012, adults with influenza-like illness (ILI) were enrolled; outpatients were followed for 14 days and inpatients for 60 days. Disease progression was defined as hospitalization and/or death for outpatients, and hospitalization for >28 days, transfer to intensive care unit (ICU) if enrolled from general ward, and/or death for inpatients. Infection was confirmed by RT-PCR. 590 FLU 002 and 392 FLU 003 patients with influenza A(H1N1)pdm09 were enrolled from 81 sites in 17 countries at 2 days (IQR 1-3) and 6 days (IQR 4-10) following ILI onset, respectively. Disease progression was experienced by 29 (1 death) outpatients (5.1%; 95% CI: 3.4-7.2%) and 80 inpatients [death (32), hospitalization >28 days (43) or ICU transfer (20)] (21.6%; 95% CI: 17.5-26.2%). Disease progression (death) for hospitalized patients was 53.1% (26.6%) and 12.8% (3.8%), respectively, for those enrolled in the ICU and general ward. In pooled analyses for both studies, predictors of disease progression were age, longer duration of symptoms at enrollment and immunosuppression. Patients hospitalized during the pandemic period had a poorer prognosis than in subsequent seasons. Conclusions: Patients with influenza A(H1N1)pdm09, particularly when requiring hospital admission, are at high risk for disease progression, especially if they are older, immunodeficient, or admitted late in infection. These data reinforce the need for international trials of novel treatment strategies for influenza infection and serve as a reminder of the need to monitor the severity of seasonal and pandemic influenza epidemics globally. C1 [Lynfield, Ruth] Minnesota Dept Hlth, Div Infect Dis, St Paul, MN 55124 USA. [Davey, Richard; Lane, H. Clifford] NIAID, NIH, Bethesda, MD 20892 USA. [Dwyer, Dominic E.] Univ Sydney, Westmead Hosp, Ctr Infect Dis & Microbiol, Dept Virol, Westmead, NSW 2145, Australia. [Dwyer, Dominic E.] Univ Sydney, Westmead, NSW 2145, Australia. [Losso, Marcelo H.] Hosp Jose Maria Ramos Mejia, Dept Med, HIV Unit, Buenos Aires, DF, Argentina. [Wentworth, Deborah; Herman-Lamin, Kathy; Lundgren, Jens] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Cozzi-Lepri, Alessandro] UCL, Res Dept Infect & Populat Hlth, London, England. [Cholewinska, Grazyna] Hosp Infect Dis, Warsaw, Poland. [David, Daniel] Hosp Rawson, Cordoba, Argentina. [Kuetter, Stefan] Marlow Med Grp, Marlow, Bucks, England. [Ternesgen, Zelalem] Mayo Clin, Rochester, MN USA. [Uyeki, Timothy M.] Ctr Dis Control & Prevent, Influenza Div, Atlanta, GA USA. [Lundgren, Jens] Univ Copenhagen Hosp, Dept Infect Dis, Rigshosp, DK-2100 Copenhagen, Denmark. [Lundgren, Jens] Univ Copenhagen, Copenhagen, Denmark. RP Lynfield, R (reprint author), Minnesota Dept Hlth, Div Infect Dis, St Paul, MN 55124 USA. EM Ruth.Lynfield@state.mn.us OI Lundgren, Jens/0000-0001-8901-7850 FU Leidos Prime [HHSN261200800001E]; NCI/NIAID FX Leidos Prime Contract HHSN261200800001E, NCI/NIAID. The funders had no role in study design, data collection and analysis, decision to Funding: publish, or preparation of the manuscript. NR 45 TC 8 Z9 8 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 8 PY 2014 VL 9 IS 7 AR e101785 DI 10.1371/journal.pone.0101785 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL6KZ UT WOS:000339242700065 PM 25004134 ER PT J AU Morken, NH Travlos, GS Wilson, RE Eggesbo, M Longnecker, MP AF Morken, Nils-Halvdan Travlos, Gregory S. Wilson, Ralph E. Eggesbo, Merete Longnecker, Matthew P. TI Maternal Glomerular Filtration Rate in Pregnancy and Fetal Size SO PLOS ONE LA English DT Article ID NORWEGIAN MOTHER; CHILD COHORT; PERFLUOROALKYL SUBSTANCES; POLYFLUOROALKYL COMPOUNDS; BIRTH-WEIGHT; PLASMA; GROWTH; WOMEN; EQUATIONS; VOLUME AB Background: The relationship of maternal glomerular filtration rate (GFR) in pregnancy to fetal size needs to be better characterized as it impacts an ongoing debate about confounding effect of maternal GFR in investigations of important environmental contaminants. We aimed to characterize the size of the association between maternal GFR and infant birth weight. Materials and Methods: A sub-cohort of 953 selected women (470 women with and 483 women without preeclampsia) in the Norwegian Mother and Child Cohort (MoBa), recruited during 2003-2007 were analyzed. GFR in the second trimester was estimated based on plasma creatinine. Birth weight was ascertained from the Medical Birth Registry of Norway. Multivariate linear regression was used to evaluate the association between maternal GFR in second trimester (estimated by the Cockroft-Gault [GFR-CG] and the modification of diet in renal disease [GFR-MDRD] formulas) and infant birth weight. Partial correlation coefficients were also calculated. Results: Maternal GFR-CG (beta: 0.73 g/ml/min, p = 0.04) and GFR-MDRD (beta: 0.83 g/ml/min, p = 0.04) were associated with infant birth weight in models adjusted for maternal weight in kilograms, preeclampsia, and gestational age at delivery (days). Partial correlation coefficients for the association between infant birth weight and GFR were 0.07 for both formulas. Although the birth weight-GFR association was stronger among the women with preeclampsia, the difference from women without preeclampsia was not statistically significant. Conclusion: These data support an association between GFR during pregnancy and infant birth weight, and indicate that GFR may confound selected epidemiologic associations. C1 [Morken, Nils-Halvdan] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. [Morken, Nils-Halvdan] Univ Bergen, Dept Clin Sci, Bergen, Norway. [Morken, Nils-Halvdan] Haukeland Hosp, Dept Obstet & Gynecol, N-5021 Bergen, Norway. [Travlos, Gregory S.; Wilson, Ralph E.] NIEHS, Cellular & Mol Pathol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Eggesbo, Merete] Norwegian Inst Publ Hlth, Div Epidemiol, Oslo, Norway. [Longnecker, Matthew P.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Morken, NH (reprint author), Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. EM nils-halvdan.morken@kk.uib.no OI Longnecker, Matthew/0000-0001-6073-5322; Eggesbo, Merete/0000-0002-0006-5336 FU University of Bergen; Unger-Vetlesen Medical Fund FX Nils-Halvdan Morken was supported with funding from the University of Bergen and the Unger-Vetlesen Medical Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 15 Z9 15 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 8 PY 2014 VL 9 IS 7 AR e101897 DI 10.1371/journal.pone.0101897 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL6KZ UT WOS:000339242700085 PM 25003331 ER PT J AU Panda, AC Sahu, I Kulkarni, SD Martindale, JL Abdelmohsen, K Vindu, A Joseph, J Gorospe, M Seshadri, V AF Panda, Amaresh C. Sahu, Itishri Kulkarni, Shardul D. Martindale, Jennifer L. Abdelmohsen, Kotb Vindu, Arya Joseph, Jomon Gorospe, Myriam Seshadri, Vasudevan TI miR-196b-Mediated Translation Regulation of Mouse Insulin2 via the 5 ' UTR SO PLOS ONE LA English DT Article ID MESSENGER-RNA; POSTTRANSCRIPTIONAL REGULATION; MICRORNA EXPRESSION; GLUCOSE; REPRESSION; RESISTANCE; PANCREAS; ISLETS; GENES; HUR AB The 5' and the 3' untranslated regions (UTR) of the insulin genes are very well conserved across species. Although microRNAs (miRNAs) are known to regulate insulin secretion process, direct regulation of insulin biosynthesis by miRNA has not been reported. Here, we show that mouse microRNA miR-196b can specifically target the 5'UTR of the long insulin2 splice isoform. Using reporter assays we show that miR-196b specifically increases the translation of the reporter protein luciferase. We further show that this translation activation is abolished when Argonaute 2 levels are knocked down after transfection with an Argonaute 2-directed siRNA. Binding of miR-196b to the target sequence in insulin 5'UTR causes the removal of HuD (a 5'UTR-associated translation inhibitor), suggesting that both miR-196b and HuD bind to the same RNA element. We present data suggesting that the RNA-binding protein HuD, which represses insulin translation, is displaced by miR-196b. Together, our findings identify a mechanism of post-transcriptional regulation of insulin biosynthesis. C1 [Panda, Amaresh C.; Sahu, Itishri; Kulkarni, Shardul D.; Vindu, Arya; Joseph, Jomon; Seshadri, Vasudevan] Natl Ctr Cell Sci, Pune, Maharashtra, India. [Panda, Amaresh C.; Martindale, Jennifer L.; Abdelmohsen, Kotb; Gorospe, Myriam] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Seshadri, V (reprint author), Natl Ctr Cell Sci, Pune, Maharashtra, India. EM seshadriv@nccs.res.in OI PANDA, AMARESH/0000-0003-3189-8995; Sahu, Itishri/0000-0002-6069-656X FU Department of Biotechnology, India [BT/PR14109/BRB/10/812/2010]; intramural grant from National Centre for Cell Science, India; Council for scientific and industrial research, India; National Institute on Aging - Intramural Research Program, National Institutes of Health FX This work was supported by grant (BT/PR14109/BRB/10/812/2010) from Department of Biotechnology, India, and intramural grant from National Centre for Cell Science, India, to VS. AV and SDK are supported by a fellowship from Council for scientific and industrial research, India. KA, JLM, and MG were supported by the National Institute on Aging - Intramural Research Program, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 4 Z9 5 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 8 PY 2014 VL 9 IS 7 AR e101084 DI 10.1371/journal.pone.0101084 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL6KZ UT WOS:000339242700018 PM 25003985 ER PT J AU Toriola, AT Stolzenberg-Solomon, R Dalidowitz, L Linehan, D Colditz, G AF Toriola, A. T. Stolzenberg-Solomon, R. Dalidowitz, L. Linehan, D. Colditz, G. TI Diabetes and pancreatic cancer survival: a prospective cohort-based study SO BRITISH JOURNAL OF CANCER LA English DT Article DE diabetes; pancreatic cancer; mortality; survival; cohort; prospective study ID SCREENING TRIAL; RISK-FACTORS; MELLITUS; PROSTATE; OBESITY; LUNG; ADENOCARCINOMA; DEATH AB Background: Diabetes is a risk factor for pancreatic cancer but its association with survival from pancreatic cancer is poorly understood. Our objective was to investigate the association of diabetes with survival among pancreatic cancer patients in a prospective cohort-based study where diabetes history was ascertained before pancreatic cancer diagnosis. Methods: We evaluated survival by baseline (1993-2001) self-reported diabetes history (n = 62) among 504 participants that developed exocrine pancreatic cancer within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality were estimated using Cox proportional hazards model, adjusted for age, sex, body mass index, race, smoking, and tumour stage (local, locally advanced, and metastatic). Results: The multivariable-adjusted HR for mortality comparing participants with diabetes to those without was 1.52 (95% CI = 1.14-2.04, P-value <0.01). After excluding those diagnosed with pancreatic cancer within 3 years of study enrolment, HR for mortality among those with diabetes was 1.45 (95% CI = 1.06-2.00, P-value = 0.02). Conclusions: Using prospectively collected data, our findings indicate that diabetes is associated with worse survival among patients with pancreatic cancer. C1 [Toriola, A. T.; Dalidowitz, L.; Colditz, G.] Washington Univ, Sch Med, Siteman Canc Ctr, Dept Surg,Div Publ Hlth Sci, St Louis, MO 63144 USA. [Stolzenberg-Solomon, R.] NCI, Branch Nutr Epidemiol, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20850 USA. [Linehan, D.] Washington Univ, Sch Med, Siteman Canc Ctr, Dept Surg,Sect Hepatopancreaticobiliary & Gastro, St Louis, MO 63144 USA. RP Toriola, AT (reprint author), Washington Univ, Sch Med, Siteman Canc Ctr, Dept Surg,Div Publ Hlth Sci, 660 South Euclid Ave,Campus Box 8100, St Louis, MO 63144 USA. EM a.toriola@wustl.edu RI Colditz, Graham/A-3963-2009; OI Colditz, Graham/0000-0002-7307-0291; Toriola, Adetunji/0000-0003-1079-2606 FU Washington University School of Medicine; Barnes-Jewish Hospital Foundation; Siteman Cancer Center FX Adetunji T Toriola is supported by the Washington University School of Medicine, Barnes-Jewish Hospital Foundation, and Siteman Cancer Center. NR 17 TC 10 Z9 12 U1 0 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JUL 8 PY 2014 VL 111 IS 1 BP 181 EP 185 DI 10.1038/bjc.2014.224 PG 5 WC Oncology SC Oncology GA AL5HC UT WOS:000339163300022 PM 24786605 ER PT J AU Aarestrup, J Gamborg, M Cook, MB Sorensen, TIA Baker, JL AF Aarestrup, J. Gamborg, M. Cook, M. B. Sorensen, T. I. A. Baker, J. L. TI Childhood body mass index and the risk of prostate cancer in adult men SO BRITISH JOURNAL OF CANCER LA English DT Article DE prostate neoplasms; body height; growth; body weights and measures; cohort studies ID HEALTH RECORDS REGISTER; DOSE-RESPONSE; HEIGHT; EPIDEMIOLOGY; COHORT; METAANALYSIS; OBESITY; SIZE; WEIGHT AB Background: Prostate cancer aetiology is poorly understood. It may have origins early in life; previously we found a positive association with childhood height. The effects of early life body mass index (BMI; kg m(-2)) on prostate cancer remain equivocal. We investigated if childhood BMI, independently and adjusted for height, is positively associated with adult prostate cancer. Methods: Subjects were a cohort of 125 208 boys formed from the Copenhagen School Health Records Register, born 1930-1969 with height and weight measurements at 7-13 years. Cases were identified through linkage to the Danish Cancer Registry. Cox proportional hazards regressions were performed. Results: Overall, 3355 men were diagnosed with prostate cancer. Body mass index during childhood was positively associated with adult prostate cancer. The hazard ratio of prostate cancer was 1.06 (95% confidence interval (CI): 1.01-1.10) per BMI z-score at age 7, and 1.05 (95% CI: 1.01-1.10) per BMI z-score at age 13. Estimates were similar and significant at all other ages. However, adjustment for childhood height attenuated the associations at all but the youngest ages as most estimates became nonsignificant. Conclusions: These results suggest that at most childhood ages, BMI does not confer an additional risk for prostate cancer beyond that of height. C1 [Aarestrup, J.; Gamborg, M.; Sorensen, T. I. A.; Baker, J. L.] Bispebjerg & Frederiksberg Hosp, Inst Prevent Med, DK-2000 Copenhagen, Denmark. [Cook, M. B.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Sorensen, T. I. A.; Baker, J. L.] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, DK-2100 Copenhagen, Denmark. RP Baker, JL (reprint author), Bispebjerg & Frederiksberg Hosp, Inst Prevent Med, Nordre Fasanvej 5, DK-2000 Copenhagen, Denmark. EM jennifer.lyn.baker@regionh.dk RI Cook, Michael/A-5641-2009; Baker, Jennifer/F-1917-2010 OI Cook, Michael/0000-0002-0533-7302; Baker, Jennifer/0000-0002-9649-6615 FU European Research Council under the European Union's Seventh Framework Programme (FP)/ERC, childgrowth2cancer [281418]; Intramural Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, USA FX The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement no. 281418, childgrowth2cancer to JLB. MBC was supported by the Intramural Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, USA. NR 38 TC 4 Z9 4 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JUL 8 PY 2014 VL 111 IS 1 BP 207 EP 212 DI 10.1038/bjc.2014.266 PG 6 WC Oncology SC Oncology GA AL5HC UT WOS:000339163300026 PM 24867696 ER PT J AU Low, JT Garcia-Miranda, P Mouzakis, KD Gorelick, RJ Butcher, SE Weeks, KM AF Low, Justin T. Garcia-Miranda, Pablo Mouzakis, Kathryn D. Gorelick, Robert J. Butcher, Samuel E. Weeks, Kevin M. TI Structure and Dynamics of the HIV-1 Frameshift Element RNA SO BIOCHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; PROGRAMMED-1 RIBOSOMAL FRAMESHIFT; LOCKED NUCLEIC-ACID; SECONDARY STRUCTURE; PROTEASE INHIBITORS; MESSENGER-RNA; DIFFERENTIAL SHAPE; TYPE-1; PSEUDOKNOTS; ACCURATE C1 [Low, Justin T.; Weeks, Kevin M.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. [Low, Justin T.] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Garcia-Miranda, Pablo; Mouzakis, Kathryn D.; Butcher, Samuel E.] Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. [Gorelick, Robert J.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick, MD 21702 USA. RP Weeks, KM (reprint author), Univ N Carolina, Dept Chem, CB 3290, Chapel Hill, NC 27599 USA. EM weeks@unc.edu RI Garcia-Miranda, Pablo/L-5213-2014 OI Garcia-Miranda, Pablo/0000-0003-2588-6904 FU National Institutes of Health [AI068462, GM072447]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Leidos Biomedical Research, Inc.; National Research Service Award [F30DA027364]; Medical Scientist Training Program [T32GM008719]; Program in Molecular and Cellular Biophysics [T32GM008570] FX This work was supported by National Institutes of Health grants AI068462 (to K.M.W.) and GM072447 (to S.E.B.). R.J.G was supported with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E with Leidos Biomedical Research, Inc. J.T.L. was supported by a National Research Service Award (F30DA027364), the Medical Scientist Training Program (T32GM008719), and the Program in Molecular and Cellular Biophysics (T32GM008570). NR 41 TC 15 Z9 15 U1 1 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 8 PY 2014 VL 53 IS 26 BP 4282 EP 4291 DI 10.1021/bi50049236 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AL0GT UT WOS:000338806100007 PM 24926888 ER PT J AU Seeley-Fallen, MK Liu, LJ Shapiro, MR Onabajo, OO Palaniyandi, S Zhu, XP Tan, TH Upadhyaya, A Song, WX AF Seeley-Fallen, Margaret K. Liu, Lisa J. Shapiro, Melanie R. Onabajo, Olusegun O. Palaniyandi, Senthilkumar Zhu, Xiaoping Tan, Tse-Hua Upadhyaya, Arpita Song, Wenxia TI Actin-binding protein 1 links B-cell antigen receptors to negative signaling pathways SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE B-lymphocytes; actin cytoskeleton; signal transduction ID PROGENITOR KINASE 1; GERMINAL-CENTERS; ADAPTER PROTEIN; ACTIVATION; CYTOSKELETON; HIP-55; SHIP; AUTOIMMUNITY; LYMPHOCYTES; ENDOCYTOSIS AB Prolonged or uncontrolled B-cell receptor (BCR) signaling is associated with autoimmunity. We previously demonstrated a role for actin in BCR signal attenuation. This study reveals that actin-binding protein 1 (Abp1/HIP-55/SH3P7) is a negative regulator of BCR signaling and links actin to negative regulatory pathways of the BCR. In both Abp1(-/-) and bone marrow chimeric mice, in which only B cells lack Abp1 expression, the number of spontaneous germinal center and marginal zone B cells and the level of autoantibody are significantly increased. Serum levels of T-independent antibody responses and total antibody are elevated, whereas T-dependent antibody responses are markedly reduced and fail to undergo affinity maturation. Upon activation, surface BCR clustering is enhanced and B-cell contraction delayed in Abp1(-/-) B cells, concurrent with slow but persistent increases in F-actin at BCR signalosomes. Furthermore, BCR signaling is enhanced in Abp1(-/-) B cells compared with wild-type B cells, including Ca2+ flux and phosphorylation of B-cell linker protein, the mitogen-activated protein kinase kinase MEK1/2, and ERK, coinciding with reductions in recruitment of the inhibitory signaling molecules hematopoietic progenitor kinase 1 and SH2-containing inositol 5-phosphatase to BCR signalosomes. Our results indicate that Abp1 negatively regulates BCR signaling by coupling actin remodeling to B-cell contraction and activation of inhibitory signaling molecules, which contributes to the regulation of peripheral B-cell development and antibody responses. C1 [Seeley-Fallen, Margaret K.; Liu, Lisa J.; Shapiro, Melanie R.; Song, Wenxia] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Onabajo, Olusegun O.] NCI, Lab Translat Genom, NIH, Bethesda, MD 20892 USA. [Palaniyandi, Senthilkumar; Zhu, Xiaoping] Univ Maryland, Lab Immunol, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Tan, Tse-Hua] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Upadhyaya, Arpita] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. RP Song, WX (reprint author), Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. EM wenxsong@umd.edu RI Palaniyandi, Senthilkumar/B-9575-2016; Tan, Tse-Hua/E-3983-2010 OI Tan, Tse-Hua/0000-0003-4969-3170 FU National Institutes of Health [AI059617]; Maryland Stem Cell Research Fund FX We thank Dr. Mark Jenkin (US Department of Agriculture), Amy Beaven (Imaging core), and Kenneth Class (Flow Cytometry core) for technical assistance. This work was supported by grants from the National Institutes of Health (AI059617) and from Maryland Stem Cell Research Fund (to W.S.). NR 33 TC 7 Z9 8 U1 6 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 8 PY 2014 VL 111 IS 27 BP 9881 EP 9886 DI 10.1073/pnas.1321971111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK6CH UT WOS:000338514800046 PM 24958882 ER PT J AU Nguyen, GH Tang, WL Robles, AI Beyer, RP Gray, LT Welsh, JA Schetter, AJ Kumamoto, K Wang, XW Hickson, ID Maizels, N Monnat, RJ Harris, CC AF Giang Huong Nguyen Tang, Weiliang Robles, Ana I. Beyer, Richard P. Gray, Lucas T. Welsh, Judith A. Schetter, Aaron J. Kumamoto, Kensuke Wang, Xin Wei Hickson, Ian D. Maizels, Nancy Monnat, Raymond J., Jr. Harris, Curtis C. TI Regulation of gene expression by the BLM helicase correlates with the presence of G-quadruplex DNA motifs SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ROTHMUND-THOMSON-SYNDROME; BLOOMS-SYNDROME; RECQ HELICASES; WERNERS-SYNDROME; HUMAN GENOME; SEQUENCES; PRODUCT; TRANSCRIPTION; MAINTENANCE; DEFICIENCY AB Bloom syndrome is a rare autosomal recessive disorder characterized by genetic instability and cancer predisposition, and caused by mutations in the gene encoding the Bloom syndrome, RecQ helicase-like (BLM) protein. To determine whether altered gene expression might be responsible for pathological features of Bloom syndrome, we analyzed mRNA and microRNA (miRNA) expression in fibroblasts from individuals with Bloom syndrome and in BLM-depleted control fibroblasts. We identified mRNA and miRNA expression differences in Bloom syndrome patient and BLM-depleted cells. Differentially expressed mRNAs are connected with cell proliferation, survival, and molecular mechanisms of cancer, and differentially expressed miRNAs target genes involved in cancer and in immune function. These and additional altered functions or pathways may contribute to the proportional dwarfism, elevated cancer risk, immune dysfunction, and other features observed in Bloom syndrome individuals. BLM binds to G-quadruplex (G4) DNA, and G4 motifs were enriched at transcription start sites (TSS) and especially within first introns (false discovery rate <= 0.001) of differentially expressed mRNAs in Bloom syndrome compared with normal cells, suggesting that G-quadruplex structures formed at these motifs are physiologic targets for BLM. These results identify a network of mRNAs and miRNAs that may drive the pathogenesis of Bloom syndrome. C1 [Giang Huong Nguyen; Robles, Ana I.; Welsh, Judith A.; Schetter, Aaron J.; Kumamoto, Kensuke; Wang, Xin Wei; Harris, Curtis C.] NCI, Lab Human Carcinogenesis, NIH, Bethesda, MD 20892 USA. [Giang Huong Nguyen; Hickson, Ian D.] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Dept Med Oncol, Oxford OX3 9DS, England. [Tang, Weiliang; Monnat, Raymond J., Jr.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Gray, Lucas T.; Maizels, Nancy] Univ Washington, Dept Immunol & Biochem, Seattle, WA 98195 USA. [Monnat, Raymond J., Jr.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Beyer, Richard P.] Univ Washington, Ctr Ecogenet & Environm Hlth, Seattle, WA 98105 USA. [Kumamoto, Kensuke] Fukushima Med Univ, Dept Organ Regulatory Surg, Fukushima 9601295, Japan. [Hickson, Ian D.] Univ Copenhagen, Nordea Ctr Hlth Aging, Dept Cellular & Mol Med, DK-2200 Copenhagen N, Denmark. RP Monnat, RJ (reprint author), Univ Washington, Dept Pathol, Seattle, WA 98195 USA. EM monnat@u.washington.edu; curtis_harris@nih.gov RI Wang, Xin/B-6162-2009; OI Gray, Lucas/0000-0002-8814-6818 FU NCI, Center for Cancer Research, NIH; NCI of NIH [P01CA77852]; NIH-Oxford MD/DPhil Fellowship Program FX We thank the staffs at the Laboratory of Molecular Technology [National Cancer Institute (NCI)-Frederick], the Center for Ecogenetics and Environmental Health Functional Genomics and Proteomics Core [University of Washington (UW)], and the Microarray Core Facility at the Ohio State University for the microarray hybridization and scanning; Yizhe Tang and Scott Hudson [Laboratory of Human Carcinogenesis, NCI, National Institutes of Health (NIH)] for valuable suggestions; Alden Hackmann for graphics support; and UW RECQ Program Project colleagues for many helpful suggestions. This work was supported by the Intramural Research Program of the NCI, Center for Cancer Research, NIH; NCI of NIH Award P01CA77852 (to R.J.M. and N.M.) and by the NIH-Oxford MD/DPhil Fellowship Program support (to G.H.N.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 51 TC 25 Z9 25 U1 3 U2 35 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 8 PY 2014 VL 111 IS 27 BP 9905 EP 9910 DI 10.1073/pnas.1404807111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK6CH UT WOS:000338514800050 PM 24958861 ER PT J AU Ohno, N Chiang, H Mahad, DJ Kidd, GJ Liu, LP Ransohoff, RM Sheng, ZH Komuro, H Trapp, BD AF Ohno, Nobuhiko Chiang, Hao Mahad, Don J. Kidd, Grahame J. Liu, LiPing Ransohoff, Richard M. Sheng, Zu-Hang Komuro, Hitoshi Trapp, Bruce D. TI Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MULTIPLE-SCLEROSIS; SODIUM-CHANNELS; WHITE-MATTER; CNS WHITE; IN-VITRO; DEGENERATION; CUPRIZONE; MYELINATION AB Axonal degeneration is a primary cause of permanent neurological disability in individuals with the CNS demyelinating disease multiple sclerosis. Dysfunction of axonal mitochondria and imbalanced energy demand and supply are implicated in degeneration of chronically demyelinated axons. The purpose of this study was to define the roles of mitochondrial volume and distribution in axonal degeneration following acute CNS demyelination. We show that the axonal mitochondrial volume increase following acute demyelination of WT CNS axons does not occur in demyelinated axons deficient in syntaphilin, an axonal molecule that immobilizes stationary mitochondria to microtubules. These findings were supported by time-lapse imaging of WT and syntaphilin-deficient axons in vitro. When demyelinated, axons deficient in syntaphilin degenerate at a significantly greater rate than WT axons, and this degeneration can be rescued by reducing axonal electrical activity with the Na+ channel blocker flecainide. These results support the concept that syntaphilin-mediated immobilization of mitochondria to microtubules is required for the volume increase of axonal mitochondria following acute demyelination and protects against axonal degeneration in the CNS. C1 [Ohno, Nobuhiko; Chiang, Hao; Mahad, Don J.; Kidd, Grahame J.; Liu, LiPing; Ransohoff, Richard M.; Komuro, Hitoshi; Trapp, Bruce D.] Cleveland Clin, Lerner Res Inst, Dept Neurosci, Cleveland, OH 44195 USA. [Sheng, Zu-Hang] NINDS, Synapt Funct Sect, NIH, Bethesda, MD 20892 USA. RP Trapp, BD (reprint author), Cleveland Clin, Lerner Res Inst, Dept Neurosci, Cleveland, OH 44195 USA. EM trappb@ccf.org FU National Institutes of Health [NS38186, NS38867]; National Multiple Sclerosis Society Postdoctoral Fellowship; Comprehensive Brain Science Network; National Institute of Neurological Disorders and Stroke, National Institutes of Health; National Institute for Physiological Sciences FX We thank Christopher Nelson for careful editorial assistance; Ansi Chang, Xinghua Yin, Danielle Klein, and Raymond Gaines for technical assistance; Ranjan Dutta for critical reading of the manuscript; and Claudia Gerwin for information to maintain syntaphilin-KO mice. This work was supported by National Institutes of Health Grants NS38186 and NS38867 (to B. D. T.); a National Multiple Sclerosis Society Postdoctoral Fellowship; the Comprehensive Brain Science Network; the Intramural Research Program of National Institute of Neurological Disorders and Stroke, National Institutes of Health (Z.-H.S.); and the Cooperative Study Program of National Institute for Physiological Sciences (N.O.). NR 51 TC 23 Z9 23 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 8 PY 2014 VL 111 IS 27 BP 9953 EP 9958 DI 10.1073/pnas.1401155111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK6CH UT WOS:000338514800058 PM 24958879 ER PT J AU Lohr, KM Bernstein, AI Stout, KA Dunn, AR Lazo, CR Alter, SP Wang, MZ Li, YJ Fan, XL Hess, EJ Yi, H Vecchio, LM Goldstein, DS Guillot, TS Salahpour, A Miller, GW AF Lohr, Kelly M. Bernstein, Alison I. Stout, Kristen A. Dunn, Amy R. Lazo, Carlos R. Alter, Shawn P. Wang, Minzheng Li, Yingjie Fan, Xueliang Hess, Ellen J. Yi, Hong Vecchio, Laura M. Goldstein, David S. Guillot, Thomas S. Salahpour, Ali Miller, Gary W. TI Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE SLC18A2; fast-scan cyclic voltammetry; serotonin; norepinephrine ID QUANTAL SIZE; MOUSE MODEL; ALPHA-SYNUCLEIN; KNOCKOUT MICE; EXPRESSION; AMPHETAMINE; STORAGE; NEURONS; COCAINE; BRAIN AB Disruption of neurotransmitter vesicle dynamics (transport, capacity, release) has been implicated in a variety of neurodegenerative and neuropsychiatric conditions. Here, we report a novel mouse model of enhanced vesicular function via bacterial artificial chromosome (BAC)-mediated overexpression of the vesicular monoamine transporter 2 (VMAT2; Slc18a2). A twofold increase in vesicular transport enhances the vesicular capacity for dopamine (56%), dopamine vesicle volume (33%), and basal tissue dopamine levels (21%) in the mouse striatum. The elevated vesicular capacity leads to an increase in stimulated dopamine release (84%) and extracellular dopamine levels (44%). VMAT2-overexpressing mice show improved outcomes on anxiety and depressive-like behaviors and increased basal locomotor activity (41%). Finally, these mice exhibit significant protection from neurotoxic insult by the dopaminergic toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), as measured by reduced dopamine terminal damage and substantia nigra pars compacta cell loss. The increased release of dopamine and neuroprotection from MPTP toxicity in the VMAT2-overexpressing mice suggest that interventions aimed at enhancing vesicular capacity may be of therapeutic benefit in Parkinson disease. C1 [Lohr, Kelly M.; Bernstein, Alison I.; Stout, Kristen A.; Dunn, Amy R.; Lazo, Carlos R.; Alter, Shawn P.; Wang, Minzheng; Li, Yingjie; Guillot, Thomas S.; Miller, Gary W.] Emory Univ, Rollins Sch Publ Hlth, Dept Environm Hlth, Atlanta, GA 30322 USA. [Fan, Xueliang; Hess, Ellen J.; Miller, Gary W.] Emory Univ, Dept Pharmacol, Atlanta, GA 30322 USA. [Hess, Ellen J.; Miller, Gary W.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Yi, Hong] Emory Univ, Robert P Apkarian Integrated Electron Microscopy, Atlanta, GA 30322 USA. [Miller, Gary W.] Emory Univ, Ctr Neurodegenerat Dis, Atlanta, GA 30322 USA. [Vecchio, Laura M.; Salahpour, Ali] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5S 1A8, Canada. [Goldstein, David S.] NINDS, Bethesda, MD 20824 USA. RP Miller, GW (reprint author), Emory Univ, Rollins Sch Publ Hlth, Dept Environm Hlth, Atlanta, GA 30322 USA. EM gary.miller@emory.edu OI Miller, Gary/0000-0001-8984-1284; Dunn, Amy/0000-0001-6437-6099 FU National Institutes of Health [P01ES016731, P30ES019776, T32ES012870, DA015040, T32GM008605, F31NS084739, P50AG025688, P50NS071669]; Canadian Institutes of Health Research [210296]; Lewis Dickey Memorial Fund FX We thank Minagi Ozawa and Patricia Sullivan for their excellent technical assistance; the Emory University Transgenic Mouse and Gene Targeting Core for BAC DNA isolation, DNA preparation, and pronuclear injections; and the Rodent Behavioral Core Facility for assistance with the locomotor activity assay. This work was supported by National Institutes of Health Grants P01ES016731, P30ES019776, T32ES012870, DA015040, T32GM008605, F31NS084739, P50AG025688, and P50NS071669; Canadian Institutes of Health Research Grant 210296; and the Lewis Dickey Memorial Fund. NR 58 TC 31 Z9 31 U1 2 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 8 PY 2014 VL 111 IS 27 BP 9977 EP 9982 DI 10.1073/pnas.1402134111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK6CH UT WOS:000338514800062 PM 24979780 ER PT J AU Ganapathy, G Howard, JT Ward, JM Li, JW Li, B Li, YR Xiong, YQ Zhang, Y Zhou, SG Schwartz, DC Schatz, M Aboukhalil, R Fedrigo, O Bukovnik, L Wang, T Wray, G Rasolonjatovo, I Winer, R Knight, JR Koren, S Warren, WC Zhang, GJ Phillippy, AM Jarvis, ED AF Ganapathy, Ganeshkumar Howard, Jason T. Ward, James M. Li, Jianwen Li, Bo Li, Yingrui Xiong, Yingqi Zhang, Yong Zhou, Shiguo Schwartz, David C. Schatz, Michael Aboukhalil, Robert Fedrigo, Olivier Bukovnik, Lisa Wang, Ty Wray, Greg Rasolonjatovo, Isabelle Winer, Roger Knight, James R. Koren, Sergey Warren, Wesley C. Zhang, Guojie Phillippy, Adam M. Jarvis, Erich D. TI High-coverage sequencing and annotated assemblies of the budgerigar genome SO GIGASCIENCE LA English DT Article DE Melopsittacus undulatus; Budgerigar; Parakeet; Next-generation sequencing; Hybrid assemblies; Optical maps; Vocal learning ID NOVO; EVOLUTION; REVEALS; READS AB Background: Parrots belong to a group of behaviorally advanced vertebrates and have an advanced ability of vocal learning relative to other vocal-learning birds. They can imitate human speech, synchronize their body movements to a rhythmic beat, and understand complex concepts of referential meaning to sounds. However, little is known about the genetics of these traits. Elucidating the genetic bases would require whole genome sequencing and a robust assembly of a parrot genome. Findings: We present a genomic resource for the budgerigar, an Australian Parakeet (Melopsittacus undulatus) - the most widely studied parrot species in neuroscience and behavior. We present genomic sequence data that includes over 300x raw read coverage from multiple sequencing technologies and chromosome optical maps from a single male animal. The reads and optical maps were used to create three hybrid assemblies representing some of the largest genomic scaffolds to date for a bird; two of which were annotated based on similarities to reference sets of non-redundant human, zebra finch and chicken proteins, and budgerigar transcriptome sequence assemblies. The sequence reads for this project were in part generated and used for both the Assemblathon 2 competition and the first de novo assembly of a giga-scale vertebrate genome utilizing PacBio single-molecule sequencing. Conclusions: Across several quality metrics, these budgerigar assemblies are comparable to or better than the chicken and zebra finch genome assemblies built from traditional Sanger sequencing reads, and are sufficient to analyze regions that are difficult to sequence and assemble, including those not yet assembled in prior bird genomes, and promoter regions of genes differentially regulated in vocal learning brain regions. This work provides valuable data and material for genome technology development and for investigating the genomics of complex behavioral traits. C1 [Ganapathy, Ganeshkumar; Howard, Jason T.; Jarvis, Erich D.] Duke Univ, Med Ctr, Dept Neurobiol, Durham, NC 27710 USA. [Ward, James M.; Wang, Ty] NIEHS, NIH, Raleigh, NC 27709 USA. [Li, Jianwen; Li, Bo; Li, Yingrui; Xiong, Yingqi; Zhang, Yong; Zhang, Guojie] BGI Shenzhen, China Natl Genebank, Shenzhen 518083, Peoples R China. [Zhou, Shiguo; Schwartz, David C.] Univ Wisconsin, Genet Lab, Lab Mol & Computat Genom, Dept Chem, Madison, WI 53706 USA. [Zhou, Shiguo; Schwartz, David C.] Univ Wisconsin, Ctr Biotechnol, Madison, WI 53706 USA. [Schatz, Michael; Aboukhalil, Robert] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Fedrigo, Olivier; Bukovnik, Lisa] Duke Univ, Inst Genome Sci & Policy, Durham, NC 27710 USA. [Wray, Greg] Duke Univ, Dept Biol, Ctr Syst Biol, Durham, NC 27710 USA. [Rasolonjatovo, Isabelle] Illumina Cambridge Ltd, Cambridge, England. [Winer, Roger; Knight, James R.] 454 Life Sci, Branford, CT 06405 USA. [Koren, Sergey; Phillippy, Adam M.] Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20740 USA. [Warren, Wesley C.] Washington Univ, Sch Med, Genome Inst, St Louis, MO 63110 USA. [Koren, Sergey; Phillippy, Adam M.] Natl Biodef Anal & Countermeasures Ctr, Frederick, MD 21702 USA. [Bukovnik, Lisa] Adv Liquid Log Morrisville, Morrisville, NC 27560 USA. RP Zhang, GJ (reprint author), BGI Shenzhen, China Natl Genebank, Shenzhen 518083, Peoples R China. EM zhanggj@genomics.cn; aphillippy@gmail.com; jarvis@neuro.duke.edu RI Zhang, Guojie/B-6188-2014; Li, Yingrui/K-1064-2015; Jarvis, Erich/A-2319-2008; OI Zhang, Guojie/0000-0001-6860-1521; Jarvis, Erich/0000-0001-8931-5049; Schatz, Michael/0000-0002-4118-4446; Howard, Jason/0000-0003-3265-5127 FU NHGRI [R01HG000225, R01HG004348] FX We thank Graham Alexander (Duke Institute for Genome Sciences & Policy [IGSP]) for his work with the 454 sequencing, James Furbee (Roche) for his role in coordinating the sequencing of the 454 MP libraries and for assisting in the optimization of the 454 FLX + chemistry, Fangfei Ye and Nicholas Hoang (both from Duke IGSP) for their work with the Illumina sequencing, and Xiaoxia Qin, from Duke IGSP, for her advice on assembling the budgie genome. We are very appreciative of Tin Le (Gentris Corporation) for his efforts on coordinating the low-density Illumina sequencing and his role in optimizing the TruSeq3 approach. We also thank Brian Kelly, Edwin Hauw and Swati Ranade (Pacific Biosciences) for supervising and assisting with the PacBio sequencing. Optical mapping was supported in part by NHGRI R01HG000225 (DCS) and R01HG004348 (1K; subcontract to DCS). We thank Roche, Illumina and Pacific Biosciences corporations for providing sequencing and computational resources. Finally, we thank the G10K group and the Assemblathon2 group for including Budgerigar as one the model genomes in the Assemblathon2 competition. NR 28 TC 20 Z9 20 U1 2 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND EI 2047-217X J9 GIGASCIENCE JI GigaScience PD JUL 8 PY 2014 VL 3 AR 11 DI 10.1186/2047-217X-3-11 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CX4FJ UT WOS:000365654100001 PM 25061512 ER PT J AU Liu, JL Finkel, T AF Liu, Julia Finkel, Toren TI Aging: The Blurry Line between Life and Death SO CURRENT BIOLOGY LA English DT Editorial Material ID MITOCHONDRIAL ROS; MIT MUTANTS; C. ELEGANS; LONGEVITY; SPAN; RESPIRATION; APOPTOSIS; MECHANISM; CASPASES; PATHWAY AB Although historically reactive oxygen species have been implicated as a potential cause of ageing, recent evidence suggests that a modest increase in oxidants can actually extend lifespan. A new study suggests that, in Caenorhabditis elegans, reactive oxygen species regulate longevity through a pathway classically linked to apoptosis. C1 [Liu, Julia; Finkel, Toren] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Liu, JL (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM finkelt@nih.gov NR 20 TC 2 Z9 2 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD JUL 7 PY 2014 VL 24 IS 13 BP R610 EP R613 DI 10.1016/j.cub.2014.05.057 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AL0EI UT WOS:000338799800011 PM 25004366 ER PT J AU Devanathan, S Whitehead, T Schweitzer, GG Fettig, N Kovacs, A Korach, KS Finck, BN Shoghi, KI AF Devanathan, Sriram Whitehead, Timothy Schweitzer, George G. Fettig, Nicole Kovacs, Attila Korach, Kenneth S. Finck, Brian N. Shoghi, Kooresh I. TI An Animal Model with a Cardiomyocyte-Specific Deletion of Estrogen Receptor Alpha: Functional, Metabolic, and Differential Network Analysis SO PLOS ONE LA English DT Article ID ER-ALPHA; GLUCOSE-HOMEOSTASIS; TISSUE DISTRIBUTION; ADIPOSE-TISSUE; BETA; GENE; MICE; EXPRESSION; MUSCLE; PATHWAYS AB Estrogen exerts diverse biological effects in multiple tissues in both animals and humans. Much of the accumulated knowledge on the role of estrogen receptor (ER) in the heart has been obtained from studies using ovariectomized mice, whole body ER gene knock-out animal models, ex vivo heart studies, or from isolated cardiac myocytes. In light of the wide systemic influence of ER signaling in regulating a host of biological functions in multiple tissues, it is difficult to infer the direct role of ER on the heart. Therefore, we developed a mouse model with a cardiomyocyte-specific deletion of the ER alpha allele (cs-ER alpha(-/-)). Male and female cs-ER alpha(-/-) mice with age/sex-matched wild type controls were examined for differences in cardiac structure and function by echocardiogram and differential gene expression microarray analysis. Our study revealed sex-differences in structural parameters in the hearts of cs-ER alpha(-/-) mice, with minimal functional differences. Analysis of microarray data revealed differential variations in the expression of 208 genes affecting multiple transcriptional networks. Furthermore, we report sex-specific differences in the expression of 56 genes. Overall, we developed a mouse model with cardiac-specific deletion of ER alpha to characterize the role of ER alpha in the heart independent of systemic effects. Our results suggest that ER alpha is involved in controlling the expression of diverse genes and networks in the cardiomyocyte in a sex-dependent manner. C1 [Devanathan, Sriram; Whitehead, Timothy; Fettig, Nicole; Shoghi, Kooresh I.] Washington Univ, Dept Radiol, St Louis, MO 63130 USA. [Schweitzer, George G.; Finck, Brian N.] Washington Univ, Dept Med, Div Geriatr & Nutr Sci, St Louis, MO USA. [Kovacs, Attila] Washington Univ, Dept Med, Cardiovasc Res Ctr, St Louis, MO USA. [Korach, Kenneth S.] NIEHS, Lab Reprod & Dev Toxicol, Receptor Biol Sect, NIH, Res Triangle Pk, NC 27709 USA. [Shoghi, Kooresh I.] Washington Univ, Dept Biomed Engn, St Louis, MO USA. [Shoghi, Kooresh I.] Washington Univ, Div Biol & Biomed Sci, St Louis, MO USA. RP Shoghi, KI (reprint author), Washington Univ, Dept Radiol, St Louis, MO 63130 USA. EM shoghik@wustl.edu RI Shoghi, Kooresh/H-7398-2014; OI Shoghi, Kooresh/0000-0003-3204-457X; Korach, Kenneth/0000-0002-7765-418X FU National Institutes of Health (NIH) [R01-EB012284]; NIH [R01-DK085298, Z01ES70065, T32-HL007275, P30-DK020579] FX The work was partially supported by research funds from the National Institutes of Health (NIH, http://www.nih.gov) grant number R01-EB012284 to KIS, NIH grant number R01-DK085298 to KIS, intramural NIH research funding Z01ES70065 to KSK, and intramural funds available to KIS. GGS was supported by NIH training grant T32-HL007275. The work utilized core services available through the Washington University School of Medicine Diabetes Research Center (DRC) supported by NIH grant number P30-DK020579. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 2 Z9 2 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 7 PY 2014 VL 9 IS 7 AR e101900 DI 10.1371/journal.pone.0101900 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK7WB UT WOS:000338637300099 PM 25000186 ER PT J AU Wang, GJ Tomasi, D Convit, A Logan, J Wong, CT Shumay, E Fowler, JS Volkow, ND AF Wang, Gene-Jack Tomasi, Dardo Convit, Antonio Logan, Jean Wong, Christopher T. Shumay, Elena Fowler, Joanna S. Volkow, Nora D. TI BMI Modulates Calorie-Dependent Dopamine Changes in Accumbens from Glucose Intake SO PLOS ONE LA English DT Article ID D2 RECEPTORS; REWARD VALUE; TASTE; FOOD; DYSFUNCTION; RACLOPRIDE; BEHAVIORS; STRIATUM; COCAINE; HUMANS AB Objective: Dopamine mediates the rewarding effects of food that can lead to overeating and obesity, which then trigger metabolic neuroadaptations that further perpetuate excessive food consumption. We tested the hypothesis that the dopamine response to calorie intake (independent of palatability) in striatal brain regions is attenuated with increases in weight. Method: We used positron emission tomography with [C-11]raclopride to measure dopamine changes triggered by calorie intake by contrasting the effects of an artificial sweetener (sucralose) devoid of calories to that of glucose to assess their association with body mass index (BMI) in nineteen healthy participants (BMI range 21-35). Results: Neither the measured blood glucose concentrations prior to the sucralose and the glucose challenge days, nor the glucose concentrations following the glucose challenge vary as a function of BMI. In contrast the dopamine changes in ventral striatum (assessed as changes in non-displaceable binding potential of [C-11] raclopride) triggered by calorie intake (contrast glucose - sucralose) were significantly correlated with BMI (r = 0.68) indicating opposite responses in lean than in obese individuals. Specifically whereas in normal weight individuals (BMI <25) consumption of calories was associated with increases in dopamine in the ventral striatum in obese individuals it was associated with decreases in dopamine. Conclusion: These findings show reduced dopamine release in ventral striatum with calorie consumption in obese subjects, which might contribute to their excessive food intake to compensate for the deficit between the expected and the actual response to food consumption. C1 [Wang, Gene-Jack; Tomasi, Dardo; Wong, Christopher T.; Shumay, Elena; Volkow, Nora D.] NIAAA, Lab Neuroimaging, Bethesda, MD 20892 USA. [Convit, Antonio; Logan, Jean] NYU, Dept Psychiat, New York, NY 10016 USA. [Convit, Antonio] Nathan S Kline Inst Psychiat Res, Orangeburg, NY USA. [Fowler, Joanna S.] Brookhaven Natl Lab, Dept Biosci, Upton, NY 11973 USA. RP Wang, GJ (reprint author), NIAAA, Lab Neuroimaging, Bethesda, MD 20892 USA. EM gene-jack.wang@nih.gov RI Tomasi, Dardo/J-2127-2015; OI Convit, Antonio/0000-0003-2201-2689; Logan, Jean/0000-0002-6993-9994 FU Royalty Funds; National Institute of Health [Z01AA000550, R01DK064087-09, K01DA025280]; U. S. Department of Energy OBER [DE-ACO2-76CH00016] FX U. S. Department of Energy OBER: DE-ACO2-76CH00016 for infrastructure support of Brookhaven National Laboratory and Royalty Funds to GJW. National Institute of Health: Z01AA000550 to NDV, R01DK064087-09 to AC, K01DA025280 to ES. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 14 Z9 14 U1 3 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 7 PY 2014 VL 9 IS 7 AR e101585 DI 10.1371/journal.pone.0101585 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK7WB UT WOS:000338637300060 PM 25000285 ER PT J AU Wang, JW Jagu, S Wang, CG Kitchener, HC Daayana, S Stern, PL Pang, S Day, PM Huh, WK Roden, RBS AF Wang, Joshua W. Jagu, Subhashini Wang, Chenguang Kitchener, Henry C. Daayana, Sai Stern, Peter L. Pang, Susana Day, Patricia M. Huh, Warner K. Roden, Richard B. S. TI Measurement of Neutralizing Serum Antibodies of Patients Vaccinated with Human Papillomavirus L1 or L2-Based Immunogens Using Furin-Cleaved HPV Pseudovirions SO PLOS ONE LA English DT Article ID VIRUS-LIKE PARTICLES; VULVAL INTRAEPITHELIAL NEOPLASIA; COTTONTAIL RABBIT PAPILLOMAVIRUS; MINOR CAPSID PROTEIN; HPV-16/18 AS04-ADJUVANTED VACCINE; CROSS-PROTECTIVE EFFICACY; L2E6E7 FUSION PROTEIN; BLIND PATRICIA TRIAL; OF-STUDY ANALYSIS; SENSITIVE MEASURE AB Antibodies specific for neutralizing epitopes in either Human papillomavirus (HPV) capsid protein L1 or L2 can mediate protection from viral challenge and thus their accurate and sensitive measurement at high throughput is likely informative for monitoring response to prophylactic vaccination. Here we compare measurement of L1 and L2-specific neutralizing antibodies in human sera using the standard Pseudovirion-Based Neutralization Assay (L1-PBNA) with the newer Furin-Cleaved Pseudovirion-Based Neutralization Assay (FC-PBNA), a modification of the L1-PBNA intended to improve sensitivity towards L2-specific neutralizing antibodies without compromising assay of L1-specific responses. For detection of L1-specific neutralizing antibodies in human sera, the FC-PBNA and L1-PBNA assays showed similar sensitivity and a high level of correlation using WHO standard sera (n = 2), and sera from patients vaccinated with Gardasil (n = 30) or an experimental human papillomavirus type 16 (HPV16) L1 VLP vaccine (n = 70). The detection of L1-specific cross-neutralizing antibodies in these sera using pseudovirions of types phylogenetically-related to those targeted by the L1 virus-like particle (VLP) vaccines was also consistent between the two assays. However, for sera from patients (n = 17) vaccinated with an L2-based immunogen (TA-CIN), the FC-PBNA was more sensitive than the L1-PBNA in detecting L2-specific neutralizing antibodies. Further, the neutralizing antibody titers measured with the FC-PBNA correlated with those determined with the L2-PBNA, another modification of the L1-PBNA that spacio-temporally separates primary and secondary receptor engagement, as well as the protective titers measured using passive transfer studies in the murine genital-challenge model. In sum, the FC-PBNA provided sensitive measurement for both L1 VLP and L2-specific neutralizing antibody in human sera. Vaccination with TA-CIN elicits weak cross-protective antibody in a subset of patients, suggesting the need for an adjuvant. C1 [Wang, Joshua W.; Jagu, Subhashini; Roden, Richard B. S.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21218 USA. [Wang, Chenguang] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Roden, Richard B. S.] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. [Roden, Richard B. S.] Johns Hopkins Univ, Dept Gynecol & Obstet, Baltimore, MD USA. [Kitchener, Henry C.; Daayana, Sai] Univ Manchester, St Marys Hosp, Inst Canc Sci, Womans Canc Ctr, Manchester M13 0JH, Lancs, England. [Stern, Peter L.] Univ Manchester, Inst Canc Sci, Manchester M13 0JH, Lancs, England. [Pang, Susana; Day, Patricia M.] NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. [Huh, Warner K.] Univ Alabama Birmingham, Div Gynecol Oncol, Birmingham, AL USA. RP Roden, RBS (reprint author), Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21218 USA. EM roden@jhmi.edu FU Public Health Service grant [P50 CA098252, RO1 CA133749, CA118790]; V foundation; Wigan Cancer Research Fund; Cancer Research UK; National Institutes of Health FX The study was funded by Public Health Service grant P50 CA098252, RO1 CA133749, and CA118790 to Richard Roden and Warner Huh, the V foundation (http://www.jimmyv.org/) to Richard Roden. Sai Daayana was funded by Wigan Cancer Research Fund; Henry Kitchener and Peter Stern were funded by Cancer Research UK (http://www.cancerresearchuk.org/), Susana Pang, Patricia M Day are funded by the National Institutes of Health intramural program (http://www.nih.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 1 Z9 1 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 7 PY 2014 VL 9 IS 7 AR e101576 DI 10.1371/journal.pone.0101576 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK7WB UT WOS:000338637300058 PM 24999962 ER PT J AU Grunwald, JE Pistilli, M Ying, GS Daniel, E Maguire, MG Xie, DW Whittock-Martin, R Ostroff, CP Lo, JC Townsend, RR Gadegbeku, CA Lash, JP Fink, JC Rahman, M Feldman, HI Kusek, JW AF Grunwald, Juan E. Pistilli, Maxwell Ying, Gui-Shuang Daniel, Ebenezer Maguire, Maureen G. Xie, Dawei Whittock-Martin, Revell Ostroff, Candace Parker Lo, Joan C. Townsend, Raymond R. Gadegbeku, Crystal A. Lash, James P. Fink, Jeffrey C. Rahman, Mahboob Feldman, Harold I. Kusek, John W. CA Chronic Renal Insufficiency Cohort TI Retinopathy and Progression of CKD: The CRIC Study SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID RETINAL MICROVASCULAR ABNORMALITIES; CHRONIC KIDNEY-DISEASE; BEAVER-DAM-EYE; ATHEROSCLEROSIS RISK; UNITED-STATES; COHORT; ASSOCIATIONS; COMMUNITIES; DIAMETER; GFR AB Background and objectives Retinal abnormalities may be associated with changes in the renal vasculature. This study assessed the association between retinopathy and progression of kidney disease in participants of the Chronic Renal Insufficiency Cohort (CRIC) study. Design, setting, participants, & measurements This was a prospective study in which patients with CKD enrolled in CRIC had nonmydriatic fundus photographs of both eyes. All CRIC participants in six clinical sites in which fundus cameras were deployed were offered participation. Photographs were reviewed at a reading center. The presence and severity of retinopathy and vessel calibers were assessed using standard protocols by graders masked to clinical information. The associations of retinal features with changes in eGFR and the need for RRT (ESRD) were assessed. Results Retinal images and renal progression outcomes were obtained from 1852 of the 2605 participants (71.1%) approached. During follow-up (median 2.3 years), 152 participants (8.2%) developed ESRD. Presence and severity of retinopathy at baseline were strongly associated with the risk of subsequent progression to ESRD and reductions in eGFR in unadjusted analyses. For example, participants with retinopathy were 4.4 times (95% confidence interval [95% CI], 3.12 to 6.31) more likely to develop ESRD than those without retinopathy (P<0.001). However, this association was not statistically significant after adjustment for initial eGFR and 24-hour proteinuria. Venular and arteriolar diameter calibers were not associated with ESRD or eGFR decline. The results showed a nonlinear relationship between mean ratio of arteriole/vein calibers and the risk of progression to ESRD; participants within the fourth arteriole/vein ratio quartile were 3.11 times (95% CI, 1.51 to 6.40) more likely to develop ESRD than those in the first quartile (P<0.001). Conclusions The presence and severity of retinopathy were not associated with ESRD and decline in eGFR after taking into account established risk factors. C1 [Grunwald, Juan E.; Pistilli, Maxwell; Ying, Gui-Shuang; Daniel, Ebenezer; Maguire, Maureen G.; Xie, Dawei; Whittock-Martin, Revell; Ostroff, Candace Parker; Townsend, Raymond R.; Feldman, Harold I.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Lo, Joan C.] Kaiser Permanente No Calif, Oakland, CA USA. [Gadegbeku, Crystal A.] Temple Univ, Dept Med, Philadelphia, PA 19122 USA. [Lash, James P.] Univ Illinois, Div Nephrol, Chicago, IL USA. [Fink, Jeffrey C.] Univ Maryland, Dept Med, Baltimore, MD 21201 USA. [Rahman, Mahboob] Case Western Reserve Univ Hosp, Case Med Ctr, Louis Stokes Cleveland Vet Affairs Med Ctr, Cleveland, OH 44106 USA. [Kusek, John W.] NIDDK, Bethesda, MD USA. RP Grunwald, JE (reprint author), Univ Penn, Perelman Sch Med, 51 North 39th St, Philadelphia, PA 19104 USA. EM juangrun@mail.med.upenn.edu OI Fink, Jeffrey/0000-0002-5622-5052; Pistilli, Maxwell/0000-0002-4266-4150 FU National Institutes of Health (NIH) [DK74151]; National Institute for Diabetes and Digestive and Kidney Diseases [U01-DK060990, U01-DK060984, U01-DK061022, U01-DK061021, U01-DK061028, U01-DK060980, U01-DK060963, U01-DK060902]; University of Pennsylvania (NIH/National Center for Advancing Translational Sciences) [UL1-TR000003]; University of Illinois at Chicago [UL1-RR029879]; Johns Hopkins University [UL1-TR000424]; University of Maryland General Clinical Research Center [M01RR-16500]; Clinical and Translational Science Collaborative of Cleveland [UL1-TR000439]; Michigan Institute for Clinical and Health Research [UL1-TR000433]; Tulane University Translational Research in Hypertension and Renal Biology [P30-GM103337]; Kaiser Permanente (NIH/National Center for Research Resources UCSF-CTSI) [UL1 RR-024131]; Vivian S. Lasko Research Fund; Nina C. Mackall Trust; Research to Prevent Blindness FX This study was supported by a grant from the National Institutes of Health (NIH) (DK74151). The CRIC study was funded by a National Institute for Diabetes and Digestive and Kidney Diseases cooperative agreement (U01-DK060990, U01-DK060984, U01-DK061022, U01-DK061021, U01-DK061028, U01-DK060980, U01-DK060963, and U01-DK060902); Clinical and Translational Science Awards from the University of Pennsylvania (NIH/National Center for Advancing Translational Sciences UL1-TR000003) and University of Illinois at Chicago (UL1-RR029879); and grants from Johns Hopkins University (UL1-TR000424), University of Maryland General Clinical Research Center (M01RR-16500), Clinical and Translational Science Collaborative of Cleveland (UL1-TR000439), Michigan Institute for Clinical and Health Research (UL1-TR000433), Tulane University Translational Research in Hypertension and Renal Biology (P30-GM103337), Kaiser Permanente (NIH/National Center for Research Resources UCSF-CTSI UL1 RR-024131), Vivian S. Lasko Research Fund, Nina C. Mackall Trust, and Research to Prevent Blindness. NR 18 TC 6 Z9 7 U1 0 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD JUL 7 PY 2014 VL 9 IS 7 BP 1217 EP 1224 DI 10.2215/CJN.11761113 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA AK7NP UT WOS:000338615300012 PM 24812423 ER PT J AU Kunduri, G Yuan, C Parthibane, V Nyswaner, KM Kanwar, R Nagashima, K Britt, SG Mehta, N Kotu, V Porterfield, M Tiemeyer, M Dolph, PJ Acharya, U Acharya, JK AF Kunduri, Govind Yuan, Changqing Parthibane, Velayoudame Nyswaner, Katherine M. Kanwar, Ritu Nagashima, Kunio Britt, Steven G. Mehta, Nickita Kotu, Varshika Porterfield, Mindy Tiemeyer, Michael Dolph, Patrick J. Acharya, Usha Acharya, Jairaj K. TI Phosphatidic acid phospholipase A1 mediates ER-Golgi transit of a family of G protein-coupled receptors SO JOURNAL OF CELL BIOLOGY LA English DT Article ID HEREDITARY SPASTIC PARAPLEGIA; MAMMALIAN SEC23P-INTERACTING PROTEIN; SITE-DIRECTED MUTAGENESIS; RETICULUM EXIT SITES; ENDOPLASMIC-RETICULUM; DROSOPHILA-MELANOGASTER; LINKED OLIGOSACCHARIDES; RHODOPSIN MATURATION; SECRETORY PATHWAY; MOLECULAR-BASIS AB The coat protein II (COPII)-coated vesicular system transports newly synthesized secretory and membrane proteins from the endoplasmic reticulum (ER) to the Golgi complex. Recruitment of cargo into COPII vesicles requires an interaction of COPII proteins either with the cargo molecules directly or with cargo receptors for anterograde trafficking. We show that cytosolic phosphatidic acid phospholipase A1 (PAPLA1) interacts with COPII protein family members and is required for the transport of Rh1 (rhodopsin 1), an N-glycosylated G protein-coupled receptor (GPCR), from the ER to the Golgi complex. In papla1 mutants, in the absence of transport to the Golgi, Rh1 is aberrantly glycosylated and is mislocalized. These defects lead to decreased levels of the protein and decreased sensitivity of the photoreceptors to light. Several GPCRs, including other rhodopsins and Bride of sevenless, are similarly affected. Our findings show that a cytosolic protein is necessary for transit of selective transmembrane receptor cargo by the COPII coat for anterograde trafficking. C1 [Kunduri, Govind; Yuan, Changqing; Parthibane, Velayoudame; Nyswaner, Katherine M.; Kanwar, Ritu; Acharya, Jairaj K.] NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. [Nagashima, Kunio] Frederick Natl Lab Canc Res, Electron Microscopy Lab, Frederick, MD 21702 USA. [Britt, Steven G.] Univ Colorado, Dept Cell & Dev Biol, Aurora, CO 80045 USA. [Mehta, Nickita; Kotu, Varshika; Porterfield, Mindy; Tiemeyer, Michael] Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA. [Dolph, Patrick J.] Dartmouth Coll, Dept Biol Sci, Hanover, NH 03755 USA. [Acharya, Usha] Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. RP Acharya, JK (reprint author), NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. EM acharyaj@mail.nih.gov FU intramural division of the National Cancer Institute, National Institutes of Health (Division of Health and Human Services); National Institutes of Health [P41GM103490, RO1EY016469] FX This study was funded by the intramural division of the National Cancer Institute, National Institutes of Health (Division of Health and Human Services). M. Tiemeyer acknowledges the support from National Institutes of Health (coequal principal investigator; P41GM103490) for MS. U. Acharya is supported by the National Institutes of Health (RO1EY016469). NR 55 TC 3 Z9 3 U1 1 U2 11 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD JUL 7 PY 2014 VL 206 IS 1 BP 79 EP 95 DI 10.1083/jcb.201405020 PG 17 WC Cell Biology SC Cell Biology GA AK9QW UT WOS:000338762800008 PM 25002678 ER PT J AU Braun, A Dang, K Buslig, F Baird, MA Davidson, MW Waterman, CM Myers, KA AF Braun, Alexander Dang, Kyvan Buslig, Felinah Baird, Michelle A. Davidson, Michael W. Waterman, Clare M. Myers, Kenneth A. TI Rac1 and Aurora A regulate MCAK to polarize microtubule growth in migrating endothelial cells SO JOURNAL OF CELL BIOLOGY LA English DT Article ID CENTROMERE-ASSOCIATED KINESIN; MITOTIC CENTROMERE; DYNAMIC INSTABILITY; DEPENDENT PHOSPHORYLATION; REGIONAL REGULATION; NEURITE INITIATION; ACTIN; DEPOLYMERIZATION; LOCALIZATION; INTERPHASE AB Endothelial cells (ECs) migrate directionally during angiogenesis and wound healing by polarizing to extracellular cues to guide directional movement. EC polarization is controlled by microtubule (MT) growth dynamics, which are regulated by MT-associated proteins (MAPs) that alter MT stability. Mitotic centromere-associated kinesin (MCAK) is a MAP that promotes MT disassembly within the mitotic spindle, yet its function in regulating MT dynamics to promote EC polarity and migration has not been investigated. We used high-resolution fluorescence microscopy coupled with computational image analysis to elucidate the role of MCAK in regulating MT growth dynamics, morphology, and directional migration of ECs. Our results show that MCAK-mediated depolymerization of MTs is specifically targeted to the trailing edge of polarized wound-edge ECs. Regulation of MCAK function is dependent on Aurora A kinase, which is regionally enhanced by signaling from the small guanosine triphosphatase, Rac1. Thus, a Rac1-Aurora A-MCAK signaling pathway mediates EC polarization and directional migration by promoting regional differences in MT dynamics in the leading and trailing cell edges. C1 [Braun, Alexander; Dang, Kyvan; Buslig, Felinah; Myers, Kenneth A.] Allegheny Univ Hlth Sci, Dept Biol Sci, Philadelphia, PA 19104 USA. [Waterman, Clare M.; Myers, Kenneth A.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Baird, Michelle A.; Davidson, Michael W.] Florida State Univ, Natl High Magnet Field Lab, Tallahassee, FL 32310 USA. [Baird, Michelle A.; Davidson, Michael W.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32310 USA. RP Myers, KA (reprint author), Allegheny Univ Hlth Sci, Dept Biol Sci, Philadelphia, PA 19104 USA. EM watermancm@nhlbi.nih.gov; k.myers@usciences.edu OI Waterman, Clare/0000-0001-6142-6775 FU National Heart, Lung and Blood Institute (NHLBI) Intramural Research Program; National Institutes of Health, NHLBI [4K22HL113069-02]; College of Graduate Studies, University of the Sciences; Department of Biological Sciences, University of the Sciences FX This work was supported by the National Heart, Lung and Blood Institute (NHLBI) Intramural Research Program (C. M. Waterman and K. A. Myers) and by Academic Career Award funding from the National Institutes of Health, NHLBI (grant number 4K22HL113069-02; to K. A. Myers). A. Braun was supported by the College of Graduate Studies, University of the Sciences, and K. Dang and F. Buslig were supported by the Department of Biological Sciences, University of the Sciences. NR 57 TC 19 Z9 21 U1 0 U2 9 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD JUL 7 PY 2014 VL 206 IS 1 BP 97 EP 112 DI 10.1083/jcb.201401063 PG 16 WC Cell Biology SC Cell Biology GA AK9QW UT WOS:000338762800009 PM 25002679 ER PT J AU Peel, AJ Pulliam, JRC Luis, AD Plowright, RK O'Shea, TJ Hayman, DTS Wood, JLN Webb, CT Restif, O AF Peel, A. J. Pulliam, J. R. C. Luis, A. D. Plowright, R. K. O'Shea, T. J. Hayman, D. T. S. Wood, J. L. N. Webb, C. T. Restif, O. TI The effect of seasonal birth pulses on pathogen persistence in wild mammal populations SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE critical community size; wildlife epidemiology; birth pulse; seasonality; stochastic model ID INFECTIOUS-DISEASES; DYNAMICS; HOST; THRESHOLDS; PLAGUE; RABIES; RATES; EMERGENCE; VIRUS; MAINTENANCE AB The notion of a critical community size (CCS), or population size that is likely to result in long-term persistence of a communicable disease, has been developed based on the empirical observations of acute immunizing infections in human populations, and extended for use in wildlife populations. Seasonal birth pulses are frequently observed in wildlife and are expected to impact infection dynamics, yet their effect on pathogen persistence and CCS have not been considered. To investigate this issue theoretically, we use stochastic epidemiological models to ask how host life-history traits and infection parameters interact to determine pathogen persistence within a closed population. We fit seasonal birth pulse models to data from diverse mammalian species in order to identify realistic parameter ranges. When varying the synchrony of the birth pulse with all other parameters being constant, our model predicted that the CCS can vary by more than two orders of magnitude. Tighter birth pulses tended to drive pathogen extinction by creating large amplitude oscillations in prevalence, especially with high demographic turnover and short infectious periods. Parameters affecting the relative timing of the epidemic and birth pulse peaks determined the intensity and direction of the effect of pre-existing immunity in the population on the pathogen's ability to persist beyond the initial epidemic following its introduction. C1 [Peel, A. J.; Wood, J. L. N.; Restif, O.] Univ Cambridge, Dept Vet Med, Dis Dynam Unit, Cambridge CB3 0ES, England. [Peel, A. J.] Zool Soc London, Inst Zool, London NW1 4RY, England. [Peel, A. J.] Griffith Univ, Environm Futures Res Inst, Brisbane, Qld 4111, Australia. [Pulliam, J. R. C.; Luis, A. D.; Hayman, D. T. S.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Pulliam, J. R. C.] Univ Florida, Dept Biol, Gainesville, FL 32611 USA. [Pulliam, J. R. C.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL 32610 USA. [Luis, A. D.; Hayman, D. T. S.; Webb, C. T.] Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA. [Plowright, R. K.] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [O'Shea, T. J.] US Geol Survey, Glen Haven, CO 80532 USA. RP Peel, AJ (reprint author), Univ Cambridge, Dept Vet Med, Dis Dynam Unit, Cambridge CB3 0ES, England. EM alisonpeel@gmail.com RI Peel, Alison/I-3202-2012; Wood, James/A-1626-2008; OI Peel, Alison/0000-0003-3538-3550; Wood, James/0000-0002-0258-3188; Restif, Olivier/0000-0001-9158-853X; Pulliam, Juliet/0000-0003-3314-8223 FU Fogarty International Center, National Institutes of Health and Science and Technology Directorate, Department of Homeland Security; Isaac Newton Trust; Royal Society; Alborada Trust; Cedar Tree Foundation FX This work was supported by the Research and Policy on Infectious Disease Dynamics (RAPIDD) Programme of the Fogarty International Center, National Institutes of Health and Science and Technology Directorate, Department of Homeland Security. Individual authors also acknowledge funding from the Isaac Newton Trust (A.J.P.), the Royal Society (O.R.), the Alborada Trust (J.L.N.W.) and the Cedar Tree Foundation (R.K.P. and D.T.S.H.). NR 49 TC 11 Z9 11 U1 4 U2 44 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 EI 1471-2954 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD JUL 7 PY 2014 VL 281 IS 1786 AR 20132962 DI 10.1098/rspb.2013.2962 PG 9 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA AI3TA UT WOS:000336784500005 ER PT J AU Fee, E AF Fee, Elizabeth TI Information on a global scale: the National Library of Medicine SO LANCET LA English DT Editorial Material C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Fee, E (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. EM feee@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUL 5 PY 2014 VL 384 IS 9937 BP 21 EP 22 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AL1XL UT WOS:000338919600011 PM 25003181 ER PT J AU Schisterman, EF Silver, RM Lesher, LL Faraggi, D Wactawski-Wende, J Townsend, JM Lynch, AM Perkins, NJ Mumford, SL Galai, N AF Schisterman, Enrique F. Silver, Robert M. Lesher, Laurie L. Faraggi, David Wactawski-Wende, Jean Townsend, Janet M. Lynch, Anne M. Perkins, Neil J. Mumford, Sunni L. Galai, Noya TI Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial SO LANCET LA English DT Article ID IN-VITRO FERTILIZATION; MOLECULAR-WEIGHT HEPARIN; RECURRENT MISCARRIAGE; ANTIPHOSPHOLIPID ANTIBODY; WOMEN; METAANALYSIS; PREVENTION; PREECLAMPSIA; IMPLANTATION; DRUGS AB Background Preconception-initiated low-dose aspirin might positively affect pregnancy outcomes, but this possibility has not been adequately assessed. Our aim was to investigate whether low-dose aspirin improved livebirth rates in women with one to two previous pregnancy losses. Methods In this multicentre, block-randomised, double-blind, placebo-controlled trial, women aged 18-40 years who were attempting to become pregnant were recruited from four medical centres in the USA. Participants were stratified by eligibility criteria-the original stratum was restricted to women with one loss at less than 20 weeks' gestation during the previous year, whereas the expanded stratum included women with one to two previous losses, with no restrictions on gestational age or time of loss. Women were block-randomised by centre and eligibility stratum in a 1: 1 ratio. Preconception-initiated daily low-dose aspirin (81 mg per day) plus folic acid was compared with placebo plus folic acid for up to six menstrual cycles; for women who conceived, study treatment continued until 36 weeks' gestation. Participants, trial staff, and investigators were masked to the assigned treatment. The primary outcome was livebirth rate, which was analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00467363. Findings Overall, 1228 women were recruited and randomly assigned between June 15, 2007, and July 15, 2011, 1078 of whom completed the trial and were included in the analysis (535 in the low-dose aspirin group and 543 in the placebo group). 309 (58%) women in the low-dose aspirin group had livebirths, compared with 286 (53%) in the placebo group (p=0.0984; absolute difference in livebirth rate 5.09% [95% CI - 0.84 to 11.02]). Pregnancy loss occurred in 68 (13%) women in the low-dose aspirin group, compared with 65 (12%) women in the placebo group (p=0.7812). In the original stratum, 151 (62%) of 242 women in the low-dose aspirin group had livebirths, compared with 133 (53%) of 250 in the placebo group (p=0.0446; absolute difference in livebirth rate 9.20% [0.51 to 17 89]). In the expanded stratum, 158 (54%) of 293 women in the low-dose aspirin group and 153 (52%) of 293 in the placebo group had livebirths (p=0.7406; absolute difference in livebirth rate 1.71% [-6.37 to 9.79]). Major adverse events were similar between treatment groups. Low-dose aspirin was associated with increased vaginal bleeding, but this adverse event was not associated with pregnancy loss. Interpretation Preconception-initiated low-dose aspirin was not significantly associated with livebirth or pregnancy loss in women with one to two previous losses. However, higher livebirth rates were seen in women with a single documented loss at less than 20 weeks' gestation during the previous year. Low-dose aspirin is not recommended for the prevention of pregnancy loss. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development (US National Institutes of Health). C1 [Schisterman, Enrique F.; Perkins, Neil J.; Mumford, Sunni L.] Eunice Kennedy Shriver NICHD, Epidemiol Branch, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. [Silver, Robert M.; Lesher, Laurie L.] Univ Utah, Hlth Sci Ctr, Sch Med, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Faraggi, David; Galai, Noya] Univ Haifa, Dept Stat, IL-31999 Haifa, Israel. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Townsend, Janet M.] Commonwealth Med Coll, Dept Family Community & Rural Hlth, Scranton, PA USA. [Lynch, Anne M.] Univ Colorado, Dept Obstet & Gynecol, Denver, CO 80202 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver NICHD, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM schistee@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (National Institutes of Health, Bethesda, MD, USA) [HHSN267200603423, HHSN267200603424, HHSN267200603426] FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (National Institutes of Health, Bethesda, MD, USA; contract numbers HHSN267200603423, HHSN267200603424, and HHSN267200603426). We thank the EAGeR participants for their extraordinary commitment to the study, all of the EAGeR investigators and staff who devoted their time and energy to the success of this trial, and the members of the data safety monitoring board for continuous oversight, constant support, and advice throughout the trial NR 26 TC 31 Z9 31 U1 2 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUL 5 PY 2014 VL 384 IS 9937 BP 29 EP 36 DI 10.1016/S0140-6736(14)60157-4 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AL1XL UT WOS:000338919600023 PM 24702835 ER PT J AU Chowell, G Erkoreka, A Viboud, C Echeverri-Davila, B AF Chowell, Gerardo Erkoreka, Anton Viboud, Cecile Echeverri-Davila, Beatriz TI Spatial-temporal excess mortality patterns of the 1918-1919 influenza pandemic in Spain SO BMC INFECTIOUS DISEASES LA English DT Article DE 1918-1919 influenza pandemic; Spain; Spanish influenza; Spring-summer wave; Excess death rates; Relative risk of death; Transmissibility; Provinces; Geography; Spatial heterogeneity ID EPIDEMIOLOGIC EVIDENCE; BACTERIAL PNEUMONIA; AGE DISTRIBUTION; DEATHS; WAVE; TRANSMISSION; COPENHAGEN; EUROPE; IMPACT; CITY AB Background: The impact of socio-demographic factors and baseline health on the mortality burden of seasonal and pandemic influenza remains debated. Here we analyzed the spatial-temporal mortality patterns of the 1918 influenza pandemic in Spain, one of the countries of Europe that experienced the highest mortality burden. Methods: We analyzed monthly death rates from respiratory diseases and all-causes across 49 provinces of Spain, including the Canary and Balearic Islands, during the period January-1915 to June-1919. We estimated the influenza-related excess death rates and risk of death relative to baseline mortality by pandemic wave and province. We then explored the association between pandemic excess mortality rates and health and socio-demographic factors, which included population size and age structure, population density, infant mortality rates, baseline death rates, and urbanization. Results: Our analysis revealed high geographic heterogeneity in pandemic mortality impact. We identified 3 pandemic waves of varying timing and intensity covering the period from Jan-1918 to Jun-1919, with the highest pandemic-related excess mortality rates occurring during the months of October-November 1918 across all Spanish provinces. Cumulative excess mortality rates followed a south-north gradient after controlling for demographic factors, with the North experiencing highest excess mortality rates. A model that included latitude, population density, and the proportion of children living in provinces explained about 40% of the geographic variability in cumulative excess death rates during 1918-19, but different factors explained mortality variation in each wave. Conclusions: A substantial fraction of the variability in excess mortality rates across Spanish provinces remained unexplained, which suggests that other unidentified factors such as comorbidities, climate and background immunity may have affected the 1918-19 pandemic mortality rates. Further archeo-epidemiological research should concentrate on identifying settings with combined availability of local historical mortality records and information on the prevalence of underlying risk factors, or patient-level clinical data, to further clarify the drivers of 1918 pandemic influenza mortality. C1 [Chowell, Gerardo; Viboud, Cecile] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Chowell, Gerardo] Arizona State Univ, Math Computat & Modeling Sci Ctr, Sch Human Evolut & Social Change, Tempe, AZ USA. [Erkoreka, Anton] Univ Basque Country, Basque Museum Hist Med & Sci, Bilbao, Spain. [Echeverri-Davila, Beatriz] Univ Complutense Madrid, Grp Estudios Poblac & Soc, Madrid, Spain. RP Chowell, G (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM gchowell@asu.edu FU Office of Global Affairs' International Influenza Unit in the Office of the Secretary of the Department of Health and Human Services FX This research was conducted in the context of the Multinational Influenza Seasonal Mortality Study (MISMS), an on-going international collaborative effort to understand influenza epidemiological and evolutionary patterns, led by the Fogarty International Center, National Institutes of Health (http://www.origem.info/misms/index.php). Funding for this project comes in part from the Office of Global Affairs' International Influenza Unit in the Office of the Secretary of the Department of Health and Human Services. NR 50 TC 4 Z9 4 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD JUL 5 PY 2014 VL 14 AR 371 DI 10.1186/1471-2334-14-371 PG 12 WC Infectious Diseases SC Infectious Diseases GA AL0CR UT WOS:000338795400001 PM 24996457 ER PT J AU Sedlacek, M Brenowitz, SD AF Sedlacek, Miloslav Brenowitz, Stephan D. TI Cell-type specific short-term plasticity at auditory nerve synapses controls feed-forward inhibition in the dorsal cochlear nucleus SO FRONTIERS IN NEURAL CIRCUITS LA English DT Article DE dorsal cochlear nucleus; auditory nerve; synaptic transmission; synaptic plasticity; feedforward inhibition ID BRAIN-STEM; NEURONS; MICE; RESPONSES; OUTPUT; INPUT; INTERNEURONS; INTEGRATION; MECHANISMS; DEPRESSION AB Feed-forward inhibition (FFI) represents a powerful mechanism by which control of the timing and fidelity of action potentials in local synaptic circuits of various brain regions is achieved. In the cochlear nucleus, the auditory nerve provides excitation to both principal neurons and inhibitory interneurons. Here, we investigated the synaptic circuit associated with fusiform cells (FCs), principal neurons of the dorsal cochlear nucleus (DCN) that receive excitation from auditory nerve fibers and inhibition from tuberculoventral cells (TVCs) on their basal dendrites in the deep layer of DCN. Despite the importance of these inputs in regulating fusiform cell firing behavior, the mechanisms determining the balance of excitation and FFI in this circuit are not well understood. Therefore, we examined the timing and plasticity of auditory nerve driven FFI onto FCs. We find that in some FCs, excitatory and inhibitory components of FFI had the same stimulation thresholds indicating they could be triggered by activation of the same fibers. In other FCs, excitation and inhibition exhibit different stimulus thresholds, suggesting FCs and TVCs might be activated by different sets of fibers. In addition, we find that during repetitive activation, synapses formed by the auditory nerve onto TVCs and FCs exhibit distinct modes of short-term plasticity. Feed forward inhibitory post synaptic currents (IPSCs) in FCs exhibit short-term depression because of prominent synaptic depression at the auditory nerve-TVC synapse. Depression of this feedforward inhibitory input causes a shift in the balance of fusiform cell synaptic input towards greater excitation and suggests that fusiform cell spike output will be enhanced by physiological patterns of auditory nerve activity. C1 [Sedlacek, Miloslav; Brenowitz, Stephan D.] NIH, Natl Inst Deafness & Other Commun Disorders, Sect Synaptic Transmiss, Bethesda, MD USA. RP Brenowitz, SD (reprint author), Howard Hughes Med Inst, Janelia Farm Res Campus, 19700 Helix Dr, Ashburn, VA 20147 USA. EM brenowitzs@janelia.hhmi.org FU National Institute on Deafness and Other Communication Disorders Intramural Research Program FX This work was supported by the National Institute on Deafness and Other Communication Disorders Intramural Research Program. NR 48 TC 3 Z9 3 U1 0 U2 3 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5110 J9 FRONT NEURAL CIRCUIT JI Front. Neural Circuits PD JUL 4 PY 2014 VL 8 AR 78 DI 10.3389/fncir.2014.00078 PG 12 WC Neurosciences SC Neurosciences & Neurology GA AL6VF UT WOS:000339270400002 PM 25071459 ER PT J AU Dal-Re, R Ndebele, P Higgs, E Sewankambo, N Wendler, D AF Dal-Re, Rafael Ndebele, Paul Higgs, Elizabeth Sewankambo, Nelson Wendler, David TI Protections for clinical trials in low and middle income countries need strengthening not weakening SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID OBLIGATIONS; PROVISION; BENEFITS; WORLD C1 [Dal-Re, Rafael] Univ Autonoma Madrid, BUC Biosci UAM CSIC Program, E-28049 Madrid, Spain. [Ndebele, Paul] Med Res Council Zimbabwe, Harare, Zimbabwe. [Higgs, Elizabeth] NIAID, Div Clin Res, Off Director, NIH, Bethesda, MD 20892 USA. [Sewankambo, Nelson] Makerere Univ, Coll Hlth Sci, Makerere, Uganda. [Wendler, David] NIH, Unit Vulnerable Populat, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Dal-Re, R (reprint author), Univ Autonoma Madrid, BUC Biosci UAM CSIC Program, Int Campus Excellence, E-28049 Madrid, Spain. EM Rafael.dalre@fuam.uam.es OI Sewankambo, Nelson/0000-0001-9362-053X NR 33 TC 6 Z9 6 U1 2 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD JUL 4 PY 2014 VL 349 AR g4254 DI 10.1136/bmj.g4254 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA AK7ZK UT WOS:000338646700001 PM 24996885 ER PT J AU Liu, SM Chen, WP Wang, J AF Liu, Song-Mei Chen, Weiping Wang, Jin TI Distinguishing between cancer cell differentiation and resistance induced by all-trans retinoic acid using transcriptional profiles and functional pathway analysis SO SCIENTIFIC REPORTS LA English DT Article ID ACUTE PROMYELOCYTIC LEUKEMIA; NUCLEAR-ENVELOPE; HL-60 CELLS; EXPRESSION; CARCINOMA; SURVIVAL; LINES; PROLIFERATION; SENSITIVITY; PROTEIN AB All-trans retinoic acid (ATRA) induces differentiation in various cell types and has been investigated extensively for its effective use in cancer prevention and treatment. Relapsed or refractory disease that is resistant to ATRA is a clinically significant problem. To identify the molecular mechanism that bridges ATRA differentiation and resistance in cancer, we selected the multidrug-resistant leukemia cell line HL-60[R] by exposing it to ATRA, followed by sequential increases of one-half log concentration. A cytotoxicity analysis revealed that HL-60[R] cells were highly resistant to ATRA, doxorubicin, and etoposide. A comparative genome hybridization analysis of HL-60[R] cells identified gains of 4q34, 9q12, and 19q13 and a loss of Yq12 compared with in the parental HL-60 cell line. Transcriptional profiles and functional pathway analyses further demonstrated that 7 genes (FEN1, RFC5, EXO1, XRCC5, PARP1, POLR2F, and GTF2H3) that were relatively up-regulated in HL-60[R] cells and repressed in cells with ATRA-induced differentiation were related to mismatch repair in eukaryotes, DNA double-strand break repair, and nucleotide excision repair pathways. Our results suggest that transcriptional time series profiles and a functional pathway analysis of drug resistance and ATRA-induced cell differentiation will be useful for identifying promyelocytic leukemia patients who are eligible for new therapeutic strategies. C1 [Liu, Song-Mei] Wuhan Univ, Zhongnan Hosp, Ctr Gene Diag, Wuhan 430071, Hubei, Peoples R China. [Chen, Weiping] NIDDK, Microarray Core, NIH, Bethesda, MD 20892 USA. [Wang, Jin] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA. RP Wang, J (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA. EM JWang4@mdanderson.org RI WANG, Jin/A-8327-2012 OI WANG, Jin/0000-0002-0062-2489 FU National Natural Science Foundation of China [81271919] FX The work described in this paper was supported by the National Natural Science Foundation of China 81271919. NR 50 TC 1 Z9 1 U1 0 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 4 PY 2014 VL 4 AR 5577 DI 10.1038/srep05577 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK5ZN UT WOS:000338506300005 PM 24993014 ER PT J AU Prochaska, JD Nolen, AB Kelley, H Sexton, K Linder, SH Sullivan, J AF Prochaska, John D. Nolen, Alexandra B. Kelley, Hilton Sexton, Ken Linder, Stephen H. Sullivan, John TI Social Determinants of Health in Environmental Justice Communities: Examining Cumulative Risk in Terms of Environmental Exposures and Social Determinants of Health SO HUMAN AND ECOLOGICAL RISK ASSESSMENT LA English DT Article DE cumulative risk; social determinants of health; environmental justice ID DISPARITIES; MULTILEVEL; RISKSCAPE; CARE AB Residents of environmental justice (EJ) communities may bear a disproportionate burden of environmental health risk, and often face additional burdens from social determinants of health. Accounting for cumulative risk should include measures of risk from both environmental sources and social determinants. This study sought to better understand cumulative health risk from both social and environmental sources in a disadvantaged community in Texas. Key outcomes were determining what data are currently available for this assessment, clarifying data needs, identifying data gaps, and considering how those gaps could be filled. Analyses suggested that the traditionally defined EJ community in Port Arthur may have a lower environmental risk from air toxics than the rest of the City of Port Arthur (although the entire city has a higher risk than the average for the state), but may have a larger burden from social determinants of health. However, the results should be interpreted in light of the availability of data, the definitions of community boundaries, and the areal unit utilized. Continued focus on environmental justice communities and the cumulative risks faced by their residents is critical to protecting these residents and, ultimately, moving toward a more equitable distribution and acceptable level of risk throughout society. C1 [Prochaska, John D.; Nolen, Alexandra B.] Univ Texas Med Branch, Ctr Eliminate Hlth Dispar, Galveston, TX 77555 USA. [Kelley, Hilton] Community In Power & Dev Assoc Inc, Port Arthur, TX USA. [Sexton, Ken] Univ Texas Brownsville, Sch Publ Hlth, Brownsville, TX 78520 USA. [Linder, Stephen H.] Univ Texas Houston, Sch Publ Hlth, Inst Hlth Policy, Houston, TX USA. [Sullivan, John] Univ Texas Med Branch, NIEHS, Ctr Environm Toxicol, Galveston, TX 77555 USA. RP Prochaska, JD (reprint author), Univ Texas Med Branch, Ctr Eliminate Hlth Dispar, 301 Univ Blvd, Galveston, TX 77555 USA. EM joprocha@utmb.edu FU National Institute on Minority Health and Health Disparities [1RC2MD004783-01] FX The authors acknowledge Dr. Jonathon Ward for his initial insights into the work that led to the development of this article. Also, special acknowledgment goes to Sayali Tarlekar for her valued assistance in helping develop this article. The authors also acknowledge the thoughtful and constructive feedback from three anonymous journal reviewers in further strengthening this article. Finally, we acknowledge the members of Community In-Power and Development Association (CIDA), Inc. for their sharing of valuable knowledge and insight about the West-Side neighborhood. This work was supported, in part, by National Institute on Minority Health and Health Disparities award 1RC2MD004783-01. NR 36 TC 4 Z9 4 U1 0 U2 27 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 520 CHESTNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1080-7039 EI 1549-7860 J9 HUM ECOL RISK ASSESS JI Hum. Ecol. Risk Assess. PD JUL 4 PY 2014 VL 20 IS 4 BP 980 EP 994 DI 10.1080/10807039.2013.805957 PG 15 WC Biodiversity Conservation; Environmental Sciences SC Biodiversity & Conservation; Environmental Sciences & Ecology GA AD7YQ UT WOS:000333483800007 PM 24771993 ER PT J AU Resnik, DB AF Resnik, David B. TI Editorial: Does RCR Education Make Students More Ethical, and Is This the Right Question to Ask? SO ACCOUNTABILITY IN RESEARCH-POLICIES AND QUALITY ASSURANCE LA English DT Editorial Material ID RESPONSIBLE CONDUCT; NATIONAL-SURVEY; INSTRUCTION; INTEGRITY; FUTURE C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Box 12233,Mail Drop CU 03, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102646-05] NR 17 TC 3 Z9 3 U1 0 U2 14 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0898-9621 EI 1545-5815 J9 ACCOUNT RES JI Account. Res. PD JUL 4 PY 2014 VL 21 IS 4 BP 211 EP 217 DI 10.1080/08989621.2013.848800 PG 7 WC Medical Ethics SC Medical Ethics GA 287TG UT WOS:000329564500002 PM 24422701 ER PT J AU Durum, SK AF Durum, Scott K. TI IL-7 and TSLP receptors: twisted sisters SO BLOOD LA English DT Editorial Material ID ACUTE LYMPHOBLASTIC-LEUKEMIA; OF-FUNCTION MUTATIONS; CRLF2; EXPRESSION; IL7R; GENE AB In this issue of Blood, Shochat et al report mutations in receptors for interleukin-7 (IL-7) and thymic stromal lymphopoietin (TSLP), resulting in a novel dimerization mechanism that drives acute lymphoblastic leukemias.(1) C1 NCI, NIH, Bethesda, MD 20892 USA. RP Durum, SK (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 10 TC 1 Z9 2 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 3 PY 2014 VL 124 IS 1 BP 4 EP 5 DI 10.1182/blood-2014-05-574327 PG 4 WC Hematology SC Hematology GA AQ2LT UT WOS:000342618300003 PM 24993875 ER PT J AU Mirabello, L Macari, ER Jessop, L Ellis, SR Myers, T Giri, N Taylor, AM McGrath, KE Humphries, JM Ballew, BJ Yeager, M Boland, JF He, J Hicks, BD Burdett, L Alter, BP Zon, L Savage, SA AF Mirabello, Lisa Macari, Elizabeth R. Jessop, Lea Ellis, Steven R. Myers, Timothy Giri, Neelam Taylor, Alison M. McGrath, Katherine E. Humphries, Jessica M. Ballew, Bari J. Yeager, Meredith Boland, Joseph F. He, Ji Hicks, Belynda D. Burdett, Laurie Alter, Blanche P. Zon, Leonard Savage, Sharon A. TI Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multicase Diamond-Blackfan anemia families SO BLOOD LA English DT Article ID PROTEIN STABILITY CHANGES; SUPPORT VECTOR MACHINES; MUTATIONS; ZEBRAFISH; DATABASE; ABNORMALITIES; PREDICTIONS; ACTIVATION; REGULATOR; SELECTION AB Diamond-Blackfan anemia (DBA) is a cancer-prone inherited bone marrow failure syndrome. Approximately half of DBA patients have a germ-line mutation in a ribosomal protein gene. We used whole-exome sequencing to identify disease-causing genes in 2 large DBA families. After filtering, 1 nonsynonymous mutation (p.I31F) in the ribosomal protein S29 (RPS29[AUQ1]) gene was present in all 5 DBA-affected individuals and the obligate carrier, and absent from the unaffected noncarrier parent in 1 DBA family. A second DBA family was found to have a different nonsynonymous mutation (p.I50T) in RPS29. Both mutations are amino acid substitutions in exon 2 predicted to be deleterious and resulted in haploinsufficiency of RPS29 expression compared with wild-type RPS29 expression from an unaffected control. The DBA proband with the p.I31F RPS29 mutation had a pre-ribosomal RNA (rRNA) processing defect compared with the healthy control. Wedemonstrated that both RPS29 mutations failed to rescue the defective erythropoiesis in the rps29(-/-) mutant zebra fish DBA model. RPS29 is a component of the small 40S ribosomal subunit and essential for rRNA processing and ribosome biogenesis. We uncovered a novel DBA causative gene, RPS29, and showed that germ-line mutations in RPS29 can cause a defective erythropoiesis phenotype using a zebra fish model. C1 [Mirabello, Lisa; Jessop, Lea; Myers, Timothy; Giri, Neelam; Ballew, Bari J.; Alter, Blanche P.; Savage, Sharon A.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Macari, Elizabeth R.; Taylor, Alison M.; McGrath, Katherine E.; Humphries, Jessica M.; Zon, Leonard] Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. [Macari, Elizabeth R.; Taylor, Alison M.; McGrath, Katherine E.; Humphries, Jessica M.; Zon, Leonard] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Macari, Elizabeth R.; Taylor, Alison M.; McGrath, Katherine E.; Humphries, Jessica M.; Zon, Leonard] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ellis, Steven R.] Univ Louisville, Dept Biochem & Mol Biol, Louisville, KY 40292 USA. [Yeager, Meredith; Boland, Joseph F.; He, Ji; Hicks, Belynda D.; Burdett, Laurie] Frederick Natl Lab Canc Res, Canc Genom Res Lab, Leidos Biomed Res, Frederick, MD USA. [Zon, Leonard] Harvard Univ, Sch Med, Boston, MA USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E454, Bethesda, MD 20892 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU Division of Cancer Epidemiology and Genetics, NCI, National Institutes of Health (NIH); Westat Inc. [N02-CP-91026, N02-CP-11019, HHSN261200655001C]; NIH National Heart, Lung, and Blood Institute [T32HL116324, 5U01HL10001-05]; NIH National Institute of Diabetes and Digestive and Kidney Diseases [5P30 DK049216-20]; Diamond Blackfan Anemia Foundation FX This study was funded by the intramural research program of the Division of Cancer Epidemiology and Genetics, NCI, National Institutes of Health (NIH); Westat Inc. (contracts N02-CP-91026, N02-CP-11019, and HHSN261200655001C); the NIH National Heart, Lung, and Blood Institute (training grant T32HL116324) (E. R. M.); NIH National Institute of Diabetes and Digestive and Kidney Diseases (5P30 DK049216-20); NIH National Heart, Lung, and Blood Institute (5U01HL10001-05); and a grant from the Diamond Blackfan Anemia Foundation. NR 44 TC 17 Z9 19 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 3 PY 2014 VL 124 IS 1 BP 24 EP 32 DI 10.1182/blood-2013-11-540278 PG 9 WC Hematology SC Hematology GA AQ2LT UT WOS:000342618300008 PM 24829207 ER PT J AU Bresciani, E Carrington, B Wincovitch, S Jones, M Gore, AV Weinstein, BM Sood, R Liu, PP AF Bresciani, Erica Carrington, Blake Wincovitch, Stephen Jones, MaryPat Gore, Aniket V. Weinstein, Brant M. Sood, Raman Liu, P. Paul TI CBF beta and RUNX1 are required at 2 different steps during the development of hematopoietic stem cells in zebrafish SO BLOOD LA English DT Article ID FETAL LIVER HEMATOPOIESIS; ZINC-FINGER NUCLEASES; CORE-BINDING-FACTOR; DEFINITIVE HEMATOPOIESIS; ADULT HEMATOPOIESIS; AORTIC ENDOTHELIUM; GENE-EXPRESSION; IN-VIVO; LEUKEMIA; MIGRATION AB CBF beta and RUNX1 form a DNA-binding heterodimer and are both required for hematopoietic stem cell (HSC) generation in mice. However, the exact role of CBF beta in the production of HSCs remains unclear. Here, we generated and characterized 2 zebrafish cbfb null mutants. The cbfb(-/-) embryos underwent primitive hematopoiesis and developed transient erythromyeloid progenitors, but they lacked definitive hematopoiesis. Unlike runx1 mutants, in which HSCs are not formed, nascent, runx1(+)/c-myb(+) HSCs were formed in cbfb(-/-) embryos. However, the nascent HSCs were not released from the aorta-gonad-mesonephros (AGM) region, as evidenced by the accumulation of runx1 1 cells in the AGM that could not enter circulation. Moreover, wild-type embryos treated with an inhibitor of RUNX1-CBF beta interaction, Ro5-3335, phenocopied the hematopoietic defects in cbfb(-/-) mutants, rather than those in runx1(-/-) mutants. Finally, we found that cbfb was downstream of the Notch pathway during HSC development. Our data suggest that runx1 and cbfb are required at 2 different steps during early HSC development. CBF beta is not required for nascent HSC emergence but is required for the release of HSCs from AGM into circulation. Our results also indicate that RUNX1 can drive the emergence of nascent HSCs in the AGM without its heterodimeric partner CBF beta. C1 [Bresciani, Erica; Sood, Raman; Liu, P. Paul] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. [Carrington, Blake; Sood, Raman] NHGRI, Zebrafish Core, NIH, Bethesda, MD 20892 USA. [Wincovitch, Stephen] NHGRI, Cytogenet & Microscopy Core, NIH, Bethesda, MD 20892 USA. [Jones, MaryPat] NHGRI, Genom Core, NIH, Bethesda, MD 20892 USA. [Gore, Aniket V.; Weinstein, Brant M.] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Liu, PP (reprint author), 49 Convent Dr,Bldg 49,Room 3A26, Bethesda, MD 20892 USA. EM pliu@mail.nih.gov FU National Human Genome Research Institute, National Institutes of Health; National Institute of Child Health and Human Development, National Institutes of Health FX The work described in this paper was supported by the Intramural Research Programs at the National Human Genome Research Institute, National Institutes of Health, and the National Institute of Child Health and Human Development, National Institutes of Health. NR 39 TC 11 Z9 11 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 3 PY 2014 VL 124 IS 1 BP 70 EP 78 DI 10.1182/blood-2013-10-531988 PG 9 WC Hematology SC Hematology GA AQ2LT UT WOS:000342618300013 PM 24850758 ER PT J AU Puhl, HL Lu, VB Won, YJ Sasson, Y Hirsch, JA Ono, F Ikeda, SR AF Puhl, Henry L., III Lu, Van B. Won, Yu-Jin Sasson, Yehezkel Hirsch, Joel A. Ono, Fumihito Ikeda, Stephen R. TI Ancient Origins of RGK Protein Function: Modulation of Voltage-Gated Calcium Channels Preceded the Protostome and Deuterostome Split SO PLOS ONE LA English DT Article ID GTP-BINDING PROTEINS; BETA-SUBUNIT; RAS-FAMILY; SYMPATHETIC NEURONS; CA2+ CHANNELS; EXPRESSION; ZEBRAFISH; REM2; MEMBER; GENE AB RGK proteins, Gem, Rad, Rem1, and Rem2, are members of the Ras superfamily of small GTP-binding proteins that interact with Ca2+ channel beta subunits to modify voltage-gated Ca2+ channel function. In addition, RGK proteins affect several cellular processes such as cytoskeletal rearrangement, neuronal dendritic complexity, and synapse formation. To probe the phylogenetic origins of RGK protein-Ca2+ channel interactions, we identified potential RGK-like protein homologs in genomes for genetically diverse organisms from both the deuterostome and protostome animal superphyla. RGK-like protein homologs cloned from Danio rerio (zebrafish) and Drosophila melanogaster (fruit flies) expressed in mammalian sympathetic neurons decreased Ca2+ current density as reported for expression of mammalian RGK proteins. Sequence alignments from evolutionarily diverse organisms spanning the protostome/deuterostome divide revealed conservation of residues within the RGK G-domain involved in RGK protein - Ca-v beta subunit interaction. In addition, the C-terminal eleven residues were highly conserved and constituted a signature sequence unique to RGK proteins but of unknown function. Taken together, these data suggest that RGK proteins, and the ability to modify Ca2+ channel function, arose from an ancestor predating the protostomes split from deuterostomes approximately 550 million years ago. C1 [Puhl, Henry L., III; Lu, Van B.; Won, Yu-Jin; Ikeda, Stephen R.] NIAAA, Lab Mol Physiol, Sect Transmitter Signaling, NIH, Rockville, MD 20852 USA. [Ono, Fumihito] NIAAA, Lab Mol Physiol, Sect Model Synapt Syst, NIH, Rockville, MD 20852 USA. [Sasson, Yehezkel; Hirsch, Joel A.] Tel Aviv Univ, Fac Life Sci, Inst Biol Struct, Dept Biochem & Mol Biol, Ramat Aviv, Israel. RP Ikeda, SR (reprint author), NIAAA, Lab Mol Physiol, Sect Transmitter Signaling, NIH, Rockville, MD 20852 USA. EM sikeda@mail.nih.gov OI Lu, Van/0000-0002-4880-6455; Puhl, Henry/0000-0003-3095-7201; Ikeda, Stephen/0000-0002-4088-9508 FU National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism; Israel Science Foundation [1519/12] FX This work was supported by the intramural program at the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism. YS and JAH were supported by the Israel Science Foundation (grant 1519/12). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 4 Z9 4 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 3 PY 2014 VL 9 IS 7 AR e100694 DI 10.1371/journal.pone.0100694 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3RT UT WOS:000341253400027 PM 24992013 ER PT J AU Zhou, TQ Zhu, J Yang, YP Gorman, J Ofek, G Srivatsan, S Druz, A Lees, CR Lu, G Soto, C Stuckey, J Burton, DR Koff, WC Connors, M Kwon, PD AF Zhou, Tongqing Zhu, Jiang Yang, Yongping Gorman, Jason Ofek, Gilad Srivatsan, Sanjay Druz, Aliaksandr Lees, Christopher R. Lu, Gabriel Soto, Cinque Stuckey, Jonathan Burton, Dennis R. Koff, Wayne C. Connors, Mark Kwon, Peter D. TI Transplanting Supersites of HIV-1 Vulnerability SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; BROADLY NEUTRALIZING ANTIBODIES; RESPIRATORY SYNCYTIAL VIRUS; HUMAN MONOCLONAL-ANTIBODY; STRUCTURE-BASED DESIGN; N-GLYCAN RECOGNITION; ENVELOPE GLYCOPROTEIN; COMPUTATIONAL DESIGN; VACCINE DEVELOPMENT; EPITOPE-SCAFFOLDS AB One strategy for isolating or eliciting antibodies against a specific target region on the envelope glycoprotein trimer (Env) of the human immunodeficiency virus type 1 (HIV-1) involves the creation of site transplants, which present the target region on a heterologous protein scaffold with preserved antibody-binding properties. If the target region is a supersite of HIV-1 vulnerability, recognized by a collection of broadly neutralizing antibodies, this strategy affords the creation of "supersite transplants", capable of binding (and potentially eliciting) antibodies similar to the template collection of effective antibodies. Here we transplant three supersites of HIV-1 vulnerability, each targeted by effective neutralizing antibodies from multiple donors. To implement our strategy, we chose a single representative antibody against each of the target supersites: antibody 10E8, which recognizes the membrane-proximal external region (MPER) on the HIV-1 gp41 glycoprotein; antibody PG9, which recognizes variable regions one and two (V1V2) on the HIV-1 gp120 glycoprotein; and antibody PGT128 which recognizes a glycopeptide supersite in variable region 3 (glycan V3) on gp120. We used a structural alignment algorithm to identify suitable acceptor proteins, and then designed, expressed, and tested antigenically over 100-supersite transplants in a 96-well microtiter-plate format. The majority of the supersite transplants failed to maintain the antigenic properties of their respective template supersite. However, seven of the glycan V3-supersite transplants exhibited nanomolar affinity to effective neutralizing antibodies from at least three donors and recapitulated the mannose(9)-N-linked glycan requirement of the template supersite. The binding of these transplants could be further enhanced by placement into self-assembling nanoparticles. Essential elements of the glycan V3 supersite, embodied by as few as 3 N-linked glycans and similar to 25 Env residues, can be segregated into acceptor scaffolds away from the immune-evading capabilities of the rest of HIV-1 Env, thereby providing a means to focus the immune response on the scaffolded supersite. C1 [Zhou, Tongqing; Zhu, Jiang; Yang, Yongping; Gorman, Jason; Ofek, Gilad; Srivatsan, Sanjay; Druz, Aliaksandr; Lees, Christopher R.; Lu, Gabriel; Soto, Cinque; Stuckey, Jonathan; Kwon, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Design, La Jolla, CA 92037 USA. [Burton, Dennis R.] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Koff, Wayne C.] IAVI, New York, NY USA. [Connors, Mark] NIAID, HIV Specif Immun Sect, NIH, Bethesda, MD 20892 USA. RP Kwon, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pdkwong@nih.gov RI Cheng, Yushao/E-6256-2011; Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 FU Intramural Research Program of the Vaccine Research Center; National Institute of Allergy and Infectious Diseases; National Institutes of Health; International AIDS Vaccine Initiative's Neutralizing Antibody Consortium; Bill & Melinda Gates Foundation; Ministry of Foreign Affairs of Denmark; Irish Aid; Ministry of Finance of Japan; Ministry of Foreign Affairs of the Netherlands; Norwegian Agency for Development Cooperation (NORAD); United Kingdom Department for International Development (DFID); United States Agency for International Development (USAID) FX Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by grants from the International AIDS Vaccine Initiative's Neutralizing Antibody Consortium. IAVI's work is made possible by generous support from many donors including: the Bill & Melinda Gates Foundation; the Ministry of Foreign Affairs of Denmark; Irish Aid; the Ministry of Finance of Japan; the Ministry of Foreign Affairs of the Netherlands; the Norwegian Agency for Development Cooperation (NORAD); the United Kingdom Department for International Development (DFID), and the United States Agency for International Development (USAID). The full list of IAVI donors is available at www. iavi. org. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 21 Z9 21 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 3 PY 2014 VL 9 IS 7 AR e99881 DI 10.1371/journal.pone.0099881 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3RT UT WOS:000341253400014 PM 24992528 ER PT J AU Liu, Y Yang, RL Liu, XB Zhou, Y Qu, CY Kikuiri, T Wang, SL Zandi, E Du, JB Ambudkar, IS Shi, ST AF Liu, Yi Yang, Ruili Liu, Xibao Zhou, Yu Qu, Cunye Kikuiri, Takashi Wang, Songlin Zandi, Ebrahim Du, Junbao Ambudkar, Indu S. Shi, Songtao TI Hydrogen Sulfide Maintains Mesenchymal Stem Cell Function and Bone Homeostasis via Regulation of Ca2+ Channel Sulfhydration SO CELL STEM CELL LA English DT Article ID CYSTATHIONINE BETA-SYNTHASE; ESCHERICHIA-COLI; STROMAL CELLS; HIP FRACTURE; RAT-LIVER; HOMOCYSTEINE; CYSTEINE; VITAMIN-B-12; EXPRESSION; H2S AB Gaseous signaling molecules such as hydrogen sulfide (H2S) are produced endogenously and mediate effects through diverse mechanisms. H2S is one such gasotransmitters that regulates multiple signaling pathways in mammalian cells, and abnormal H2S metabolism has been linked to defects in bone homeostasis. Here, we demonstrate that bone marrow mesenchymal stem cells (BMMSCs) produce H2S in order to regulate their self-renewal and osteogenic differentiation, and H2S deficiency results in defects in BMMSC differentiation. H2S deficiency causes aberrant intracellular Ca2+ influx because of reduced sulfhydration of cysteine residues on multiple Ca2+ TRP channels. This decreased Ca2+ flux downregulates PKC/Erk-mediated Wnt/beta-catenin signaling which controls osteogenic differentiation of BMMSCs. Consistently, H2S-deficient mice display an osteoporotic phenotype that can be rescued by small molecules that release H2S. These results demonstrate that H2S regulates BMMSCs and that restoring H2S levels via nontoxic donors may provide treatments for diseases such as osteoporosis that can arise from H2S deficiencies. C1 [Liu, Yi; Yang, Ruili; Qu, Cunye; Kikuiri, Takashi; Shi, Songtao] Univ So Calif, Ostrow Sch Dent, Ctr Craniofacial Mol Biol, Los Angeles, CA 90033 USA. [Liu, Yi; Wang, Songlin] Capital Med Univ, Sch Stomatol, Dept Periodont, Beijing 100050, Peoples R China. [Liu, Xibao; Ambudkar, Indu S.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, Bethesda, MD 20892 USA. [Zhou, Yu; Zandi, Ebrahim] Univ So Calif, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA. [Du, Junbao] Peking Univ, Hosp 1, Dept Pediat, Beijing 100034, Peoples R China. RP Liu, Y (reprint author), Univ So Calif, Ostrow Sch Dent, Ctr Craniofacial Mol Biol, 2250 Alcazar St,CSA 103, Los Angeles, CA 90033 USA. EM liuyi@ccmu.edu.cn; songtaos@usc.edu RI Zhou, Yu/M-7975-2014 FU National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services [R01DE017449, R01 DE019932]; National Natural Science Foundation of China [81222011]; Science and Technology Activities of Beijing Overseas Students Preferred Foundation FX This work was supported by grants from the National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services (R01DE017449 and R01 DE019932 to S.S.), the National Natural Science Foundation of China (81222011 to Y.L), and Science and Technology Activities of Beijing Overseas Students Preferred Foundation (to Y.L.). NR 50 TC 26 Z9 26 U1 2 U2 25 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD JUL 3 PY 2014 VL 15 IS 1 BP 66 EP 78 DI 10.1016/j.stem.2014.03.005 PG 13 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AN8TX UT WOS:000340878600012 PM 24726192 ER PT J AU Yoon, KJ Nguyen, HN Ursini, G Zhang, FY Kim, NS Wen, ZX Makri, G Nauen, D Shin, JH Park, Y Chung, R Pekle, E Zhang, C Towe, M Mohammed, S Hussaini, Q Lee, Y Rujescu, D St Clair, D Kleinman, JE Hyde, TM Krauss, G Christian, KM Rapoport, JL Weinberger, DR Song, HJ Ming, GL AF Yoon, Ki-Jun Ha Nam Nguyen Ursini, Gianluca Zhang, Fengyu Kim, Nam-Shik Wen, Zhexing Makri, Georgia Nauen, David Shin, Joo Heon Park, Youngbin Chung, Raeeun Pekle, Eva Zhang, Ce Towe, Maxwell Mohammed, Syed Hussaini, Qasim Lee, Yohan Rujescu, Dan St Clair, David Kleinman, Joel E. Hyde, Thomas M. Krauss, Gregory Christian, Kimberly M. Rapoport, Judith L. Weinberger, Daniel R. Song, Hongjun Ming, Guo-li TI Modeling a Genetic Risk for Schizophrenia in iPSCs and Mice Reveals Neural Stem Cell Deficits Associated with Adherens Junctions and Polarity SO CELL STEM CELL LA English DT Article ID COPY NUMBER VARIANTS; RECURRENT MICRODELETIONS; NEURONAL MIGRATION; CEREBRAL-CORTEX; PROTEIN; AUTISM; DROSOPHILA; 15Q11.2; WAVE2; PATHOGENESIS AB Defects in brain development are believed to contribute toward the onset of neuropsychiatric disorders, but identifying specific underlying mechanisms has proven difficult. Here, we took a multifaceted approach to investigate why 15q11.2 copy number variants are prominent risk factors for schizophrenia and autism. First, we show that human iPSC-derived neural progenitors carrying 15q11.2 microdeletion exhibit deficits in adherens junctions and apical polarity. This results from haploinsufficiency of CYFIP1, a gene within 15q11.2 that encodes a subunit of the WAVE complex, which regulates cytoskeletal dynamics. In developing mouse cortex, deficiency in CYFIP1 and WAVE signaling similarly affects radial glial cells, leading to their ectopic localization outside of the ventricular zone. Finally, targeted human genetic association analyses revealed an epistatic interaction between CYFIP1 and WAVE signaling mediator ACTR2 and risk for schizophrenia. Our findings provide insight into how CYFIP1 regulates neural stem cell function and may contribute to the susceptibility of neuropsychiatric disorders. C1 [Yoon, Ki-Jun; Ha Nam Nguyen; Kim, Nam-Shik; Wen, Zhexing; Makri, Georgia; Nauen, David; Park, Youngbin; Chung, Raeeun; Pekle, Eva; Zhang, Ce; Towe, Maxwell; Mohammed, Syed; Christian, Kimberly M.; Song, Hongjun; Ming, Guo-li] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21205 USA. [Yoon, Ki-Jun; Kim, Nam-Shik; Wen, Zhexing; Makri, Georgia; Zhang, Ce; Krauss, Gregory; Christian, Kimberly M.; Weinberger, Daniel R.; Song, Hongjun; Ming, Guo-li] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Ha Nam Nguyen; Song, Hongjun; Ming, Guo-li] Johns Hopkins Univ, Sch Med, Grad Program Cellular & Mol Med, Baltimore, MD 21205 USA. [Ursini, Gianluca; Zhang, Fengyu; Shin, Joo Heon; Kleinman, Joel E.; Hyde, Thomas M.; Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Nauen, David] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Lee, Yohan; Rapoport, Judith L.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Rujescu, Dan] Univ Munich, Dept Psychiat, D-80336 Munich, Germany. [St Clair, David] Univ Aberdeen, Royal Cornhill Hosp, Aberdeen AB25 2ZD, Scotland. [Weinberger, Daniel R.; Song, Hongjun; Ming, Guo-li] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA. RP Ming, GL (reprint author), Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21205 USA. EM shongju1@jhmi.edu; gming1@jhmi.edu RI Wen, Zhexing/B-9313-2014 FU NIH [NS048271, HD069184, NS047344, MH087874, F31MH102978]; Brain and Behavior Research Foundation (NARSAD); Maryland Stem Cell Research Fund (MSCRF); Simons Foundation Autism Research Initiative (SFARI); International Mental Health Research Organization (IMHRO); Lieber Institute for Brain Development; NARSAD; MSCRF; HFSP FX We would like to thank members of G.-l.M. and H.S. laboratories for discussion, ICE stem cell core and H. Kim for generating some iPSC lines, K. Ahn, T. Andersen, V. Villagomez, L. Liu, and Y. Cai for technical support and help. This work was supported by NIH (NS048271, HD069184), the Brain and Behavior Research Foundation (NARSAD), and the Maryland Stem Cell Research Fund (MSCRF) (to G.-l. M.), the Simons Foundation Autism Research Initiative (SFARI), NIH (NS047344, MH087874), and the International Mental Health Research Organization (IMHRO) to H. S., the Lieber Institute for Brain Development to D.R.W., J.E.K., and T.M.H., NARSAD and MSCRF to K.M.C., by fellowships from HFSP to K-j.Y. and MSCRF to G.M., N.-S.K., and Z.W., and from NIH (F31MH102978) to H.N.N. NR 53 TC 50 Z9 50 U1 2 U2 27 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD JUL 3 PY 2014 VL 15 IS 1 BP 79 EP 91 DI 10.1016/j.stem.2014.05.003 PG 13 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AN8TX UT WOS:000340878600013 PM 24996170 ER PT J AU Plank, JL Dean, A AF Plank, Jennifer L. Dean, Ann TI Enhancer Function: Mechanistic and Genome-Wide Insights Come Together SO MOLECULAR CELL LA English DT Review ID EMBRYONIC STEM-CELLS; BETA-GLOBIN LOCUS; MASTER TRANSCRIPTION FACTORS; DYNAMIC DNA METHYLATION; GENE-EXPRESSION; CHROMATIN INTERACTIONS; REGULATORY ELEMENTS; LINEAGE COMMITMENT; ACTIVATION; COHESIN AB Enhancers establish spatial or temporal patterns of gene expression that are critical for development, yet our understanding of how these DNA cis-regulatory elements function from a distance to increase transcription of their target genes and shape the cellular transcriptome has been gleaned primarily from studies of individual genes or gene families. High-throughput sequencing studies place enhancer-gene interactions within the 3D context of chromosome folding, inviting a new look at enhancer function and stimulating provocative new questions. Here, we integrate these whole-genome studies with recent mechanistic studies to illuminate how enhancers physically interact with target genes, how enhancer activity is regulated during development, and the role of noncoding RNAs transcribed from enhancers in their function. C1 [Plank, Jennifer L.; Dean, Ann] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Dean, A (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM anndean@helix.nih.gov FU NIDDK, NIH FX We apologize to colleagues whose work we were unable to mention or cite dues to space limitations. We thank Vittorio Sartorelli, Elissa Lei, Judith Kassis, and Ivan Krivega for critical comments on the manuscript. This work was supported by the Intramural Program, NIDDK, NIH. NR 95 TC 47 Z9 49 U1 5 U2 35 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD JUL 3 PY 2014 VL 55 IS 1 BP 5 EP 14 DI 10.1016/j.molcel.2014.06.015 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN5LO UT WOS:000340632900003 PM 24996062 ER PT J AU Zhang, JW Ferre-D'Amare, AR AF Zhang, Jinwei Ferre-D'Amare, Adrian R. TI Direct Evaluation of tRNA Aminoacylation Status by the T-Box Riboswitch Using tRNA-mRNA Stacking and Steric Readout SO MOLECULAR CELL LA English DT Article ID ELONGATION-FACTOR-TU; ANTITERMINATION IN-VITRO; UNCHARGED TRANSFER-RNA; TRANSCRIPTION ANTITERMINATION; BACILLUS-SUBTILIS; ESCHERICHIA-COLI; BASE STACKING; LEADER RNA; PYRROLO-C; EF-TU AB T-boxes are gene-regulatory mRNA elements with which Gram-positive bacteria sense amino acid availability. T-boxes have two functional domains. Stem I recognizes the overall shape and anticodon of tRNA, while a 30 domain evaluates its aminoacylation status, overcoming an otherwise stable transcriptional terminator if the bound tRNA is uncharged. Although T-boxes are believed to evaluate tRNA charge status without using any proteins, this has not been demonstrated experimentally because of the instability of aminoacyl-tRNA. Using a simple method to prepare homogeneous aminoacyl-tRNA, we show that the Bacillus subtilis glyQS T-box functions independently of any tRNA-binding protein. Comparison of aminoacyl-tRNA analogs demonstrates that the T-box detects the molecular volume of tRNA 30-substituents. Calorimetry and fluorescence lifetime analysis of labeled RNAs shows that the tRNA acceptor end coaxially stacks on a helix in the T-box 30 domain. This intimate intermolecular association, selective for uncharged tRNA, stabilizes the antiterminator conformation of the T-box. C1 [Zhang, Jinwei; Ferre-D'Amare, Adrian R.] NHLBI, Bethesda, MD 20892 USA. RP Ferre-D'Amare, AR (reprint author), NHLBI, 50 South Dr,MSC 8012, Bethesda, MD 20892 USA. EM adrian.ferre@nih.gov FU NHLBI, NIH FX We thank J. Posakony for assistance with chemical synthesis and NMR analysis, Y. Goto and H. Suga for a gift of dinitrobenzylglycine and suggestions on flexizyme use, S. Hecht for suggesting the use of the pentenoyl protecting group, N. Tjandra for access to NMR, G. Piszczek for fluorescence and ITC support, R. Levine and D.-Y. Lee for help with mass spectrometry, and N. Baird, J. Brunelle, K. Fredrick, R. Green, J. Hogg, M. Ibba, M. Lau, J. Lee, P. Nissen, C. Jones, O. Uhlenbeck, A. Roll-Mecak, and K. Warner for discussions. This work employed the Biochemistry and Biophysics core facilities of the National Heart, Lung and Blood Institute (NHLBI) and was supported in part by the intramural program of the NHLBI, NIH. NR 44 TC 9 Z9 10 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD JUL 3 PY 2014 VL 55 IS 1 BP 148 EP 155 DI 10.1016/j.molcel.2014.05.017 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN5LO UT WOS:000340632900014 PM 24954903 ER PT J AU Shigunov, P Sotelo-Silveira, J Stimamiglio, MA Kuligovski, C Irigoin, F Badano, JL Munroe, D Correa, A Dallagiovanna, B AF Shigunov, Patricia Sotelo-Silveira, Jose Stimamiglio, Marco Augusto Kuligovski, Crisciele Irigoin, Florencia Badano, Jose L. Munroe, David Correa, Alejandro Dallagiovanna, Bruno TI Ribonomic analysis of human DZIP1 reveals its involvement in ribonucleoprotein complexes and stress granules SO BMC MOLECULAR BIOLOGY LA English DT Article DE DZIP1; Ribonucleoprotein; Stress granules; Polysome; Hedgehog signaling ID HEDGEHOG SIGNAL-TRANSDUCTION; DAZ INTERACTING PROTEIN-1; EMBRYONIC STEM-CELLS; GERM-CELLS; BINDING PROTEINS; MESSENGER-RNAS; GLI TURNOVER; TRANSLATION; GENES; ZEBRAFISH AB Background: DZIP1 (DAZ-interacting protein 1) has been described as a component of the Hh signaling pathway with a putative regulatory role in ciliogenesis. DZIP1 interacts with DAZ RNA binding proteins in embryonic stem cells and human germ cells suggesting a role in mRNA regulation. Results: We investigated DZIP1 function in HeLa cells and its involvement in ribonucleoprotein complexes. DZIP1 was predominantly located in granules in the cytoplasm. Under oxidative stress conditions, DZIP1 re-localized to stress granules. DZIP appears to be important for the formation of stress granules during the stress response. We used immunoprecipitation assays with antibodies against DZIP1 and microarray hybridization to identify mRNAs associated with DZIP1. The genetic networks formed by the DZIP1-associated mRNAs were involved in cell cycle and gene expression regulation. DZIP1 is involved in the Hedgehog signaling pathway. We used cyclopamine, a specific inhibitor of this pathway, to analyze the expression of DZIP1 and its associated mRNAs. The abundance of DZIP1-associated mRNAs increased with treatment; however, the silencing or overexpression of DZIP1 in HeLa cells had no effect on the accumulation of the associated mRNAs. Polysomal profile analysis by sucrose gradient centrifugation demonstrated the presence of DZIP1 in the polysomal fraction. Conclusions: Our results suggest that DZIP1 is part of an RNP complex that occupies various subcellular locations. The diversity of the mRNAs associated with DZIP1 suggests that this protein is a component of different RNPs associated with translating polysomes and with RNA granules. C1 [Shigunov, Patricia; Stimamiglio, Marco Augusto; Kuligovski, Crisciele; Correa, Alejandro; Dallagiovanna, Bruno] Fiocruz MS, Inst Carlos Chagas, Stem Cells Basic Biol Lab, BR-81350010 Curitiba, Parana, Brazil. [Sotelo-Silveira, Jose] Inst Invest Biol Clemente Estable, Genom Dept, Montevideo 11600, Uruguay. [Sotelo-Silveira, Jose] Univ Republ Uruguay, Fac Ciencias, Cell & Mol Biol Dept, Montevideo 11600, Uruguay. [Irigoin, Florencia; Badano, Jose L.] Inst Pasteur Montevideo, Montevideo 11400, Uruguay. [Irigoin, Florencia] Univ Republica, Fac Med, Dept Histol & Embriol, Montevideo 11800, Uruguay. [Munroe, David] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Frederick, MD 21702 USA. RP Dallagiovanna, B (reprint author), Fiocruz MS, Inst Carlos Chagas, Stem Cells Basic Biol Lab, Algacyr Munhoz Mader 3775, BR-81350010 Curitiba, Parana, Brazil. EM brunod@tecpar.br FU Ministerio da Sa de and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico - CNPq [17/2008]; Fundacao Araucaria; FIOCRUZ; National Cancer Institute; National Institute of Health [HSN261200800001E]; CNPq; CAPES FX This work was supported by grants from the Ministerio da Sa de and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico - CNPq (CT- Saude/MS/SCTIE/DECIT/MCT/CNPq No. 17/2008), Fundacao Araucaria and FIOCRUZ. This project was funded in part with federal funds from the National Cancer Institute, National Institute of Health, under the contract HSN261200800001E. The content of this article does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does it mention of trade names, commercial products, or organizations endorsed by the U.S. Government. B.D. received fellowships from CNPq and P.S. from CAPES. NR 34 TC 2 Z9 2 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2199 J9 BMC MOL BIOL JI BMC Mol. Biol. PD JUL 3 PY 2014 VL 15 AR 12 DI 10.1186/1471-2199-15-12 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AL4RF UT WOS:000339119600001 PM 24993635 ER PT J AU Castro, FA Dominguez, A Puschel, K Van De Wyngard, V Snijders, PJF Franceschi, S Pawlita, M Ferreccio, C AF Castro, Felipe A. Dominguez, Angelica Puschel, Klaus Van De Wyngard, Vanessa Snijders, Peter J. F. Franceschi, Silvia Pawlita, Michael Ferreccio, Catterina TI Serological prevalence and persistence of high-risk human papillomavirus infection among women in Santiago, Chile SO BMC INFECTIOUS DISEASES LA English DT Article DE Human papillomavirus; Seropersistence; Cohort; Serology; Antibodies; Natural history ID INVASIVE CERVICAL-CANCER; POPULATION-BASED COHORT; YOUNG-WOMEN; COSTA-RICA; ANTIBODY-RESPONSES; NATURAL-HISTORY; CHINESE WOMEN; HPV INFECTION; SEROPREVALENCE; WORLDWIDE AB Background: Human papillomavirus (HPV) serology is a main factor for designing vaccination programs and surveillance strategies; nevertheless, there are few reports of HPV seroprevalence in the general population, especially in Latin America. This study aimed to describe high-risk HPV serological prevalence, persistence, and association with concurrent cervical infection, in Chilean women. Methods: 1021 women from the general population, aged 15-85 years, were studied in 2001 of whom 600 were reexamined in 2006. The assessments at both time points included cervical HPV DNA testing, HPV antibody testing, cervical cytology and a sociodemographic/behavioral questionnaire. HPV DNA and antibodies against L1 protein of types 16, 18, 31, 33, 35, 45, 52, and 58 were assessed by reverse line blot and multiplex serology, respectively. Results: Seropositivity was high at both baseline (43.2%) and follow-up (50.2%) and increased with age (p < 0.001); corresponding DNA prevalences were 6.7% and 8.7%. DNA and seroprevalence were associated at baseline (p = 0.01 for any HPV). Early age at first sexual intercourse and having had two or more sexual partners were independently associated with seropositivity. Most (82.0%) initially seropositive women remained seropositive at follow-up; 21.6% of initially seronegative women seroconverted, reaching 17.5% among women older than 60 years of age. ASCUS or worse cytology was correlated with HPV DNA positivity but not with HPV seropositivity. Conclusion: HPV seroprevalence studies are a useful tool for learning about the dynamics of HPV infection in a community. This study contributes to understanding the natural history of HPV infection and provides a baseline assessment before the incorporation of HPV vaccination into a national program. C1 [Castro, Felipe A.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Dominguez, Angelica; Puschel, Klaus; Van De Wyngard, Vanessa; Ferreccio, Catterina] Pontificia Univ Catolica Chile, Fac Med, Santiago 8330073, Chile. [Snijders, Peter J. F.] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, NL-1081 HV Amsterdam, Netherlands. [Franceschi, Silvia] Int Agcy Res Canc, F-69372 Lyon 08, France. [Pawlita, Michael] German Canc Res Ctr, Div Genome Modificat & Carcinogenesis, D-69120 Heidelberg, Germany. [Ferreccio, Catterina] Adv Ctr Chron Dis ACCDiS, Ctr FONDAP, Santiago 8330073, Chile. [Castro, Felipe A.] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany. RP Ferreccio, C (reprint author), Pontificia Univ Catolica Chile, Fac Med, Marcoleta 434, Santiago 8330073, Chile. EM cferrec@med.puc.cl RI Franceschi, Silvia/M-2452-2014; Waterboer, Tim/G-1252-2010; OI Pawlita, Michael/0000-0002-4720-8306 FU IARC; PAHO; FONDECYT Chile [1060645]; Intramural Research Program of the National Institute of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, USA; Advanced Center for Chronic Diseases (ACCDiS) Fifth National Competition for Research Centers in Priority Areas FONDAP Chile [15130011] FX The baseline study was co-funded by IARC and PAHO and the follow-up study was funded by FONDECYT Chile (Grant 1060645). The study was also supported by the Intramural Research Program of the National Institute of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, USA, and by the Advanced Center for Chronic Diseases (ACCDiS) Fifth National Competition for Research Centers in Priority Areas FONDAP Chile (Grant 15130011). The funding sources had no role in the study design, data collection, analysis and interpretation, or in the writing of this manuscript. NR 38 TC 4 Z9 4 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD JUL 3 PY 2014 VL 14 AR 361 DI 10.1186/1471-2334-14-361 PG 8 WC Infectious Diseases SC Infectious Diseases GA AK9EG UT WOS:000338729800001 PM 24990706 ER EF