FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Roy, S Wang, WT Carass, A Prince, JL Butman, JA Pham, DL AF Roy, Snehashis Wang, Wen-Tung Carass, Aaron Prince, Jerry L. Butman, John A. Pham, Dzung L. TI PET Attenuation Correction Using Synthetic CT from Ultrashort Echo-Time MR Imaging SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE attenuation correction; PET/CT; PET/MRI; CT; UTE ID PET/MRI; TISSUE; BRAIN; SEGMENTATION; REGISTRATION; ATLAS; CLASSIFICATION AB Integrated PET/MR systems are becoming increasingly popular in clinical and research applications. Quantitative PET reconstruction requires correction for gamma-photon attenuations using an attenuation coefficient map (mu map) that is a measure of the electron density. One challenge of PET/MR, in contrast to PET/CT, lies in the accurate computation of mu maps. Unlike CT, MR imaging measures physical properties not directly related to electron density. Previous approaches have computed the attenuation coefficients using a segmentation of MR images or using deformable registration of atlas CT images to the space of the subject MR images. Methods: In this work, we propose a patch-based method to generate whole-head mu maps from ultrashort echo-time (UTE) MR imaging sequences. UTE images are preferred to other MR sequences because of the increased signal from bone. To generate a synthetic CT image, we use patches from a reference dataset, which consists of dual-echo UTE images and a coregistered CT scan from the same subject. Matching of patches between the reference and target images allows corresponding patches from the reference CT scan to be combined via a Bayesian framework. No registration or segmentation is required. Results: For evaluation, UTE, CT, and PET data acquired from 5 patients under an institutional review board-approved protocol were used. Another patient (with UTE and CT data only) was selected to be the reference to generate synthetic CT images for these 5 patients. PET reconstructions were attenuation-corrected using the original CT, our synthetic CT, Siemens Dixon-based mu maps, Siemens UTE-based mu maps, and deformable registration-based CT. Our synthetic CT-based PET reconstruction showed higher correlation (average rho = 0.996, R-2 = 0.991) to the original CT-based PET, as compared with the segmentation-and registration-based methods. Synthetic CT-based reconstruction had minimal bias (regression slope, 0.990), as compared with the segmentation-based methods (regression slope, 0.905). A peak signal-to-noise ratio of 35.98 dB in the reconstructed PET activity was observed, compared with 29.767, 29.34, and 27.43 dB for the Siemens Dixon-, UTE-, and registration-based mu maps. Conclusion: A patch-matching approach to synthesize CT images from dual-echo UTE images leads to significantly improved accuracy of PET reconstruction as compared with actual CT scans. The PET reconstruction is improved over segmentation- (Dixon and Siemens UTE) and registration-based methods, even in subjects with pathologic findings. C1 [Roy, Snehashis; Wang, Wen-Tung; Pham, Dzung L.] Henry Jackson Fdn, Ctr Neurosci & Regenerat Med, Bethesda, MD 20817 USA. [Carass, Aaron; Prince, Jerry L.] Johns Hopkins Univ, Image Anal & Commun Lab, Baltimore, MD USA. [Butman, John A.] NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. RP Roy, S (reprint author), 10 Ctr Dr,Bldg 10,Room B1N264, Bethesda, MD 20814 USA. EM snehashis.roy@gmail.com RI Butman, John/J-2780-2013; OI Butman, John/0000-0002-1547-9195; Roy, Snehashis/0000-0002-7997-3993; Carass, Aaron/0000-0003-4939-5085 FU Department of Defense in the Center for Neuroscience and Regenerative Medicine; Intramural Research Program of the Clinical Center at the National Institutes of Health; NIH/NIBIB [R21EB012765, 1R01EB017743]; NIH/NINDS [R01NS070906] 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. Support for this work included funding from the Department of Defense in the Center for Neuroscience and Regenerative Medicine and the Intramural Research Program of the Clinical Center at the National Institutes of Health. This work was also supported in part by the grants NIH/NIBIB R21EB012765, 1R01EB017743, and NIH/NINDS R01NS070906. No other potential conflict of interest relevant to this article was reported. NR 21 TC 17 Z9 17 U1 2 U2 8 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 DEC PY 2014 VL 55 IS 12 BP 2071 EP 2077 DI 10.2967/jnumed.114.143958 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AU8EC UT WOS:000345828300027 PM 25413135 ER PT J AU Venkat, VL Shneider, BL Magee, JC Turmelle, Y Arnon, R Bezerra, JA Hertel, PM Karpen, SJ Kerkar, N Loomes, KM Molleston, J Murray, KF Ng, VL Raghunathan, T Rosenthal, P Schwartz, K Sherker, AH Sokol, RJ Teckman, J Wang, K Whitington, PF Heubi, JE AF Venkat, Veena L. Shneider, Benjamin L. Magee, John C. Turmelle, Yumirle Arnon, Ronen Bezerra, Jorge A. Hertel, Paula M. Karpen, Saul J. Kerkar, Nanda Loomes, Kathleen M. Molleston, Jean Murray, Karen F. Ng, Vicky L. Raghunathan, Trivellore Rosenthal, Philip Schwartz, Kathleen Sherker, Averell H. Sokol, Ronald J. Teckman, Jeffrey Wang, Kasper Whitington, Peter F. Heubi, James E. CA Childhood Liver Dis Res Educ TI Total Serum Bilirubin Predicts Fat-Soluble Vitamin Deficiency Better Than Serum Bile Acids in Infants With Biliary Atresia SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Article DE biliary atresia; bilirubin; cholestasis; fat-soluble vitamin; serum bile acid ID LIVER-DISEASE; K DEFICIENCY; CHOLESTASIS; PREVALENCE; DIAGNOSIS; CHILDREN AB Objective: Fat-soluble vitamin (FSV) deficiency is a well-recognized consequence of cholestatic liver disease and reduced intestinal intraluminal bile acid. We hypothesized that serum bile acid (SBA) would predict biochemical FSV deficiency better than serum total bilirubin (TB) level in infants with biliary atresia. Methods: Infants enrolled in the Trial of Corticosteroid Therapy in Infants with Biliary Atresia after hepatoportoenterostomy were the subjects of this investigation. Infants received standardized FSV supplementation and monitoring of TB, SBA, and vitamin levels at 1, 3, and 6 months. A logistic regression model was used with the binary indicator variable insufficient/sufficient as the outcome variable. Linear and nonparametric correlations were made between specific vitamin measurement levels and either TB or SBA. Results: The degree of correlation for any particular vitamin at a specific time point was higher with TB than with SBA (higher for TB in 31 circumstances vs 3 circumstances for SBA). Receiver operating characteristic curve shows that TB performed better than SBA (area under the curve 0.998 vs 0.821). Including both TB and SBA did not perform better than TB alone (area under the curve 0.998). Conclusions: We found that TB was a better predictor of FSV deficiency than SBA in infants with biliary atresia. The role of SBA as a surrogate marker of FSV deficiency in other cholestatic liver diseases, such as progressive familial intrahepatic cholestasis, alpha-1-antitrypsin deficiency, and Alagille syndrome in which the pathophysiology is dominated by intrahepatic cholestasis, warrants further study. C1 [Venkat, Veena L.; Shneider, Benjamin L.] UPMC, Childrens Hosp Pittsburgh, Dept Pediat, Pittsburgh, PA 15224 USA. [Magee, John C.] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA. [Magee, John C.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Turmelle, Yumirle] Washington Univ, Dept Pediat, St Louis, MO 63130 USA. [Arnon, Ronen] Mt Sinai Med Ctr, Dept Pediat, New York, NY 10029 USA. [Bezerra, Jorge A.; Heubi, James E.] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA. [Hertel, Paula M.] Texas Childrens Hosp, Dept Pediat, Houston, TX 77030 USA. [Karpen, Saul J.] Childrens Hlth Care Atlanta, Dept Pediat, Atlanta, GA USA. [Kerkar, Nanda] Childrens Hosp Los Angeles, Dept Gastroenterol, Los Angeles, CA 90027 USA. [Loomes, Kathleen M.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Molleston, Jean] James Whitcomb Riley Hosp Children, Dept Pediat, Indianapolis, IN 46202 USA. [Murray, Karen F.] Seattle Childrens Hosp, Dept Pediat, Seattle, WA USA. [Ng, Vicky L.] Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada. [Raghunathan, Trivellore] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Rosenthal, Philip] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. [Loomes, Kathleen M.] Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21218 USA. [Sherker, Averell H.] NIDDK, NIH, Bethesda, MD USA. [Sokol, Ronald J.] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO USA. [Sokol, Ronald J.] Childrens Hosp Colorado, Aurora, CO USA. [Teckman, Jeffrey] St Louis Univ, Sch Med, Dept Pediat, St Louis, MO 63104 USA. [Wang, Kasper] Childrens Hosp Los Angeles, Dept Pediat Surg, Los Angeles, CA 90027 USA. [Whitington, Peter F.] Childrens Mem Hosp, Dept Pediat, Chicago, IL 60614 USA. RP Venkat, VL (reprint author), UPMC, Childrens Hosp Pittsburgh, Div Gastroenterol Hepatol & Nutr, 4401 Penn Ave, Pittsburgh, PA 15224 USA. EM veena.venkat@chp.edu FU National Institute of Diabetes, Digestive and Kidney Disease [DK62453, DK84538, DK62500, DK62470, DK62436, DK84536, DK62503, DK62452, DK62445, DK62497, DK62481, DK62466, DK84575]; CTSA from the National Center for Advancing Translational Sciences [Colorado] [UL1TR000154]; CTSA from the National Center for Advancing Translational Sciences [Los Angeles] [UL1TR000130]; CTSA from the National Center for Advancing Translational Sciences [San Francisco] [UL1TR000004]; CTSA from the National Center for Advancing Translational Sciences [Atlanta] [UL1TR000454]; CTSA from the National Center for Advancing Translational Sciences [Chicago] [UL1TR000150]; CTSA from the National Center for Advancing Translational Sciences [Indianapolis] [UL1TR000006]; CTSA from the National Center for Advancing Translational Sciences [Baltimore] [Ul1TR000424]; CTSA from the National Center for Advancing Translational Sciences [St Louis] [UL1TR000448]; CTSA from the National Center for Advancing Translational Sciences [Cincinnati] [UL1TR000077]; CTSA from the National Center for Advancing Translational Sciences [Philadelphia] [UL1TR000003]; CTSA from the National Center for Advancing Translational Sciences [Pittsburgh] [UL1TR000005]; CTSA from the National Center for Advancing Translational Sciences [Seattle] [UL1TR000423]; National Institutes of Health FX This work was supported by U01 grants from the National Institute of Diabetes, Digestive and Kidney Disease (DK62453 [R.J.S.], DK84538 [K.W.], DK62500 [P.R.], DK62470 [S.J.K.], DK62436 [P.F.W.], DK84536 [J.M.], DK62503 [K.S.], DK62452 [Y.M.], DK62445 [R.A.], DK62497 [J.A.B.], DK62481 [K.M.L.], DK62466 [B.L.S.], DK84575 [K.F.M.], DK62470 [P.M.H.]) and CTSA grants from the National Center for Advancing Translational Sciences (UL1TR000154 [Colorado], UL1TR000130 [Los Angeles], UL1TR000004 [San Francisco], UL1TR000454 [Atlanta], UL1TR000150 [Chicago], UL1TR000006 [Indianapolis], Ul1TR000424 [Baltimore], UL1TR000448 [St Louis], UL1TR000077 [Cincinnati], UL1TR000003 [Philadelphia], UL1TR000005 [Pittsburgh], UL1TR000423 [Seattle]. This study was also funded by the National Institutes of Health. NR 19 TC 4 Z9 4 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-2116 EI 1536-4801 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD DEC PY 2014 VL 59 IS 6 BP 702 EP 707 DI 10.1097/MPG.0000000000000547 PG 6 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA AU8NS UT WOS:000345853800010 PM 25419594 ER PT J AU Ford, DW Hartman, TJ Still, C Wood, C Mitchell, DC Bailey, R Smiciklas-Wright, H Coffman, DL Jensen, GL AF Ford, Dara W. Hartman, Terryl J. Still, Christopher Wood, Craig Mitchell, Diane C. Bailey, Regan Smiciklas-Wright, Helen Coffman, Donna L. Jensen, Gordon L. TI Diet Quality and Body Mass Index Are Associated with Health Care Resource Use in Rural Older Adults SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE Diet quality; Body mass index; Health care resource use; Aging ID ALL-CAUSE MORTALITY; VEGETABLE CONSUMPTION; CHRONIC DISEASE; MEDICARE COSTS; SERVICES USE; FRUIT; COHORT; OVERWEIGHT; OBESITY; RISK AB Health care resource consumption is a growing concern. The aim of this study was to examine the associations between diet quality and body mass index with health care resource use (HRU) in a cohort of advanced age. Participants in the Geisinger Rural Aging Study (n=5,993) were mailed demographic and dietary questionnaires in 2009. Of those eligible, 2,995 (50%; 1,267 male, 1,728 female; mean age 81.4 +/- 4.4 years) provided completed surveys. Multivariate negative binomial models were used to estimate relative risk and 95% CI of HRU outcomes with diet quality as assessed by the Dietary Screening Tool score and body mass index determined from self-reported height and weight. Poor diet quality was associated with a 20% increased risk for emergency room (ER) visits. Fruit and vegetable consumption was grouped into quintiles of intake, with the highest quintile serving as the reference group in analyses. The three lowest fruit and vegetable quintiles were associated with increased risk for ER visits (23% to 31%); the lowest quintile increased risk for inpatient visits (27%). Obesity increased risk of outpatient visits; however, individuals with class I obesity were less likely than normal-weight individuals to have ER visits (relative risk=0.84; 95% CI 0.70 to 0.99). Diets of greater quality, particularly with greater fruit and vegetable intake, are associated with favorable effects on HRU outcomes among older adults. Overweight and obesity are associated with increased outpatient HRU and, among obese individuals, with decreased ER visits. These findings suggest that BMI and diet quality beyond age 74 years continue to affect HRU measures. C1 [Ford, Dara W.; Hartman, Terryl J.] Emory Univ, Sch Publ Hlth, Atlanta, GA 30322 USA. [Still, Christopher; Wood, Craig] Geisingers Obes Inst, Danville, PA USA. [Still, Christopher; Smiciklas-Wright, Helen] Penn State Univ, University Pk, PA 16802 USA. [Still, Christopher] Ctr Nutr & Weight Management, Danville, PA USA. [Mitchell, Diane C.] Penn State Diet Assessment Ctr, University Pk, PA USA. [Bailey, Regan] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Coffman, Donna L.] Penn State Univ, Coll Hlth & Human Dev, University Pk, PA 16802 USA. [Jensen, Gordon L.] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. RP Jensen, GL (reprint author), Penn State Univ, Dept Nutr Sci, 110 Chandlee Lab, University Pk, PA 16802 USA. EM glj1@psu.edu FU US Department of Agriculture (USDA) grant (USDA) [1950-51530-010-00] FX D. W. Ford, G. L. Jensen, D. C. Mitchell, and H. Smiciklas-Wright were supported by a US Department of Agriculture (USDA) grant (USDA no. 1950-51530-010-00) to The Pennsylvania State University. D. L. Coffman was supported in this research with money paid to her and to The Pennsylvania State University through a USDA grant. T. J. Hartman was supported in this research by money paid to Emory University through a USDA grant. NR 43 TC 0 Z9 0 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 EI 2212-2680 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD DEC PY 2014 VL 114 IS 12 BP 1932 EP 1938 DI 10.1016/j.jand.2014.02.016 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AU4FK UT WOS:000345565100008 PM 24746773 ER PT J AU Pihlstrom, BL Buse, JB AF Pihlstrom, Bruce L. Buse, John B. TI Diabetes and periodontal therapy SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Editorial Material ID HEMOGLOBIN A(1C) LEVELS; RISK C1 [Pihlstrom, Bruce L.] Univ Minnesota, Sch Dent, Dept Surg & Dev Sci, Minneapolis, MN 55455 USA. [Pihlstrom, Bruce L.] Natl Inst Dent & Craniofacial Res, Extramural Div Clin Res, Bethesda, MD USA. [Buse, John B.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Buse, John B.] Univ N Carolina, Sch Med, Div Endocrinol, Chapel Hill, NC USA. [Buse, John B.] Univ N Carolina, Sch Med, Diabet Care Ctr, Chapel Hill, NC USA. [Buse, John B.] Amer Diabet Assoc, Alexandria, VA USA. RP Pihlstrom, BL (reprint author), Univ Minnesota, Sch Dent, Dept Surg & Dev Sci, Minneapolis, MN 55455 USA. NR 14 TC 4 Z9 4 U1 0 U2 0 PU AMER DENTAL ASSOC PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 EI 1943-4723 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD DEC PY 2014 VL 145 IS 12 BP 1208 EP 1210 PG 3 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AU5GF UT WOS:000345634400001 PM 25429029 ER PT J AU McMahon, GM Olden, M Garnaas, M Yang, Q Liu, X Hwang, SJ Larson, MG Goessling, W Fox, CS AF McMahon, Gearoid M. Olden, Matthias Garnaas, Maija Yang, Qiong Liu, Xuan Hwang, Shih-Jen Larson, Martin G. Goessling, Wolfram Fox, Caroline S. CA CKDGen Consortium TI Sequencing of LRP2 Reveals Multiple Rare Variants Associated with Urinary Trefoil Factor-3 SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GLOMERULAR-FILTRATION-RATE; CHRONIC KIDNEY-DISEASE; CYSTATIN-C LEVELS; SERUM CREATININE; PROXIMAL TUBULE; MEGALIN; INJURY; BIOMARKERS; CUBILIN; PANEL AB Novel biomarkers are being investigated to identify patients with kidney disease. We measured a panel of 13 urinary biomarkers in participants from the Offspring Cohort of the Framingham Heart Study. Using an Affymetrix chip with imputation to 2.5 M single-nucleotide polymorphisnns (SNPs), we conducted a GWAS of these biomarkers (n=2640) followed by exonic sequencing and genotyping. Functional studies in zebrafish were used to investigate histologic correlation with renal function. Across all 13 biomarkers, there were 97 significant SNPs at three loci. Lead SNPs at each locus were rs6555820 (P=6.7 x 10(-49); minor allele frequency [MAF]=0.49) in HAVCR1 (associated with kidney injury molecule-1), rs7565788 (P=2.15 x10(-16); MAF=0.22) in LRP2 (associated with trefoil factor 3 [TFF3]), and rs11048230 (P=4.77 x 10(-8); MAF=0.10) in an intergenic region near RASSF8 (associated with vascular endothelial growth factor). Validation in the CKDGen Consortium (n=67,093) showed that only rs7565788 at LRP2, which encodes megalin, was associated with eGFR (P=0.003). Sequencing of exons 16-72 of LRP2 in 200 unrelated individuals at extremes of urinary TFF3 levels identified 197 variants (152 rare; MAF<0.05), 31 of which (27 rare) were nonsynonymous. In aggregate testing, rare variants were associated with urinary TFF3 levels (P=0.003), and the lead GWAS signal was not explained by these variants. Knockdown of LRP2 in zebrafish did not alter the renal phenotype in static or kidney injury models. In conclusion, this study revealed common variants associated with urinary levels of TFF3, kidney injury molecule-1, and vascular endothelial growth factor and identified a cluster of rare variants independently associated with TFF3. C1 [McMahon, Gearoid M.; Olden, Matthias; Hwang, Shih-Jen; Larson, Martin G.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [McMahon, Gearoid M.] Brigham & Womens Hosp, Div Nephrol, Boston, MA 02115 USA. [Garnaas, Maija; Goessling, Wolfram] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Garnaas, Maija; Goessling, Wolfram] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Endocrinol & Metab, Boston, MA 02115 USA. [Yang, Qiong; Liu, Xuan; Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Fox, CS (reprint author), 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI McMahon, Gearoid/0000-0002-7723-2198; Goessling, Wolfram/0000-0001-9972-1569 FU [N01-HC-25195] FX The Framingham Heart Study of the National Heart, Lung, and Blood Institute is supported by Contract N01-HC-25195. NR 29 TC 2 Z9 2 U1 0 U2 8 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 DEC PY 2014 VL 25 IS 12 BP 2896 EP 2905 DI 10.1681/ASN.2013111240 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA AU4UT UT WOS:000345607500024 PM 24876117 ER PT J AU Clayton, JA Brooks, CE Kornstein, SG AF Clayton, Janine A. Brooks, Claudette E. Kornstein, Susan G. TI Toward More Individualized Medicine: Introducing the Women of Color Health Data Book, Fourth Edition (vol 23, pg 781, 2014 SO JOURNAL OF WOMENS HEALTH LA English DT Correction C1 [Brooks, Claudette E.] NIH, Off Res Womens Hlth, Bethesda, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD DEC 1 PY 2014 VL 23 IS 12 BP 1054 EP 1054 DI 10.1089/jwh.2014.1508.crx PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA AW1SM UT WOS:000346070200011 ER PT J AU Garcia, HH Nash, TE Del Brutto, OH AF Garcia, Hector H. Nash, Theodore E. Del Brutto, Oscar H. TI Clinical symptoms, diagnosis, and treatment of neurocysticercosis SO LANCET NEUROLOGY LA English DT Review ID SOLITARY CYSTICERCUS GRANULOMA; TAENIA-SOLIUM TAENIASIS; RANDOMIZED CONTROLLED-TRIAL; CENTRAL-NERVOUS-SYSTEM; CALCIFIED NEUROCYSTICERCOSIS; CEREBRAL CYSTICERCOSIS; FOLLOW-UP; CEREBROSPINAL-FLUID; SEIZURE RECURRENCE; TAPEWORM CARRIERS AB The infection of the nervous system by the cystic larvae of Taenia solium (neurocysticercosis) is a frequent cause of seizure disorders. Neurocysticercosis is endemic or presumed to be endemic in many low-income countries. The lifecycle of the worm and the clinical manifestations of neurocysticercosis are well established, and CT and MRI have substantially improved knowledge of the disease course. Improvements in immunodiagnosis have further advanced comprehension of the pathophysiology of this disease. This knowledge has led to individualised treatment approaches that account for the involvement of parenchymal or extraparenchymal spaces, the number and form of parasites, and the extent of degeneration and associated inflammation. Clinical investigations are focused on development of effective treatments and reduction of side-effects induced by treatment, such as seizures, hydrocephalus, infarcts, and neuroinjury. C1 [Garcia, Hector H.] Inst Ciencias Neurol, Cysticercosis Unit, Lima 1, Peru. [Garcia, Hector H.] Univ Peruana Cayetano Heredia, Ctr Global Hlth Tumbes, Lima, Peru. [Garcia, Hector H.] Univ Peruana Cayetano Heredia, Sch Sci, Dept Microbiol, Lima, Peru. [Nash, Theodore E.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Del Brutto, Oscar H.] Univ Espiritu Santo Ecuador, Sch Med, Guayaquil, Ecuador. [Del Brutto, Oscar H.] Hosp Clin Kennedy, Dept Neurol Sci, Guayaquil, Ecuador. RP Garcia, HH (reprint author), Inst Ciencias Neurol, Cysticercosis Unit, Lima 1, Peru. EM hgarcia@jhsph.edu FU Wellcome Trust through an International Senior Research Fellowship; National Institutes for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA FX Our work is supported by the Wellcome Trust through an International Senior Research Fellowship to HHG, and the National Institutes for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA through intramural research resources. NR 141 TC 42 Z9 44 U1 2 U2 30 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 DEC PY 2014 VL 13 IS 12 BP 1202 EP 1215 PG 14 WC Clinical Neurology SC Neurosciences & Neurology GA AU5XG UT WOS:000345676300010 PM 25453460 ER PT J AU Keshavan, MS Giedd, J Lau, JYF Lewis, DA Paus, T AF Keshavan, Matcheri S. Giedd, Jay Lau, Jennifer Y. F. Lewis, David A. Paus, Tomas TI Changes in the adolescent brain and the pathophysiology of psychotic disorders SO LANCET PSYCHIATRY LA English DT Article ID MONKEY PREFRONTAL CORTEX; HUMAN CORTICAL DEVELOPMENT; CANNABINOID CB1 RECEPTOR; SPATIAL WORKING-MEMORY; NEURON AXON TERMINALS; HUMAN CEREBRAL-CORTEX; FUNCTIONAL CONNECTIVITY; POSTNATAL-DEVELOPMENT; MENTAL-HEALTH; WHITE-MATTER AB Adolescence is a time of extensive neuroanatomical, functional, and chemical reorganisation of the brain which parallels substantial maturational changes in cognition and affect regulation. This period is characterised by stabilisation of synapses to diminish redundancy and increase efficiency of neural function, fine-tuning of excitatory and inhibitory neurotransmitter systems, beginning of integration between late maturing and early maturing brain structures, and development of effective connections. In effect, these so-called moving parts create a state of dynamic change that might underlie adolescent behaviours. Imbalances or changes in timing of these developmental processes clearly increase the risk for psychiatric disorders. Genetic, environmental, and epigenetic factors that shape brain development and hormonal changes that affect stress reactivity could be reasons why some, but not all, adolescents are at a heightened risk of developing a psychopathological disorder. In this Series paper, we assess the neurobiology of the changing adolescent brain, implications of this knowledge, and future research in major psychiatric disorders, particularly for psychotic disorders. C1 [Keshavan, Matcheri S.] Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Keshavan, Matcheri S.] Harvard Univ, Sch Med, Boston, MA USA. [Giedd, Jay] NIMH, Brain Imaging Sect, Child Psychiat Branch, Bethesda, MD 20892 USA. [Lau, Jennifer Y. F.] Inst Psychiat, Dept Psychol, London SE5 8AF, England. [Keshavan, Matcheri S.; Lewis, David A.] Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA USA. [Paus, Tomas] Univ Toronto, Rotman Res Inst, Toronto, ON, Canada. [Paus, Tomas] Univ Toronto, Dept Psychol, Toronto, ON M5S 1A1, Canada. [Paus, Tomas] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. RP Keshavan, MS (reprint author), Beth Israel Deaconess Med Ctr, Dept Psychiat, Boston, MA 02115 USA. EM mkeshava@bidmc.harvard.edu RI Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-2002-8978 FU Sunovion; Bristol-Myers Squibb; Pfizer; National Institute of Health (NIH) [MH051234, DA023109]; Canadian Institutes of Health Research; NIH [MH085772]; Economic and Social Research Council [ES/I032959/1]; British Academy [SG102416]; NIMH [MH 64023, 92440, 78113] FX MSK has received grant support from Sunovion between 2012 and 2014. DAL has received investigator-initiated research support from Bristol-Myers Squibb and Pfizer and in 2012-14, served as a consultant in the areas of target identification and validation and new compound development to Autifony, Bristol-Myers Squibb, Concert Pharmaceuticals, and Sunovion. Cited work done by DAL was supported by National Institute of Health (NIH) grants (MH051234 and DA023109), work in TP's laboratory was supported by the Canadian Institutes of Health Research and an NIH grant (MH085772). Cited work by JL was funded by the Economic and Social Research Council (ES/I032959/1) and British Academy (SG102416). Work by MSK was supported by NIMH grants (MH 64023, 92440 and 78113). JG, JYFL, and TP declare no competing interests. NR 120 TC 17 Z9 17 U1 7 U2 33 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2215-0374 J9 LANCET PSYCHIAT JI Lancet Psychiatry PD DEC PY 2014 VL 1 IS 7 BP 549 EP 558 PG 10 WC Psychiatry SC Psychiatry GA AU5GR UT WOS:000345635600025 PM 26361314 ER PT J AU Alekel, DL Genschel, U Koehler, KJ Hofmann, H Van Loan, MD Beer, BS Hanson, LN Peterson, CT Kurzer, MS AF Alekel, D. Lee Genschel, Ulrike Koehler, Kenneth J. Hofmann, Heike Van Loan, Marta D. Beer, Bonnie S. Hanson, Laura N. Peterson, Charles T. Kurzer, Mindy S. TI Soy Isoflavones for Reducing Bone Loss (SIRBL) Study: Effect of a three-year trial on hormones, adverse events, and endometrial thickness in postmenopausal women SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Meeting Abstract CT 25th Annual Meeting of the North-American-Menopause-Society CY OCT 15-18, 2014 CL Washington, DC SP N Amer Menopause Soc C1 [Alekel, D. Lee] NIH, NCCAM, Bethesda, MD 20892 USA. [Genschel, Ulrike; Koehler, Kenneth J.; Hofmann, Heike] Iowa State Univ, Ames, IA USA. [Van Loan, Marta D.] Univ Calif Davis, USDA, ARS, Western Human Nutr Res Ctr, Davis, CA 95616 USA. [Beer, Bonnie S.] McFarland Clin, Ames, IA USA. [Hanson, Laura N.] Mayo Validat Support Serv, Rochester, MN USA. [Peterson, Charles T.] US FDA, Ctr Devices & Radiol Hlth, White Oak, MD USA. [Kurzer, Mindy S.] Univ Minnesota, St Paul, MN 55108 USA. 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 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD DEC PY 2014 VL 21 IS 12 MA S-8 BP 1328 EP 1329 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AU8KY UT WOS:000345846600047 ER PT J AU Harrington, LB Rossouw, JE Cushman, M Blondon, M Kaunitz, A McKnight, B Heckbert, SR Woods, NF LaCroix, A Allison, MA Martin, LW Johnson, KC Smith, NL AF Harrington, Laura B. Rossouw, Jacques E. Cushman, Mary Blondon, Marc Kaunitz, Andrew McKnight, Barbara Heckbert, Susan R. Woods, Nancy F. LaCroix, Andrea Allison, Matthew A. Martin, Lisa W. Johnson, Karen C. Smith, Nicholas L. TI The Association between Vasomotor Symptoms and Hemostatic Factors in Postmenopausal Women SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Meeting Abstract CT 25th Annual Meeting of the North-American-Menopause-Society CY OCT 15-18, 2014 CL Washington, DC SP N Amer Menopause Soc C1 [Harrington, Laura B.; Heckbert, Susan R.; LaCroix, Andrea; Smith, Nicholas L.] Univ Washington, Seattle, WA 98195 USA. [Rossouw, Jacques E.] NHLBI, Bethesda, MD 20892 USA. [Cushman, Mary] Univ Vermont, Burlington, VT USA. [Blondon, Marc] Univ Hosp Geneva, Geneva, Switzerland. [Kaunitz, Andrew] Univ Florida, Coll Med Jacksonville, Jacksonville, FL USA. [McKnight, Barbara] Univ Washington, Seattle, WA 98195 USA. [Woods, Nancy F.] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. [Allison, Matthew A.] Univ Calif San Diego, San Diego, CA 92103 USA. [Martin, Lisa W.] George Washington Univ, Washington, DC USA. [Johnson, Karen C.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 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 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD DEC PY 2014 VL 21 IS 12 MA S-19 BP 1332 EP 1333 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AU8KY UT WOS:000345846600058 ER PT J AU Harrington, LB Rossouw, JE Cushman, M Blondon, M Kaunitz, AM McKnight, B Heckbert, SR Woods, NF LaCroix, AZ Allison, MA Martin, LW Johnson, KC Smith, NL AF Harrington, Laura B. Rossouw, Jacques E. Cushman, Mary Blondon, Marc Kaunitz, Andrew M. McKnight, Barbara Heckbert, Susan R. Woods, Nancy F. LaCroix, Andrea Z. Allison, Matthew A. Martin, Lisa W. Johnson, Karen C. Smith, Nicholas L. TI The Association between Vasomotor Symptoms and Hemostatic Factors in Postmenopausal Women SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Meeting Abstract CT 25th Annual Meeting of the North-American-Menopause-Society CY OCT 15-18, 2014 CL Washington, DC SP N Amer Menopause Soc C1 [Harrington, Laura B.; Heckbert, Susan R.; LaCroix, Andrea Z.; Smith, Nicholas L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Rossouw, Jacques E.] NHLBI, Bethesda, MD 20892 USA. [Cushman, Mary] Univ Vermont, Dept Med, Burlington, VT USA. [Blondon, Marc] Univ Hosp Geneva, Div Angiol & Haemostasis, Geneva, Switzerland. [Kaunitz, Andrew M.] Univ Florida, Dept Obstet & Gynecol, Coll Med Jacksonville, Jacksonville, FL USA. [McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Woods, Nancy F.] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. [Allison, Matthew A.] Univ Calif San Diego, Dept Prevent Med, San Diego, CA 92103 USA. [Martin, Lisa W.] George Washington Univ, Dept Med, Washington, DC USA. [Johnson, Karen C.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 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 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD DEC PY 2014 VL 21 IS 12 BP 1367 EP 1367 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AU8KY UT WOS:000345846600176 ER PT J AU Dave, KA Norris, EL Bukreyev, AA Headlam, MJ Buchholz, UJ Singh, T Collins, PL Gorman, JJ AF Dave, Keyur A. Norris, Emma L. Bukreyev, Alexander A. Headlam, Madeleine J. Buchholz, Ursula J. Singh, Toshna Collins, Peter L. Gorman, Jeffrey J. TI A Comprehensive Proteomic View of Responses of A549 Type II Alveolar Epithelial Cells to Human Respiratory Syncytial Virus Infection SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; DIFFERENTIAL EXPRESSION ANALYSIS; INTERFERON REGULATORY FACTOR-3; NONSTRUCTURAL PROTEINS NS1; GENE ONTOLOGY; QUANTITATIVE PROTEOMICS; SUPEROXIDE-DISMUTASE; REVERSE GENETICS; IFN-GAMMA AB Human respiratory syncytial virus is a major respiratory pathogen for which there are no suitable antivirals or vaccines. A better understanding of the host cell response to this virus may redress this problem. The present report concerns analysis of multiple independent biological replicates of control and 24 h infected lysates of A549 cells by two different proteomic workflows. One workflow involved fractionation of lysates by in-solution protein IEF and individual fractions were digested using trypsin prior to capillary HPLC-LTQ-OrbitrapXL-MS/MS. A second workflow involved digestion of whole cell lysates and analysis by nanoUltraHPLC-LTQ-OrbitrapElite-MS/MS. Both workflows resulted in the quantification of viral proteins exclusively in lysates of infected cells in the relative abundances anticipated from previous studies. Unprecedented numbers (3247 - 5010) of host cell protein groups were also quantified and the infection-specific regulation of a large number (191) of these protein groups was evident based on a stringent false discovery rate cut-off (<1%). Bioinformatic analyses revealed that most of the regulated proteins were potentially regulated by type I, II, and III interferon, TNF-alpha and noncanonical NF-kappa B2 mediated antiviral response pathways. Regulation of specific protein groups by infection was validated by quantitative Western blotting and the cytokine-/key regulator-specific nature of their regulation was confirmed by comparable analyses of cytokine treated A549 cells. Overall, it is evident that the workflows described herein have produced the most comprehensive proteomic characterization of host cell responses to human respiratory syncytial virus published to date. These workflows will form the basis for analysis of the impacts of specific genes of human respiratory syncytial virus responses of A549 and other cell lines using a gene-deleted version of the virus. They should also prove valuable for the analysis of the impact of other infectious agents on host cells. C1 [Dave, Keyur A.; Norris, Emma L.; Headlam, Madeleine J.; Singh, Toshna; Gorman, Jeffrey J.] QIMR Berghofer Med Res Inst, Prot Discovery Ctr, Herston, Qld 4029, Australia. [Bukreyev, Alexander A.; Buchholz, Ursula J.; Collins, Peter L.] NIAID, Resp Virus Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Gorman, JJ (reprint author), Royal Brisbane Hosp, Prot Discovery Ctr, QIMR Berghofer, Locked Bag 2000, Herston, Qld 4029, Australia. EM jeff.gorman@qimr.edu.au RI Dave, Keyur /L-2862-2016; OI Dave, Keyur /0000-0002-6476-8399; Headlam, Madeleine/0000-0001-6812-2459 FU NHMRC Australia; NIAID, NIH, Intramural Program; Bioplatforms Australia; Queensland State Government through the Australian Government National Collaborative Infrastructure Scheme (NCRIS); Queensland State Government through the Education Investment Fund (EIF) FX This work was supported in-part by project grant funding from NHMRC Australia. Preparation of infected cell lysates described in this work was funded by the NIAID, NIH, Intramural Program. Access to proteomic infrastructure in the QIMR Berghofer Protein Discovery Centre was made possible by funding from Bioplatforms Australia and the Queensland State Government provided through the Australian Government National Collaborative Infrastructure Scheme (NCRIS) and Education Investment Fund (EIF). NR 79 TC 7 Z9 7 U1 1 U2 15 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD DEC PY 2014 VL 13 IS 12 BP 3250 EP 3269 DI 10.1074/mcp.M114.041129 PG 20 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AU5DC UT WOS:000345626400003 PM 25106423 ER PT J AU El-Amouri, SS Dai, M Han, JF Brady, RO Pan, D AF El-Amouri, Salim S. Dai, Mei Han, Jing-Fen Brady, Roscoe O. Pan, Dao TI Normalization and Improvement of CNS Deficits in Mice With Hurler Syndrome After Long-term Peripheral Delivery of BBB-targeted Iduronidase SO MOLECULAR THERAPY LA English DT Article ID MUCOPOLYSACCHARIDOSIS TYPE-I; BLOOD-BRAIN-BARRIER; CELL GENE-THERAPY; LYSOSOMAL-ENZYME; NERVOUS-SYSTEM; MOUSE MODELS; AAV VECTORS; STEM-CELLS; RECEPTOR; TISSUES AB Mucopolysaccharidosis type I (MPS I) is a progressive lysosonnal storage disorder with systemic and central nervous system (CNS) involvement due to deficiency of alpha-L-iduronidase (IDUA). We previously identified a receptor-binding peptide from apolipoprotein E (e) that facilitated a widespread delivery of IDUAe fusion protein into CNS. In this study, we evaluated the long-term CNS biodistribution, dose-correlation, and therapeutic benefits of IDUAe after systemic, sustained delivery via hematopoietic stem cell (HSC)-mediated gene therapy with expression restricted to erythroid/megakaryocyte lineages. Compared to the highest dosage group treated by nontargeted control IDUAc (165 U/ml), physiological levels of IDUAe in the circulation (12 U/ml) led to better CNS benefits in MPS I mice as demonstrated in glycosaminoglycan accumulation, histopathology analysis, and neurological behavior. Long-term brain metabolic correction and normalization of exploratory behavior deficits in MPS I mice were observed by peripheral enzyme therapy with physiological levels of IDUAe derived from clinically attainable levels of HSC transduction efficiency (0.1). Importantly, these levels of IDUAe proved to be more beneficial on correction of cerebrum pathology and behavioral deficits in MPS I mice than wild-type HSCs fully engrafted in MPS I chimeras. These results provide compelling evidence for CNS efficacy of IDUAe and its prospective translation to clinical application. C1 [El-Amouri, Salim S.; Dai, Mei; Han, Jing-Fen; Pan, Dao] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Mol & Cell Therapy Program, Cincinnati, OH 45229 USA. [Brady, Roscoe O.] NINDS, NIH, Bethesda, MD 20892 USA. [Pan, Dao] Univ Cincinnati, Sch Med, Dept Pediat, Cincinnati, OH USA. RP Pan, D (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Mol & Cell Therapy Program, 3333 Burnet Ave, Cincinnati, OH 45229 USA. EM dao.pan@cchmc.org FU National Institutes of Health [NS064330, NS086134] FX We are grateful for the technical assistance of Phuong Cao, Meghan Bromwell, John Strickley, and the Comprehensive Mouse Core. This work was supported by grants from the National Institutes of Health (NS064330 and NS086134). NR 47 TC 4 Z9 4 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD DEC PY 2014 VL 22 IS 12 BP 2028 EP 2037 DI 10.1038/mt.2014.152 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA AU8BW UT WOS:000345822600003 PM 25088464 ER PT J AU Hodgson, SH Choudhary, P Elias, SC Milne, KH Rampling, TW Biswas, S Poulton, ID Miura, K Douglas, AD Alanine, DGW Illingworth, JJ de Cassan, SC Zhu, DM Nicosia, A Long, CA Moyle, S Berrie, E Lawrie, AM Wu, YM Ellis, RD Hill, AVS Draper, SJ AF Hodgson, Susanne H. Choudhary, Prateek Elias, Sean C. Milne, Kathryn H. Rampling, Thomas W. Biswas, Sumi Poulton, Ian D. Miura, Kazutoyo Douglas, Alexander D. Alanine, Daniel G. W. Illingworth, Joseph J. de Cassan, Simone C. Zhu, Daming Nicosia, Alfredo Long, Carole A. Moyle, Sarah Berrie, Eleanor Lawrie, Alison M. Wu, Yimin Ellis, Ruth D. Hill, Adrian V. S. Draper, Simon J. TI Combining Viral Vectored and Protein-in-adjuvant Vaccines Against the Blood-stage Malaria Antigen AMA1: Report on a Phase 1a Clinical Trial SO MOLECULAR THERAPY LA English DT Article ID APICAL MEMBRANE ANTIGEN-1; PLASMODIUM-FALCIPARUM MALARIA; IMMUNODEFICIENCY-VIRUS TYPE-1; RECOMBINANT ADENOVIRUS; RHESUS MACAQUES; IMMUNE-RESPONSES; CELL RESPONSES; IMMUNOGENICITY; ANTIBODY; IMMUNIZATION AB The development of effective vaccines against difficult disease targets will require the identification of new subunit vaccination strategies that can induce and maintain effective immune responses in humans. Here we report on a phase la clinical trial using the AMA1 antigen from the blood-stage Plasmodium falciparum malaria parasite delivered either as recombinant protein formulated with Alhydrogel adjuvant with and without CPG 7909, or using recombinant vectored vaccines-chimpanzee adenovirus ChAd63 and the orthopoxvirus MVA. A variety of promising "mixed-modality" regimens were tested. All volunteers were primed with ChAd63, and then subsequently boosted with MVA and/or protein-in-adjuvant using either an 8- or 16-week prime-boost interval. We report on the safety of these regimens, as well as the T cell, B cell, and serum antibody responses. Notably, IgG antibody responses primed by ChAd63 were comparably boosted by AMA1 protein vaccine, irrespective of whether CPG 7909 was included in the Alhydrogel adjuvant. The ability to improve the potency of a relatively weak aluminium-based adjuvant in humans, by previously priming with an adenoviral vaccine vector encoding the same antigen, thus offers a novel vaccination strategy for difficult or neglected disease targets when access to more potent adjuvants is not possible. C1 [Hodgson, Susanne H.; Choudhary, Prateek; Elias, Sean C.; Milne, Kathryn H.; Rampling, Thomas W.; Biswas, Sumi; Douglas, Alexander D.; Alanine, Daniel G. W.; Illingworth, Joseph J.; de Cassan, Simone C.; Hill, Adrian V. S.; Draper, Simon J.] Univ Oxford, Jenner Inst Labs, Oxford OX3 7DQ, England. [Hodgson, Susanne H.; Rampling, Thomas W.; Lawrie, Alison M.] Univ Oxford, Jenner Inst, Ctr Clin Vaccinol & Trop Med, Churchill Hosp, Oxford OX3 7DQ, England. [Miura, Kazutoyo; Zhu, Daming; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Nicosia, Alfredo] Okairos, Rome, Italy. [Nicosia, Alfredo] CEINGE, Naples, Italy. [Nicosia, Alfredo] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, Naples, Italy. [Moyle, Sarah; Berrie, Eleanor] Univ Oxford, Clin Biomfg Facil, Churchill Hosp, Oxford OX3 7DQ, England. [Wu, Yimin; Ellis, Ruth D.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. RP Hodgson, SH (reprint author), Univ Oxford, Jenner Inst Labs, Old Rd Campus Res Bldg, Oxford OX3 7DQ, England. EM susanne.hodgson@ndm.ox.ac.uk RI Douglas, Alexander/E-7040-2012; OI Douglas, Alexander/0000-0002-5410-7562; Rampling, Tommy/0000-0001-9111-2486; Draper, Simon/0000-0002-9415-1357 FU EMVDA (European Malaria Vaccine Development Association); European Commission (EC) FP6-funded consortium [LSHP-CT-2007-037506]; UK National Institute of Health Research through the Oxford Biomedical Research Centre (NIHR-BRC) [A91301]; Wellcome Trust [084113/Z/07/Z]; EC FP7-funded programme [242095]; PATH Malaria Vaccine Initiative; Intramural Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases; Wellcome Trust Research Training Fellowship [097940/Z/11/Z] FX We thank M Smith, R Lopez-Ramon, N Anagnostou, R Antrobus, and J Meyer for clinical assistance; N Lelia and S French for logistical support; J Furze and D Worth for laboratory assistance; the Jenner Institute Flow Cytometry Core Facility for technical assistance; S Moretz, A Diouf, and G Tullo for technical support performing the GIA assays; Yves Durocher (CNRC-NRC, Canada) for provision of HEK293E cells; and all the study volunteers. This work was supported by the EMVDA (European Malaria Vaccine Development Association), a European Commission (EC) FP6-funded consortium (LSHP-CT-2007-037506); the UK National Institute of Health Research through the Oxford Biomedical Research Centre (NIHR-BRC) (A91301 Adult Vaccine); the Wellcome Trust (084113/Z/07/Z); and EVIMalaR, an EC FP7-funded programme (Grant agreement No. 242095). The GIA work was supported by the PATH Malaria Vaccine Initiative and the Intramural Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. AVSH and SJD are Jenner Investigators; SHH holds a Wellcome Trust Research Training Fellowship (097940/Z/11/Z); SB is a NDM Leadership Fellow and junior Research Fellow of St Catherine's College, Oxford University; and SP is a UK MRC Career Development Fellow (G1000527) and Lister Institute Prize Research Fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. A.D.D., J.J.I., S.C.dC., A.V.S.H., and S.J.D. are named inventors on patent applications covering malaria vaccines and immunization regimens. A.N. is an employee of and/or shareholder in Okairos, which is developing vectored vaccines for malaria and other diseases. The manufacture and QC control of AMA1-C1/Alhydrogel vaccine was supported by the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, USA. NR 59 TC 19 Z9 19 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD DEC PY 2014 VL 22 IS 12 BP 2142 EP 2154 DI 10.1038/mt.2014.157 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA AU8BW UT WOS:000345822600013 PM 25156127 ER PT J AU Swerdlow, SJ Schaaper, RM AF Swerdlow, Sarah J. Schaaper, Roel M. TI Mutagenesis in the lacI gene target of E-coli: Improved analysis for lacI(d) and lacO mutants SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE Mutagenesis; lacI spectra; lacO, lacI(d) mutants ID SPONTANEOUS MUTATION; MECHANISMS; SPECTRA; REPAIR; REPRESSOR AB The lad gene of Escherichia coli has been a highly useful target for studies of mutagenesis, particularly for analysis of the specificity (spectrum) of mutations generated under a variety of conditions and in various genetic backgrounds. The gene encodes the repressor of the lac operon, and lad-defective mutants displaying constitutive expression of the operon are readily selected. DNA sequencing of the lad mutants has often been confined to the N-terminal region of the protein, as it presents a conveniently short target with a high density of detectably mutable sites. Mutants in this region are easily selected due to their dominance in a genetic complementation test (lacI(d) mutants). A potential complication in these studies is that constitutive expression of lac may also arise due to mutations in the lac operator (lacO mutants). Under some conditions, for example when analyzing spontaneous mutations, lacO mutants can comprise a very high fraction of the constitutive mutants due to a strong base-substitution hotspot in the lac operator. Such mutational hot spots diminish the return of the sequencing effort and do not yield significant new information. For this reason, a procedure to eliminate the lacO mutants prior to DNA sequencing is desirable. Here, we report a simple method that allows screening out of lacO mutants. This method is based on the lack of resistance of lacO mutants to kanamycin under conditions when the kan gene is expressed from a plasmid under control of the lac promoter-operator (lacPO). We show data validating the new approach with sets of known lacI(d) and lacO mutants, and further apply it to the generation of a new collection of spontaneous mutations, where lacO mutants have historically been a significant contributor. (C) 2014 Published by Elsevier B.V. C1 [Swerdlow, Sarah J.; Schaaper, Roel M.] NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. [Swerdlow, Sarah J.] Thiel Coll, Dept Biol, Greenville, PA 16125 USA. RP Schaaper, RM (reprint author), NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM schaaper@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES065086] FX We thank Drs. Kelly D. Daughtry and Scott A. Lujan of the NIEHS for their careful reading of the manuscript for this paper. We also thank the NIEHS DNA sequencing Core facility for performing the DNA sequence analysis of the lac mutants. This work was supported by project number Z01 ES065086 of the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 16 TC 0 Z9 0 U1 15 U2 42 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 EI 1873-135X J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD DEC PY 2014 VL 770 BP 79 EP 84 DI 10.1016/j.mrfmmm.2014.09.004 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA AU5LC UT WOS:000345647400010 PM 25771873 ER PT J AU Moriyama, B Gordon, LA McCarthy, M Henning, SA Walsh, TJ Penzak, SR AF Moriyama, Brad Gordon, Lori A. McCarthy, Matthew Henning, Stacey A. Walsh, Thomas J. Penzak, Scott R. TI Emerging drugs and vaccines for Candidemia SO MYCOSES LA English DT Review DE Antifungal agents; Candida; Candidemia; investigational; vaccines ID BROAD-SPECTRUM ANTIFUNGAL; INFECTIOUS-DISEASES SOCIETY; HUMAN RECOMBINANT ANTIBODY; IN-VITRO ACTIVITIES; INVASIVE FUNGAL-INFECTIONS; GLUCAN SYNTHASE INHIBITOR; BLOOD-STREAM INFECTIONS; AMPHOTERICIN-B; DISSEMINATED CANDIDIASIS; MONOCLONAL-ANTIBODY AB Candidemia and other forms of invasive candidiasis are important causes of morbidity and mortality. The evolving challenge of antimicrobial resistance among fungal pathogens continues to highlight the need for potent, new antifungal agents. MEDLINE, EMBASE, Scopus and Web of Science searches (up to January 2014) of the English-language literature were performed with the keywords Candida' or Candidemia' or Candidiasis' and terms describing investigational drugs with activity against Candida spp. Conference abstracts and the bibliographies of pertinent articles were also reviewed for relevant reports. ClinicalTrials.gov was searched for relevant clinical trials. Currently available antifungal agents for the treatment of candidemia are summarised. Investigational antifungal agents with potential activity against Candida bloodstream infections and other forms of invasive candidiasis and vaccines for prevention of Candida infections are also reviewed as are selected antifungal agents no longer in development. Antifungal agents currently in clinical trials include isavuconazole, albaconazole, SCY-078, VT-1161 and T-2307. Further data are needed to determine the role of these compounds in the treatment of candidemia and other forms of invasive candidiasis. The progressive reduction in antimicrobial drug development may result in a decline in antifungal drug discovery. Still, there remains a critical need for new antifungal agents to treat and prevent invasive candidiasis and other life-threatening mycoses. C1 [Moriyama, Brad; Henning, Stacey A.] NIH, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. [Gordon, Lori A.] Xavier Univ, Louisiana Coll Pharm, New Orleans, LA 70125 USA. [McCarthy, Matthew; Walsh, Thomas J.] Cornell Univ, Weill Cornell Med Ctr, Transplantat Oncol Infect Dis Program, New York, NY 10021 USA. [Penzak, Scott R.] Univ North Texas Syst, Dept Pharmacotherapy, Coll Pharm, Ft Worth, TX USA. RP Moriyama, B (reprint author), NIH, Dept Pharm, Ctr Clin, 10 Ctr Dr, Bethesda, MD 20892 USA. EM bmoriyama@cc.nih.gov FU Novartis; Astellas; Merck; ContraFect; Pfizer FX Dr. Moriyama: Stock: Merck. Dr. Walsh: Research Grants: Novartis, Astellas, Merck, ContraFect, Pfizer. Consultancies: Vestagen, ICo Therapeutics, Inc, Trius, Sigma Tau, Astellas, and Drais Pharmaceuticals, ContraFect, Novartis, Pfizer, Methylgene. NR 129 TC 6 Z9 6 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0933-7407 EI 1439-0507 J9 MYCOSES JI Mycoses PD DEC PY 2014 VL 57 IS 12 BP 718 EP 733 DI 10.1111/myc.12265 PG 16 WC Dermatology; Mycology SC Dermatology; Mycology GA AU6ED UT WOS:000345694900002 PM 25294098 ER PT J AU Roberts, SA Gordenin, DA AF Roberts, Steven A. Gordenin, Dmitry A. TI Hypermutation in human cancer genomes: footprints and mechanisms SO NATURE REVIEWS CANCER LA English DT Review ID BREAK-INDUCED REPLICATION; COMPREHENSIVE MOLECULAR CHARACTERIZATION; CHRONIC LYMPHOCYTIC-LEUKEMIA; FAMILIAL COLORECTAL-CANCER; DNA-DAMAGE RESPONSE; SINGLE-STRANDED-DNA; CELL LUNG-CANCER; MISMATCH REPAIR; SOMATIC HYPERMUTATION; MICROSATELLITE INSTABILITY AB A role for somatic mutations in carcinogenesis is well accepted, but the degree to which mutation rates influence cancer initiation and development is under continuous debate. Recently accumulated genomic data have revealed that thousands of tumour samples are riddled by hypermutation, broadening support for the idea that many cancers acquire a mutator phenotype. This major expansion of cancer mutation data sets has provided unprecedented statistical power for the analysis of mutation spectra, which has confirmed several classical sources of mutation in cancer, highlighted new prominent mutation sources (such as apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) enzymes) and empowered the search for cancer drivers. The confluence of cancer mutation genonnics and mechanistic insight provides great promise for understanding the basic development of cancer through mutations. C1 [Roberts, Steven A.; Gordenin, Dmitry A.] NIEHS, Mol Genet Lab, NIH, DHHS, Durham, NC 27709 USA. [Roberts, Steven A.] Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. RP Gordenin, DA (reprint author), NIEHS, Mol Genet Lab, NIH, DHHS, Durham, NC 27709 USA. EM gordenin@niehs.nih.gov OI Gordenin, Dmitry/0000-0002-8399-1836 FU Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences; NIH Pathway to Independence Award [K99ES022633-01] FX The authors are grateful to D. Kwiatkowski, D. Zaykin and K. Chan for advice on the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (D.A.G. and S.A.R.) and by an NIH Pathway to Independence Award K99ES022633-01 (S.A.R.) NR 171 TC 81 Z9 82 U1 9 U2 50 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD DEC PY 2014 VL 14 IS 12 BP 786 EP 800 DI 10.1038/nrc3816 PG 15 WC Oncology SC Oncology GA AU8AE UT WOS:000345818400008 PM 25568919 ER PT J AU Gill, ML Byrd, RA AF Gill, Michelle L. Byrd, R. Andrew TI Dynamic activation of apoptosis: conformational ensembles of cIAP1 are linked to a spring-loaded mechanism SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Editorial Material ID ALPHA-DEPENDENT APOPTOSIS; INFLUENZA HEMAGGLUTININ; ANTAGONISTS INDUCE; AUTOUBIQUITINATION; TARGETS; CANCER; IAPS C1 [Gill, Michelle L.; Byrd, R. Andrew] NCI, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21701 USA. RP Gill, ML (reprint author), NCI, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21701 USA. EM byrdra@mail.nih.gov RI Byrd, R. Andrew/F-8042-2015; OI Byrd, R. Andrew/0000-0003-3625-4232; Gill, Michelle/0000-0002-2861-355X NR 10 TC 0 Z9 0 U1 2 U2 8 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 DEC PY 2014 VL 21 IS 12 BP 1022 EP 1023 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AU9EC UT WOS:000345893300002 PM 25469840 ER PT J AU Kanno, T Kanno, Y LeRoy, G Campos, E Sun, HW Brooks, SR Vahedi, G Heightman, TD Garcia, BA Reinberg, D Siebenlist, U O'Shea, JJ Ozato, K AF Kanno, Tomohiko Kanno, Yuka LeRoy, Gary Campos, Eric Sun, Hong-Wei Brooks, Stephen R. Vahedi, Golnaz Heightman, Tom D. Garcia, Benjamin A. Reinberg, Danny Siebenlist, Ulrich O'Shea, John J. Ozato, Keiko TI BRD4 assists elongation of both coding and enhancer RNAs by interacting with acetylated histones SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID BROMODOMAIN PROTEIN BRD4; TRANSCRIPTIONAL PAUSE RELEASE; B-CELL LYMPHOMA; P-TEFB; POLYMERASE-II; SELECTIVE-INHIBITION; C-MYC; GENE-TRANSCRIPTION; BET BROMODOMAINS; SUPER-ENHANCERS AB Small-molecule BET inhibitors interfere with the epigenetic interactions between acetylated histones and the bromodomains of the BET family proteins, including BRD4, and they potently inhibit growth of malignant cells by targeting cancer-promoting genes. BRD4 interacts with the pause-release factor P-TEFb and has been proposed to release RNA polymerase II (Pol II) from promoter-proximal pausing. We show that BRD4 occupies widespread genomic regions in mouse cells and directly stimulates elongation of both protein-coding transcripts and noncoding enhancer RNAs (eRNAs), in a manner dependent on bromodomain function. BRD4 interacts with elongating Pol II complexes and assists Pol II in progression through hyperacetylated nucleosomes by interacting with acetylated histones via bromodomains. On active enhancers, the BET inhibitor JQ1 antagonizes BRD4-associated eRNA synthesis. Thus, BRD4 is involved in multiple steps of the transcription hierarchy, primarily by facilitating transcript elongation both at enhancers and on gene bodies independently of P-TEFb. C1 [Kanno, Tomohiko; Siebenlist, Ulrich] NIAID, Lab Mol Immunol, Bethesda, MD 20892 USA. [Kanno, Tomohiko; Ozato, Keiko] NICHHD, Program Genom Differentiat, Bethesda, MD USA. [Kanno, Yuka; Vahedi, Golnaz; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. [LeRoy, Gary; Campos, Eric; Reinberg, Danny] NYU, Dept Mol Pharmacol & Biochem, Sch Med, New York, NY USA. [Sun, Hong-Wei; Brooks, Stephen R.] NIAMSD, Biodata Min & Discovery Sect, Bethesda, MD 20892 USA. [Heightman, Tom D.] Univ Oxford, Nuffield Dept Clin Med, Struct Genom Consortium, Oxford, England. [Garcia, Benjamin A.] Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. RP Kanno, T (reprint author), NIAID, Lab Mol Immunol, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kannot@mail.nih.gov; osheaj@arb.niams.nih.gov; ozatok@mail.nih.gov RI Kanno, Yuka/B-5802-2013; OI Campos, Eric I./0000-0001-8152-3994; Kanno, Yuka/0000-0001-5668-9319 FU US National Institutes of Health NICHD; NIAMS; NIAID FX We thank L.J. Core and J.T. Lis (Cornell University) for the global run-on sequencing (GRO-seq) protocol, V. Sartorelli and D. Clark for critical discussion and reading of the manuscript and J. Kadonaga (University of California, San Diego) for ND423. This work was supported by the Intramural Research Programs of the US National Institutes of Health NICHD, NIAMS and NIAID. NR 60 TC 43 Z9 43 U1 3 U2 19 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 DEC PY 2014 VL 21 IS 12 BP 1047 EP 1057 DI 10.1038/nsmb.2912 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AU9EC UT WOS:000345893300008 PM 25383670 ER PT J AU Bird, GH Irimia, A Ofek, G Kwong, PD Wilson, IA Walensky, LD AF Bird, Gregory H. Irimia, Adriana Ofek, Gilad Kwong, Peter D. Wilson, Ian A. Walensky, Loren D. TI Stapled HIV-1 peptides recapitulate antigenic structures and engage broadly neutralizing antibodies SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PROXIMAL EXTERNAL REGION; ENVELOPE GLYCOPROTEIN; MONOCLONAL-ANTIBODY; EPITOPE-SCAFFOLDS; VACCINE DESIGN; GP41; MEMBRANE; 4E10; 2F5 AB Hydrocarbon stapling can restore bioactive a-helical structure to natural peptides, yielding research tools and prototype therapeutics to dissect and target protein interactions. Here we explore the capacity of peptide stapling to generate high-fidelity, protease-resistant mimics of antigenic structures for vaccine development. HIV-1 has been refractory to vaccine technologies thus far, although select human antibodies can broadly neutralize HIV-1 by targeting sequences of the gp41 juxtamembrane fusion apparatus. To develop candidate HIV-1 immunogens, we generated and characterized stabilized alpha-helices of the membrane-proximal external region (SAH-MPER) of gp41. SAH-MPER peptides were remarkably protease resistant and bound to the broadly neutralizing 4E10 and 10E8 antibodies with high affinity, recapitulating the structure of the MPER epitope when differentially engaged by the two anti-HIV Fabs. Thus, stapled peptides may provide a new opportunity to develop chemically stabilized antigens for vaccination. C1 [Bird, Gregory H.; Walensky, Loren D.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Bird, Gregory H.; Walensky, Loren D.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Bird, Gregory H.; Walensky, Loren D.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Irimia, Adriana; Wilson, Ian A.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Irimia, Adriana; Wilson, Ian A.] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. [Irimia, Adriana; Wilson, Ian A.] Scripps Res Inst, Scripps Ctr HIV AIDS Vaccine Immunol & Immunogen, La Jolla, CA 92037 USA. [Ofek, Gilad; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Walensky, LD (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM loren_walensky@dfci.harvard.edu FU NIH [1R01 AI084102, R01 AI084817]; Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) [UM1 AI100663]; International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, IAVI Collaboration for AIDS Vaccine Discovery; Bill and Melinda Gates Foundation; Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-39, DE-AC02-06CH11357] FX We thank E. Smith for graphics assistance, D. Ekiert and E. Reinherz for insightful discussions, M. Connors (National Institute of Allergy and Infectious Diseases) for his generosity in providing us with a sample of 10E8 antibody and Y. Yang and P. Acharya for technical support. We are grateful to the US National Institutes of Health (NIH) AIDS Reagent Program for providing us with 4E10 and 10E8 antibodies. This work was supported by NIH grants 1R01 AI084102 (L.D.W.) and R01 AI084817 (I.A.W.); Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) grant UM1 AI100663 (I.A.W.); the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, IAVI Collaboration for AIDS Vaccine Discovery; the Bill and Melinda Gates Foundation; and the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH. Use of the 22-ID and 23-ID sectors at Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract nos. W-31-109-Eng-39 and DE-AC02-06CH11357. NR 57 TC 18 Z9 18 U1 4 U2 35 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 DEC PY 2014 VL 21 IS 12 BP 1058 EP 1067 DI 10.1038/nsmb.2922 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AU9EC UT WOS:000345893300009 PM 25420104 ER PT J AU Goldstein, DS Kopin, IJ Sharabi, Y AF Goldstein, David S. Kopin, Irwin J. Sharabi, Yehonatan TI Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Alpha-synuclein; Autotoxicity; Catecholamine; DOPAL; Parkinson disease ID VESICULAR MONOAMINE TRANSPORTER-2; TOXIC DOPAMINE METABOLITE; PLURIPOTENT STEM-CELLS; PERFORMANCE LIQUID-CHROMATOGRAPHY; NEUROBLASTOMA SH-SY5Y CELLS; HYDROGEN-PEROXIDE TOXICITY; OXIDASE-B INHIBITOR; ALPHA-SYNUCLEIN; ALDEHYDE DEHYDROGENASE; IN-VIVO AB Several neurodegenerative diseases involve loss of catecholamine neurons Parkinson disease is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are vulnerable in PD and related disorders has been mysterious. Accumulating evidence supports the concept of "autotoxicity" inherent cytotoxicity of catecholamines and their metabolites in the cells in which they are produced. According to the "catecholaldehyde hypothesis" for the pathogenesis of Parkinson disease, long-term increased build-up of 3,4-dihydroxyphenylacetaldehyde (DOPAL), the catecholaldehyde metabolite of dopamine, causes or contributes to the eventual death of dopaminergic neurons. Lewy bodies, a neuropathologic hallmark of PD, contain precipitated alpha-synuclein. Bases for the tendency of alpha-synuclein to precipitate in the cytoplasm of catecholaminergic neurons have also been mysterious. Since DOPAL potently oligomerizes and aggregates alpha-synuclein, the catecholaldehyde hypothesis provides a link between alpha-synucleinopathy and catecholamine neuron loss in Lewy body diseases. The concept developed here is that DOPAL and alpha-synuclein are nodes in a complex nexus of interacting homeostatic systems. Dysfunctions of several processes, including decreased vesicular sequestration of cytoplasmic catecholamines, decreased aldehyde dehydrogenase activity, and oligomerization of alpha-synuclein, lead to conversion from the stability afforded by negative feedback regulation to the instability, degeneration, and system failure caused by induction of positive feedback loops. These dysfunctions result from diverse combinations of genetic predispositions, environmental exposures, stress, and time. The notion of catecholamine autotoxicity has several implications for treatment, disease modification, and prevention. Conversely, disease modification clinical trials would provide key tests of the catecholaldehyde hypothesis. Published by Elsevier Inc. C1 [Goldstein, David S.; Kopin, Irwin J.] NINDS, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, Bethesda, MD 20892 USA. [Sharabi, Yehonatan] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. RP Goldstein, DS (reprint author), CNP DIR NINDS NIH, Clin Neurocardiol Sect, 9000 Rockville Pike,Bldg 10 Room 5N220, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU Division of Intramural Research, NINDS FX Writing this review was supported by the Division of Intramural Research, NINDS. NR 229 TC 7 Z9 7 U1 1 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD DEC PY 2014 VL 144 IS 3 BP 268 EP 282 DI 10.1016/j.pharmthera.2014.06.006 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AU6PL UT WOS:000345724500003 PM 24945828 ER PT J AU Rivers, RC Kinsinger, C Boja, ES Hiltke, T Mesri, M Rodriguez, H AF Rivers, Robert C. Kinsinger, Christopher Boja, Emily S. Hiltke, Tara Mesri, Mehdi Rodriguez, Henry TI Linking cancer genome to proteome: NCI's investment into proteogenomics SO PROTEOMICS LA English DT Editorial Material DE Bioinformatics; Cancer; Proteogenomics ID TANDEM MASS-SPECTROMETRY; REPRODUCIBILITY; PERFORMANCE AB Advances in both targeted and unbiased MS-based proteomics are now at a mature stage for comprehensively and reproducibly characterizing a large part of the cancer proteome. These developments combined with the extensive genomic characterization of several cancer types by large-scale initiatives such as the International Cancer Genome Consortium and Cancer Genome Atlas Project have paved the way for proteogenomic analysis of omics datasets and integration methods. The advances serve as the basis for the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium and this article highlights its current work and future steps in the area of proteogenomics. C1 [Rivers, Robert C.; Kinsinger, Christopher; Boja, Emily S.; Hiltke, Tara; Mesri, Mehdi; Rodriguez, Henry] NCI, Off Canc Clin Prote Res, Bethesda, MD 20892 USA. RP Rivers, RC (reprint author), NCI, Off Canc Clin Prote Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM robert.rivers@nih.gov NR 11 TC 4 Z9 4 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1615-9853 EI 1615-9861 J9 PROTEOMICS JI Proteomics PD DEC PY 2014 VL 14 IS 23-24 SI SI BP 2633 EP 2636 DI 10.1002/pmic.201400193 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU9LU UT WOS:000345915200002 PM 25187343 ER PT J AU Nguyen, AB Moser, R Chou, WY AF Nguyen, A. B. Moser, R. Chou, W. -Y. TI Race and health profiles in the United States: an examination of the social gradient through the 2009 CHIS adult survey SO PUBLIC HEALTH LA English DT Article DE Health disparities; SES; Race; Ethnicity; Social gradient ID CORONARY-HEART-DISEASE; SOCIOECONOMIC-STATUS; PHYSICAL-ACTIVITY; ASIAN-AMERICANS; MENTAL-HEALTH; DISPARITIES; WOMEN; CARE; ACCESS; US AB Objective: To examine the role of the social gradient on multiple health outcomes and behaviors. It was predicted that higher levels of SES, measured by educational attainment and family income, would be associated with positive health behaviors (i.e., smoking, drinking, physical activity, and diet) and health status (i.e., limited physical activity due to chronic condition, blood pressure, obesity, diabetes, BMI, and perceived health condition). The study also examined the differential effects of the social gradient in health among different racial/ethnic groups (i.e., non-Hispanic Whites, Blacks, Asian, Hispanics, and American Indians). Study design: Cross-sectional study. Methods: The data were from the adult 2009 California Health Interview Survey (CHIS). Weighted multivariable linear and logistic regression models were conducted to examine trends found between SES and health conditions and health behaviors. Polynomial trends were examined for all linear and logistic models to test for the possible effects (linear, quadratic, and cubic) of the social gradient on health behaviors and outcomes stratified by race/ethnicity. Results: Findings indicated that, in general, Whites had more favorable health profiles in comparison to other racial/ethnic groups with the exception of Asians who were likely to be as healthy as or healthier than Whites. Predicted marginals indicated that Asians in the upper two strata of social class display the healthiest outcomes of health status among all other racial/ethnic groups. Also, the social gradient was differentially associated with health outcomes across race/ethnicity groups. While the social gradient was most consistently observed for Whites, education did not have the same protective effect on health among Blacks and American Indians. Also, compared to other minority groups, Hispanics and Asians were more likely to display curvilinear trends of the social gradient: an initial increase from low SES to mid-level SES was associated with worse health outcomes and behaviors; however, continued increase from mid-SES to high SES saw returns to healthy outcomes and behaviors. Conclusion: The study contributes to the literature by illustrating unique patterns and trends of the social gradient across various racial/ethnic populations in a nationally representative sample. Future studies should further explore temporal trends to track the impact of the social gradient for different racial and ethnic populations in tandem with indices of national income inequalities. Published by Elsevier Ltd on behalf of The Royal Society for Public Health. C1 [Nguyen, A. B.; Moser, R.; Chou, W. -Y.] NCI, DCCPS, Rockville, MD 20850 USA. RP Nguyen, AB (reprint author), NCI, DCCPS, 9609 Med Ctr Dr,Rm 3E638, Rockville, MD 20850 USA. EM Anh.Nguyen3@nih.gov; moserr@mail.nih.gov; chouws@mail.nih.gov NR 63 TC 4 Z9 5 U1 2 U2 20 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0033-3506 EI 1476-5616 J9 PUBLIC HEALTH JI Public Health PD DEC PY 2014 VL 128 IS 12 BP 1076 EP 1086 DI 10.1016/j.puhe.2014.10.003 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AU8PC UT WOS:000345857600005 PM 25457801 ER PT J AU Van Itallie, CM Anderson, JM AF Van Itallie, Christina M. Anderson, James M. TI Architecture of tight junctions and principles of molecular composition SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE Tight junction; Epithelium; ZO-1; Claudin; Occludin; Actin ID EPITHELIAL APICAL JUNCTIONS; TUMOR-SUPPRESSOR PROTEIN; ZONULA OCCLUDENS-1 AND-2; ACTIN-BINDING REGION; ADHESION-MOLECULE; PDZ DOMAIN; CELL-CELL; BARRIER FUNCTION; TRANSMEMBRANE PROTEIN; PERIPHERAL COMPONENT AB The tight junction creates an intercellular barrier limiting paracellular movement of solutes and material across epithelia. Currently many proteins have been identified as components of the tight junction and understanding their architectural organization and interactions is critical to understanding the biology of the barrier. In general the architecture can be conceptualized into compartments with the transmembrane barrier proteins (claudins, occludin, JAM-A, etc.), linked to peripheral scaffolding proteins (such as ZO-1, afadin, MAGI1, etc.) which are in turned linked to actin and microtubules through numerous linkers (cingulin, myosins, protein 4.1, etc.). Within this complex network are associated many signaling proteins that affect the barrier and broader cell functions. The PDZ domain is a commonly used motif to specifically link individual junction protein pairs. Here we review some of the key proteins defining the tight junction and general themes of their organization with the perspective that much will be learned about function by characterizing the detailed architecture and subcompartments within the junction. Published by Elsevier Ltd. C1 [Van Itallie, Christina M.; Anderson, James M.] NHLBI, Lab Tight Junct Struct & Funct, NIH, Bethesda, MD 20892 USA. RP Van Itallie, CM (reprint author), NHLBI, Lab Tight Junct Struct & Funct, NIH, Bldg 50,Room 4525,50 South Dr, Bethesda, MD 20892 USA. EM christina.vanitallie@nih.gov; james.anderson2@nih.gov OI Anderson, James/0000-0003-2765-7996 FU Division of Intramural Research (CMV); Office of the Director (JMA); National Institutes of Health, USA FX The authors are supported by the Division of Intramural Research (CMV) and the Office of the Director (JMA), National Institutes of Health, USA. We apologize to all colleagues whose work could not be cited because of lack of space. We acknowledge the help of Dr. Xufeng Wu in the NHLBI Light Microscopy Core with the SIM images. NR 124 TC 55 Z9 55 U1 8 U2 35 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD DEC PY 2014 VL 36 BP 157 EP 165 DI 10.1016/j.semcdb.2014.08.011 PG 9 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA AU3NC UT WOS:000345519300020 PM 25171873 ER PT J AU Schroder, J Cheng, B Ebinger, M Kohrmann, M Wu, O Kang, DW Liebeskind, DS Tourdias, T Singer, OC Christensen, S Campbell, B Luby, M Warach, S Fiehler, J Fiebach, JB Gerloff, C Thomalla, G AF Schroeder, Julian Cheng, Bastian Ebinger, Martin Koehrmann, Martin Wu, Ona Kang, Dong-Wha Liebeskind, David S. Tourdias, Thomas Singer, Oliver C. Christensen, Soren Campbell, Bruce Luby, Marie Warach, Steven Fiehler, Jens Fiebach, Jochen B. Gerloff, Christian Thomalla, Goetz CA STIR Vista Imaging Investigators TI Validity of Acute Stroke Lesion Volume Estimation by Diffusion-Weighted Imaging-Alberta Stroke Program Early Computed Tomographic Score Depends on Lesion Location in 496 Patients With Middle Cerebral Artery Stroke SO STROKE LA English DT Article DE brain ischemia; diffusion magnetic resonance imaging; magnetic resonance imaging; middle cerebral artery; neuroimaging; severity of illness index; stroke ID ACUTE ISCHEMIC-STROKE; DWI-ASPECTS; PREDICTS; ONSET; CT AB Background and Purpose-Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) has been used to estimate diffusion-weighted imaging (DWI) lesion volume in acute stroke. We aimed to assess correlations of DWI-ASPECTS with lesion volume in different middle cerebral artery (MCA) subregions and reproduce existing ASPECTS thresholds of a malignant profile defined by lesion volume >= 100 mL. Methods-We analyzed data of patients with MCA stroke from a prospective observational study of DWI and fluid-attenuated inversion recovery in acute stroke. DWI-ASPECTS and lesion volume were calculated. The population was divided into subgroups based on lesion localization (superficial MCA territory, deep MCA territory, or both). Correlation of ASPECTS and infarct volume was calculated, and receiver-operating characteristics curve analysis was performed to identify the optimal ASPECTS threshold for >= 100-mL lesion volume. Results-A total of 496 patients were included. There was a significant negative correlation between ASPECTS and DWI lesion volume (r=-0.78; P<0.0001). With regards to lesion localization, correlation was weaker in deep MCA region (r=-0.19; P=0.038) when compared with superficial (r=-0.72; P<0.001) or combined superficial and deep MCA lesions (r=-0.72; P<0.001). Receiver-operating characteristics analysis revealed ASPECTS <= 6 as best cutoff to identify >= 100-mL DWI lesion volume; however, positive predictive value was low (0.35). Conclusions-ASPECTS has limitations when lesion location is not considered. Identification of patients with malignant profile by DWI-ASPECTS may be unreliable. ASPECTS may be a useful tool for the evaluation of noncontrast computed tomography. However, if MRI is used, ASPECTS seems dispensable because lesion volume can easily be quantified on DWI maps. C1 [Schroeder, Julian; Cheng, Bastian; Gerloff, Christian; Thomalla, Goetz] Univ Klinikum Hamburg Eppendorf, Klin & Poliklin Neurol, Kopf & Neurozentrum, Hamburg, Germany. [Ebinger, Martin; Fiebach, Jochen B.] Charite, Ctr Schlaganfallforsch Berlin, D-13353 Berlin, Germany. [Koehrmann, Martin] Univ Erlangen Nurnberg, Neurol Klin, Erlangen, Germany. [Wu, Ona] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp,Athinoula A Martinos Ctr B, Boston, MA 02115 USA. [Kang, Dong-Wha] Univ Ulsan, Coll Med, Dept Neurol, Asan Med Ctr, Seoul, South Korea. [Liebeskind, David S.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Tourdias, Thomas] Univ Bordeaux, CHU Bordeaux, Serv NeuroImagerie Diagnost Therapeut, Bordeaux, France. [Singer, Oliver C.] Univ Frankfurt Klinikum, Neurol Klin, Frankfurt, Germany. [Christensen, Soren; Campbell, Bruce] Univ Melbourne, Royal Melbourne Hosp, Dept Med & Neurol, Melbourne Brain Ctr, Parkville, Vic, Australia. [Luby, Marie] NINDS, Bethesda, MD 20892 USA. [Warach, Steven] UT SW Med Ctr, Dept Neurol & Neurotherapeut, Seton UT SW Clin Res Inst Austin, Austin, TX USA. [Fiehler, Jens] Unv Klinikum Hamburg Eppendorf, Klin & Poliklin Neuroradiol Diagnost & Intervent, Hamburg, Germany. RP Schroder, J (reprint author), Martinistr 52, D-20246 Hamburg, Germany. EM jul.schroeder@uke.de RI Thijs, Vincent/C-3647-2009; OI Thijs, Vincent/0000-0002-6614-8417; Fiebach, Jochen B./0000-0002-7936-6958; Campbell, Bruce/0000-0003-3632-9433; DOUSSET, VINCENT/0000-0003-0427-3236; Donnan, Geoffrey/0000-0001-6324-3403 FU Intramural NIH HHS [Z99 NS999999]; NINDS NIH HHS [P50 NS051343, R01 NS059775, R01 NS063925] NR 14 TC 4 Z9 5 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD DEC PY 2014 VL 45 IS 12 BP 3583 EP 3588 DI 10.1161/STROKEAHA.114.006694 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AU3ME UT WOS:000345516600248 PM 25316278 ER PT J AU Ay, H Arsava, EM Andsberg, G Benner, T Brown, RD Chapman, SN Cole, JW Delavaran, H Dichgans, M Engstrom, G Giralt-Steinhauer, E Grewal, RP Gwinn, K Jern, C Jimenez-Conde, J Jood, K Katsnelson, M Kissela, B Kittner, SJ Kleindorfer, DO Labovitz, DL Lanfranconi, S Lee, JM Lehm, M Lemmens, R Levi, C Li, LX Lindgren, A Markus, HS McArdle, PF Melander, O Norrving, B Peddareddygari, LR Pedersen, A Pera, J Rannikmae, K Rexrode, KM Rhodes, D Rich, SS Roquer, J Rosand, J Rothwell, PM Rundek, T Sacco, RL Schmidt, R Schurks, M Seiler, S Sharma, P Slowik, A Sudlow, C Thijs, V Woodfield, R Worrall, BB Meschia, JF AF Ay, Hakan Arsava, Ethem Murat Andsberg, Gunnar Benner, Thomas Brown, Robert D., Jr. Chapman, Sherita N. Cole, John W. Delavaran, Hossein Dichgans, Martin Engstroem, Gunnar Giralt-Steinhauer, Eva Grewal, Raji P. Gwinn, Katrina Jern, Christina Jimenez-Conde, Jordi Jood, Katarina Katsnelson, Michael Kissela, Brett Kittner, Steven J. Kleindorfer, Dawn O. Labovitz, Daniel L. Lanfranconi, Silvia Lee, Jin-Moo Lehm, Manuel Lemmens, Robin Levi, Chris Li, Linxin Lindgren, Arne Markus, Hugh S. McArdle, Patrick F. Melander, Olle Norrving, Bo Peddareddygari, Leema Reddy Pedersen, Annie Pera, Joanna Rannikmaee, Kristiina Rexrode, Kathryn M. Rhodes, David Rich, Stephen S. Roquer, Jaume Rosand, Jonathan Rothwell, Peter M. Rundek, Tatjana Sacco, Ralph L. Schmidt, Reinhold Schuerks, Markus Seiler, Stephan Sharma, Pankaj Slowik, Agnieszka Sudlow, Cathie Thijs, Vincent Woodfield, Rebecca Worrall, Bradford B. Meschia, James F. TI Pathogenic Ischemic Stroke Phenotypes in the NINDS-Stroke Genetics Network SO STROKE LA English DT Article DE classification; pathogenesis; phenotype ID CAUSATIVE CLASSIFICATION; INTEROBSERVER RELIABILITY; ATHEROSCLEROTIC STROKE; AGREEMENT; VARIANTS; SYSTEM; SUBTYPES; RISK AB Background and Purpose-NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. Methods-Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases. Results-The distribution of pathogenic categories varied by study, age, sex, and race (P<0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (kappa 0.72; 95% confidence interval, 0.69-0.75) and phenotypic classifications (kappa 0.73; 95% confidence interval, 0.70-0.75). Conclusions-This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke. C1 [Ay, Hakan; Arsava, Ethem Murat; Benner, Thomas] Harvard Univ, AA Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Dept Radiol,Med Sch, Charlestown, MA 02129 USA. [Ay, Hakan; Roquer, Jaume] Harvard Univ, Stroke Serv, Massachusetts Gen Hosp, Dept Neurol,Med Sch, Charlestown, MA 02129 USA. [Roquer, Jaume] Harvard Univ, Ctr Human Genet Res, Massachusetts Gen Hosp, Sch Med, Charlestown, MA 02129 USA. [Andsberg, Gunnar; Delavaran, Hossein; Lindgren, Arne; Melander, Olle; Norrving, Bo] Skane Univ Hosp, Dept Neurol & Rehabil Med, Lund, Sweden. [Brown, Robert D., Jr.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Chapman, Sherita N.; Worrall, Bradford B.] Univ Virginia, Dept Neurol, Charlottesville, VA USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Worrall, Bradford B.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Cole, John W.; Kittner, Steven J.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. [McArdle, Patrick F.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Dept Med, Baltimore, MD 21201 USA. [Dichgans, Martin; Lehm, Manuel] Univ Munich, Inst Stroke & Dementia Res, Klinikum Univ Munchen, Munich, Germany. [Engstroem, Gunnar; Norrving, Bo] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Giralt-Steinhauer, Eva; Jimenez-Conde, Jordi; Rosand, Jonathan] Univ Pompeu Fabra, Dept Neurol, Neurovasc Res Grp, IMIM,Hosp del Mar,Univ Autonoma Barcelona,DCEXS, Barcelona, Spain. [Grewal, Raji P.; Peddareddygari, Leema Reddy] St Francis Med Ctr, Neurosci Inst, Trenton, NJ USA. [Gwinn, Katrina] NINDS, NIH, Bethesda, MD 20892 USA. [Jern, Christina; Pedersen, Annie] Univ Gothenburg, Inst Biomed, Sahlgrenska Acad, Gothenburg, Sweden. [Jood, Katarina] Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Gothenburg, Sweden. [Katsnelson, Michael; Rundek, Tatjana; Sacco, Ralph L.] Univ Miami, Dept Neurol, Miller Sch Med, Coral Gables, FL 33124 USA. [Kissela, Brett; Kleindorfer, Dawn O.] Univ Cincinnati, Dept Neurol, Coll Med, Cincinnati, OH 45221 USA. [Labovitz, Daniel L.] Albert Einstein Coll Med, Stern Stroke Ctr, Dept Neurol, Bronx, NY 10467 USA. [Lanfranconi, Silvia] Policlin Hosp Fdn IRCCS Ca Granda, Dept Neurosci & Sensory Organs, Milan, Italy. [Lee, Jin-Moo] Washington Univ, Dept Neurol, St Louis, MO USA. [Lemmens, Robin; Thijs, Vincent] Univ Hosp Leuven, Dept Neurol, Louvain, Belgium. [Levi, Chris] Univ Newcastle, John Hunter Hosp, Dept Neurol, Callaghan, NSW 2308, Australia. [Li, Linxin; Rothwell, Peter M.] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford OX1 2JD, England. [Markus, Hugh S.] Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 1TN, England. [Pera, Joanna; Slowik, Agnieszka] Jagiellonian Univ, Dept Neurol, Coll Med, Krakow, Poland. [Rannikmaee, Kristiina; Sudlow, Cathie; Woodfield, Rebecca] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH8 9YL, Midlothian, Scotland. [Rexrode, Kathryn M.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Rhodes, David] Univ Alabama Birmingham, Sch Publ Hlth, Birmingham, AL USA. [Schmidt, Reinhold; Seiler, Stephan] Med Univ Graz, Dept Neurol, Graz, Austria. [Schuerks, Markus] Univ Hosp Essen, Dept Neurol, Essen, Germany. [Sharma, Pankaj] Imperial Coll London, Dept Med, Cerebrovasc Res Unit, London, England. [Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. RP Ay, H (reprint author), Harvard Univ, AA Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Sch Med, 149 13th St,Room 2301, Charlestown, MA 02129 USA. EM hay@mgh.harvard.edu RI Thijs, Vincent/C-3647-2009; Lee, Jin-Moo/K-2024-2015; JIMENEZ-CONDE, JORDI/C-1941-2012; OI Gwinn, Katrina/0000-0002-8277-651X; Kissela, Brett/0000-0002-9773-4013; Thijs, Vincent/0000-0002-6614-8417; Lee, Jin-Moo/0000-0002-3979-0906; Engstrom, Gunnar/0000-0002-8618-9152; Rexrode, Kathryn/0000-0003-3387-8429 FU Austrian Science Fund FWF [I 904]; NCI NIH HHS [P01 CA087969, R01 CA049449, U01 CA049449]; NCRR NIH HHS [U54 RR020278]; NHGRI NIH HHS [HHSN268200782096C, U01 HG004436, U01 HG004446]; NHLBI NIH HHS [R01 HL034594, R01 HL088521]; NIA NIH HHS [Z01 AG000015, Z01 AG000954]; NIDDK NIH HHS [P30 DK072488]; NINDS NIH HHS [R01 NS059727, K23 NS042695, K23 NS042720, P50 NS055977, R01 NS030678, R01 NS039987, R01 NS042618, R01 NS042733, R01 NS045012, R01 NS073346, R01 NS085419, R37 NS029993, U01 NS038529, U01 NS041588, U01 NS069208]; The Dunhill Medical Trust [OSRP2/1006]; WHI NIH HHS [N01WH22110]; Wellcome Trust [084724, 095626] NR 16 TC 3 Z9 4 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD DEC PY 2014 VL 45 IS 12 BP 3589 EP + DI 10.1161/STROKEAHA.114.007362 PG 14 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AU3ME UT WOS:000345516600249 PM 25378430 ER PT J AU Broderick, JP Palesch, YY Demchuk, AM Yeatts, SD Khatri, P Hill, MD Jauch, EC Jovin, TG Yan, B von Kummer, R Molina, CA Goyal, M Mazighi, M Schonewille, WJ Engelter, ST Anderson, C Spilker, J Carrozzella, J Janis, LS Foster, LD Tomsick, TA AF Broderick, Joseph P. Palesch, Yuko Y. Demchuk, Andrew M. Yeatts, Sharon D. Khatri, Pooja Hill, Michael D. Jauch, Edward C. Jovin, Tudor G. Yan, Bernard von Kummer, Ruediger Molina, Carlos A. Goyal, Mayank Mazighi, Mikael Schonewille, Wouter J. Engelter, Stefan T. Anderson, Craig Spilker, Judith Carrozzella, Janice Janis, L. Scott Foster, Lydia D. Tomsick, Thomas A. CA Interventional Management Stroke I TI Evolution of Practice During the Interventional Management of Stroke III Trial and Implications for Ongoing Trials SO STROKE LA English DT Article DE clinical trial; therapeutic thrombolysis; tissue-type plasminogen activator ID ACUTE ISCHEMIC-STROKE; INTRAARTERIAL; THERAPY; TIME; REVASCULARIZATION; RECANALIZATION; REPERFUSION; RETRIEVER; SCORE AB Background and Purpose-We explored changes in the patient population and practice of endovascular therapy during the course of the Interventional Management of Stroke (IMS) III Trial. Methods-Changes in baseline characteristics, use of baseline CT angiography, treatment times and specifics, and outcomes were compared between the first 4 protocols and the fifth and final protocol. Results-Compared with subjects treated in the first 4 protocol versions (n=610), subjects treated in fifth and final protocol (n=46) were older (75 versus 68 years, P<0.0002) and less likely to have a pretreatment Rankin of 0 (76% versus 89%, P=0.01), were more likely to have a pretreatment CT angiography (65% versus 45%, P=0.009), had quicker median times in the endovascular arm from onset to start of intra-arterial therapy (209 versus 250 minutes, P=0.002) and to reperfusion (269 versus 344 minutes, P<0.0001), had a higher mean dose of total tissue-type plasminogen activator in the endovascular arm (74.0 versus 63.7 mg, P<0.0001), and were less likely to receive intra-arterial tissue-type plasminogen activator as part of the endovascular procedure (16% versus 44%, P=0.015). There were no significant differences in functional and safety outcomes between subjects treated in the 2 treatments arms in either the first 4 protocols or fifth protocol although the small sample size in the fifth protocol provided limited power. Conclusions-Endovascular technology and diagnostic approaches to acute stroke patients changed substantially during the IMS III Trial. Efforts to decrease the time to delivery of endovascular therapy were successful. C1 [Broderick, Joseph P.; Khatri, Pooja; Spilker, Judith; Carrozzella, Janice; Tomsick, Thomas A.] Univ Cincinnati, Acad Hlth Ctr, Neurosci Inst, Dept Neurol & Rehabil Med, Cincinnati, OH 45267 USA. [Broderick, Joseph P.; Khatri, Pooja; Spilker, Judith; Carrozzella, Janice; Tomsick, Thomas A.] Univ Cincinnati, Acad Hlth Ctr, Neurosci Inst, Dept Radiol, Cincinnati, OH 45267 USA. [Palesch, Yuko Y.; Yeatts, Sharon D.; Foster, Lydia D.] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC USA. [Jauch, Edward C.] Med Univ S Carolina, Div Emergency Med, Charleston, SC USA. [Demchuk, Andrew M.; Hill, Michael D.; Goyal, Mayank] Univ Calgary, Seaman Family MR Res Ctr, Calgary Stroke Program, Dept Clin Neurosci,Hotchkiss Brain Inst, Calgary, AB, Canada. [Demchuk, Andrew M.; Hill, Michael D.; Goyal, Mayank] Univ Calgary, Seaman Family MR Res Ctr, Calgary Stroke Program, Dept Radiol,Hotchkiss Brain Inst, Calgary, AB, Canada. [Jovin, Tudor G.] Univ Pittsburgh, Med Ctr, Stroke Inst, Pittsburgh, PA USA. [Yan, Bernard] Univ Melbourne, Royal Melbourne Hosp, Melbourne Brain Ctr, Melbourne, Vic 3050, Australia. [von Kummer, Ruediger] Dresden Univ, Dept Neuroradiol, Stroke Ctr, Univ Hosp, Dresden, Germany. [Molina, Carlos A.] Hosp Univ Vall dHebron, Dept Neurol, Neurovasc Unit, Barcelona, Spain. [Schonewille, Wouter J.] Univ Med Ctr Utrecht, Dept Neurol, Utrecht, Netherlands. [Schonewille, Wouter J.] Univ Med Ctr Utrecht, Rudolph Magnus Inst Neurosci, Utrecht, Netherlands. [Schonewille, Wouter J.] St Antonius Hosp, Nieuwegein, Netherlands. [Mazighi, Mikael] Lariboisiere Hosp, Dept Neurol, Paris, France. [Mazighi, Mikael] Lariboisiere Hosp, Stroke Ctr, Paris, France. [Engelter, Stefan T.] Univ Basel Hosp, Dept Neurol, CH-4031 Basel, Switzerland. [Anderson, Craig] Univ Sydney, Royal Prince Alfred Hosp, George Inst Global Hlth, Sydney, NSW 2006, Australia. [Janis, L. Scott] NINDS, NIH, Bethesda, MD 20892 USA. RP Broderick, JP (reprint author), Univ Cincinnati, Dept Neurol & Rehabil Med, Neurosci Inst, 260 Stetson St,Suite 2300,POB 670525, Cincinnati, OH 45267 USA. EM joseph.broderick@uc.edu OI Yan, Bernard/0000-0001-8802-9606 FU NINDS NIH HHS [U01 NS054630, R01 NS039160, U01 NS052220, U01 NS077304, U01NS052220, U01NS054630, U01NS077304] NR 21 TC 8 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD DEC PY 2014 VL 45 IS 12 BP 3606 EP + DI 10.1161/STROKEAHA.114.005952 PG 10 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AU3ME UT WOS:000345516600251 PM 25325911 ER PT J AU Mott, M Pahigiannis, K Koroshetz, W AF Mott, Meghan Pahigiannis, Katherine Koroshetz, Walter TI Small Blood Vessels: Big Health Problems National Institute of Neurological Disorders and Stroke Update SO STROKE LA English DT Editorial Material DE dementia; dementia, vascular; leukoencephalopathies; stroke C1 [Mott, Meghan; Pahigiannis, Katherine; Koroshetz, Walter] NINDS, NIH, Bethesda, MD 20892 USA. RP Koroshetz, W (reprint author), NINDS, NIH, Bldg 31,Room 8A52,31 Ctr Dr,MSC 2540, Bethesda, MD 20892 USA. EM koroshetzw@mail.nih.gov FU Intramural NIH HHS [Z99 NS999999] NR 0 TC 1 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD DEC PY 2014 VL 45 IS 12 BP E257 EP E258 DI 10.1161/STROKEAHA.114.007113 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AU3ME UT WOS:000345516600004 PM 25316274 ER PT J AU Rawal, S Hoffman, HJ Chapo, AK Duffy, VB AF Rawal, Shristi Hoffman, Howard J. Chapo, Audrey K. Duffy, Valerie B. TI Sensitivity and Specificity of Self-Reported Olfactory Function in a Home-Based Study of Independent-Living, Healthy Older Women SO CHEMOSENSORY PERCEPTION LA English DT Article DE Health status; Smell; Odor threshold; Odor identification; Aging; Females ID OF-PENNSYLVANIA SMELL; ODOR IDENTIFICATION; ADULT-POPULATION; LIFE-SPAN; DYSFUNCTION; IMPAIRMENT; AGE; PREVALENCE; ASSOCIATION; PERCEPTION AB The 2011-14 US National Health and Nutrition Examination Survey chemosensory protocol asks adults to self-rate their orthonasal (via nostrils) and retronasal (via mouth) smell abilities for subsequent odor identification testing. From data collected with a similar protocol, we aimed to identify a self-reported olfactory index that showed the best sensitivity (correctly identifying dysfunction) and specificity (correctly indentifying normosmia) with measured olfaction. In home-based testing, 121 independent-living older women (age 73 +/- 7 years) reported their olfactory function by interviewer-administered survey. Olfactory function was measured orthonasally via composite (odor threshold, identification task) or identification task alone. Only 16 % of women self-rated "below average" smell function. More women perceived loss of smell (38 %) or flavor (30 %) with aging. The rate of measured dysfunction was 30 % by composite (threshold and identification) and 21.5 % by identification task, the latter misclassifying some mild dysfunction as normosmia. An index of self-rated smell function and perceived loss yielded the most favorable sensitivity (65 %) and specificity (77 %) to measured function. Self-rated olfaction showed better agreement with severe measured dysfunction; mild dysfunction was less noticed. Self-reported indices that query about current and perceived changes in smell and flavor with aging showed better sensitivity estimates than those previously reported. Specificity was somewhat lower-some older adults may correctly perceive loss unidentified in a single assessment, or have a retronasal impairment that was undetected by an orthonasal measure. Our findings should inform self-rated measures that screen for severe olfactory dysfunction in clinical/community settings where testing is not routine. C1 [Rawal, Shristi; Chapo, Audrey K.; Duffy, Valerie B.] Univ Connecticut UCONN, Dept Allied Hlth Sci, Coll Agr Hlth & Nat Resources, Storrs, CT 06269 USA. [Hoffman, Howard J.] NIDCD, Epidemiol & Stat Program, Div Sci Programs, NIH, Bethesda, MD 20892 USA. RP Duffy, VB (reprint author), Univ Connecticut UCONN, Dept Allied Hlth Sci, Coll Agr Hlth & Nat Resources, 358 Mansfield Rd,Box U1101, Storrs, CT 06269 USA. EM valerie.duffy@uconn.edu FU US Department of Agriculture Hatch Project 396 [CONS00827, PEN04332]; NIH/NIDCD Interagency Agreement [Y1-DC-0013]; CDC/NCHS FX We extend a special thanks to the study participants. This project was supported in part by funds from the US Department of Agriculture Hatch Project 396 [CONS00827 and PEN04332] and the NIH/NIDCD Interagency Agreement (Y1-DC-0013) with CDC/NCHS for support of the NHANES Chemosensory (Taste and Smell) Protocol. NR 55 TC 7 Z9 7 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1936-5802 EI 1936-5810 J9 CHEMOSENS PERCEPT JI Chemosens. Percept. PD DEC PY 2014 VL 7 IS 3-4 BP 108 EP 116 DI 10.1007/s12078-014-9170-7 PG 9 WC Food Science & Technology; Neurosciences SC Food Science & Technology; Neurosciences & Neurology GA AU6YR UT WOS:000345748300002 PM 25866597 ER PT J AU Moser, RP Arndt, J Han, PK Waters, EA Amsellem, M Hesse, BW AF Moser, Richard P. Arndt, Jamie Han, Paul K. Waters, Erika A. Amsellem, Marni Hesse, Bradford W. TI Perceptions of cancer as a death sentence: Prevalence and consequences SO JOURNAL OF HEALTH PSYCHOLOGY LA English DT Article DE cancer; health behavior; health psychology; perception; public health psychology ID HEALTH-CARE; INFORMATION; WOMEN; IMPACT; THREAT; DELAY; MODEL AB Research suggests that perceiving cancer as a death sentence is a critical determinant of health care-seeking behaviors. However, there is limited information regarding the prevalence of this perception in the US population. Cross-sectional analysis of data (n = 7674 adults) from the 2007-2008 administration of the nationally representative Health Information National Trends Survey (HINTS 3) was performed. A majority (61.6%) of respondents perceived cancer as death sentence, and more than one-third (36%) of respondents reported that they avoid seeing their physicians. In the adult US population, perceiving cancer as a death sentence is common and is associated with education level and avoidance of physicians. C1 [Moser, Richard P.; Hesse, Bradford W.] NCI, Bethesda, MD 20892 USA. [Arndt, Jamie] Univ Missouri, Columbia, MO 65211 USA. [Han, Paul K.] Maine Med Ctr, Portland, ME USA. [Waters, Erika A.] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Amsellem, Marni] NCI, SAIC Frederick, Bethesda, MD 20892 USA. RP Moser, RP (reprint author), NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,MSC 9761,Room 3E604, Bethesda, MD 20892 USA. EM moserr@mail.nih.gov OI Waters, Erika/0000-0001-7402-0133; Han, Paul/0000-0003-0165-1940; Hesse, Bradford/0000-0003-1142-1161 FU Intramural NIH HHS [Z99 CA999999] NR 29 TC 6 Z9 6 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1359-1053 EI 1461-7277 J9 J HEALTH PSYCHOL JI J. Health Psychol. PD DEC PY 2014 VL 19 IS 12 BP 1518 EP 1524 DI 10.1177/1359105313494924 PG 7 WC Psychology, Clinical SC Psychology GA AU7ED UT WOS:000345762600004 PM 23864071 ER PT J AU Valapala, M Edwards, M Hose, S Grebe, R Bhutto, IA Cano, M Berger, T Mak, TW Wawrousek, E Handa, JT Lutty, GA Zigler, JS Sinha, D AF Valapala, Mallika Edwards, Malia Hose, Stacey Grebe, Rhonda Bhutto, Imran A. Cano, Marisol Berger, Thorsten Mak, Tak W. Wawrousek, Eric Handa, James T. Lutty, Gerard A. Zigler, J. Samuel, Jr. Sinha, Debasish TI Increased Lipocalin-2 in the retinal pigment epithelium of Cryba1 cKO mice is associated with a chronic inflammatory response SO AGING CELL LA English DT Editorial Material DE age-related macular degeneration; Cryba1 cKO mice; inflammation; lipocalin-2; lysosomes; retinal pigment epithelium ID MACULAR DEGENERATION; ACTIVATION; INFECTION; CELLS AB Although chronic inflammation is believed to contribute to the pathology of age-related macular degeneration (AMD), knowledge regarding the events that elicit the change from para-inflammation to chronic inflammation in the pathogenesis of AMD is lacking. We propose here that lipocalin-2 (LCN2), a mammalian innate immunity protein that is trafficked to the lysosomes, may contribute to this process. It accumulates significantly with age in retinal pigment epithelial (RPE) cells of Cryba1 conditional knockout (cKO) mice, but not in control mice. We have recently shown that these mice, which lack A3/A1-crystallin specifically in RPE, have defective lysosomal clearance. The age-related increase in LCN2 in the cKO mice is accompanied by increases in chemokine (C-C motif) ligand 2 (CCL2), reactive gliosis, and immune cell infiltration. LCN2 may contribute to induction of a chronic inflammatory response in this mouse model with AMD-like pathology. C1 [Valapala, Mallika; Edwards, Malia; Hose, Stacey; Grebe, Rhonda; Bhutto, Imran A.; Cano, Marisol; Handa, James T.; Lutty, Gerard A.; Zigler, J. Samuel, Jr.; Sinha, Debasish] Johns Hopkins Univ, Wilmer Eye Inst, Sch Med, Baltimore, MD 21287 USA. [Berger, Thorsten; Mak, Tak W.] Univ Hlth Network, Campbell Family Inst Breast Canc Res, Toronto, ON, Canada. [Berger, Thorsten; Mak, Tak W.] Univ Hlth Network, Ontario Canc Inst, Toronto, ON, Canada. [Wawrousek, Eric] NEI, NIH, Bethesda, MD 20892 USA. RP Sinha, D (reprint author), Johns Hopkins Univ, Wilmer Eye Inst, Sch Med, Baltimore, MD 21287 USA. EM debasish@jhmi.edu FU NEI NIH HHS [EY019037-S, EY019904, EY14005, P30 EY001765, R01 EY014005, R01 EY016151, R01 EY019037, R01 EY019904] NR 20 TC 9 Z9 9 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD DEC PY 2014 VL 13 IS 6 BP 1091 EP 1094 DI 10.1111/acel.12274 PG 4 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA AU2ON UT WOS:000345457900014 PM 25257511 ER PT J AU Viscoli, CM Brass, LM Carolei, A Conwit, R Ford, GA Furie, KL Gorman, M Guarino, PD Inzucchi, SE Lovejoy, AM Parsons, MW Peduzzi, PN Ringleb, PA Schwartz, GG Spence, JD Tanne, D Young, LH Kernan, WN AF Viscoli, Catherine M. Brass, Lawrence M. Carolei, Antonio Conwit, Robin Ford, Gary A. Furie, Karen L. Gorman, Mark Guarino, Peter D. Inzucchi, Silvio E. Lovejoy, Anne M. Parsons, Mark W. Peduzzi, Peter N. Ringleb, Peter A. Schwartz, Gregory G. Spence, J. David Tanne, David Young, Lawrence H. Kernan, Walter N. CA IRIS Trial Investigators TI Pioglitazone for secondary prevention after ischemic stroke and transient ischemic attack: Rationale and design of the Insulin Resistance Intervention after Stroke Trial SO AMERICAN HEART JOURNAL LA English DT Article ID HOMEOSTASIS MODEL ASSESSMENT; CLINICAL-TRIALS; MYOCARDIAL-INFARCTION; CARDIOVASCULAR-DISEASE; MACROVASCULAR EVENTS; NONDIABETIC PATIENTS; METABOLIC SYNDROME; HEART-DISEASE; RISK; ASSOCIATION AB Background Recurrent vascular events remain a major source of morbidity and mortality after stroke or transient ischemic attack (TIA). The IRIS Trial is evaluating an approach to secondary prevention based on the established association between insulin resistance and increased risk for ischemic vascular events. Specifically, IRIS will test the effectiveness of pioglitazone, an insulin-sensitizing drug of the thiazolidinedione class, for reducing the risk for stroke and myocardial infarction (MI) among insulin resistant, nondiabetic patients with a recent ischemic stroke or TIA. Design Eligible patients for IRIS must have had insulin resistance defined by a Homeostasis Model Assessment-Insulin Resistance >3.0 without meeting criteria for diabetes. Within 6 months of the index stroke or TIA, patients were randomly assigned to pioglitazone (titrated from 15 to 45 mg/d) or matching placebo and followed for up to 5 years. The primary outcome is time to stroke or MI. Secondary outcomes include time to stroke alone, acute coronary syndrome, diabetes, cognitive decline, and all-cause mortality. Enrollment of 3,876 participants from 179 sites in 7 countries was completed in January 2013. Participant follow-up will continue until July 2015. Summary The IRIS Trial will determine whether treatment with pioglitazone improves cardiovascular outcomes of nondiabetic, insulin-resistant patients with stroke or TIA. Results are expected in early 2016. C1 [Viscoli, Catherine M.; Brass, Lawrence M.; Inzucchi, Silvio E.; Lovejoy, Anne M.; Young, Lawrence H.; Kernan, Walter N.] Yale Univ, Sch Med, New Haven, CT USA. [Carolei, Antonio] Univ Aquila, I-67100 Laquila, Italy. [Conwit, Robin] NINDS, Bethesda, MD 20892 USA. [Ford, Gary A.] Univ Oxford, Oxford, England. [Furie, Karen L.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Gorman, Mark] Univ Vermont, Sch Med, Burlington, VT 05405 USA. [Guarino, Peter D.; Peduzzi, Peter N.] VA Connecticut Healthcare Syst, Cooperat Studies Program Coordinating Ctr, West Haven, CT USA. [Guarino, Peter D.; Peduzzi, Peter N.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Parsons, Mark W.] Univ Newcastle, Newcastle, NSW 2300, Australia. [Ringleb, Peter A.] Heidelberg Univ, Heidelberg, Germany. [Schwartz, Gregory G.] VA Med Ctr, Denver, CO USA. [Schwartz, Gregory G.] Univ Colorado, Sch Med, Denver, CO USA. [Spence, J. David] Univ Western Ontario, London, ON, Canada. [Tanne, David] Tel Aviv Univ, IL-69978 Tel Aviv, Israel. RP Viscoli, CM (reprint author), 2 Church St South,Suite 515, New Haven, CT 06519 USA. EM catherine.viscoli@yale.edu RI Spence, J. David/K-6396-2013; Tanne, David/F-2560-2010 OI Spence, J. David/0000-0001-7478-1098; Tanne, David/0000-0002-6699-2220 FU NCATS NIH HHS [UL1 TR000142, UL1 TR000439]; NINDS NIH HHS [U01 NS044876] NR 48 TC 10 Z9 10 U1 1 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD DEC PY 2014 VL 168 IS 6 BP 823 EP + DI 10.1016/j.ahj.2014.07.016 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AU3IN UT WOS:000345506100003 PM 25458644 ER PT J AU Landgren, O Gormley, N Turley, D Owen, RG Rawstron, A Paiva, B Barnett, D Arroz, M Wallace, P Durie, B Yuan, C Dogan, A Stetler-Stevenson, M Marti, GE AF Landgren, Ola Gormley, Nicole Turley, Danielle Owen, Roger G. Rawstron, Andy Paiva, Bruno Barnett, David Arroz, Maria Wallace, Paul Durie, Brian Yuan, Constance Dogan, Ahmet Stetler-Stevenson, Maryalice Marti, Gerald E. TI Flow cytometry detection of minimal residual disease in multiple myeloma: Lessons learned at FDA-NCI roundtable symposium SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Letter ID STEM-CELL TRANSPLANTATION C1 [Landgren, Ola; Yuan, Constance; Stetler-Stevenson, Maryalice] NCI, Bethesda, MD 20892 USA. [Gormley, Nicole; Turley, Danielle; Marti, Gerald E.] US FDA, Silver Spring, MD USA. [Owen, Roger G.; Rawstron, Andy] St Jamess Inst Oncol, HMDS Lab, Leeds, W Yorkshire, England. [Paiva, Bruno] Univ Navarra Clin, Pamplona, Spain. [Paiva, Bruno] CIMA, Pamplona, Spain. [Barnett, David] Royal Hallamshire Hosp, UK NEQAS Leucocyte Immunophenotyping, Shefield, England. [Arroz, Maria] CHLO, HSFX, Dept Clin Pathol, Lisbon, Portugal. [Wallace, Paul] Roswell Pk Canc Inst, Dept Flow & Image Cytometry, Buffalo, NY 14263 USA. [Durie, Brian] Cedars Sinai Comprehens Canc Ctr, Los Angeles, CA USA. [Dogan, Ahmet] Mem Sloan Kettering Canc Ctr, Hematopathol Serv, New York, NY 10021 USA. RP Landgren, O (reprint author), NCI, Bethesda, MD 20892 USA. EM landgrec@mskcc.org OI Rawstron, Andy/0000-0003-0798-9790 NR 8 TC 21 Z9 21 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD DEC PY 2014 VL 89 IS 12 BP 1159 EP 1160 DI 10.1002/ajh.23831 PG 2 WC Hematology SC Hematology GA AU1CK UT WOS:000345358600026 PM 25132630 ER PT J AU Plotkin, SR Albers, AC Babovic-Vuksanovic, D Blakeley, JO Breakefield, XO Dunn, CM Evans, DG Fisher, MJ Friedman, JM Giovannini, M Gutmann, DH Kalamarides, M McClatchey, AI Messiaen, L Morrison, H Parkinson, DB Stemmer-Rachamimov, AO Van Raamsdonk, CD Riccardi, VM Rosser, T Schindeler, A Smith, MJ Stevenson, DA Ullrich, NJ van der Vaart, T Weiss, B Widemann, BC Zhu, Y Bakker, AC Lloyd, AC AF Plotkin, Scott R. Albers, Anne C. Babovic-Vuksanovic, Dusica Blakeley, Jaishri O. Breakefield, Xandra O. Dunn, Courtney M. Evans, D. Gareth Fisher, Michael J. Friedman, Jan M. Giovannini, Marco Gutmann, David H. Kalamarides, Michel McClatchey, Andrea I. Messiaen, Ludwine Morrison, Helen Parkinson, David B. Stemmer-Rachamimov, Anat O. Van Raamsdonk, Catherine D. Riccardi, Vincent M. Rosser, Tena Schindeler, Aaron Smith, Miriam J. Stevenson, David A. Ullrich, Nicole J. van der Vaart, Thijs Weiss, Brian Widemann, Brigitte C. Zhu, Yuan Bakker, Annette C. Lloyd, Alison C. TI Update from the 2013 International Neurofibromatosis Conference SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE NF1; NF2; SMARCB1; neurofibromatosis 1; neurofibromatosis 2; schwannomatosis; tumor suppressor; merlin; neurofibromin; preclinical models ID VESTIBULAR-SCHWANNOMA; MUSCLE DEVELOPMENT; CONTROLLED-TRIAL; SKELETAL-MUSCLE; NORTH-WEST; TYPE-1; NF1; MENINGIOMAS; POPULATION; CHILDREN C1 [Plotkin, Scott R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. [Albers, Anne C.; Dunn, Courtney M.; Gutmann, David H.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Babovic-Vuksanovic, Dusica] Mayo Clin, Dept Med Genet, Rochester, MN USA. [Blakeley, Jaishri O.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Breakefield, Xandra O.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosci Ctr,Ctr Mol Imaging, Boston, MA USA. [Evans, D. Gareth; Smith, Miriam J.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Ctr Genom Med, St Marys Hosp, Manchester, Lancs, England. [Fisher, Michael J.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Friedman, Jan M.; Van Raamsdonk, Catherine D.] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. [Giovannini, Marco] House Res Inst, Ctr Neural Tumor Res, Los Angeles, CA USA. [Kalamarides, Michel] Hop La Pitie Salpetriere, Dept Neurosurg, Paris, France. [McClatchey, Andrea I.; Stemmer-Rachamimov, Anat O.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Messiaen, Ludwine] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA. [Morrison, Helen] Leibniz Inst Age Res, Jena, Germany. [Parkinson, David B.] Univ Plymouth, Peninsula Coll Med & Dent, Ctr Biomed Res, Plymouth PL4 8AA, Devon, England. [Riccardi, Vincent M.] Neurofibromatosis Inst, La Crescenta, CA USA. [Rosser, Tena] Univ So Calif, Childrens Hosp, Dept Neurol, Los Angeles, CA 90027 USA. [Schindeler, Aaron] Univ Sydney, Childrens Hosp Westmead, Kids Res Inst, Westmead, NSW 2145, Australia. [Stevenson, David A.] Univ Utah, Dept Pediat, Div Med Genet, Salt Lake City, UT USA. [Ullrich, Nicole J.] Harvard Univ, Boston Childrens Hosp, Sch Med, Dept Neurol, Boston, MA USA. [van der Vaart, Thijs] Erasmus MC, ENCORE Ctr NF1, Rotterdam, Netherlands. [Weiss, Brian] Cincinnati Childrens Hosp Med Ctr, Div Hematol Oncol, Cincinnati, OH 45229 USA. [Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Zhu, Yuan] Childrens Natl Med Ctr, Gilbert Neurofibromatosis Inst, Washington, DC 20010 USA. [Bakker, Annette C.] Childrens Tumor Fdn, New York, NY USA. [Lloyd, Alison C.] UCL, MRC Lab Mol Cell Biol, London, England. [Plotkin, Scott R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA USA. [Breakefield, Xandra O.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. [Ullrich, Nicole J.] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Pediat Oncol, Boston, MA USA. RP Plotkin, SR (reprint author), Massachusetts Gen Hosp, Yawkey 9E,55 Fruit St, Boston, MA 02114 USA. EM splotkin@partners.org; alison.lloyd@ucl.ac.uk RI Smith, Miriam/J-4001-2015; Van Raamsdonk, Catherine/B-6207-2017; Morrison, Helen/B-3984-2017; OI Evans, Gareth/0000-0002-8482-5784; Smith, Miriam/0000-0002-3184-0817; Van Raamsdonk, Catherine/0000-0002-4309-3513; Morrison, Helen/0000-0003-4938-1409; Friedman, Jan/0000-0002-7482-9570 FU National Institutes of Health [1R13NS084619-01] FX Grant sponsor: National Institutes of Health Grant Award; Grant number: 1R13NS084619-01. NR 40 TC 6 Z9 6 U1 5 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD DEC PY 2014 VL 164 IS 12 BP 2969 EP 2978 DI 10.1002/ajmg.a.36754 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA AU0DJ UT WOS:000345293300003 PM 25255738 ER PT J AU Zangl, Q Martignoni, A Jackson, SH Ohta, A Klaunberg, B Kaufmann, I Lukashev, D Ward, JM Sitkovsky, M Thiel, M Chouker, A AF Zangl, Quirin Martignoni, Andre Jackson, Sharon H. Ohta, Akio Klaunberg, Brenda Kaufmann, Ines Lukashev, Dimitry Ward, Jerrold M. Sitkovsky, Michail Thiel, Manfred Chouker, Alexander TI Postoperative Hyperoxia (60%) Worsens Hepatic Injury in Mice SO ANESTHESIOLOGY LA English DT Article ID ISCHEMIA-REPERFUSION INJURY; IN-VIVO; INFLAMMATORY MEDIATORS; CYTOCHROME-C; OXYGEN; LIVER; ISCHEMIA/REPERFUSION; PATHOPHYSIOLOGY; MITOCHONDRIAL; NEUTROPHILS AB Background: Liver damage by ischemia and reperfusion injury is a risk factor for morbidity and mortality after liver surgery. Postoperative oxygen treatment is routinely applied in the postanesthesia and intensive care unit after liver surgery. The risks of aggravating the injury by increasing inspiratory oxygen from 21 to 60% in the postoperative period were investigated in mice. Methods: Parameters of liver injury were compared after induction of hepatic ischemia-reperfusion injury, by clamping the left liver lobe for 45 min, and reperfusion for 24 h either under normoxic (21% oxygen) or hyperoxic (60% oxygen) conditions (n = 22 per group). The extent of tissue injury and oxidative responses was analyzed in the presence or absence of polymorphonuclear leukocytes, functional Kupffer cells, and the p47phox unit of the nicotinamide adenine dinucleotide phosphate oxidase (n = 6 to 11 per group). Results: Compared with postoperative normoxic conditions, hyperoxia increased cell damage (glutamate-pyruvate transaminase: 1,870 [+/- 968 SD] vs. 60% 2,981 [+/- 1,038 SD], 21 vs. 60% oxygen, in U/l as mean +/- SD; P < 0.01), liver weights (341 +/- 52 vs. 383 +/- 44, 21 vs. 60% oxygen, in mg as mean +/- SD; P = 0.02), damage scores (1.9 +/- 0.8 vs. 3.1 +/- 1.0, 21 vs. 60% oxygen, score as mean +/- SD; P = 0.02), and reactive oxygen species (15.0 +/- 12.0 vs. 30.4 +/- 19.2, 21 vs. 60% oxygen, in mu mol/l as mean +/- SD; P < 0.05). The aggravation of the tissue damaging effects as a result of hyperoxia was not seen in mice with depletions of polymorphonuclear leukocytes or Kupffer cells, or with nonfunctioning nicotinamide adenine dinucleotide phosphate oxidase. Conclusion: Liver injury after ischemia was significantly aggravated by hyperoxia as a consequence of immune cell-mediated oxidative burst. Further studies are needed to elucidate whether routine delivery of high inspirational oxygen concentrations postoperatively should be limited. C1 [Zangl, Quirin; Martignoni, Andre; Kaufmann, Ines; Chouker, Alexander] Univ Munich, Dept Anesthesiol, Klinikum Grosshadern, Univ Hosp, D-81377 Munich, Germany. [Jackson, Sharon H.] Natl Inst Minor Hlth & Hlth Dispar, NIH, Div Intramural Res, Bethesda, MD USA. [Ohta, Akio; Lukashev, Dimitry; Ward, Jerrold M.; Sitkovsky, Michail; Chouker, Alexander] NIAID, NIH, Bethesda, MD 20892 USA. [Ohta, Akio; Lukashev, Dimitry; Sitkovsky, Michail] Northeastern Univ, New England Inflammat & Tissue Protect Inst Conso, Boston, MA 02115 USA. [Klaunberg, Brenda] NINDS, Mouse Imaging Facil, NIH, Bethesda, MD 20892 USA. [Thiel, Manfred] Heidelberg Univ, Med Fac Mannheim, Dept Anaesthesiol & Intens Care, Mannheim, Germany. RP Chouker, A (reprint author), Univ Munich, Dept Anaesthesiol, Marchioninistr 15, D-81377 Munich, Germany. EM achouker@med.uni-muenchen.de FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; medical faculty of the Ludwig-Maximilians-University through the facilitation program for research and education of the Ludwig-Maximilians-University, Munich, Germany FX This research work was supported, in part, by the Intramural Research Program and a John E. Fogarty research grant awarded to Dr. Chouker by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland. Financial support was also awarded by the medical faculty of the Ludwig-Maximilians-University through the facilitation program for research and education of the Ludwig-Maximilians-University, Munich, Germany (to Dr. Martignoni). In-house support was provided by the Department of Anesthesiology, Ludwig-Maximilian-University of Munich, Munich, Germany (to Drs. Zangl, Martignoni, and Chouker). NR 49 TC 4 Z9 4 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD DEC PY 2014 VL 121 IS 6 BP 1217 EP 1225 DI 10.1097/ALN.0000000000000447 PG 9 WC Anesthesiology SC Anesthesiology GA AU2FB UT WOS:000345430700013 PM 25225820 ER PT J AU Aiello, CM Nussear, KE Walde, AD Esque, TC Emblidge, PG Sah, P Bansal, S Hudson, PJ AF Aiello, C. M. Nussear, K. E. Walde, A. D. Esque, T. C. Emblidge, P. G. Sah, P. Bansal, S. Hudson, P. J. TI Disease dynamics during wildlife translocations: disruptions to the host population and potential consequences for transmission in desert tortoise contact networks SO ANIMAL CONSERVATION LA English DT Article DE translocation; disease risk; pathogen transmission dynamics; contact networks; desert tortoise; Mycoplasma ID RESPIRATORY-TRACT DISEASE; GOPHERUS-AGASSIZII; SOCIAL NETWORKS; MOJAVE DESERT; TRICHOSURUS-VULPECULA; CONSERVATION TOOL; RISK-ASSESSMENT; HOME-RANGE; STRESS; INDIVIDUALS AB Wildlife managers consider animal translocation a means of increasing the viability of a local population. However, augmentation may disrupt existing resident disease dynamics and initiate an outbreak that would effectively offset any advantages the translocation may have achieved. This paper examines fundamental concepts of disease ecology and identifies the conditions that will increase the likelihood of a disease outbreak following translocation. We highlight the importance of susceptibility to infection, population size and population connectivity a characteristic likely affected by translocation but not often considered in risk assessments - in estimating outbreak risk due to translocation. We then explore these features in a species of conservation concern often translocated in the presence of infectious disease, the Mojave Desert tortoise, and use data from experimental tortoise translocations to detect changes in population connectivity that may influence pathogen transmission. Preliminary analyses comparing contact networks inferred from spatial data at control and translocation plots and infection simulation results through these networks suggest increased outbreak risk following translocation due to dispersal-driven changes in contact frequency and network structure. We outline future research goals to test these concepts and aid managers in designing effective risk assessment and intervention strategies that will improve translocation success. C1 [Aiello, C. M.; Nussear, K. E.; Esque, T. C.] US Geol Survey, Western Ecol Res Ctr, Henderson, NV 89074 USA. [Aiello, C. M.; Emblidge, P. G.; Hudson, P. J.] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Walde, A. D.] Walde Res & Environm Consulting, Atascadero, CA USA. [Sah, P.; Bansal, S.] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. [Bansal, S.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Aiello, CM (reprint author), US Geol Survey, Las Vegas Field Stn, 160 N Stephanie St, Henderson, NV 89074 USA. EM caiello@usgs.gov OI Sah, Pratha/0000-0001-8936-5871; Aiello, Christina/0000-0002-2399-5464; Bansal, Shweta/0000-0002-1740-5421 FU National Science Foundation Ecology of Infections Diseases [1216054]; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, U.S. Department of Homeland Security; Fogarty International Center, NIH; U.S. Department of Defense, Fort Irwin, California FX We thank W. Boarman, A. Peter Woodman and C. Everly for collaboration and logistical support. We thank R. Averill-Murray and anonymous reviewers for helpful comments to improve the quality of this paper. Earlier versions of this paper benefitted from review and discussions with K. Drake, R. Inman, D. Shyrock, J. Germano, A. Berger, M. Walden and F. Chen. The content of this paper was stimulated by the collaboration and discussions of members of the desert tortoise disease assessment workgroup including N. Lamberski, B. Rideout, J. Simecka, R. Swaisgood, C. R. Tracy and several others. This work was funded by the National Science Foundation Ecology of Infections Diseases grant #1216054 Invasion and Infection: Translocation and Transmission: An Experimental Study with Mycoplasma in Desert Tortoises. P. J. H. and S. B. acknowledge the support and stimulation from the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, U.S. Department of Homeland Security, and the Fogarty International Center, NIH. Desert tortoise translocation research was conducted under California Fish and Game and U.S. Fish and Wildlife Service permits and funded by the U.S. Department of Defense, Fort Irwin, California. Any use of trade, product or firm names in this publication is for descriptive purposes only and does not imply endorsement by the U.S. government. NR 89 TC 11 Z9 11 U1 7 U2 55 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1367-9430 EI 1469-1795 J9 ANIM CONSERV JI Anim. Conserv. PD DEC PY 2014 VL 17 SU 1 SI SI BP 27 EP 39 DI 10.1111/acv.12147 PG 13 WC Biodiversity Conservation; Ecology SC Biodiversity & Conservation; Environmental Sciences & Ecology GA AT8XS UT WOS:000345213000004 ER PT J AU Boghossian, NS Yeung, E Mendola, P Hinkle, SN Laughon, SK Zhang, CL Albert, PS AF Boghossian, Nansi S. Yeung, Edwina Mendola, Pauline Hinkle, Stefanie N. Laughon, S. Katherine Zhang, Cuilin Albert, Paul S. TI Risk factors differ between recurrent and incident preeclampsia: a hospital-based cohort study SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Preeclampsia; Recurrent; Incident; Obesity; Body mass index ID BODY-MASS INDEX; HYPERTENSIVE DISORDERS; GESTATIONAL HYPERTENSION; CHANGING PATERNITY; 2ND PREGNANCY; WEIGHT-CHANGE; MANAGEMENT; OUTCOMES; WOMEN AB Purpose: To examine whether risk factors, including prepregnancy body mass index (BMI), differ between recurrent and incident preeclampsia. Methods: Data included electronic medical records of nulliparas (n = 26,613) delivering 2 times or more in Utah (2002-2010). Modified Poisson regression models were used to examine (1) adjusted relative risks (RR) of preeclampsia and 95% confidence intervals (CI) associated with prepregnancy BMI; (2) maternal risk factor differences between incident and recurrent preeclampsia among primiparous women. Results: In the first pregnancy, compared with normal weight women (BMI: 18.5-24.9), preeclampsia risks for overweight (BMI: 25-29.9), obese class I (BMI: 30-34.9), and obese class II/III (BMI: >= 35) women were 1.82 (95% CI = 1.60-2.06); 2.10 (95% CI = 1.76-2.50), and 2.84 (95% CI = 2.32-3.47), respectively, whereas second pregnancy incident preeclampsia risks were 1.66 (95% CI = 1.27-2.16), 2.31 (95% CI = 1.67-3.20), and 4.29 (95% CI = 3.16-5.82), respectively. Recurrent preeclampsia risks associated with BMI were highest among obese class I women (RR = 1.60; 95% CI = 1.06-2.42) without increasing in a dose-response manner. Nonwhite women had higher recurrence risk than white women (RR = 1.70; 95% CI = 1.16-2.50), whereas second pregnancy incident preeclampsia risk did not differ by race. Conclusion: Prepregnancy BMI appeared to have stronger associations with risk of incident preeclampsia either in the first or second pregnancy, than with recurrence risk. Nonwhite women had higher recurrence risk. Published by Elsevier Inc. C1 [Boghossian, Nansi S.; Yeung, Edwina; Mendola, Pauline; Hinkle, Stefanie N.; Laughon, S. Katherine; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Boghossian, Nansi S.] Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. RP Yeung, E (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Execut Blvd Room 7B03, Bethesda, MD 20892 USA. EM yeungedw@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; 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 (Contracts numbers: HHSN275200800002I, HHSN27500004). NR 34 TC 4 Z9 5 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD DEC PY 2014 VL 24 IS 12 BP 871 EP 877 DI 10.1016/j.annepidem.2014.10.003 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AU3FE UT WOS:000345497100001 PM 25453345 ER PT J AU Prasad, A Schisterman, EF Schliep, KC Ahrens, KA Sjaarda, LA Perkins, NJ Matyas, R Wactawski-Wende, J Mumford, SL AF Prasad, Ankita Schisterman, Enrique F. Schliep, Karen C. Ahrens, Katherine A. Sjaarda, Lindsey A. Perkins, Neil J. Matyas, Rebecca Wactawski-Wende, Jean Mumford, Sunni L. TI Depressive symptoms and their relationship with endogenous reproductive hormones and sporadic anovulation in premenopausal women SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Depression; Depressive symptoms; Menstrual cycle; Ovulation; Reproductive hormones; Mental health; Women's health ID IN-VITRO FERTILIZATION; MENSTRUAL-CYCLE; HEALTHY CONTROLS; DISORDER; ASSOCIATIONS; DYSFUNCTION; BIOCYCLE; ESTROGEN; STRESS AB Purpose: To determine whether depressive symptoms are associated with ovulation or reproductive hormone concentrations in eumenorrheic women without a reported diagnosis of clinical depression. Methods: A prospective cohort of 248 regularly menstruating women, aged 18 to 44 years (27.3 +/- 8.2) were evaluated for depressive symptoms at baseline using the 20-item Center for Epidemiological Studies Depression (CES-D) scale and categorized dichotomously (<16, no depressive symptoms [92%] vs. >16, depressive symptoms [8%]). Serum concentrations of estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone were measured up to eight times per cycle for up to two menstrual cycles. Linear mixed models estimated associations between depressive symptoms and hormone concentrations, whereas generalized linear mixed models assessed their relationship with sporadic anovulation. Results: No significant associations were identified between depressive symptoms and reproductive hormone levels (all P >.05) or the odds of sporadic anovulation (adjusted odds ratio,1.1; 95% confidence interval, [0.02-5.0]), after adjusting for age, race, body mass index, perceived stress level, and alcohol consumption. Conclusions: Despite reported associations between mental health and menstrual cycle dysfunction, depressive symptoms were not associated with reproductive hormone concentrations or sporadic anovulation in this cohort of regularly menstruating women with no recent (within 1 year) self-reported history of clinical depression. Published by Elsevier Inc. C1 [Prasad, Ankita; Schisterman, Enrique F.; Schliep, Karen C.; Ahrens, Katherine A.; Sjaarda, Lindsey A.; Perkins, Neil J.; Matyas, Rebecca; Mumford, Sunni L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, NIH, Rockville, MD 20852 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Mumford, SL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, 6100 Executive Blvd,7B03M, Rockville, MD 20852 USA. EM mumfords@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Sjaarda, Lindsey/0000-0003-0539-8110; Schisterman, Enrique/0000-0003-3757-641X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland [HH5N275200403394 C] FX This work was supported by Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland (Contract # HH5N275200403394 C). NR 25 TC 2 Z9 2 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD DEC PY 2014 VL 24 IS 12 BP 920 EP 924 DI 10.1016/j.annepidem.2014.10.005 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AU3FE UT WOS:000345497100009 PM 25453349 ER PT J AU Reis, JP AF Reis, Jared P. TI Dietary Fatty Acids and Coronary Heart Disease SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Editorial Material DE Editorial; atherosclerosis; coronary artery disease; diet; fatty acids ID RISK C1 NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Reis, JP (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Suite 10186, Bethesda, MD 20892 USA. EM reisjp@mail.nih.gov NR 6 TC 0 Z9 0 U1 1 U2 6 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 DEC PY 2014 VL 34 IS 12 BP 2520 EP 2521 DI 10.1161/ATVBAHA.114.304620 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AU2JG UT WOS:000345443400002 PM 25411104 ER PT J AU Weiss, PF Colbert, RA Xiao, R Feudtner, C Beukelman, T DeWitt, EM Pagnini, I Wright, TB Wallace, CA AF Weiss, Pamela F. Colbert, Robert A. Xiao, Rui Feudtner, Chris Beukelman, Timothy DeWitt, Esi Morgan Pagnini, Ilaria Wright, Tracey B. Wallace, Carol A. TI Development and Retrospective Validation of the Juvenile Spondyloarthritis Disease Activity Index SO ARTHRITIS CARE & RESEARCH LA English DT Article ID ENTHESITIS-RELATED ARTHRITIS; QUALITY-OF-LIFE; IDIOPATHIC ARTHRITIS; RHEUMATOID-ARTHRITIS; ANKYLOSING-SPONDYLITIS; CLINICAL REMISSION; SELECT CATEGORIES; OMERACT FILTER; ACTIVITY SCORE; CHILDREN AB Objective. To develop and validate the Juvenile Spondyloarthritis Disease Activity Index (JSpADA) for use in clinical practice and research. Methods. Using modified Delphi consensus techniques, 10 items were selected by participants in the international pediatric rheumatology listserv, the Childhood Arthritis and Rheumatology Research Alliance, and the listserv for the pediatric section of the American College of Rheumatology. Validation was performed in a retrospective multicenter cohort of 244 children. Results. In total, 106 physicians representing 14 countries completed the initial questionnaire. Completion rates for the subsequent questionnaires were 84%, 75%, and 77% of the original respondents. Ten items exceeded 80% consensus: arthritis, enthesitis, patient pain assessment, inflammatory markers, morning stiffness, clinical sacroiliitis, uveitis, back mobility, and patient and physician assessments of disease activity. After item analysis, 2 items were eliminated (patient and physician assessments of disease activity). Factor analysis identified 3 primary domains that explained 58% of the variance: peripheral disease, axial disease, and uveitis. The Cronbach's alpha coefficient was 0.66. The JSpADA had high or moderate correlations with the Juvenile Arthritis Disease Activity Score (r = 0.81), patient and physician assessments of disease activity (r = 0.70 and r = 0.66, respectively), and the Childhood Health Assessment Questionnaire (r = 0.56). The JSpADA discriminated well between subjects with active versus inactive disease (P < 0.001) and was responsive to improvement or worsening in disease activity over time (P < 0.001). Conclusion. Using international input and consensus formation techniques, we developed and validated the first disease activity assessment for juvenile spondyloarthritis. Future studies should validate the JSpADA in a prospective multicenter cohort. C1 [Weiss, Pamela F.; Xiao, Rui; Feudtner, Chris] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Weiss, Pamela F.; Feudtner, Chris] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Colbert, Robert A.] NIAMSD, Bethesda, MD 20892 USA. [Beukelman, Timothy] Univ Alabama Birmingham, Birmingham, AL USA. [DeWitt, Esi Morgan] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Pagnini, Ilaria] Univ Florence, Florence, Italy. [Pagnini, Ilaria] Anna Meyer Childrens Hosp, Florence, Italy. [Wright, Tracey B.] Univ Texas Southwestern, Texas Scottish Rite Hosp Children, Dallas, TX USA. [Wallace, Carol A.] Univ Washington, Seattle, WA 98195 USA. [Wallace, Carol A.] Seattle Childrens Hosp, Seattle, WA USA. RP Weiss, PF (reprint author), Childrens Hosp Philadelphia, 3535 Market St,Room 1526, Philadelphia, PA 19104 USA. EM weisspa@email.chop.edu FU Intramural NIH HHS; NIAMS NIH HHS [K23 AR059749, 1-K23-AR-059749-01A1, Z01-AR-041184] NR 30 TC 9 Z9 9 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD DEC PY 2014 VL 66 IS 12 BP 1775 EP 1782 DI 10.1002/acr.22411 PG 8 WC Rheumatology SC Rheumatology GA AU3MY UT WOS:000345518800003 PM 25047959 ER PT J AU Ward, MM Guthrie, LC Alba, MI AF Ward, Michael M. Guthrie, Lori C. Alba, Maria I. TI Clinically Important Changes in Short Form 36 Health Survey Scales for Use in Rheumatoid Arthritis Clinical Trials: The Impact of Low Responsiveness SO ARTHRITIS CARE & RESEARCH LA English DT Article ID QUALITY-OF-LIFE; PATIENT-REPORTED OUTCOMES; NECROSIS FACTOR THERAPY; IMPORTANT DIFFERENCE; SURVEY SF-36; DISEASE; INSTRUMENTS; RELIABILITY; ABATACEPT; VALIDITY AB Objective. Despite wide use of the Short-Form 36 (SF-36) health survey in clinical trials of rheumatoid arthritis (RA), estimates of minimum clinically important improvement (MCII) for its scales are not well-established. We estimated MCIIs for SF-36 scales in patients with active RA. Methods. In this prospective longitudinal study, we studied 243 patients who had active RA and who completed the SF-36 before and after treatment escalation. We first assessed responsiveness with standardized response means (SRMs). For scales with adequate responsiveness (SRM >= 0.50), we used patient judgments of improvement in arthritis status as anchors for estimating MCIIs. We used receiver operating characteristic curve analysis to identify the MCIIs as the change associated with a specificity of 0.80 for improvement. Results. Patients had substantial improvement in RA activity with treatment. However, among SF-36 scales, only the physical functioning and bodily pain scales and the physical component summary had adequate responsiveness. Using 0.80 specificity for improvement as the criterion, the MCIIs were 7.1 for the physical functioning scale, 4.9 for the bodily pain scale, and 7.2 for the physical component summary. Conclusion. Low responsiveness precluded estimation of valid MCIIs for many SF-36 scales in patients with RA, particularly the scales assessing mental health. Although the SF-36 has been included in many clinical trials to broaden the assessment of health status, low responsiveness limits the interpretation of changes in its mental health-related scales. C1 [Ward, Michael M.; Guthrie, Lori C.; Alba, Maria I.] NIAMSD, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMSD, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural NIH HHS [Z01 AR041153-03] NR 47 TC 2 Z9 2 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD DEC PY 2014 VL 66 IS 12 BP 1783 EP 1789 DI 10.1002/acr.22392 PG 7 WC Rheumatology SC Rheumatology GA AU3MY UT WOS:000345518800004 PM 24980417 ER PT J AU Liu, ZD Zhang, RD Li, YS Chen, Z Su, CY Han, Y AF Liu, Zhidong Zhang, Ruidong Li, Yunsong Chen, Zhong Su, Chongyu Han, Yi TI CIRCULATING TUMOR CELLS IN PERIPHERAL AND PULMONARY VENOUS BLOOD PREDICT POOR LONG-TERM SURVIVAL IN SURGICALLY RESECTED NON-SMALL CELL LUNG CANCER PATIENTS SO ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Liu, Zhidong; Li, Yunsong; Su, Chongyu; Han, Yi] Capital Med Univ, Beijing Chest Hosp, Beijing, Peoples R China. [Zhang, Ruidong] Beijing Childrens Hosp, Beijing, Peoples R China. [Chen, Zhong] NIDCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD USA. 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 1743-7555 EI 1743-7563 J9 ASIA-PAC J CLIN ONCO JI Asia-Pac. J. Clin. Oncol. PD DEC PY 2014 VL 10 SU 8 SI SI MA 305 BP 159 EP 159 PG 1 WC Oncology SC Oncology GA AU0ZN UT WOS:000345350900253 ER PT J AU Covian, R French, S Kusnetz, H Balaban, RS AF Covian, Raul French, Stephanie Kusnetz, Heather Balaban, Robert S. TI Stimulation of oxidative phosphorylation by calcium in cardiac mitochondria is not influenced by cAMP and PKA activity SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Article DE Cardiac metabolism; Mitochondrial respiration; Protein kinase A; cAMP; Calcium; Cytochromes ID DEPENDENT PROTEIN-KINASE; SOLUBLE ADENYLYL-CYCLASE; COMPLEX-I; HEART-MITOCHONDRIA; CA2+; METABOLISM; MATRIX; INNER; ACTIVATION; F1-ATPASE AB Cardiac oxidative ATP generation is finely tuned to match several-fold increases in energy demand. Calcium has been proposed to play a role in the activation of ATP production via PKA phosphorylation in response to intramitochondrial cAMP generation. We evaluated the effect of cAMP, its membrane permeable analogs (dibutyryl-cAMP, 8-bromo-cAMP), and the PICA inhibitor H89 on respiration of isolated pig heart mitochondria. cAMP analogs did not stimulate State 3 respiration of Ca2+-depleted mitochondria (822 +/- 3.6% of control), in contrast to the 2-fold activation induced by 0.95 mu M free Ca2+, which was unaffected by H89. Using fluorescence and integrating sphere spectroscopy, we determined that Ca2+ increased the reduction of NADH (8%), and of cytochromes b(H) (3%), c(1) (3%), c (4%), and a (2%), together with a doubling of conductances for Complex I + III and Complex IV. None of these changes were induced by cAMP analogs nor abolished by H89. In Ca2+-undepleted mitochondria, we observed only slight changes in State 3 respiration rates upon addition of 50 mu M cAMP (85 +/- 9.9%), dibutyryl-cAMP (80.1 +/- 5.2%), 8-bromo-cAMP (88.6 +/- 33%), or 1 mu M H89 (89.7 +/- 19.9%) with respect to controls. Similar results were obtained when measuring respiration in heart homogenates. Addition of exogenous PICA with dibutyryl-cAMP or the constitutively active catalytic subunit of PICA to isolated mitochondria decreased State 3 respiration by only 5-15%. These functional studies suggest that alterations in mitochondria cAMP and PICA activity do not contribute significantly to the acute Ca2+ stimulation of oxidative phosphorylation. Published by Elsevier B.V. C1 [Covian, Raul; French, Stephanie; Kusnetz, Heather; Balaban, Robert S.] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Covian, R (reprint author), NHLBI, Cardiac Energet Lab, NIH, 10 Ctr Dr,Room 81D416, Bethesda, MD 20892 USA. EM raul.coviangarcia@nih.gov FU intramural funding of the Division of Intramural Research of the National Heart, Lung, and Blood Institute FX This study was supported by the intramural funding of the Division of Intramural Research of the National Heart, Lung, and Blood Institute. NR 46 TC 3 Z9 3 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 EI 0006-3002 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD DEC PY 2014 VL 1837 IS 12 BP 1913 EP 1921 DI 10.1016/j.bbabio.2014.08.006 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AU6RO UT WOS:000345729800001 PM 25178840 ER PT J AU Grossman, J Cuellar-Rodriguez, J Gea-Banacloche, J Zerbe, C Calvo, K Hughes, T Hakim, F Cole, K Parta, M Freeman, A Holland, SM Hickstein, DD AF Grossman, Jennifer Cuellar-Rodriguez, Jennifer Gea-Banacloche, Juan Zerbe, Christa Calvo, Katherine Hughes, Thomas Hakim, Fran Cole, Kristen Parta, Mark Freeman, Alexandra Holland, Steven M. Hickstein, Dennis D. TI Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation for GATA2 Deficiency SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE GATA2; Hematopoietic stem cell transplantation; Myelodysplastic syndrome; Familial acute myelogenous leukemia ID ACUTE MYELOID-LEUKEMIA; HEMATOLOGIC MALIGNANCIES; SPORADIC MONOCYTOPENIA; AUTOSOMAL-DOMINANT; PRIMARY LYMPHEDEMA; EMBERGER SYNDROME; MONOMAC SYNDROME; MUTATIONS; MYELODYSPLASIA; CYCLOPHOSPHAMIDE AB We treated 14 patients with GATA2 deficiency using a nonmyeloablative allogeneic hematopoietic stem cell transplantation regimen. Four patients received peripheral blood stem cells from matched related donors (MRD), 4 patients received peripheral blood stem cells from matched unrelated donors (URD), 4 patients received hematopoietic stem cells from umbilical cord blood donors (UCB), and 2 patients received bone marrow cells from haploidentical related donors. MRD and URD recipients received conditioning with 3 days of fludarabine and 200 cGy total body irradiation (TBI). Haploidentical related donor recipients and UCB recipients received cyclophosphamide and 2 additional days of fludarabine along with 200 cGY TBI. MRD, URD, and UCB recipients received tacrolimus and sirolimus for post-transplantation immunosuppression, whereas haploidentical recipients received high-dose cyclophosphamide followed by tacrolimus and mycophenolate mofetil. Eight patients are alive with reconstitution of the severely deficient monocyte, B cell, and natural killer cell populations and reversal of the clinical phenotype at a median follow-up of 3.5 years. Two patients (I URD recipient and 1 UCB recipient) rejected the donor graft and 1 MRD recipient relapsed with myelodysplastic syndrome after transplantation. We are currently using a high-dose conditioning regimen with busulfan and fludarabine in patients with GATA2 deficiency to achieve more consistent engraftment and eradication of the malignant myeloid clones. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation. C1 [Grossman, Jennifer] Alberta Hlth Serv, Div Hematol & Hematol Malignancies, Calgary, AB, Canada. [Cuellar-Rodriguez, Jennifer; Zerbe, Christa; Freeman, Alexandra; Holland, Steven M.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Gea-Banacloche, Juan; Hakim, Fran; Cole, Kristen; Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Calvo, Katherine] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Hughes, Thomas] NIH, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. [Parta, Mark] Leidos Biomed Res Inc, Frederick, MD USA. [Parta, Mark] NIAID, Intramural Clin Management & Operat Branch, Bethesda, MD 20892 USA. RP Hickstein, DD (reprint author), 9000 Rockville Pike,MSC1203,Bldg 10 CRC,Rm 3-3142, Bethesda, MD 20892 USA. EM hicksted@mail.nih.gov OI Calvo, Katherine/0000-0002-0771-4191 FU Intramural Research program of the National Institutes of Health; United States, including the National Cancer Institute [1ZIABC010549]; National Institute of Allergy and Infectious Diseases [HHSN261200800001E] FX This research was supported in part by the Intramural Research program of the National Institutes of Health, United States, including the National Cancer Institute (Grant 1ZIABC010549 to D.D.H.), and the National Institute of Allergy and Infectious Diseases; and in part under contract number HHSN261200800001E. 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 21 TC 10 Z9 10 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD DEC PY 2014 VL 20 IS 12 BP 1940 EP 1948 DI 10.1016/j.bbmt.2014.08.004 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AU4UJ UT WOS:000345606500012 PM 25111582 ER PT J AU Johnson, KE Tachibana, C Coronado, GD Dember, LM Glasgow, RE Huang, SS Martin, PJ Richards, J Rosenthal, G Septimus, E Simon, GE Solberg, L Suls, J Thompson, E Larson, EB AF Johnson, Karin E. Tachibana, Chris Coronado, Gloria D. Dember, Laura M. Glasgow, Russell E. Huang, Susan S. Martin, Paul J. Richards, Julie Rosenthal, Gary Septimus, Ed Simon, Gregory E. Solberg, Leif Suls, Jerry Thompson, Ella Larson, Eric B. TI A guide to research partnerships for pragmatic clinical trials SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID POLICY C1 [Johnson, Karin E.; Tachibana, Chris; Richards, Julie; Simon, Gregory E.; Thompson, Ella; Larson, Eric B.] Grp Hlth Res Inst, Seattle, WA 98101 USA. [Coronado, Gloria D.] Kaiser Permanente Ctr Hlth Res, Portland, OR 97227 USA. [Dember, Laura M.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Glasgow, Russell E.] Univ Colorado, Colorado Hlth Outcomes Program, Sch Med, Aurora, CO 80045 USA. [Huang, Susan S.] Univ Calif Irvine, Sch Med, Irvine, CA 92697 USA. [Martin, Paul J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Rosenthal, Gary] Univ Iowa, Iowa City, IA 52242 USA. [Septimus, Ed] Hosp Corp Amer, Clin Serv Grp, Nashville, TN 37402 USA. [Solberg, Leif] HealthPartners Inst Educ & Res, Bloomington, MN 55425 USA. [Suls, Jerry] NCI, Bethesda, MD 20892 USA. RP Johnson, KE (reprint author), Grp Hlth Res Inst, Seattle, WA 98101 USA. EM johnson.ke@ghc.org FU NIH Common Fund for the NIH Health Care Systems Research Collaboratory [U54 AT007748] FX All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: this work was supported by a cooperative agreement (U54 AT007748) from the NIH Common Fund for the NIH Health Care Systems Research Collaboratory; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; SSH received non-financial support from Sage Products and Molnlycke. NR 20 TC 12 Z9 13 U1 0 U2 3 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 DEC 1 PY 2014 VL 349 AR g6826 DI 10.1136/bmj.g6826 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA AW2KJ UT WOS:000346116200002 PM 25446054 ER PT J AU Loud, JT AF Loud, Jennifer T. TI Circulating estrogens and estrogens within the breast among postmenopausal BRCA1/2 mutation carriers SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Letter C1 NCI, Clin Genet Branch, DCEG, NIH,DHHS, Rockville, MD 20850 USA. RP Loud, JT (reprint author), NCI, Clin Genet Branch, DCEG, NIH,DHHS, 9609 Med Ctr Dr,Room 6E536, Rockville, MD 20850 USA. EM loudj@mail.nih.gov NR 3 TC 1 Z9 1 U1 0 U2 0 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 DEC PY 2014 VL 148 IS 3 BP 691 EP 692 DI 10.1007/s10549-014-3186-1 PG 2 WC Oncology SC Oncology GA AU1HC UT WOS:000345370600026 PM 25403808 ER PT J AU Cronin, KA Ries, LAG Edwards, BK AF Cronin, Kathleen A. Ries, Lynn A. G. Edwards, Brenda K. TI Collaborative Staging and Its Impact on Cancer Registry Data: Information for Data Users on Analysis and Interpretation of Registry Data Preface SO CANCER LA English DT Editorial Material C1 [Cronin, Kathleen A.; Ries, Lynn A. G.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Edwards, Brenda K.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Cronin, KA (reprint author), 6116 Execut Blvd, Bethesda, MD 20892 USA. EM cronink@mail.nih.gov NR 2 TC 2 Z9 3 U1 0 U2 0 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 DEC 1 PY 2014 VL 120 IS 23 SU S BP 3755 EP 3757 DI 10.1002/cncr.29049 PG 3 WC Oncology SC Oncology GA AU0WM UT WOS:000345342900001 PM 25412387 ER PT J AU Schymura, MJ Sun, L Percy-Laurry, A AF Schymura, Maria J. Sun, Leon Percy-Laurry, Antoinette TI Prostate Cancer Collaborative Stage Data Items-Their Definitions, Quality, Usage, and Clinical Implications: A Review of SEER Data for 2004-2010 SO CANCER LA English DT Review DE prostate cancer; collaborative stage; American Joint Committee on Cancer staging; TNM stage; Gleason score; prostate specific antigen; prognosis ID RADICAL PROSTATECTOMY; ANTIGEN; BIOPSY; CLASSIFICATION; TRENDS; LEVEL; MEN AB BACKGROUNDVersion 2 of the Collaborative Stage Data Collection System (CSv2) became effective with cases diagnosed in 2010. This report focuses on the CSv2 components required to derive the American Joint Committee on Cancer (AJCC) stage for prostate cancer and on the site-specific factors for prostate cancer captured in CSv2. The report also highlights differences between the AJCC 6th and 7th editions for classifying prostate cancer stage. METHODSData from 18 Surveillance, Epidemiology, and End Results (SEER) Program population-based registries (SEER-18) were analyzed for the years 2004-2010, which included 400,591 prostate cancer cases. RESULTSCSv2 provides specificity with regard to the Gleason grading system by distinguishing between clinical and pathologic patterns and scores. The AJCC 7th edition incorporates prostate-specific antigen values into staging, subdivides stage II into IIA and IIB, and reclassifies extraprostatic invasion with microscopic bladder neck invasion from T4 in the 6th edition to T3a; this latter change affected the AJCC stage of 283 cases in 2010. Of the 44,578 prostate cancer cases diagnosed in 2010 that would have been classified as stage II in the AJCC 6th edition, 32.7%, 27.5%, and 39.8% are classified as stages I, IIA, and IIB, respectively, in the 7th edition. CONCLUSIONSCSv2 provides more information than was previously available to researchers using SEER prostate data. The absence of a clearly defined clinical stage for each prostate case is the overriding limitation that researchers face in relying on Collaborative Stage information to analyze prostate cancer data. Cancer 2014;120(23 suppl):3758-70. (c) 2014 American Cancer Society. This report focuses on aspects of the Collaborative Stage Data Collection System for prostate cancer that researchers should be aware of when analyzing SEER or other North American cancer registry data. This report also highlights differences between the American Joint Committee on Cancer's 6th and 7th editions for classifying prostate cancer stage. C1 [Schymura, Maria J.] New York State Dept Hlth, New York State Canc Registry, Div Chron Dis Prevent, Albany, NY 12204 USA. [Sun, Leon; Percy-Laurry, Antoinette] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Schymura, MJ (reprint author), New York State Dept Hlth, Bur Canc Epidemiol, 150 Broadway,Suite 361, Albany, NY 12204 USA. EM maria.schymura@health.ny.gov FU National Cancer Institute; University of Southern California [HHSN261201300004I]; Cancer Prevention Institute of California [HHSN261201300005I]; University of Hawaii [HHSN261201300009I]; University of New Mexico [HHSN261201300010I]; Rutgers University [HHSN261201300021I]; Connecticut Department of Health [HHSN261201300019I]; University of Iowa [HHSN261201300020I]; Emory University [HHSN261201300015I]; Louisiana State University [HHSN261201300016I]; University of Utah [HHSN2612 01300017I]; Wayne State University [HHSN261201300011I]; Fred Hutchinson Cancer Center [HHSN261201300012I]; University of Kentucky [HHSN261201300013O]; Public Health Institute [HHSN261201300014I]; Information Management Services, Inc. [HHSN261201100007I] FX This supplement edition of Cancer has been sponsored by the National Cancer Institute. Data used in the production of this supplement was supported under Contract HHSN261201300004I (University of Southern California), HHSN261201300005I (Cancer Prevention Institute of California, HHSN261201300009I (University of Hawaii), HHSN261201300010I (University of New Mexico), HHSN261201300021I (Rutgers University), HHSN261201300019I (Connecticut Department of Health), HHSN261201300020I (University of Iowa), HHSN261201300015I (Emory University), HHSN261201300016I (Louisiana State University), HHSN2612 01300017I (University of Utah), HHSN261201300011I (Wayne State University), HHSN261201300012I (Fred Hutchinson Cancer Center), HHSN261201300013O (University of Kentucky), and HHSN261201300014I (Public Health Institute). Technical support was provided under contract HHSN261201100007I (Information Management Services, Inc.). NR 32 TC 6 Z9 6 U1 1 U2 7 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 DEC 1 PY 2014 VL 120 IS 23 SU S BP 3758 EP 3770 DI 10.1002/cncr.29052 PG 13 WC Oncology SC Oncology GA AU0WM UT WOS:000345342900002 PM 25412388 ER PT J AU Howlader, N Chen, VW Ries, LAG Loch, MM Lee, R DeSantis, C Lin, CC Ruhl, J Cronin, KA AF Howlader, Nadia Chen, Vivien W. Ries, Lynn A. G. Loch, Michelle M. Lee, Richard DeSantis, Carol Lin, Chun Chieh Ruhl, Jennifer Cronin, Kathleen A. TI Overview of Breast Cancer Collaborative Stage Data Items-Their Definitions, Quality, Usage, and Clinical Implications: A Review of SEER Data for 2004-2010 SO CANCER LA English DT Review DE breast cancer; collaborative stage; AJCC; prognostic; site-specific factors ID AMERICAN SOCIETY; SUBTYPES; ESTROGEN; WOMEN; RECOMMENDATIONS; STATISTICS; SURVIVAL; REGISTRY AB BACKGROUNDSurveillance, Epidemiology, and End Results (SEER) Program registries began collecting new data items, known as site-specific factors (SSFs), related to breast cancer treatment, prediction, and prognosis under the Collaborative Stage version 2 (CSv2) Data Collection System for cases diagnosed in 2010. The objectives of this report are to: 1) assess the completeness of the new SSFs and discuss their limitations and 2) discuss key changes in American Joint Committee on Cancer (AJCC) staging between the 6th and 7th editions. METHODSWe used data from the 18 SEER population-based registries (SEER-18), which included 71,983 women diagnosed with breast cancer in 2010. RESULTSOf the 18 SSFs examined in this study, 6 SSFs were more than 75% complete. Information on estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), was available for more than 90% of the invasive breast cancer cases. These data are required to categorize the distinct subtypes of breast cancer. The majority of cases also had information on other prognostic factors such as Bloom-Richardson score/grade (83%) and the size of invasive component in the tumor (76%). As a result of changes in staging criteria, nearly 10% of cases categorized as stage IIA according to the 6th edition of the AJCC staging manual were downstaged to stage IB under the 7th edition. CONCLUSIONSThe Collaborative Stage data collection system enables registries to collect current, relevant, and standardized data items that are consistent with the evolving view of breast cancer as a heterogeneous disease. Cancer 2014;120(23 suppl):3771-80. (c) 2014 American Cancer Society. This report discusses the utility and limitations of the new breast cancer variables to be collected under the Collaborative Stage Data Collection System for researchers who intend to analyze these variables using population-based SEER or other North American cancer registry data. The report also highlights differences between the American Joint Committee on Cancer's (AJCC) 6th and 7th editions for classifying breast cancer stage. C1 [Howlader, Nadia; Ries, Lynn A. G.; Ruhl, Jennifer; Cronin, Kathleen A.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Chen, Vivien W.] Louisiana State Univ, Hlth Sci Ctr, Louisiana Tumor Registry & Epidemiol Program, Sch Publ Hlth, New Orleans, LA USA. [Ries, Lynn A. G.] RiesSearch LLC, Rockville, MD USA. [Loch, Michelle M.] Louisiana State Univ, Sch Med, Dept Hematol Oncol, Hlth Sci Ctr, New Orleans, LA USA. [Lee, Richard] Informat Management Syst Inc, Silver Spring, MD USA. [DeSantis, Carol; Lin, Chun Chieh] Amer Canc Soc, Surveillance & Hlth Serv Res Program, Atlanta, GA 30329 USA. RP Howlader, N (reprint author), NCI, Surveillance Res Program, Data Anal & Interpretat Branch, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 4E528, Bethesda, MD 20892 USA. EM howladern@mail.nih.gov FU National Cancer Institute; University of Southern California [HHSN261201300004I]; Cancer Prevention Institute of California [HHSN261201300005I]; University of Hawaii [HHSN261201300009I]; University of New Mexico [HHSN261201300010I]; Rutgers University [HHSN261201300021I]; Connecticut Department of Health [HHSN261201300019I]; University of Iowa [HHSN261201300020I]; Emory University [HHSN261201300015I]; Louisiana State University [HHSN261201300016I]; University of Utah [HHSN261201300017I]; Wayne State University [HHSN261201300011I]; Fred Hutchinson Cancer Center [HHSN261201300012I]; University of Kentucky [HHSN261201300013O]; Public Health Institute [HHSN261201300014I]; Information Management Services, Inc. [HHSN261201100007I] FX This supplement edition of Cancer has been sponsored by the National Cancer Institute. Data used in the production of this supplement was supported under Contract HHSN261201300004I (University of Southern California), HHSN261201300005I (Cancer Prevention Institute of California, HHSN261201300009I (University of Hawaii), HHSN261201300010I (University of New Mexico), HHSN261201300021I (Rutgers University), HHSN261201300019I (Connecticut Department of Health), HHSN261201300020I (University of Iowa), HHSN261201300015I (Emory University), HHSN261201300016I (Louisiana State University), HHSN261201300017I (University of Utah), HHSN261201300011I (Wayne State University), HHSN261201300012I (Fred Hutchinson Cancer Center), HHSN261201300013O (University of Kentucky), and HHSN261201300014I (Public Health Institute). Technical support was provided under contract HHSN261201100007I (Information Management Services, Inc.). NR 28 TC 14 Z9 15 U1 0 U2 17 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 DEC 1 PY 2014 VL 120 IS 23 SU S BP 3771 EP 3780 DI 10.1002/cncr.29059 PG 10 WC Oncology SC Oncology GA AU0WM UT WOS:000345342900003 PM 25412389 ER PT J AU Chen, VW Ruiz, BA Hsieh, MC Wu, XC Ries, LAG Lewis, DR AF Chen, Vivien W. Ruiz, Bernardo A. Hsieh, Mei-Chin Wu, Xiao-Cheng Ries, Lynn A. G. Lewis, Denise R. TI Analysis of Stage and Clinical/Prognostic Factors for Lung Cancer From SEER Registries: AJCC Staging and Collaborative Stage Data Collection System SO CANCER LA English DT Article DE lung cancer; collaborative stage; AJCC; prognostic site-specific factors ID FORTHCOMING 7TH EDITION; TNM CLASSIFICATION; MALIGNANT-TUMORS; PROPOSALS; PROJECT; REVISION; DESCRIPTORS; SURVIVAL; ASSOCIATION; GROUPINGS AB BACKGROUNDThe American Joint Committee on Cancer (AJCC) 7th edition introduced major changes in the staging of lung cancer, including the tumor (T), node (N), metastasis (M)TNMsystem and new stage/prognostic site-specific factors (SSFs), collected under the Collaborative Stage Version 2 (CSv2) Data Collection System. The intent was to improve the stage precision that could guide treatment options and ultimately lead to better survival. This report examines stage trends, the change in stage distributions from the AJCC 6th to the 7th edition, and findings of the prognostic SSFs for 2010 lung cancer cases. METHODSData were from the November 2012 submission of 18 Surveillance, Epidemiology, and End Results (SEER) Program population-based registries. A total of 344,797 cases of lung cancer, diagnosed in 2004-2010, were analyzed. RESULTSThe percentages of small tumors and early-stage lung cancer cases increased from 2004 to 2010. The AJCC 7th edition, implemented for 2010 diagnosis year, subclassified tumor size and reclassified multiple tumor nodules, pleural effusions, and involvement of tumors in the contralateral lung, resulting in a slight decrease in stage IB and stage IIIB and a small increase in stage IIA and stage IV. Overall about 80% of cases remained the same stage group in the AJCC 6th and 7th editions. About 21% of lung cancer patients had separate tumor nodules in the ipsilateral (same) lung, and 23% of the surgically resected patients had visceral pleural invasion, both adverse prognostic factors. CONCLUSIONSIt is feasible for high-quality population-based registries such as the SEER Program to collect more refined staging and prognostic SSFs that allows better categorization of lung cancer patients with different clinical outcomes and to assess their survival. Cancer 2014;120(23 suppl):3781-92. (c) 2014 American Cancer Society. This report highlights the stage trends and changes in stage distributions for lung cancer as AJCC moved from the 6th to the 7th edition. Significant findings include an increase in small tumors over time and substantial stage shift both within and between stage groups that requires extra caution in data interpretation. About 21% of lung cancer cases had separate tumor nodules in the ipsilateral lung, and 23% of the surgically resected patients had pleural invasion, both adverse prognostic factors. C1 [Chen, Vivien W.; Hsieh, Mei-Chin; Wu, Xiao-Cheng] Louisiana State Univ, Hlth Sci Ctr, Sch Publ Hlth, Louisiana Tumor Registry, New Orleans, LA 70112 USA. [Chen, Vivien W.; Hsieh, Mei-Chin; Wu, Xiao-Cheng] Louisiana State Univ, Hlth Sci Ctr, Sch Publ Hlth, Program Epidemiol, New Orleans, LA 70112 USA. [Ruiz, Bernardo A.] Louisiana State Univ, Hlth Sci Ctr, Sch Med, Dept Pathol, New Orleans, LA 70112 USA. [Ries, Lynn A. G.; Lewis, Denise R.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, NIH, Rockville, MD USA. RP Chen, VW (reprint author), Louisiana State Univ, Hlth Sci Ctr, Sch Publ Hlth, Louisiana Tumor Registry, 2020 Gravier St,3-F, New Orleans, LA 70112 USA. EM vchen@lsuhsc.edu FU National Cancer Institute; University of Southern California [HHSN261201300004I]; Cancer Prevention Institute of California [HHSN261201300005I]; University of Hawaii [HHSN261201300009I]; University of New Mexico [HHSN261201300010I]; Rutgers University [HHSN261201300021I]; Connecticut Department of Health [HHSN 261201300019I]; University of Iowa [HHSN 261201300020I]; Emory University [HHSN261201300015I]; Louisiana State University [HHSN261201300016I]; University of Utah [HHSN261201300017I]; Wayne State University [HHSN 261201300011I]; Fred Hutchinson Cancer Center [HHSN261201300012I]; University of Kentucky [HHSN261201300013O]; Public Health Institute [HHSN261201300014I]; Information Management Services, Inc. [HHSN261201100007I]; NIH/NCI [HHSN261201000030C, HHSN261201200422P]; Louisiana State University Health Sciences Center; RiesSearch, LLC FX This supplement edition of Cancer has been sponsored by the National Cancer Institute. Data used in the production of this supplement was supported under Contract HHSN261201300004I (University of Southern California), HHSN261201300005I (Cancer Prevention Institute of California, HHSN261201300009I (University of Hawaii), HHSN261201300010I (University of New Mexico), HHSN261201300021I (Rutgers University), HHSN 261201300019I (Connecticut Department of Health), HHSN 261201300020I (University of Iowa), HHSN261201300015I (Emory University), HHSN261201300016I (Louisiana State University), HHSN261201300017I (University of Utah), HHSN 261201300011I (Wayne State University), HHSN261201300012I (Fred Hutchinson Cancer Center), HHSN261201300013O (University of Kentucky), and HHSN261201300014I (Public Health Institute). Technical support was provided under contract HHSN261201100007I (Information Management Services, Inc.). This work was supported in part under NIH/NCI contract number HHSN261201000030C with Louisiana State University Health Sciences Center (to V.W.C., B.A.R., M.C.H., X.C.W.) and NIH/NCI contract number HHSN261201200422P with RiesSearch, LLC (to L.A.R.). NR 31 TC 6 Z9 6 U1 0 U2 5 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 DEC 1 PY 2014 VL 120 IS 23 SU S BP 3781 EP 3792 DI 10.1002/cncr.29045 PG 12 WC Oncology SC Oncology GA AU0WM UT WOS:000345342900004 PM 25412390 ER PT J AU Chen, VW Hsieh, MC Charlton, ME Ruiz, BA Karlitz, J Altekruse, SF Ries, LAG Jessup, JM AF Chen, Vivien W. Hsieh, Mei-Chin Charlton, Mary E. Ruiz, Bernardo A. Karlitz, Jordan Altekruse, Sean F. Ries, Lynn A. G. Jessup, J. Milburn TI Analysis of Stage and Clinical/Prognostic Factors for Colon and Rectal Cancer From SEER Registries: AJCC and Collaborative Stage Data Collection System SO CANCER LA English DT Article DE colon; rectum; collaborative stage; AJCC; prognostic site-specific factors ID COLORECTAL-CANCER; PROGNOSTIC-FACTOR; TUMOR DEPOSITS; SURVEILLANCE; STATISTICS; CARCINOMA; RESECTION; THERAPY; SOCIETY; MARKERS AB BACKGROUNDThe Collaborative Stage (CS) Data Collection System enables multiple cancer registration programs to document anatomic and molecular pathology features that contribute to the Tumor (T), Node (N), Metastasis (M) TNM system of the American Joint Committee on Cancer (AJCC). This article highlights changes in CS for colon and rectal carcinomas as TNM moved from the AJCC 6th to the 7th editions. METHODSData from 18 Surveillance, Epidemiology, and End Results (SEER) population-based registries were analyzed for the years 2004-2010, which included 191,361colon and 73,341 rectal carcinomas. RESULTSOverall, the incidence of colon and rectal cancers declined, with the greatest decrease in stage 0. The AJCC's 7th edition introduction of changes in the subcategorization of T4, N1, and N2 caused shifting within stage groups in 25,577 colon and 10,150 rectal cancers diagnosed in 2010. Several site-specific factors (SSFs) introduced in the 7th edition had interesting findings: 1) approximately 10% of colon and rectal cancers had tumor deposits about 30%-40% occurred without lymph node metastases, which resulted in 2.5% of colon and 3.3% of rectal cases becoming N1c (stage III A/B) in the AJCC 7th edition; 2) 10% of colon and 12% of rectal cases had circumferential radial margins <1 mm; 3) about 46% of colorectal cases did not have a carcinoembryonic antigen (CEA) testing or documented CEA information; and 4) about 10% of colorectal cases had perineural invasion. CONCLUSIONSAdoption of the AJCC 7th edition by the SEER program provides an assessment tool for staging and SSFs on clinical outcomes. This evidence can be used for education and improved treatment for colorectal carcinomas. Cancer 2014;120(23 suppl):3793-806. (c) 2014 American Cancer Society. This report highlights the changes in Collaborative Stage for colon and rectal carcinoma as TNM moved from the AJCC 6th to the 7th edition. Significant findings include the presence of tumor deposits that resulted in upstaging 2.5% of colon and 3.3% or rectal cases from stages I/II to stage III and that 10-12% of resections had circumferential radial margins that were closer than accepted standard of practice. C1 [Chen, Vivien W.; Hsieh, Mei-Chin] Louisiana State Univ, Hlth Sci Ctr, Sch Publ Hlth, Louisiana Tumor Registry, New Orleans, LA 70112 USA. [Chen, Vivien W.; Hsieh, Mei-Chin] Louisiana State Univ, Hlth Sci Ctr, Sch Publ Hlth, Program Epidemiol, New Orleans, LA 70112 USA. [Charlton, Mary E.] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. [Ruiz, Bernardo A.] Louisiana State Univ, Hlth Sci Ctr, Sch Med, Dept Pathol, New Orleans, LA 70112 USA. [Karlitz, Jordan] Tulane Univ, Sch Med, Div Gastroenterol, New Orleans, LA 70112 USA. [Altekruse, Sean F.; Ries, Lynn A. G.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Jessup, J. Milburn] NCI, Canc Diag Program, Div Canc Treatment & Diag, Rockville, MD USA. RP Chen, VW (reprint author), Louisiana State Univ, Hlth Sci Ctr, Sch Publ Hlth, Louisiana Tumor Registry, 2020 Gravier St,3-F, New Orleans, LA 70112 USA. EM vchen@lsuhsc.edu FU National Cancer Institute; University of Southern California [HHSN261201300004I]; Cancer Prevention Institute of California [HHSN261201300005I]; University of Hawaii [HHSN261201300009I]; University of New Mexico [HHSN261201300010I]; Rutgers University [HHSN261201300021I]; Connecticut Department of Health [HHSN261201300019I]; University of Iowa [HHSN261201300020I]; Emory University [HHSN261201300015I]; Louisiana State University [HHSN261201300016I]; University of Utah [HHSN261201300017I]; Wayne State University [HHSN261201300011I]; Fred Hutchinson Cancer Center [HHSN261201300012I]; University of Kentucky [HHSN261201300013O]; Public Health Institute [HHSN261201300014I]; Information Management Services, Inc. [HHSN261201100007I]; NIH/NCI [HHSN261201000030C, HHSN261201000032C, HHSN261201200422P]; Louisiana State University Health Sciences Center; University of Iowa; RiesSearch, LLC FX This supplement edition of Cancer has been sponsored by the National Cancer Institute. Data used in the production of this supplement was supported under Contract HHSN261201300004I (University of Southern California), HHSN261201300005I (Cancer Prevention Institute of California, HHSN261201300009I (University of Hawaii), HHSN261201300010I (University of New Mexico), HHSN261201300021I (Rutgers University), HHSN261201300019I (Connecticut Department of Health), HHSN261201300020I (University of Iowa), HHSN261201300015I (Emory University), HHSN261201300016I (Louisiana State University), HHSN261201300017I (University of Utah), HHSN261201300011I (Wayne State University), HHSN261201300012I (Fred Hutchinson Cancer Center), HHSN261201300013O (University of Kentucky), and HHSN261201300014I (Public Health Institute). Technical support was provided under contract HHSN261201100007I (Information Management Services, Inc.). This work was supported in part under NIH/NCI contract number HHSN261201000030C with Louisiana State University Health Sciences Center (to V.W.C., M.C.H., B.A.R.), NIH/NCI contract number HHSN261201000032C with University of Iowa (to M.E.C.), and NIH/NCI contract number HHSN261201200422P with RiesSearch, LLC (to L.A.R.). NR 33 TC 7 Z9 8 U1 1 U2 9 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 DEC 1 PY 2014 VL 120 IS 23 SU S BP 3793 EP 3806 DI 10.1002/cncr.29056 PG 14 WC Oncology SC Oncology GA AU0WM UT WOS:000345342900005 PM 25412391 ER PT J AU Kosary, CL Altekruse, SF Ruhl, J Lee, R Dickie, L AF Kosary, Carol L. Altekruse, Sean F. Ruhl, Jennifer Lee, Richard Dickie, Lois TI Clinical and Prognostic Factors for Melanoma of the Skin Using SEER Registries: Collaborative Stage Data Collection System, Version 1 and Version 2 SO CANCER LA English DT Article DE melanoma; skin; cutaneous; cancer staging ID PRIMARY CUTANEOUS MELANOMA; AMERICAN JOINT COMMITTEE; LYMPH-NODE POSITIVITY; TUMOR MITOTIC RATE; GROWTH-PHASE; BIOPSY AB BACKGROUNDThe objectives of this article are to assess the completeness of the data collected on site-specific factors (SSFs) as a part of Collaborative Stage (CS) version 2 and the impact of the transition from the American Joint Committee on Cancer's (AJCC) 6th to 7th edition guidelines on stage distribution. METHODSIncidence data for melanomas of the skin from 18 Surveillance, Epidemiology, and End Results (SEER) registries (SEER-18) were analyzed. Percentages of unknown cases for 7 SSFs were examined, along with staging trends from 2004 to 2010 and differences in AJCC 6th and 7th edition stage distributions for 2010 cases. RESULTSFewer than 10% of cases were coded as unknown for SSFs 1 (measured thickness), 2 (ulceration), and 3 (lymph node metastasis). For the remaining SSFs, 36-81% of cases were coded as unknown. Stage distributions were relatively consistent across time and between the AJCC 6th and 7th editions, with the exception of stage IA and stage INOS (not otherwise specified), for which a shift in cases was observed between the AJCC 6th and 7th edition guidelines fOR 2010 cases. CONCLUSIONSA shift of cases out of stage IA and into stage INOS was observed between the AJCC 6th and 7th edition guidelines for 2010 cases. This was attributed to the high number of cases coded as unknown for SSF7 (primary tumor mitotic count/rate). The percentage of cases coded as unknown varied by SSF. Data completeness presents an issue for SSFs introduced in CS version 2. Cancer 2014;120(23 suppl):3807-14. (c) 2014 American Cancer Society. This report highlights the changes in Collaborative Stage for melanomas of the skin as TNM moved from the AJCC 6th to the 7th edition. Stage distributions were relatively consistent across time and between the AJCC 6th and 7th editions, with the exception of stage IA, for whichbecause of the addition of mitotic rate in the assignment of stage IA in the 7th edition and the large number of cases missing this informationa shift into stage INOS was observed. C1 [Kosary, Carol L.; Altekruse, Sean F.; Ruhl, Jennifer; Dickie, Lois] NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [Lee, Richard] Informat Management Serv Inc, Silver Spring, MD USA. RP Kosary, CL (reprint author), NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 4E132, Rockville, MD 20852 USA. EM kosaryc@mail.nih.gov FU National Cancer Institute; University of Southern California [HHSN261201300004I]; Cancer Prevention Institute of California [HHSN261201300005I]; University of Hawaii [HHSN261201300009I]; University of New Mexico [HHSN261201300010I]; Rutgers University [HHSN261201300021I]; Connecticut Department of Health [HHSN261201300019I]; University of Iowa [HHSN261201300020I]; Emory University [HHSN261201300015I]; Louisiana State University [HHSN261201300016I]; University of Utah [HHSN261 201300017I]; Wayne State University [HHSN261201300011I]; Fred Hutchinson Cancer Center [HHSN261201300012I]; University of Kentucky [HHSN261201300013O]; Public Health Institute [HHSN261201300014I]; Information Management Services, Inc. [HHSN261201100007I]; NIH/NCI [HHSN261200900022C]; Information Management Services, Inc. FX This supplement edition of Cancer has been sponsored by the National Cancer Institute. Data used in the production of this supplement was supported under Contract HHSN261201300004I (University of Southern California), HHSN261201300005I (Cancer Prevention Institute of California, HHSN261201300009I (University of Hawaii), HHSN261201300010I (University of New Mexico), HHSN261201300021I (Rutgers University), HHSN261201300019I (Connecticut Department of Health), HHSN261201300020I (University of Iowa), HHSN261201300015I (Emory University), HHSN261201300016I (Louisiana State University), HHSN261 201300017I (University of Utah), HHSN261201300011I (Wayne State University), HHSN261201300012I (Fred Hutchinson Cancer Center), HHSN261201300013O (University of Kentucky), and HHSN261201300014I (Public Health Institute). Technical support was provided under contract HHSN261201100007I (Information Management Services, Inc.). This work was supported in part under NIH/NCI contract number HHSN261200900022C with Information Management Services, Inc. (to R.L.). NR 31 TC 8 Z9 8 U1 1 U2 2 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 DEC 1 PY 2014 VL 120 IS 23 SU S BP 3807 EP 3814 DI 10.1002/cncr.29050 PG 8 WC Oncology SC Oncology GA AU0WM UT WOS:000345342900006 PM 25412392 ER PT J AU Charlton, ME Adamo, M Sun, L Deorah, S AF Charlton, Mary E. Adamo, Margaret (Peggy) Sun, Leon Deorah, Sundeep TI Bladder Cancer Collaborative Stage Variables and Their Data Quality, Usage, and Clinical Implications: A Review of SEER Data, 2004-2010 SO CANCER LA English DT Review DE bladder cancer; staging; data quality; SEER ID LYMPH-NODE METASTASES; ORGANIZATION INTERNATIONAL SOCIETY; RADICAL CYSTECTOMY; CLASSIFICATION; CARCINOMA AB BACKGROUNDSeveral changes were made to bladder cancer staging guidelines between the 6th and 7th editions of the American Joint Committee on Cancer (AJCC) Staging Manual. Also, Collaborative Stage (CS) Data Collection System version 2 (CSv2) implemented for 2010 Surveillance, Epidemiology, and End Results (SEER) cases involved collection of 3 new site-specific factors (SSFs): World Health Organization/International Society of Urological pathology grade (SSF1), size of metastasis in regional lymph nodes (SSF2), and extranodal extension (SSF3). Our objective was to evaluate these new SSFs to assist researchers in their use/interpretation and to describe data quality issues to be addressed moving forward. METHODSStaging trends were assessed for invasive and noninvasive bladder cancer cases from 2004 to 2010. Among 2010 cases, staging was compared using the AJCC 6th and 7th edition guidelines, and evaluation of completeness/quality of the SSFs was performed in relevant subgroups. RESULTSAge-adjusted incidence rates and proportions of cases by stage remained steady from 2004 to 2010. Changes from the AJCC 6th to 7th editions caused no substantial movement between stages. SSF1 had a known value in 82% of cases, which was higher than the traditional SEER grade/differentiation variable. SSF2 and SSF3 were less complete, with 41% and 37% having known values, respectively, among cases with lymph node involvement (according to CS lymph node variable). CONCLUSIONSSSF1 was more complete and straightforward to interpret than the traditional grade/differentiation variable. SSF2 and SSF3 were less complete, may be associated with data quality issues, and should only be used among cases with known lymph node involvement Cancer 2014;120(23 suppl):3815-25. (c) 2014 American Cancer Society. This report describes the changes made in bladder cancer staging from the AJCC 6th to the 7th edition and the new site specific factors (SSFs) collected for 2010 cases. The WHO/ISUP Grade (SSF1) had a known value in 82% of cases, whereas size of metastasis in regional lymph nodes (SSF2) and extranodal extension (SSF3) only had known values in 41% and 37% of cases with known lymph node involvement, respectively. C1 [Charlton, Mary E.] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA 52242 USA. [Charlton, Mary E.] Univ Iowa, State Hlth Registry Iowa, Coll Publ Hlth, Iowa City, IA 52242 USA. [Adamo, Margaret (Peggy); Sun, Leon] NCI, Surveillance Res Program, Bethesda, MD 20892 USA. [Deorah, Sundeep] Univ Iowa, Dept Urol, Carver Coll Med, Iowa City, IA 52242 USA. RP Charlton, ME (reprint author), Univ Iowa, Dept Epidemiol, Coll Publ Hlth, 105 River St,Room S453, Iowa City, IA 52242 USA. EM mary-charlton@uiowa.edu FU National Cancer Institute; University of Southern California [HHSN261201-300004I]; Cancer Prevention Institute of California [HHSN261201-300005I]; University of Hawaii [HHSN261-201300009I]; University of New Mexico [HHSN261201300010I]; Rutgers University [HHSN261201300021I]; Connecticut Department of Health [HHSN261201300019I]; University of Iowa [HHSN261201300020I]; Emory University [HHSN261-201300015I]; Louisiana State University [HHSN261201300016I]; University of Utah [HHSN261201300017I]; Wayne State University [HHSN261201300011I]; Fred Hutchinson Cancer Center [HHSN2-61201300012I]; University of Kentucky [HHSN2-61201300013O]; Public Health Institute [HHSN261201300014I]; Information Management Services, Inc. [HHSN261201100007I]; NIH/NCI [HHSN261201000032C]; University of Iowa FX This supplement edition of Cancer has been sponsored by the National Cancer Institute. Data used in the production of this supplement was supported under Contract HHSN261201-300004I (University of Southern California), HHSN261201-300005I (Cancer Prevention Institute of California, HHSN261-201300009I (University of Hawaii), HHSN261201300010I (University of New Mexico), HHSN261201300021I (Rutgers University), HHSN261201300019I (Connecticut Department of Health), HHSN261201300020I (University of Iowa), HHSN261-201300015I (Emory University), HHSN261201300016I (Louisiana State University), HHSN261201300017I (University of Utah), HHSN261201300011I (Wayne State University), HHSN2-61201300012I (Fred Hutchinson Cancer Center), HHSN2-61201300013O (University of Kentucky), and HHSN261201300014I (Public Health Institute). Technical support was provided under contract HHSN261201100007I (Information Management Services, Inc.). This work was supported in part under NIH/NCI contract number HHSN261201000032C with the University of Iowa (to M.E.C.). NR 16 TC 1 Z9 1 U1 1 U2 3 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 DEC 1 PY 2014 VL 120 IS 23 SU S BP 3815 EP 3825 DI 10.1002/cncr.29047 PG 11 WC Oncology SC Oncology GA AU0WM UT WOS:000345342900007 PM 25412393 ER PT J AU Altekruse, SF Dickie, L Wu, XC Hsieh, MC Wu, MX Lee, R Delacroix, S AF Altekruse, Sean F. Dickie, Lois Wu, Xiao-Cheng Hsieh, Mei-Chin Wu, Manxia Lee, Richard Delacroix, Scott, Jr. TI Clinical and Prognostic Factors for Renal Parenchymal, Pelvis, and Ureter Cancers in SEER Registries: Collaborative Stage Data Collection System, Version 2 SO CANCER LA English DT Article DE kidney; renal pelvis; cancer; AJCC collaborative stage; site-specific factors ID INTERNATIONAL MULTICENTER EXPERIENCE; ADRENAL-GLAND INVOLVEMENT; CELL CARCINOMA; RADICAL NEPHROURETERECTOMY; UROTHELIAL CARCINOMA; CONSENSUS CLASSIFICATION; LYMPH-NODES; TUMOR SIZE; SURVIVAL; IMPACT AB BACKGROUNDThe American Joint Committee on Cancer's (AJCC) 7th edition cancer staging manual reflects recent changes in cancer care practices. This report assesses changes from the AJCC 6th to the AJCC 7th edition stage distributions and the quality of site-specific factors (SSFs). METHODSIncidence data for renal parenchyma and pelvis and ureter cancers from 18 Surveillance, Epidemiology, and End Results (SEER) registries were examined, including staging trends during 2004-2010, stage distribution changes between the AJCC 6th and 7th editions, and SSF completeness for cases diagnosed in 2010. RESULTSFrom 2004 to 2010, the percentage of stage I renal parenchyma cancers increased from 50% to 58%, whereas stage IV and unknown stage cases decreased (18% to 15%, and 10% to 6%, respectively). During this period, the percentage of stage 0a renal pelvis and ureter cancers increased from 21% to 25%, and stage IV and unknown stage tumors decreased (20% to 18%, and 7% to 5%, respectively). Stage distributions under the AJCC 6th and 7th editions were about the same. For renal parenchymal cancers, 71%-90% of cases had known values for 6 required SSFs. For renal pelvis and ureter cancers, 74% of cases were coded as known for SSF1 (WHO/ISUP grade) and 47% as known for SSF2 (depth of renal parenchymal invasion). SSF values were known for larger proportions of cases with reported resections. CONCLUSIONSStage distributions between the AJCC 6th and 7th editions were similar. SSFs were known for more than two-thirds of cases, providing more detail in the SEER database relevant to prognosis. Cancer 2014;120(23 suppl):3826-35. (c) 2014 American Cancer Society. The percentage of early-stage cases increased, whereas late- and known-stage cases decreased over time for renal parenchymal and pelvic and ureter cancers. Stage distributions between the AJCC 6th and 7th editions are about the same, and site-specific factors were known for more than two-thirds of the cases. C1 [Altekruse, Sean F.; Dickie, Lois] NCI, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Wu, Xiao-Cheng; Hsieh, Mei-Chin] Louisiana State Univ, Sch Publ Hlth, Louisiana Tumor Registry, New Orleans, LA USA. [Wu, Manxia] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. [Lee, Richard] Informat Management Serv Inc, Calverton, MD USA. [Delacroix, Scott, Jr.] Louisiana State Univ, Sch Med, Stanley S Scott Canc Ctr, New Orleans, LA USA. RP Altekruse, SF (reprint author), NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 4E536, Rockville, MD 20850 USA. EM altekrusesf@mail.nih.gov FU National Cancer Institute; University of Southern California [HHSN261201300004I]; Cancer Prevention Institute of California [HHSN261201300005I]; University of Hawaii [HHSN261201300009I]; University of New Mexico [HHSN261201300010I]; Rutgers University [HHSN261201300021I]; Connecticut Department of Health [HHSN261201300019I]; University of Iowa [HHSN 261201300020I]; Emory University [HHSN261201300015I]; Louisiana State University [HHSN261201300016I]; University of Utah [HHSN 261201300017I]; Wayne State University [HHSN261201300011I]; Fred Hutchinson Cancer Center [HHSN261201300012I]; University of Kentucky [HHSN261201300013O]; Public Health Institute [HHSN26120 1300014I]; Information Management Services, Inc. [HHSN261201100007I] FX This supplement edition of Cancer has been sponsored by the National Cancer Institute. Data used in the production of this supplement was supported under Contract HHSN261201300004I (University of Southern California), HHSN261201300005I (Cancer Prevention Institute of California, HHSN261201300009I (University of Hawaii), HHSN261201300010I (University of New Mexico), HHSN261201300021I (Rutgers University), HHSN261201300019I (Connecticut Department of Health), HHSN 261201300020I (University of Iowa), HHSN261201300015I (Emory University), HHSN261201300016I (Louisiana State University), HHSN 261201300017I (University of Utah), HHSN261201300011I (Wayne State University), HHSN261201300012I (Fred Hutchinson Cancer Center), HHSN261201300013O (University of Kentucky), and HHSN26120 1300014I (Public Health Institute). Technical support was provided under contract HHSN261201100007I (Information Management Services, Inc.). NR 50 TC 1 Z9 1 U1 2 U2 2 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 DEC 1 PY 2014 VL 120 IS 23 SU S BP 3826 EP 3835 DI 10.1002/cncr.29051 PG 10 WC Oncology SC Oncology GA AU0WM UT WOS:000345342900008 PM 25412394 ER PT J AU Jamison, PM Altekruse, SF Chang, JT Zahn, J Lee, R Noone, AM Barroilhet, L AF Jamison, Patricia M. Altekruse, Sean F. Chang, Joanne T. Zahn, Jennifer Lee, Richard Noone, Anne-Michelle Barroilhet, Lisa TI Site-Specific Factors for Cancer of the Corpus Uteri From SEER Registries: Collaborative Stage Data Collection System, Version 1 and Version 2 SO CANCER LA English DT Article DE corpus uteri; cancer staging; SEER; collaborative stage ID ENDOMETRIAL CANCER; PERITONEAL CYTOLOGY; CARCINOMA; LYMPHADENECTOMY; ADENOCARCINOMA; MORTALITY; DISEASE; RISK AB BACKGROUNDUterine cancer is the fourth leading cancer among US women. Changes in uterine cancer staging were made from the American Joint Committee on Cancer (AJCC) 6th to 7th edition staging manuals, and 8 site-specific factors (SSFs) and 3 histologic schemas were introduced. Carcinomas account for 95% of cases and are the focus of this report. METHODSDistributions of SSF values were examined for 11,601 cases of malignant cancer of the corpus uteri and uterus, NOS (not otherwise specified) diagnosed in Surveillance, Epidemiology, and End Results (SEER) Program registries during 2010. AJCC 6th and 7th edition staging distributions were compared for 11,176 cases using data in both staging systems. AJCC 6th edition staging distributions during 2004-2010 were examined. AJCC 7th edition SSFs required by SEER were International Federation of Gynecology and Obstetrics stage (SSF1), peritoneal cytology (SSF2), number of positive pelvic lymph nodes (SSF3), number of pelvic lymph nodes examined (SSF4), number of positive para-aortic lymph nodes (SSF5), and number of para-aortic lymph nodes examined (SSF6). RESULTSFor SSFs related to lymph nodes, a third of cases were classified as not applicable, reflecting that lymph node dissection is not indicated for cases with stage1A and stage 4 diagnoses. AJCC 7th edition criteria assigned more cases to stage I (72.9%) than AJCC 6th edition criteria (68.7%). Annual counts significantly increased during 2004-2010, as did counts for AJCC 6th edition stages INOS, IA, IB, IC, IIIA, IIIB, IIIC, and IVB. The proportion of cases diagnosed with stage I cancer was stable, whereas stages II and IV decreased and stage III increased. CONCLUSIONSFive SSFs were suitable for analysis: peritoneal cytology results (SSF2), numbers of positive pelvic lymph nodes (SSF3), pelvic lymph nodes examined (SSF4), positive para-aortic lymph nodes (SSF5), and para-aortic lymph nodes examined (SSF6). Cancer 2014;120(23 suppl):3836-45. (c) 2014 American Cancer Society. Five predictive and prognostic site-specific factors that were collected in the 7th edition of the AJCC are suitable for analysis. Staging differences between the AJCC 6th and 7th editions reflected structural changes in staging to more closely correspond with FIGO staging guidelines. C1 [Jamison, Patricia M.; Altekruse, Sean F.; Chang, Joanne T.; Noone, Anne-Michelle] NCI, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Zahn, Jennifer] Care Commun Inc, Chicago, IL USA. [Lee, Richard] Informat Management Serv Inc, Calverton, MD USA. [Chang, Joanne T.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Barroilhet, Lisa] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. RP Noone, AM (reprint author), NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 4E552, Rockville, MD 20850 USA. EM noonea@mail.nih.gov OI Chang, Joanne/0000-0002-3974-8089 FU National Cancer Institute; University of Southern California [HHSN261201300004I]; Cancer Prevention Institute of California [HHSN261201300005I]; University of Hawaii [HHSN261201300009I]; University of New Mexico [HHSN261201300010I]; Rutgers University [HHSN261201300021I]; Connecticut Department of Health [HHSN261201300019I]; University of Iowa [HHSN261201300020I]; Emory University [HHSN261201300015I]; Louisiana State University [HHSN261201300016I]; University of Utah [HHSN261201300017I]; Wayne State University [HHSN261201300011I]; Fred Hutchinson Cancer Center [HHSN261201300012I]; University of Kentucky [HHSN 261201300013O]; Public Health Institute [HHSN26120 1300014I]; Information Management Services, Inc. [HHSN261201100007I] FX This supplement edition of Cancer has been sponsored by the National Cancer Institute. Data used in the production of this supplement was supported under Contract HHSN261201300004I (University of Southern California), HHSN261201300005I (Cancer Prevention Institute of California, HHSN261201300009I (University of Hawaii), HHSN261201300010I (University of New Mexico), HHSN261201300021I (Rutgers University), HHSN261201300019I (Connecticut Department of Health), HHSN261201300020I (University of Iowa), HHSN261201300015I (Emory University), HHSN261201300016I (Louisiana State University), HHSN261201300017I (University of Utah), HHSN261201300011I (Wayne State University), HHSN261201300012I (Fred Hutchinson Cancer Center), HHSN 261201300013O (University of Kentucky), and HHSN26120 1300014I (Public Health Institute). Technical support was provided under contract HHSN261201100007I (Information Management Services, Inc.). NR 29 TC 4 Z9 4 U1 1 U2 2 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 DEC 1 PY 2014 VL 120 IS 23 SU S BP 3836 EP 3845 DI 10.1002/cncr.29054 PG 10 WC Oncology SC Oncology GA AU0WM UT WOS:000345342900009 PM 25412395 ER PT J AU Trabert, B Falk, R Figueroa, J Graubard, B Garcia-Closas, M Lissowska, J Peplonska, B Fox, S Brinton, L AF Trabert, Britton Falk, Roni T. Figueroa, Jonine D. Graubard, Barry I. Garcia-Closas, Montserrat Lissowska, Jolanta Peplonska, Beata Fox, Stephen D. Brinton, Louise A. TI ' Urinary bisphenol A-glucuronide and postmenopausal breast cancer in Poland SO CANCER CAUSES & CONTROL LA English DT Article DE Breast cancer; Bisphenol A-glucuronide; Postmenopausal; Case-control ID ESTROGEN-RECEPTOR-ALPHA; RISK-FACTORS; EXPOSURE; CELLS; 4-NONYLPHENOL; ASSOCIATION; VARIABILITY; POPULATION; DISEASE; OBESITY AB Concerns regarding a possible link between bisphenol A (BPA) and breast cancer have been mounting, but studies in human populations are lacking. We evaluated the association between the major urinary BPA metabolite [BPA-glucuronide (BPA-G)] and postmenopausal breast cancer risk in a large population-based case-control study conducted in two cities in Poland (2000-2003); we further explored the association of BPA-G levels with known postmenopausal breast cancer risk factors in our control population. We analyzed creatinine-adjusted urinary BPA-G levels among 575 postmenopausal cases matched on age and study site to 575 controls without breast cancer using a recently developed assay. Odds ratios and 95 % confidence intervals were used to estimate the association between urinary BPA-G level and breast cancer using conditional logistic regression. Among controls, geometric mean BPA-G levels were compared across categories of breast cancer risk factors using linear regression models. There was no indication that increased BPA-G was associated with postmenopausal breast cancer (p-trend = 0.59). Among controls, mean BPA-G was higher among women reporting extended use of menopausal hormones, a prior screening mammogram, and residence in Warsaw. Other comparisons across strata of postmenopausal breast cancer risk factors were not related to differences in BPA-G. Urinary BPA-G, measured at the time of diagnosis, is not linked to postmenopausal breast cancer. C1 [Trabert, Britton; Falk, Roni T.; Figueroa, Jonine D.; Graubard, Barry I.; Brinton, Louise A.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Garcia-Closas, Montserrat] Inst Canc Res, London SW3 6JB, England. [Lissowska, Jolanta] Ctr Canc, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] M Sklodowska Curie Inst Oncol, Warsaw, Poland. [Peplonska, Beata] Nofer Inst Occupat Med, Dept Environm Epidemiol, Lodz, Poland. [Fox, Stephen D.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Canc Res Technol Program, Prot Characterizat Lab, Frederick, MD USA. RP Trabert, B (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, 9609 Med Ctr Dr,Room 7E-228, Bethesda, MD 20892 USA. EM britton.trabert@nih.gov RI Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Trabert, Britton/F-8051-2015 OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 27 TC 5 Z9 5 U1 2 U2 12 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 DEC PY 2014 VL 25 IS 12 BP 1587 EP 1593 DI 10.1007/s10552-014-0461-8 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9ZZ UT WOS:000345284100001 PM 25189422 ER PT J AU Anuradha, R George, PJ Kumaran, P Nutman, TB Babu, S AF Anuradha, Rajamanickam George, Parakkal Jovvian Kumaran, Paul Nutman, Thomas B. Babu, Subash TI Interleukin-10-and Transforming Growth Factor beta-Independent Regulation of CD8(+) T Cells Expressing Type 1 and Type 2 Cytokines in Human Lymphatic Filariasis SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID BANCROFTIAN FILARIASIS; BRUGIA-PAHANGI; SUBPOPULATIONS; INFECTIONS; LYMPHEDEMA; MECHANISMS; EXPANSION; MICE AB Lymphatic filariasis is known to be associated with diminished CD4(+) Th1 and elevated CD4(+) Th2 responses to parasite-specific antigens. The roles of cytokine-expressing CD8(+) T cells in immune responses to filarial infections are not well defined. To study the roles of CD8(+) T cells expressing type 1, type 2, and type 17 cytokines in filarial infections, we examined the frequencies of these cells in clinically asymptomatic, patently infected (INF) individuals, directly ex vivo and in response to parasite or nonparasite antigens; these frequencies were compared with the results for individuals with filarial lymphedema (i.e., clinical pathology [CP]) and those without active infection or pathology (i.e., endemic normal [EN]). INF individuals exhibited significant decreases in the frequencies of CD8(+) T cells expressing tumor necrosis factor alpha (TNF-alpha), gamma interferon (IFN-gamma), and interleukin-22 (IL-22) at baseline and/or in response to filarial antigens, compared with CP and EN individuals. In contrast, the same individuals exhibited significant increases in the frequencies of CD8(+) T cells expressing IL-4, IL-5, IL-9, IL-13, and IL-21, compared with CP and/or EN individuals. Curative treatment resulted in significantly increased frequencies of CD8(+) T cells expressing IL-2 and significantly decreased frequencies of CD8(+) T cells expressing type 2 cytokines. Finally, the regulation of these responses appears to be independent of IL-10 and transforming growth factor beta (TGF-beta), since blockade of IL-10 or TGF-beta signaling did not significantly alter the frequencies of type 1 or type 2 cytokine-expressing CD8(+) T cells. Our findings suggest that alterations in the frequencies of cytokine-expressing CD8(+) T cells are characteristic features of lymphatic filarial infections. C1 [Anuradha, Rajamanickam; George, Parakkal Jovvian; Babu, Subash] Int Ctr Excellence Res, Natl Inst Hlth, Madras, Tamil Nadu, India. [Kumaran, Paul] Natl Inst Res TB, Madras, Tamil Nadu, India. [Nutman, Thomas B.; Babu, Subash] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Babu, S (reprint author), Int Ctr Excellence Res, Natl Inst Hlth, Madras, Tamil Nadu, India. EM sbabu@mail.nih.gov FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX 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 22 TC 1 Z9 1 U1 2 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD DEC PY 2014 VL 21 IS 12 BP 1620 EP 1627 DI 10.1128/CVI.00598-14 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AU3RX UT WOS:000345532300003 PM 25253667 ER PT J AU Selinger, C Strbo, N Gonzalez, L Aicher, L Weiss, JM Law, GL Palermo, RE Vaccari, M Franchini, G Podack, ER Katze, MG AF Selinger, Christian Strbo, Natasa Gonzalez, Louis Aicher, Lauri Weiss, Jeffrey M. Law, G. Lynn Palermo, Robert E. Vaccari, Monica Franchini, Genoveffa Podack, Eckhard R. Katze, Michael G. TI Multiple Low-Dose Challenges in a Rhesus Macaque AIDS Vaccine Trial Result in an Evolving Host Response That Affects Protective Outcome SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; I INTERFERON RESPONSES; AFRICAN-GREEN MONKEYS; T-CELL RESPONSES; SIV INFECTION; CUTTING EDGE; ANTIVIRAL ACTIVITY; CROSS-PRESENTATION; DENDRITIC CELLS; PROTEIN AB Using whole-blood transcriptional profiling, we investigated differences in the host response to vaccination and challenge in a rhesus macaque AIDS vaccine trial. Samples were collected from animals prior to and after vaccination with live, irradiated vaccine cells secreting the modified endoplasmic reticulum chaperone gp96-Ig loaded with simian immunodeficiency virus (SIV) peptides, either alone or in combination with a SIV-gp120 protein boost. Additional samples were collected following multiple low-dose rectal challenges with SIVmac251. Animals in the boosted group had a 73% reduced risk of infection. Surprisingly, few changes in gene expression were observed during the vaccination phase. Focusing on postchallenge comparisons, in particular for protected animals, we identified a host response signature of protection comprised of strong interferon signaling after the first challenge, which then largely abated after further challenges. We also identified a host response signature, comprised of early macrophage-mediated inflammatory responses, in animals with undetectable viral loads 5 days after the first challenge but with unusually high viral titers after subsequent challenges. Statistical analysis showed that prime-boost vaccination significantly lowered the probability of infection in a time-consistent manner throughout several challenges. Given that humoral responses in the prime-boost group were highly significant prechallenge correlates of protection, the strong innate signaling after the first challenge suggests that interferon signaling may enhance vaccine-induced antibody responses and is an important contributor to protection from infection during repeated low-dose exposure to SIV. C1 [Selinger, Christian; Aicher, Lauri; Weiss, Jeffrey M.; Law, G. Lynn; Palermo, Robert E.; Katze, Michael G.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Palermo, Robert E.; Katze, Michael G.] Univ Washington, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA. [Strbo, Natasa; Gonzalez, Louis; Podack, Eckhard R.] Univ Miami, Miller Sch Med, Dept Microbiol & Immunol, Miami, FL 33136 USA. [Vaccari, Monica; Franchini, Genoveffa] NCI, Bethesda, MD 20892 USA. RP Katze, MG (reprint author), Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. EM honey@uw.edu OI Selinger, Christian/0000-0002-4361-549X FU National Institutes of Health, Department of Health and Human Services, under National Institute of Allergy and Infectious Diseases [HHSN272201300010C, P01AI096396]; DAIDS Reagent Resource Support Program for AIDS Vaccine Development, Quality Biological, Gaithersburg, MD [N01-A30018]; Office of the Director [P51OD010425] FX This project was funded with federal funds from the National Institutes of Health, Department of Health and Human Services, under National Institute of Allergy and Infectious Diseases contract HHSN272201300010C (grant P01AI096396), by the DAIDS Reagent Resource Support Program for AIDS Vaccine Development, Quality Biological, Gaithersburg, MD (contract N01-A30018), and by the Office of the Director (grant P51OD010425). NR 45 TC 3 Z9 3 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD DEC PY 2014 VL 21 IS 12 BP 1650 EP 1660 DI 10.1128/CVI.00455-14 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AU3RX UT WOS:000345532300007 PM 25274805 ER PT J AU Huang, Y Jensen, JT Brache, V Cochon, L Williams, A Miranda, MJ Croxatto, H Kumar, N Sussman, H Hoskin, E Plagianos, M Roberts, K Merkatz, R Blithe, D Sitruk-Ware, R AF Huang, YongMei Jensen, Jeffrey T. Brache, Vivian Cochon, Leila Williams, Alistair Miranda, Maria-Jose Croxatto, Horacio Kumar, Narender Sussman, Heather Hoskin, Elena Plagianos, Marlena Roberts, Kevin Merkatz, Ruth Blithe, Diana Sitruk-Ware, Regine TI A randomized study on pharmacodynamic effects of vaginal rings delivering the progesterone receptor modulator ulipristal acetate: research for a novel estrogen-free, method of contraception SO CONTRACEPTION LA English DT Article DE Ulipristal acetate; Contraception; Pharmacodynamics; Endometrium; Vaginal ring ID EMERGENCY CONTRACEPTION; NORMAL WOMEN; ENDOMETRIUM; LEVONORGESTREL; MIFEPRISTONE; OVULATION; PLACEBO; TRIAL AB Objective: To determine whether a 3-month contraceptive vaginal ring (CVR) delivering ulipristal acetate (UPA) can inhibit ovulation in 90% of cycles. Study Design: This was a randomized dose-finding parallel group clinical trial. Fifty-five healthy women with normal ovulation at baseline were randomized to receive a low-dose (1500 mu g/day) or a high-dose (2500 mu g/day) UPA-CVR for two consecutive 12-week treatment periods, followed by a recovery cycle. A subgroup of women received levonorgestrel (LNG) 1.5 mg orally twice (at the end of both 12-week ring periods) or once (at the end of the 24-week treatment). The primary outcome was ovulation suppression assessed by transvaginal ultrasound and hormone levels. Secondary outcomes included endometrial safety and bleeding patterns. Results: All subjects showed normal ovulation at baseline and recovery. Ovulation suppression was seen in 81.8% (95% CI: 73.3%, 88.5%) and 86.1% (95% CI: 78.1%, 92%) of treatment cycles with low and high-dose, respectively. Benign progesterone receptor modulator associated endometrial changes (PAEC) were seen during treatment; 78.8% at week 24, but resolved at recovery cycle. A few cases of heavy bleeding occurred near the end of the 24-week treatment, but a single dose of LNG every 12 weeks reduced the increase in endometrial thickness during the second treatment period and prevented excessive bleeding. Conclusion: The 3-month UPA-CVR may become an effective long-acting, user-controlled estrogen-free contraceptive. The greatest suppression of ovulation was seen with the 2500-mu g/day ring. Implications: The 3-month CVR delivering UPA 2500 mu g/day can become an effective user-controlled estrogen-free contraceptive method. Benign PAEC during treatment returns to normal after discontinuation. The prevention of occasional excessive withdrawal bleeding, either by a progestin or by using higher UPA levels to increase follicle suppression may permit prolonged treatment. (C) 2014 Elsevier Inc. All rights reserved. C1 [Huang, YongMei; Kumar, Narender; Sussman, Heather; Hoskin, Elena; Plagianos, Marlena; Roberts, Kevin; Merkatz, Ruth; Sitruk-Ware, Regine] Populat Council, Ctr Biomed Res, New York, NY 10065 USA. [Jensen, Jeffrey T.] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Brache, Vivian; Cochon, Leila] Profamilia, Santo Domingo, Dominican Rep. [Williams, Alistair] Univ Edinburgh, Edinburgh EH16 4SA, Midlothian, Scotland. [Williams, Alistair] Royal Infirm Edinburgh NHS Trust, Edinburgh EH16 4SA, Midlothian, Scotland. [Miranda, Maria-Jose] Inst Chileno Med Reprod ICMER, Santiago, Chile. [Croxatto, Horacio] Univ Andres Bello, Santiago, Chile. [Blithe, Diana] NICHD, Contracept Discovery & Dev Branch, Bethesda, MD USA. RP Sitruk-Ware, R (reprint author), Populat Council, Ctr Biomed Res, 1230 York Ave, New York, NY 10065 USA. EM regine@popcbr.rockefeller.edu OI BRACHE, VIVIAN/0000-0003-2621-4739; Jensen, Jeffrey/0000-0002-4733-1224 FU NICHD U54 [5U54HD9990, 3U54HD029990-17S1]; HRA Pharma, France FX The study was supported by NICHD U54 Grant # 5U54HD9990 and 3U54HD029990-17S1, and a complementary clinical grant from HRA Pharma, France as well as an educational grant from HRA Pharma contributing to the fellowship of Dr. YongMei Huang at the Population Council. NR 23 TC 6 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0010-7824 EI 1879-0518 J9 CONTRACEPTION JI Contraception PD DEC PY 2014 VL 90 IS 6 BP 565 EP 574 DI 10.1016/j.contraception.2014.08.006 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AU4TQ UT WOS:000345604700003 PM 25193534 ER PT J AU Quintana, AM Geiger, EA Achilly, N Rosenblatt, DS Maclean, KN Stabler, SP Artinger, KB Appel, B Shaikh, TH AF Quintana, Anita M. Geiger, Elizabeth A. Achilly, Nate Rosenblatt, David S. Maclean, Kenneth N. Stabler, Sally P. Artinger, Kristin B. Appel, Bruce Shaikh, Tamim H. TI Hcfc1b, a zebrafish ortholog of HCFC1, regulates craniofacial development by modulating mmachc expression SO DEVELOPMENTAL BIOLOGY LA English DT Article DE HCFC1; Cobalamin; Craniofacial defects; Facial dysmorphia; MMACHC ID EMBRYONIC STEM-CELLS; COMBINED METHYLMALONIC ACIDURIA; NEURAL CREST; CLEFT-PALATE; COBALAMIN METABOLISM; FOLATE-DEFICIENCY; ORAL CLEFTS; FOLIC-ACID; GENE; MUTATIONS AB Mutations in HCFC1 (MIM300019), have been recently associated with cblX (MIM309541), an X-linked, recessive disorder characterized by multiple congenital anomalies including craniofacial abnormalities. HCFC1 is a transcriptional co-regulator that modulates the expression of numerous downstream target genes including MMACHC, but it is not clear how these HCFC1 targets play a role in the clinical manifestations of cblX. To begin to elucidate the mechanism by which HCFC1 modulates disease phenotypes, we have carried out loss of function analyses in the developing zebrafish. Of the two HCFC1 orthologs in zebrafish, hcfc1a and hcfc1b, the loss of hcfc1b specifically results in defects in craniofacial development. Subsequent analysis revealed that hcfc1a regulates cranial neural crest cell differentiation and proliferation within the posterior pharyngeal arches. Further, the hcfc1b-mediated craniofacial abnormalities were rescued by expression of human MMACHC, a downstream target of HCFC1 that is aberrantly expressed in cblX. Furthermore, we tested distinct human HCFC1 mutations for their role in craniofacial development and demonstrated variable effects on MMACHC expression in humans and craniofacial development in zebrafish. Notably, several individuals with mutations in either HCFC1 or MMACHC have been reported to have mild to moderate facial dysmorphia. Thus, our data demonstrates that HCFC1 plays a role in craniofacial development, which is in part mediated through the regulation of MMACHC expression. (C) 2014 Elsevier Inc. All rights reserved. C1 [Quintana, Anita M.; Geiger, Elizabeth A.; Maclean, Kenneth N.; Appel, Bruce; Shaikh, Tamim H.] Univ Colorado, Dept Pediat, SOM, Aurora, CO 80045 USA. [Achilly, Nate] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Rosenblatt, David S.] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada. [Maclean, Kenneth N.; Shaikh, Tamim H.] Univ Colorado, Sch Med, Genet Sect, Aurora, CO 80045 USA. [Stabler, Sally P.] Univ Colorado, Dept Med, Sch Med, Aurora, CO 80045 USA. [Artinger, Kristin B.] Univ Colorado, Dept Craniofacial Biol, Sch Dent Med, Aurora, CO 80045 USA. RP Shaikh, TH (reprint author), Univ Colorado, Dept Pediat, SOM, MSC 8313, Aurora, CO 80045 USA. EM anita.quintana@ucdenver.edu; elizabeth.geiger@ucdenver.edu; nate.achilly@nih.gov; david.rosenblatt@mcgill.ca; ken.maclean@ucdenver.edu; sally.stabler@ucdenver.edu; kristin.artinger@ucdenver.edu; bruce.appel@ucdenver.edu; tamim.shaikh@ucdenver.edu FU Institutional Postdoctoral Research Training Grant [T32MH015442]; NIH [GM081519/S1, NS062717, P30 NS048154] FX A.M.Q was supported by an Institutional Postdoctoral Research Training Grant T32MH015442. This work was supported in part by an NIH Grant GM081519/S1 and institutional funds to T.H.S; NIH Grant NS062717 and a gift from the Gates Frontiers Fund to B.A. The University of Colorado Anschutz Medical Campus Zebrafish Core Facility is supported by NIH P30 NS048154. We thank Alison Brebner for her help in organizing patient derived material. NR 63 TC 6 Z9 6 U1 2 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD DEC 1 PY 2014 VL 396 IS 1 BP 94 EP 106 DI 10.1016/j.ydbio.2014.09.026 PG 13 WC Developmental Biology SC Developmental Biology GA AU3YY UT WOS:000345547600009 PM 25281006 ER PT J AU Lam, T Williams, PL Lee, MM Korrick, SA Birnbaum, LS Burns, JS Sergeyev, O Revich, B Altshul, LM Patterson, DG Turner, WE Hauser, R AF Lam, Thuy Williams, Paige L. Lee, Mary M. Korrick, Susan A. Birnbaum, Linda S. Burns, Jane S. Sergeyev, Oleg Revich, Boris Altshul, Larisa M. Patterson, Donald G., Jr. Turner, Wayman E. Hauser, Russ TI Prepubertal organochlorine pesticide concentrations and age of pubertal onset among Russian boys SO ENVIRONMENT INTERNATIONAL LA English DT Article DE beta-HCH; HCB; Organochlorine pesticides; Male puberty; p,p '-DDE ID SECONDARY SEXUAL CHARACTERISTICS; NUTRITION EXAMINATION SURVEY; BLOOD LEAD LEVELS; POLYCHLORINATED-BIPHENYLS; HUMAN-SERUM; REPRODUCTIVE DEVELOPMENT; HEXACHLOROBENZENE HCB; NATIONAL-HEALTH; DIOXIN EXPOSURE; SECULAR TRENDS AB Background: In animal studies, organochlorine pesticide (OCP) exposure alters pubertal development; however, epidemiological data are limited and inconsistent. Objective: To evaluate the associations of serum OCP concentrations [hexachlorobenzene (HCB), beta-hexachlorocyclohexane (beta-HCH), and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE)] with male pubertal onset Methods: In Chapaevsk, Russia, a town environmentally contaminated with OCPs, 350 8-9 year old boys with measured OCPs were enrolled during 2003-2005 and were followed annually for eight years. We evaluated three measures of pubertal onset: testicular volume (TV) >3 mL in either testis, or stage 2 or greater for genitalia (G2+), or pubic hair (P2+). We used multivariable interval-censored models to evaluate associations of OCPs (quartiles) with physician-assessed pubertal onset. Results: In adjusted models, boys with higher HCB concentrations had later mean ages of TV > 3 mL and P2+ (but not G2+). Mean age at attaining TV > 3 mL was delayed 3.6 (95% CI: -2.6, 9.7), 7.9 (95% CI: 1.7, 14.0), and 4.7 months (95% CI: -1.4, 10.9) for HCB Q2, Q3, and Q4, respectively, compared to Q1 (trend p: 0.06). Boys with higher HCB concentrations reached P2+ 0.1 months earlier (95% CI: -5.8, 5.6) for Q2, 4.7 months later (95% CI: -1.0, 10.3) for Q3 and 4.6 months later (95% CI: -1.1, 10.3) for Q4 compared to Q1 (trend p: 0.04). There were no associations of serum beta-HCH and p,p'-DDE concentrations with age of pubertal onset. Conclusion: Higher prepubertal serum HCB concentrations were associated with later age of gonadarche and pubarche. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Lam, Thuy; Korrick, Susan A.; Burns, Jane S.; Hauser, Russ] Harvard Univ, Environm & Occupat Med & Epidemiol Program, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Lam, Thuy] Quintiles, Cambridge, MA USA. [Williams, Paige L.] Harvard Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02115 USA. [Williams, Paige L.] Harvard Univ, Dept Epidemiol, Sch Publ Hlth, Boston, MA 02115 USA. [Lee, Mary M.] Univ Massachusetts, Sch Med, Dept Pediat, Pediat Endocrine Div, Worcester, MA USA. [Lee, Mary M.] Univ Massachusetts, Sch Med, Dept Cell & Dev Biol, Worcester, MA USA. [Korrick, Susan A.] Harvard Univ, Brigham & Womens Hosp, Channing Div Network Med, Dept Med,Med Sch, Boston, MA 02115 USA. [Birnbaum, Linda S.] NCI, NIH, US Dept HHS, Res Triangle Pk, NC USA. [Sergeyev, Oleg] Samara State Med Univ, Dept Phys Educ & Hlth, Samara, Russia. [Sergeyev, Oleg] Chapaevsk Med Assoc, Chapaevsk, Samara Region, Russia. [Revich, Boris] Russian Acad Sci, Inst Forecasting, Moscow, Russia. [Altshul, Larisa M.] Harvard Univ, Dept Environm Hlth, Sch Publ Hlth, Exposure Epidemiol & Risk Program, Boston, MA 02115 USA. [Altshul, Larisa M.] Environm Hlth & Engn Inc, Needham, MA USA. [Patterson, Donald G., Jr.] EnviroSolut Consulting Inc, Auburn, GA USA. [Patterson, Donald G., Jr.] Axys Analyt Solut, Sidney, BC, Canada. [Patterson, Donald G., Jr.] Exponent Inc, Maynard, MA USA. [Turner, Wayman E.] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Hauser, R (reprint author), Harvard Univ, Environm & Occupat Med & Epidemiol Program, Sch Publ Hlth, 665 Huntington Ave,Bldg 1,Room 1409, Boston, MA 02115 USA. EM rhauser@hsph.harvard.edu OI Sergeyev, Oleg/0000-0002-5745-3348 FU U.S. Environmental Protection Agency [R82943701]; National Institute of Environmental Health Sciences [R01 ES014370, P30 ES000002, R03 ES017117]; intramural program of the National Cancer Institute, National Institutes of Health; National Institute for Occupational Safety and Health training grant [T42-OH008416-09] FX This work was funded by the U.S. Environmental Protection Agency (grant R82943701), the National Institute of Environmental Health Sciences (grant R01 ES014370, P30 ES000002, and R03 ES017117), and the intramural program of the National Cancer Institute, National Institutes of Health. TL was supported by the National Institute for Occupational Safety and Health training grant T42-OH008416-09. NR 71 TC 5 Z9 5 U1 5 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0160-4120 EI 1873-6750 J9 ENVIRON INT JI Environ. Int. PD DEC PY 2014 VL 73 BP 135 EP 142 DI 10.1016/j.envint.2014.06.020 PG 8 WC Environmental Sciences SC Environmental Sciences & Ecology GA AU3WE UT WOS:000345540700016 PM 25118086 ER PT J AU Surolia, I Gulley, J Madan, RA AF Surolia, Ira Gulley, James Madan, Ravi A. TI Recent advances in the use of therapeutic cancer vaccines in genitourinary malignancies SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE bladder cancer; cancer vaccines; combination strategies; immunotherapy; prostate cancer; renal cell carcinoma; tumor-associated antigen ID RENAL-CELL CARCINOMA; RESISTANT PROSTATE-CANCER; ACTIVE-SPECIFIC IMMUNOTHERAPY; POXVIRAL-BASED VACCINE; ANTIGEN 5T4 TROVAX; BLADDER-CANCER; PHASE-I; T-CELL; INTERFERON-ALPHA; IMMUNE-RESPONSE AB Introduction: Despite a recent increase in US FDA-approved treatments, genitourinary malignancies remain a source of significant morbidity and mortality. One focus of research is the use of therapeutic cancer vaccines in these diseases, and a significant body of clinical trial experience now exists for refining vaccine strategies to enhance antitumor efficacy and develop immune-based combination regimens. Areas covered: In recent years, clinical data from multiple trials in genitourinary malignancies have enhanced our understanding of the potential for immunotherapy in these cancers. There are also emerging clinical strategies that combine cancer vaccines with chemotherapy, radiation, androgen-deprivation therapy and immune checkpoint inhibitors. This review is based on a search of relevant literature for data presented over the past 5 years from clinical trials of cancer vaccines in prostate, bladder and renal carcinomas. Expert opinion: In the coming years, clinical trials informed by decades of preclinical data and emerging clinical data will help to define the role of immunotherapy in genitourinary malignancies. Combination strategies that capitalize on the immune properties of standard treatments will bring greater clinical benefits, and immune-based combinations will likely be moved to the neoadjuvant setting, where they may have optimal clinical impact. C1 [Surolia, Ira] NIH, Bethesda, MD 20892 USA. [Gulley, James] NIH, Lab Tumor Immunol & Biol, Bethesda, MD 20892 USA. [Madan, Ravi A.] NCI, NIH, Lab Tumor Immunol & Biol, Bethesda, MD 20892 USA. RP Gulley, J (reprint author), NIH, Lab Tumor Immunol & Biol, 10 Ctr Dr,MSC 1750, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov FU ACGME clinical training fellowship funding at the National Institutes of Health (NIH); intramural NIH funds FX I Surolia is supported by ACGME clinical training fellowship funding at the National Institutes of Health (NIH). J Gulley and R Madan are employees of the US federal government with support from intramural NIH funds. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 101 TC 0 Z9 0 U1 2 U2 6 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 DEC PY 2014 VL 14 IS 12 BP 1769 EP 1781 DI 10.1517/14712598.2014.955010 PG 13 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA AU4TT UT WOS:000345605000006 PM 25212872 ER PT J AU Ojemuyiwa, MA Madan, RA Dahut, WL AF Ojemuyiwa, Michelle A. Madan, Ravi A. Dahut, William L. TI Tyrosine kinase inhibitors in the treatment of prostate cancer: taking the next step in clinical development SO EXPERT OPINION ON EMERGING DRUGS LA English DT Review DE castrate-resistant metastatic prostate cancer; c-Src family kinases; EGFR; platelet-derived growth factor; prostate cancer; tyrosine kinase inhibitor; VEGF ID GROWTH-FACTOR RECEPTOR; PHASE-II TRIAL; ANDROGEN DEPRIVATION THERAPY; RENAL-CELL CARCINOMA; SRC FAMILY KINASES; ANTITUMOR-ACTIVITY; PLUS PREDNISONE; OPEN-LABEL; HEPATOCELLULAR-CARCINOMA; TUMOR ANGIOGENESIS AB Introduction: Prostate cancer (PCa) is the most frequently diagnosed, non-cutaneous malignancy in Western countries. Until recently, few therapeutic options were available for patients with advanced PCa. Although these treatments may delay progression of disease, none are curative. Therefore, research continues to investigate other treatments for advanced PCa. Tyrosine kinase inhibitors (TKIs) have been extensively studied as a treatment for multiple malignancies and may represent an additional strategy. In addition to limiting cellular proliferation and metastasis, there is also growing interest in using these treatments to impact the bone microenvironment and reduce associated morbidity from PCa. Areas covered: Several TKIs have been evaluated in the preclinical setting in advanced PCa. Targets reviewed include the epidermal growth factor family, VEGF receptor, c-Src family kinases, platelet-derived growth factor and c-Met. Expert opinion: Despite strong biological rationale for the use of TKIs therapy for the treatment of PCa, Phase III clinical trials have produced disappointing results. As TKI strategies move forward, the failures of past trials need to be better understood. New approaches with these treatments will also have to take into account modern anti-androgens and a treatment landscape that now includes immunotherapy. C1 [Ojemuyiwa, Michelle A.; Madan, Ravi A.; Dahut, William L.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Dahut, WL (reprint author), NCI, Med Oncol Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dahutw@mail.nih.gov FU National Cancer Institute intramural funding FX The authors received National Cancer Institute intramural funding. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 105 TC 6 Z9 6 U1 0 U2 9 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1472-8214 EI 1744-7623 J9 EXPERT OPIN EMERG DR JI Expert Opin Emerg. Drugs PD DEC PY 2014 VL 19 IS 4 BP 459 EP 470 DI 10.1517/14728214.2014.969239 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AU3JL UT WOS:000345508800002 PM 25345821 ER PT J AU Ghany, MG Liang, TJ AF Ghany, Marc G. Liang, T. Jake TI Building Bridges and Providing Transparency to the Hepatitis C Virus Drug Approval Process SO GASTROENTEROLOGY LA English DT Editorial Material ID UNITED-STATES; INFECTION; DISEASE; BOCEPREVIR; BURDEN; THERAPY; COHORT; MODEL C1 [Ghany, Marc G.; Liang, T. Jake] NIH, Bethesda, MD 20892 USA. RP Ghany, MG (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. FU Intramural NIH HHS; NIDDK NIH HHS [Z01-DK054503, Z01-DK054504, Z01-DK075009] NR 16 TC 0 Z9 0 U1 4 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 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD DEC PY 2014 VL 147 IS 6 BP 1201 EP 1203 DI 10.1053/j.gastro.2014.10.028 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AU3PC UT WOS:000345524800010 PM 25449025 ER PT J AU Allende, ML Proia, RL AF Allende, Maria Laura Proia, Richard L. TI Simplifying complexity: genetically resculpting glycosphingolipid synthesis pathways in mice to reveal function SO GLYCOCONJUGATE JOURNAL LA English DT Review DE Glycosphingolipids; Glycosyltransferases; Gangliosides; Mouse models; Gene targeting ID POLYCYSTIC KIDNEY-DISEASE; GM3 SYNTHASE DEFICIENCY; LACKING GANGLIOSIDE GM3; NERVOUS-SYSTEM; KNOCKOUT MICE; GLUCOSYLCERAMIDE SYNTHASE; CERAMIDE GLUCOSYLTRANSFERASE; MOUSE MODELS; T-CELLS; SULFATIDE AB Glycosphingolipids (GSLs) are a group of plasma-membrane lipids notable for their extremely diverse glycan head groups. The metabolic pathways for GSLs, including the identity of the biosynthetic enzymes needed for synthesis of their glycans, are now well understood. Many of their cellular functions, which include plasma-membrane organization, regulation of cell signaling, endocytosis, and serving as binding sites for pathogens and endogenous receptors, have also been established. However, an understanding of their functions in vivo had been lagging. Studies employing genetic manipulations of the GSL synthesis pathways in mice have been used to systematically reduce the large numbers and complexity of GSL glycan structures, allowing the in vivo functions of GSLs to be revealed from analysis of the resulting phenotypes. Findings from these studies have produced a clearer picture of the role of GSLs in mammalian physiology, which is the topic of this review. C1 [Allende, Maria Laura; Proia, Richard L.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Proia, RL (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bldg 10,Room 9D-06 10 Ctr DR MSC 1821, Bethesda, MD 20892 USA. EM proia@nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 76 TC 9 Z9 9 U1 0 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0282-0080 EI 1573-4986 J9 GLYCOCONJUGATE J JI Glycoconjugate J. PD DEC PY 2014 VL 31 IS 9 BP 613 EP 622 DI 10.1007/s10719-014-9563-5 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU4NQ UT WOS:000345588700002 PM 25351657 ER PT J AU Horner-Johnson, W Dobbertin, K Lee, JC Andresen, EM AF Horner-Johnson, Willi Dobbertin, Konrad Lee, Jae Chul Andresen, Elena M. CA Expert Panel Disability Hlth Dispa TI Disparities in Health Care Access and Receipt of Preventive Services by Disability Type: Analysis of the Medical Expenditure Panel Survey SO HEALTH SERVICES RESEARCH LA English DT Article DE People with disabilities; health care disparities; insurance coverage; adult; population surveillance ID BREAST-CANCER; SCREENING MAMMOGRAPHY; INTERVIEW SURVEY; WOMEN; BARRIERS; POPULATION; QUALITY; PEOPLE; ADULTS AB ObjectiveTo examine differences in access to health care and receipt of clinical preventive services by type of disability among working-age adults with disabilities. Data SourceSecondary analysis of Medical Expenditure Panel Survey (MEPS) data from 2002 to 2008. Study DesignWe conducted cross-sectional logistic regression analyses comparing people with different types of disabilities on health insurance status and type; presence of a usual source of health care; delayed or forgone care; and receipt of dental checkups and cancer screening. Data CollectionWe pooled annualized MEPS data files across years. Our analytic sample consisted of adults (18-64years) with physical, sensory, or cognitive disabilities and nonmissing data for all variables of interest. Principal FindingsIndividuals with hearing impairment had better health care access and receipt than people with other disability types. People with multiple types of limitations were especially likely to have health care access problems and unmet health care needs. ConclusionsThere are differences in health care access and receipt of preventive care depending on what type of disability people have. More in-depth research is needed to identify specific causes of these disparities and assess interventions to address health care barriers for particular disability groups. C1 [Horner-Johnson, Willi; Dobbertin, Konrad; Andresen, Elena M.] Oregon Hlth & Sci Univ, Inst Dev & Disabil, Portland, OR 97239 USA. [Lee, Jae Chul] NIH, Dept Rehabil Med, Clin Res Ctr, Bethesda, MD 20892 USA. RP Horner-Johnson, W (reprint author), Oregon Hlth & Sci Univ, Inst Dev & Disabil, 707 SW Gaines St, Portland, OR 97239 USA. EM hornerjo@ohsu.edu OI Horner-Johnson, Willi/0000-0003-3568-1400 FU National Institute on Disability and Rehabilitation Research, U.S. Department of Education [H133A080031]; National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention [U59DD00942]; Administration on Intellectual and Developmental Disabilities [90DD0684]; Institute on Development and Disability at Oregon Health and Science University FX This work was supported in part by grant H133A080031 from the National Institute on Disability and Rehabilitation Research, U.S. Department of Education. However, the contents do not necessarily represent the policy of the Department of Education, and you should not assume endorsement by the Federal Government. Additional support was provided by cooperative agreement U59DD00942 from the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention; grant 90DD0684 from the Administration on Intellectual and Developmental Disabilities; and the Institute on Development and Disability at Oregon Health and Science University. The authors thank Henry T. Ireys, Ph.D., for his input during the development of the research design; Barbara M. Altman, Ph.D., Elizabeth K. Rasch, P. T., Ph.D., and Stephen P. Gulley, Ph.D., M. S. W., for consultation on identifying people with disabilities in MEPS data; and Amy Sharer for assistance with reference formatting. NR 40 TC 11 Z9 11 U1 2 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-9124 EI 1475-6773 J9 HEALTH SERV RES JI Health Serv. Res. PD DEC PY 2014 VL 49 IS 6 BP 1980 EP 1999 DI 10.1111/1475-6773.12195 PG 20 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AU0XT UT WOS:000345346300016 PM 24962662 ER PT J AU Guedj, J Rotman, Y Cotler, SJ Koh, C Schmid, P Albrecht, J Haynes-Williams, V Liang, TJ Hoofnagle, JH Heller, T Dahari, H AF Guedj, Jeremie Rotman, Yaron Cotler, Scott J. Koh, Christopher Schmid, Peter Albrecht, Jeff Haynes-Williams, Vanessa Liang, T. Jake Hoofnagle, Jay H. Heller, Theo Dahari, Harel TI Understanding Early Serum Hepatitis D Virus and Hepatitis B Surface Antigen Kinetics During Pegylated Interferon-alpha Therapy Via Mathematical Modeling SO HEPATOLOGY LA English DT Article ID N-LINKED GLYCANS; C-VIRUS; ENVELOPE GLYCOPROTEIN; NEUTRALIZING ANTIBODIES; GLUCOSIDASE INHIBITORS; ANTIVIRAL ACTIVITY; HCV INFECTION; RNA KINETICS; EFFICACY; CELLS AB There is little information on the early kinetics of hepatitis delta virus (HDV) and hepatitis B surface antigen (HBsAg) during interferon-a therapy. Here a mathematical model was developed and fitted to frequent HDV and HBsAg kinetic data from 10 patients during the first 28 weeks of pegylated-interferon-alpha 2a (peg-IFN) therapy. Three patients achieved a complete virological response (CVR), defined as undetectable HDV 6 months after treatment stopped with loss of HBsAg and anti-HBsAg seroconversion. After initiation of therapy, a median delay of 9 days (interquartile range [IQR]: 5-15) was observed with no significant changes in HDV level. Thereafter, HDV declined in a biphasic manner, where a rapid first phase lasting for 25 days (IQR: 23-58) was followed by a slower or plateau second phase. The model predicts that the main effect of peg-IFN is to reduce HDV production/release with a median effectiveness of 96% (IQR: 93-99.8). Median serum HDV half-life (t1/2) was estimated as 2.9 days (IQR: 1.5-5.3) corresponding to a pretreatment production and clearance of about 10(10) (IQR: 10(9.7)-10(10.7)) virions/day. None of the patients with flat second phase in HDV achieved CVR. HBsAg kinetics of decline paralleled the second phase of HDV decline consistent with HBsAg-productive-infected cells being the main source of production of HDV, with a median t(1/2) of 135 days (IQR: 20-460). The interferon lambda-3 polymorphism (rs12979860) was not associated with kinetic parameters. Conclusion: Modeling results provide insights into HDV-host dynamics, the relationship between serum HBsAg levels and HBsAg-infected cells, IFN's mode of action, and its effectiveness. The observation that a flat second phase in HDV and HBsAg kinetics was associated with failure to achieve CVR provides the basis to develop early stopping rules during peg-IFN treatment in HDV-infected patients. C1 [Guedj, Jeremie; Dahari, Harel] Los Alamos Natl Lab, Los Alamos, NM USA. [Guedj, Jeremie] Univ Paris 07, INSERM, UMR 1137, IAME, F-75018 Paris, France. [Guedj, Jeremie] Univ Paris 07, Sorbonne Paris Cite, UMR 1137, IAME, F-75018 Paris, France. [Rotman, Yaron; Koh, Christopher; Haynes-Williams, Vanessa; Liang, T. Jake; Hoofnagle, Jay H.; Heller, Theo] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Cotler, Scott J.; Dahari, Harel] Loyola Univ, Med Ctr, Dept Med, Program Expt & Theoret Modeling,Div Hepatol, Maywood, IL 60153 USA. [Schmid, Peter; Albrecht, Jeff] Natl Inst Genet, Los Angeles, CA USA. RP Dahari, H (reprint author), Loyola Univ, Med Ctr, Dept Med, Program Expt & Theoret Modeling,Div Hepatol, Maywood, IL 60153 USA. EM theoh@intra.niddk.nih.gov; hdahari@lumc.edu RI Guedj, Jeremie/A-6842-2017 OI Guedj, Jeremie/0000-0002-5534-5482 FU NIGMS NIH HHS [P20 GM103452, P30 GM110907, P20-GM103452] NR 33 TC 12 Z9 12 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 DEC PY 2014 VL 60 IS 6 BP 1902 EP 1910 DI 10.1002/hep.27357 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AU3MI UT WOS:000345517000055 PM 25098971 ER PT J AU Murphy, G Michel, A Taylor, PR Albanes, D Weinstein, SJ Virtamo, J Parisi, D Snyder, K Butt, J McGlynn, KA Koshiol, J Pawlita, M Lai, GY Abnet, CC Dawsey, SM Freedman, ND AF Murphy, Gwen Michel, Angelika Taylor, Philip R. Albanes, Demetrius Weinstein, Stephanie J. Virtamo, Jarmo Parisi, Dominick Snyder, Kirk Butt, Julia McGlynn, Katherine A. Koshiol, Jill Pawlita, Michael Lai, Gabriel Y. Abnet, Christian C. Dawsey, Sanford M. Freedman, Neal D. TI Association of Seropositivity to Helicobacter Species and Biliary Tract Cancer in the ATBC Study SO HEPATOLOGY LA English DT Article ID HEPATOCELLULAR-CARCINOMA; LIVER-TRANSPLANTATION; ALLOCATION SYSTEM; WAITING-LIST; IMPACT; MORTALITY; SURVIVAL AB Helicobacter have been detected in human bile and hepatobiliary tissue. Despite evidence that Helicobacter species promote gallstone formation and hepatobiliary tumors in laboratory studies, it remains unclear whether Helicobacter species contribute to these cancers in humans. We used a multiplex panel to assess whether seropositivity to 15 Helicobacter pylori proteins was associated with subsequent incidence of hepatobiliary cancers in the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We included 64 biliary cancers, 122 liver cancers, and 224 age-matched controls which occurred over the course of 22 years. Helicobacter pylori seropositivity was defined as those positive to >= 4 antigens. Odds ratios (OR) and 95% confidence intervals were adjusted for major hepatobiliary cancer risk factors. Among the controls, 88% were seropositive to H. pylori at baseline. Among those who subsequently developed hepatobiliary cancer, the prevalence of seropositivity was higher: 100% for gallbladder cancer, 97% of extrahepatic bile duct cancer, 91% of ampula of Vater cancer, 96% of intrahepatic bile duct cancer, and 94% of hepatocellular carcinoma. Although the OR for gallbladder cancer could not be calculated, the OR for the other sites were 7.01 (95% confidence interval [ CI]: 0.79-62.33), 2.21 (0.19-25.52), 10.67 (0.76-150.08), and 1.20 (0.42-3.45), respectively, with an OR of 5.47 (95% CI: 1.17-25.65) observed for the biliary tract cancers combined. ORs above 1 were observed for many of the investigated antigens, although most of these associations were not statistically significant. Conclusion: Seropositivity to H. pylori proteins was associated with an increased risk of biliary tract cancers in ATBC. Further studies are needed to confirm our findings and to determine how H. pylori might influence the risk of biliary tract cancer. C1 [Murphy, Gwen; Taylor, Philip R.; Albanes, Demetrius; Weinstein, Stephanie J.; McGlynn, Katherine A.; Koshiol, Jill; Lai, Gabriel Y.; Abnet, Christian C.; Dawsey, Sanford M.; Freedman, Neal D.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Michel, Angelika; Butt, Julia; Pawlita, Michael] German Canc Res Ctr, Res Program Infect & Canc, Div Genome Modificat & Carcinogenesis, Heidelberg, Germany. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Parisi, Dominick; Snyder, Kirk] Informat Management Serv Inc, Rockville, MD USA. RP Murphy, G (reprint author), NCI, Nutr Epidemiol Branch, DCEG, 9609 Med Ctr Dr,Rm 6E-314, Bethesda, MD 20892 USA. EM murphygw@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; Abnet, Christian/C-4111-2015; Murphy, Gwen/G-7443-2015; Freedman, Neal/B-9741-2015; Waterboer, Tim/G-1252-2010; OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098; Pawlita, Michael/0000-0002-4720-8306 FU CCR NIH HHS [N01-RC-45035, N01RC37004]; Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [N01 CN045165] NR 13 TC 10 Z9 10 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 DEC PY 2014 VL 60 IS 6 BP 1963 EP 1971 DI 10.1002/hep.27193 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AU3MI UT WOS:000345517000061 PM 24797247 ER PT J AU Xiao, Q Sinha, R Graubard, BI Freedman, ND AF Xiao, Qian Sinha, Rashmi Graubard, Barry I. Freedman, Neal D. TI Inverse Associations of Total and Decaffeinated Coffee With Liver Enzyme Levels in National Health and Nutrition Examination Survey 1999-2010 SO HEPATOLOGY LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; GENE-EXPRESSION SIGNATURE; HEPATOCELLULAR-CARCINOMA; CROSS-TALK; CELL-LINE; CANCER; HEPATOCYTES; IL-6; PROGRESSION; PROGENITOR AB Coffee may have hepatoprotective effects and higher coffee consumption has been associated inversely with levels of liver enzymatic markers. However, it is unclear whether decaffeinated coffee is also associated with liver enzymes. The study population included 27,793 participants, age 20 or older, in the U. S. National Health and Nutrition Examination Survey (1999-2010). Coffee intake was evaluated by 24-hour dietary recall. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transaminase (GGT) were measured. We examined the relationship between coffee intake and enzymatic levels using weighted multiple variable logistic (abnormally elevated levels of enzymes) and linear regression (continuous enzymatic levels). Total coffee consumption was inversely associated with abnormal levels of all four liver enzymes and continuous levels of AST, ALP, and GGT. Compared to those reporting no coffee consumption, participants reporting 3 cups per day had an odds ratio (OR; 95% confidence interval [CI]) of 0.75 (0.63, 0.89), 0.82 (0.68, 0.98), 0.73 (0.55, 0.95), and 0.69 (0.57, 0.83) for abnormal levels of ALT, AST, ALP, and GGT, respectively. Similar inverse associations were found with decaffeinated coffee intake and abnormal levels of ALT (OR (>= 2) (vs 0 cup/d): 0.62 [0.41, 0.94]), AST (0.74 [0.49, 1.11]), and GGT (0.70 [0.49-1.00]). Conclusion: Higher intakes of coffee, regardless of its caffeine content, were associated with lower levels of liver enzymes. C1 [Xiao, Qian; Sinha, Rashmi; Freedman, Neal D.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Graubard, Barry I.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. RP Xiao, Q (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM qian.xiao@nih.gov RI Sinha, Rashmi/G-7446-2015; Freedman, Neal/B-9741-2015 OI Sinha, Rashmi/0000-0002-2466-7462; Freedman, Neal/0000-0003-0074-1098 FU Intramural NIH HHS [Z99 CA999999] NR 49 TC 10 Z9 10 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 DEC PY 2014 VL 60 IS 6 BP 2091 EP 2098 DI 10.1002/hep.27367 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AU3MI UT WOS:000345517000072 PM 25124935 ER PT J AU Wang, FS Fan, JG Zhang, Z Gao, B Wang, HY AF Wang, Fu-Sheng Fan, Jian-Gao Zhang, Zheng Gao, Bin Wang, Hong-Yang TI The Global Burden of Liver Disease: The Major Impact of China SO HEPATOLOGY LA English DT Article ID GAMMA-GLUTAMYL-TRANSFERASE; DOSE-RESPONSE METAANALYSIS; SELF-DEFENSE OFFICIALS; AGED JAPANESE MEN; BODY-MASS INDEX; COFFEE CONSUMPTION; UNITED-STATES; ALCOHOL; RISK; DETERMINANTS AB Liver disease is a major cause of illness and death worldwide. In China alone, liver diseases, primarily viral hepatitis (predominantly hepatitis B virus [HBV]), nonalcoholic fatty liver disease, and alcoholic liver disease, affect approximately 300 million people. The establishment of the Expanded Program on Immunization in 1992 has resulted in a substantial decline in the number of newly HBV-infected patients; however, the number of patients with alcoholic and nonalcoholic fatty liver diseases is rising at an alarming rate. Liver cancer, one of the most deadly cancers, is the second-most common cancer in China. Approximately 383,000 people die from liver cancer every year in China, which accounts for 51% of the deaths from liver cancer worldwide. Over the past 10 years, China has made some significant efforts to shed its " leader in liver diseases" title by investing large amounts of money in funding research, vaccines, and drug development for liver diseases and by recruiting many Western-trained hepatologists and scientists. Over the last two decades, hepatologists and scientists in China have made significant improvements in liver disease prevention, diagnosis, management, and therapy. They have been very active in liver disease research, as shown by the dramatic increase in the number of publications in HEPATOLOGY. Nevertheless, many challenges remain that must be tackled collaboratively. In this review, we discuss the epidemiology and characteristics of liver diseases and liver-related research in China. C1 [Wang, Fu-Sheng; Zhang, Zheng] Beijing 302 Hosp, Res Ctr Biol Therapy, Beijing 100039, Peoples R China. [Wang, Fu-Sheng] Zhejiang Univ, Sch Med, Collaborat Innovat Ctr Diag & Treatment Infect Di, Hangzhou 310003, Zhejiang, Peoples R China. [Fan, Jian-Gao] Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Gastroenterol, Shanghai 200030, Peoples R China. [Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. [Wang, Hong-Yang] Eastern Hepatobiliary Surg Hosp, Natl Ctr Liver Canc, Shanghai 200438, Peoples R China. RP Wang, FS (reprint author), Beijing 302 Hosp, Res Ctr Biol Therapy, 100 Western 4th Ring Middle Rd, Beijing 100039, Peoples R China. EM fswang302@163.com; hywangk@vip.sina.com FU Intramural NIH HHS [Z01 AA000368-07, Z01 AA000369-06] NR 31 TC 77 Z9 102 U1 15 U2 48 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 DEC PY 2014 VL 60 IS 6 BP 2099 EP 2108 DI 10.1002/hep.27406 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AU3MI UT WOS:000345517000073 PM 25164003 ER PT J AU Kumari, D Bhattacharya, A Nadel, J Moulton, K Zeak, NM Glicksman, A Dobkin, C Brick, DJ Schwartz, PH Smith, CB Klann, E Usdin, K AF Kumari, Daman Bhattacharya, Aditi Nadel, Jeffrey Moulton, Kristen Zeak, Nicole M. Glicksman, Anne Dobkin, Carl Brick, David J. Schwartz, Philip H. Smith, Carolyn B. Klann, Eric Usdin, Karen TI Identification of Fragile X Syndrome Specific Molecular Markers in Human Fibroblasts: A Useful Model to Test the Efficacy of Therapeutic Drugs SO HUMAN MUTATION LA English DT Article DE Fragile X syndrome; FMR1; FMRP; protein synthesis; S6K1; fibroblasts ID CEREBRAL PROTEIN-SYNTHESIS; TISSUE-SPECIFIC EXPRESSION; MOUSE MODEL; MESSENGER-RNA; TRANSLATIONAL CONTROL; SYNAPTIC PLASTICITY; MENTAL-RETARDATION; KNOCKOUT MICE; STEM-CELLS; FMRP AB Fragile X syndrome (FXS) is the most frequent cause of inherited intellectual disability and autism. It is caused by the absence of the fragile X mental retardation 1 (FMR1) gene product, fragile X mental retardation protein (FMRP), an RNA-binding protein involved in the regulation of translation of a subset of brain mRNAs. In Fmr1 knockout mice, the absence of FMRP results in elevated protein synthesis in the brain as well as increased signaling of many translational regulators. Whether protein synthesis is also dysregulated in FXS patients is not firmly established. Here, we demonstrate that fibroblasts from FXS patients have significantly elevated rates of basal protein synthesis along with increased levels of phosphorylated mechanistic target of rapamycin (p-mTOR), phosphorylated extracellular signal regulated kinase 1/2, and phosphorylated p70 ribosomal S6 kinase 1 (p-S6K1). The treatment with small molecules that inhibit S6K1 and a known FMRP target, phosphoinositide 3-kinase (PI3K) catalytic subunit p110, lowered the rates of protein synthesis in both control and patient fibroblasts. Our data thus demonstrate that fibroblasts from FXS patients may be a useful in vitro model to test the efficacy and toxicity of potential therapeutics prior to clinical trials, as well as for drug screening and designing personalized treatment approaches. C1 [Kumari, Daman; Usdin, Karen] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Bhattacharya, Aditi; Zeak, Nicole M.; Klann, Eric] NYU, Ctr Neural Sci, New York, NY 10003 USA. [Nadel, Jeffrey; Moulton, Kristen; Smith, Carolyn B.] NIMH, Sect Neuroadaptat & Prot Metab, NIH, Bethesda, MD 20892 USA. [Glicksman, Anne; Dobkin, Carl] New York State Inst Basic Res Dev Disabil, Dept Human Genet, New York, NY USA. [Brick, David J.; Schwartz, Philip H.] Childrens Hosp Orange Cty Res Inst, Orange, CA USA. RP Kumari, D (reprint author), NIDDK, Lab Cell & Mol Biol, NIH, 8 Ctr Dr,Bldg 8,Room 2A19, Bethesda, MD 20892 USA. EM damank@helix.nih.gov FU Intramural Research Programs of the National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health Center for Regenerative Medicine; National Institute of Mental Health [NS034007, NS047384]; New York State Department of People with Developmental Disabilities; Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health [R01HD059967] FX Contract grant sponsors: Intramural Research Programs of the National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health Center for Regenerative Medicine and the National Institute of Mental Health; Extramural Program of the National Institutes of Health (NS034007 and NS047384 to E.K.); New York State Department of People with Developmental Disabilities; Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (R01HD059967). NR 52 TC 21 Z9 21 U1 0 U2 8 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 DEC PY 2014 VL 35 IS 12 BP 1485 EP 1494 DI 10.1002/humu.22699 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA AU3MK UT WOS:000345517300012 PM 25224527 ER PT J AU Chaplin, TM Hansen, A Simmons, J Mayes, LC Hommer, RE Crowley, MJ AF Chaplin, Tara M. Hansen, Amysue Simmons, Jessica Mayes, Linda C. Hommer, Rebecca E. Crowley, Michael J. TI Parental-Adolescent Drug Use Discussions: Physiological Responses and Associated Outcomes SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Adolescence; Substance use; Parenting; Parent-adolescent interactions; Drug use discussions; Cortisol ID SUBSTANCE USE; CHILD COMMUNICATION; FAMILY ENVIRONMENT; BEHAVIOR PROBLEMS; ALCOHOL-USE; RISK; YOUTH; SOCIALIZATION; PREDICTORS; MECHANISMS AB Purpose: Although talking to youth about drugs is often recommended to parents, we know little about how parents actually discuss drugs with their children in the moment and how parental advice is linked to youth arousal and substance use. This study examined observed parental drug use advice and parenting behaviors during parent-adolescent drug use discussions and associations with adolescent physiological responses and substance use. Methods: Fifty-eight 12-17 year olds and their primary caregivers participated in a laboratory session in which parents and youth discussed the topic of alcohol and/or drug use for 10 minutes. This discussion was videotaped and coded for drug use advice (rules against drug use, information on drug use consequences, scenarios or learning advice [discussing drug use scenarios and what the child has learned about drugs]) and general parenting behaviors (parental warmth and/or support, negative and/or critical parenting). Before, during, and after the discussions, adolescents' heart rate, blood pressure (BP), and salivary cortisol levels were assessed. Results: Parental discussion of scenarios and/or learning was associated with lower adolescent BP responses to the discussions and lower likelihood of substance use. Parental discussion of rules against drug use was associated with higher heart rate and BP responses and greater likelihood of substance use. Criticism and/or negative parenting was associated with higher cortisol responses and greater likelihood of substance use at a trend level. Conclusions: Parenting characterized by greater discussion of drug use scenarios and less stating of rules against drug use and criticism may make youth feel more comfortable and be linked to lower substance use. (C) 2014 Society for Adolescent Health and Medicine. All rights reserved. C1 [Chaplin, Tara M.] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Hansen, Amysue; Simmons, Jessica] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Mayes, Linda C.; Crowley, Michael J.] Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT USA. [Hommer, Rebecca E.] NIMH, Emot & Dev Branch, NIH, Bethesda, MD 20892 USA. RP Chaplin, TM (reprint author), George Mason Univ, Dept Psychol, 4400 Univ Dr,MSN 3F5, Fairfax, VA 22030 USA. EM tchaplin@gmu.edu FU National Institutes of Health [K01-DA-024759, K01DA034125, UL1-DE19586, R01-DA-033431]; ABMRF/Foundation for Alcohol Research [R10629]; American Academy of Child and Adolescent Psychiatry FX Support for this project was provided by the National Institutes of Health through grants K01-DA-024759 (PI: T. M. C.), K01DA034125 (PI: M.J.C.), UL1-DE19586 pilot grant (PI: M.J.C.), and R01-DA-033431 (PI: T. M. C.) and grants from the ABMRF/Foundation for Alcohol Research (PI: T. M. C.; grant number R10629) and from the American Academy of Child and Adolescent Psychiatry (PI: R.E.H.). NR 31 TC 4 Z9 4 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X EI 1879-1972 J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD DEC PY 2014 VL 55 IS 6 BP 730 EP 735 DI 10.1016/j.jadohealth.2014.05.001 PG 6 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA AU1QM UT WOS:000345395200003 PM 24957574 ER PT J AU Boyer, CB Robles-Schrader, GM Li, SX Miller, RL Korelitz, J Price, GN Torres, CMR Chutuape, KS Stines, SJ Straub, DM Peralta, L Febo, I Hightow-Weidman, L Gonin, R Kapogiannis, BG Ellen, JM AF Boyer, Cherrie B. Robles-Schrader, Grisel M. Li, Su X. Miller, Robin L. Korelitz, James Price, Georgine N. Torres, Carmen M. Rivera Chutuape, Kate S. Stines, Stephanie J. Straub, Diane M. Peralta, Ligia Febo, Irma Hightow-Weidman, Lisa Gonin, Rene Kapogiannis, Bill G. Ellen, Jonathan M. TI A Comparison of Network-Based Strategies for Screening At-Risk Hispanic/Latino Adolescents and Young Adults for Undiagnosed Asymptomatic HIV Infection SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Hispanic/Latino adolescents and young adults; HIV testing/screening; Network-based HIV screening ID UNITED-STATES; WOMEN; POPULATIONS; BARRIERS; MEN; IDENTIFICATION; TRANSMISSION; PREVENTION; HIV/AIDS; PROJECT AB Purpose: Hispanic/Latino adolescents and young adults are disproportionately impacted by the HIV/AIDS epidemic; yet little is known about the best strategies to increase HIV testing in this group. Network-based approaches are feasible and acceptable means for screening at-risk adults for HIV infection, but it is unknown whether these approaches are appropriate for at-risk young Hispanics/Latinos. Thus, we compared an alternative venue-based testing (AVT) strategy with a social and sexual network-based interviewing and HIV testing (SSNIT) strategy. Methods: All participants were Hispanics/Latinos aged 13-24 years with self-reported HIV risk; they were recruited from 11 cities in the United States and Puerto Rico and completed an audio computer-assisted self-interview and underwent HIV screening. Results: A total of 1,596 participants (94.5% of those approached) were enrolled: 784 (49.1%) through AVT and 812 (50.9%) through SSNIT. HIV infection was identified in three SSNIT (.37%) and four AVT (.51%) participants (p = .7213). Conclusions: Despite high levels of HIV risk, a low prevalence of HIV infection was identified with no differences by recruitment strategy. We found overwhelming support for the acceptability and feasibility of AVT and SSNIT for engaging and screening at-risk young Hispanics/Latinos. Further research is needed to better understand how to strategically implement such strategies to improve identification of undiagnosed HIV infection. (C) 2014 Society for Adolescent Health and Medicine. All rights reserved. C1 [Boyer, Cherrie B.; Robles-Schrader, Grisel M.] Univ Calif San Francisco, Div Adolescent & Young Adult Med, Dept Pediat, San Francisco, CA 94118 USA. [Li, Su X.; Korelitz, James; Price, Georgine N.; Gonin, Rene] WESTAT Corp, Rockville, MD 20850 USA. [Miller, Robin L.] Michigan State Univ, E Lansing, MI 48824 USA. [Torres, Carmen M. Rivera; Febo, Irma] Univ Puerto Rico, Sch Med, Dept Pediat, San Juan, PR 00936 USA. [Chutuape, Kate S.; Ellen, Jonathan M.] Johns Hopkins Univ, Dept Pediat, Bayview Med Ctr, Baltimore, MD 21218 USA. [Stines, Stephanie J.] Childrens Natl Med Ctr, Div Adolescent & Young Adult Med, Washington, DC 20010 USA. [Straub, Diane M.] Univ S Florida, Div Adolescent Med, Tampa, FL USA. [Peralta, Ligia] Univ Maryland, Dept Pediat, Div Adolescent & Young Adult Med, Baltimore, MD 21201 USA. [Hightow-Weidman, Lisa] Univ N Carolina, Dept Med, Div Infect Dis, Chapel Hill, NC USA. [Kapogiannis, Bill G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, PAMAB, Bethesda, MD USA. RP Boyer, CB (reprint author), Univ Calif San Francisco, Div Adolescent & Young Adult Med, 3333 Calif St,Suite 245, San Francisco, CA 94118 USA. EM boyerc@peds.ucsf.edu FU National Institutes of Health through the Eunice Kennedy Shriver National Institute of Child Health and Human Development [5U01HD40533, 5U01HD40474]; National Institutes on Drug Abuse and Mental Health; National Institute of Child Health and Human Development; Office of AIDS Research FX The Adolescent Medicine Trials Network for HIV/AIDS Interventions is funded by (grant numbers 5U01HD40533 and 5U01HD40474) from the National Institutes of Health through the Eunice Kennedy Shriver National Institute of Child Health and Human Development with supplemental funding from the National Institutes on Drug Abuse and Mental Health. This research was cofunded by National Institute of Child Health and Human Development and the Office of AIDS Research. NR 39 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 1054-139X EI 1879-1972 J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD DEC PY 2014 VL 55 IS 6 BP 765 EP 773 DI 10.1016/j.jadohealth.2014.07.009 PG 9 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA AU1QM UT WOS:000345395200008 PM 25223476 ER PT J AU Flanders, KC Heger, CD Conway, C Tang, BW Sato, M Dengler, SL Goldsmith, PK Hewitt, SM Wakefield, LM AF Flanders, Kathleen C. Heger, Christopher D. Conway, Catherine Tang, Binwu Sato, Misako Dengler, Samuel L. Goldsmith, Paul K. Hewitt, Stephen M. Wakefield, Lalage M. TI Brightfield Proximity Ligation Assay Reveals Both Canonical and Mixed Transforming Growth Factor-beta/Bone Morphogenetic Protein Smad Signaling Complexes in Tissue Sections SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE transforming growth factor-; Smads; proximity ligation assay; brightfield; breast cancer; development; tissue microarray ID TGF-BETA SUPERFAMILY; BREAST-CANCER; IN-SITU; TRANSGENIC MICE; EXPRESSION; MECHANISMS; PHOSPHORYLATION; RECEPTORS; PROGRESSION; ACTIVATION AB Transforming growth factor- (TGF-) is an important regulator of cellular homeostasis and disease pathogenesis. Canonical TGF- signaling occurs through Smad2/3-Smad4 complexes; however, recent in vitro studies suggest that elevated levels of TGF- may activate a novel mixed Smad complex (Smad2/3-Smad1/5/9), which is required for some of the pro-oncogenic activities of TGF-. To determine if mixed Smad complexes are evident in vivo, we developed antibodies that can be used with a proximity ligation assay to detect either canonical or mixed Smad complexes in formalin-fixed paraffin-embedded sections. We demonstrate high expression of mixed Smad complexes in the tissues from mice genetically engineered to express high levels of TGF-1. Mixed Smad complexes were also prominent in 15-16 day gestation mouse embryos and in breast cancer xenografts, suggesting important roles in embryonic development and tumorigenesis. In contrast, mixed Smad complexes were expressed at extremely low levels in normal adult mouse tissue, where canonical complexes were correspondingly higher. We show that this methodology can be used in archival patient samples and tissue microarrays, and we have developed an algorithm to quantitate the brightfield read-out. These methods will allow quantitative analysis of cell type-specific Smad signaling pathways in physiological and pathological processes. C1 [Flanders, Kathleen C.; Tang, Binwu; Sato, Misako; Dengler, Samuel L.; Wakefield, Lalage M.] NCI, LCBG, Ctr Canc Res, Bethesda, MD 20892 USA. [Heger, Christopher D.; Goldsmith, Paul K.] NCI, Antibody & Prot Purificat Unit, Ctr Canc Res, Bethesda, MD 20892 USA. [Conway, Catherine; Hewitt, Stephen M.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Flanders, KC (reprint author), NCI, LCBG, NIH, 37 Convent Dr,Bldg 37 Rm 5046B, Bethesda, MD 20892 USA. EM flanderk@mail.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788 FU Intramural Research Program of the NIH, NCI FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the Intramural Research Program of the NIH, NCI. NR 31 TC 2 Z9 2 U1 0 U2 6 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0022-1554 EI 1551-5044 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD DEC PY 2014 VL 62 IS 12 BP 846 EP 863 DI 10.1369/0022155414550163 PG 18 WC Cell Biology SC Cell Biology GA AU4OB UT WOS:000345589800002 PM 25141865 ER PT J AU Oksanen, A Aittomaki, S Jankovic, D Ortutay, Z Pulkkinen, K Hamalainen, S Rokka, A Corthals, GL Watford, WT Junttila, I O'Shea, JJ Pesu, M AF Oksanen, Anna Aittomaki, Saara Jankovic, Dragana Ortutay, Zsuzsanna Pulkkinen, Kati Hamalainen, Sanna Rokka, Anne Corthals, Garry L. Watford, Wendy T. Junttila, Ilkka O'Shea, John J. Pesu, Marko TI Proprotein Convertase FURIN Constrains Th2 Differentiation and Is Critical for Host Resistance against Toxoplasma gondii SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HELPER TYPE-2 DIFFERENTIATION; CELL-MEDIATED-IMMUNITY; TGF-BETA ACTIVATION; CD4(+) T-CELLS; INTERFERON-GAMMA; CUTTING EDGE; EXPRESSION; DISEASE; IDENTIFICATION; MECHANISMS AB The proprotein convertase subtilisin/kexin enzymes proteolytically convert immature proproteins into bioactive molecules, and thereby they serve as key regulators of cellular homeostasis. The archetype proprotein convertase subtilisin/kexin, FURIN, is a direct target gene of the IL-12/STAT4 pathway and it is upregulated in Th1 cells. We have previously demonstrated that FURIN expression in T cells critically regulates the maintenance of peripheral immune tolerance and the functional maturation of pro-TGF-beta 1 in vivo, but FURIN's role in cell-mediated immunity and Th polarization has remained elusive. In this article, we show that T cell-expressed FURIN is essential for host resistance against a prototypic Th1 pathogen, Toxoplasma gondii, and for the generation of pathogen-specific Th1 lymphocytes, including Th1-IL-10 cells. FURIN-deficient Th cells instead show elevated expression of IL-4R subunit a on cell surface, sensitized IL-4/STAT6 signaling, and a propensity to polarize toward the Th2 phenotype. By exploring FURIN-interacting proteins in Jurkat T cells with Strep-Tag purification and mass spectrometry, we further identify an association with a cytoskeleton modifying Ras-related C3 botulinum toxin substrate/dedicator of cytokinesis 2 protein complex and unravel that FURIN promotes F-actin polymerization, which has previously been shown to downregulate IL-4R subunit a cell surface expression and promote Th1 responses. In conclusion, our results demonstrate that in addition to peripheral immune tolerance, T cell-expressed FURIN is also a central regulator of cell-mediated immunity and Th1/2 cell balance. C1 [Oksanen, Anna; Aittomaki, Saara; Ortutay, Zsuzsanna; Pulkkinen, Kati; Hamalainen, Sanna; Pesu, Marko] Univ Tampere, BioMediTech, Immunoregulat Lab, Tampere 33014, Finland. [Jankovic, Dragana] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Jankovic, Dragana] Univ Turku, Turku Ctr Biotechnol, Turku 20520, Finland. [Jankovic, Dragana] Abo Akad Univ, Turku 20520, Finland. [Corthals, Garry L.] Univ Amsterdam, Vant Hoff Inst Mol Sci, NL-1090 GD Amsterdam, Netherlands. [Watford, Wendy T.; O'Shea, John J.] NIAMSD, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Watford, Wendy T.] Univ Georgia, Coll Vet Med, Dept Infect Dis, Athens, GA 30602 USA. [Junttila, Ilkka; Pesu, Marko] Pirkanmaa Hosp Dist, Fimlab Labs, Tampere 33101, Finland. [Junttila, Ilkka] Univ Tampere, Sch Med, Tampere 33014, Finland. [Pesu, Marko] Pirkanmaa Hosp Dist, Dept Dermatol, Tampere 33101, Finland. RP Pesu, M (reprint author), Univ Tampere, BioMediTech, Biokatu 8 FinnMedi 2, Tampere 33520, Finland. EM marko.pesu@uta.fi RI Corthals, Garry/G-9417-2016 OI Corthals, Garry/0000-0001-9423-5596 FU Academy of Finland Projects [128623, 135980]; 7th European Community Framework Programme Marie Curie International Reintegration Grant; Emil Aaltonen Foundation; Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Tampere University Hospital Competitive Research Funding Grants [9M080, 9N056, 9N018]; Fimlab Grant [X51409]; Doctoral Programme in Biomedicine and Biotechnology, University of Tampere; Finnish Cultural Foundation; Laboratoriolaaketieteen Edistamissaatio; Intramural Research Program of the National Institutes of Health; National Institute of Arthritis and Musculoskeletal and Skin Disease; National Institute of Allergy and Infectious Diseases FX This work was supported by Academy of Finland Projects 128623 and 135980 (to M.P.), a 7th European Community Framework Programme Marie Curie International Reintegration Grant (to M.P.), the Emil Aaltonen Foundation (to M.P. and A.O.), the Sigrid Juselius Foundation (to M.P. and I.J.), the Tampere Tuberculosis Foundation (to M.P. and I.J.), Tampere University Hospital Competitive Research Funding Grants 9M080 and 9N056 (to M.P.) and 9N018 (to I.J.), Fimlab Grant X51409 (to I.J.), the Doctoral Programme in Biomedicine and Biotechnology, University of Tampere (to A.O.), the Finnish Cultural Foundation (to A.O.), and the Laboratoriolaaketieteen Edistamissaatio (to A.O.). This work was also supported by the Intramural Research Program of the National Institutes of Health, the National Institute of Arthritis and Musculoskeletal and Skin Disease, and the National Institute of Allergy and Infectious Diseases. NR 52 TC 6 Z9 6 U1 0 U2 8 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 DEC 1 PY 2014 VL 193 IS 11 BP 5470 EP 5479 DI 10.4049/jimmunol.1401629 PG 10 WC Immunology SC Immunology GA AU2JC UT WOS:000345443000014 PM 25355923 ER PT J AU Fujihara, C Williams, JA Watanabe, M Jeon, H Sharrow, SO Hodes, RJ AF Fujihara, Chiharu Williams, Joy A. Watanabe, Masashi Jeon, Hyein Sharrow, Susan O. Hodes, Richard J. TI T Cell-B Cell Thymic Cross-Talk: Maintenance and Function of Thymic B Cells Requires Cognate CD40-CD40 Ligand Interaction SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NEGATIVE SELECTION; EPITHELIAL-CELLS; IN-VIVO; POSITIVE SELECTION; CLONAL DELETION; SELF-ANTIGENS; THYMOCYTES; CD40; EXPRESSION; TOLERANCE AB Thymic development requires bidirectional interaction or cross-talk between developing T cells and thymic stromal cells, a relationship that has been best characterized for the interaction between thymocytes and thymic epithelial cells. We have characterized in this article the requirement for similar cross-talk in the maintenance and function of thymic B cells, another population that plays a role in selection of developing thymic T cells. We found that maintenance of thymic B cells is strongly dependent on the presence of mature single-positive thymocytes and on the interactions of these T cells with specific Ag ligand. Maintenance of thymic B cell number is strongly dependent on B cell-autonomous expression of CD40, but not MHC class II, indicating that direct engagement of CD40 on thymic B cells is necessary to support their maintenance and proliferation. Thymic B cells can mediate negative selection of superantigen-specific, self-reactive, single-positive thymocytes, and we show that CD40 expression on B cells is critical for this negative selection. Cross-talk with thymic T cells is thus required to support the thymic B cell population through a pathway that requires cell-autonomous expression of CD40, and that reciprocally functions in negative selection of autoreactive T cells. C1 [Fujihara, Chiharu; Williams, Joy A.; Watanabe, Masashi; Jeon, Hyein; Sharrow, Susan O.; Hodes, Richard J.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Hodes, RJ (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM hodesr@31.nia.nih.gov FU National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institutes of Health. NR 50 TC 9 Z9 9 U1 1 U2 5 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 DEC 1 PY 2014 VL 193 IS 11 BP 5534 EP 5544 DI 10.4049/jimmunol.1401655 PG 11 WC Immunology SC Immunology GA AU2JC UT WOS:000345443000021 PM 25344473 ER PT J AU Hill, BJ Darrah, PA Ende, Z Ambrozak, DR Quinn, KM Darko, S Gostick, E Wooldridge, L van den Berg, HA Venturi, V Larsen, M Davenport, MP Seder, RA Price, DA Douek, DC AF Hill, Brenna J. Darrah, Patricia A. Ende, Zachary Ambrozak, David R. Quinn, Kylie M. Darko, Sam Gostick, Emma Wooldridge, Linda van den Berg, Hugo A. Venturi, Vanessa Larsen, Martin Davenport, Miles P. Seder, Robert A. Price, David A. Douek, Daniel C. TI Epitope Specificity Delimits the Functional Capabilities of Vaccine-Induced CD8 T Cell Populations SO JOURNAL OF IMMUNOLOGY LA English DT Article ID POLYCHROMATIC FLOW-CYTOMETRY; HIV-1 INFECTION; VIRAL LOAD; PRECURSOR FREQUENCIES; LYMPHOCYTE ACTIVATION; REPERTOIRE DIVERSITY; PERFORIN EXPRESSION; PROTECTIVE CAPACITY; RECEPTOR REPERTOIRE; VIRUS-REPLICATION AB Despite progress toward understanding the correlates of protective T cell immunity in HIV infection, the optimal approach to Ag delivery by vaccination remains uncertain. We characterized two immunodominant CD8 T cell populations generated in response to immunization of BALB/c mice with a replication-deficient adenovirus serotype 5 vector expressing the HIV-derived Gag and Pol proteins at equivalent levels. The Gag-AI9/H-2K(d) epitope elicited high-avidity CD8 T cell populations with architecturally diverse clonotypic repertoires that displayed potent lytic activity in vivo. In contrast, the Pol-LI9/H-2D(d) epitope elicited motif-constrained CD8 T cell repertoires that displayed lower levels of physical avidity and lytic activity despite equivalent measures of overall clonality. Although low-dose vaccination enhanced the functional profiles of both epitope-specific CD8 T cell populations, greater polyfunctionality was apparent within the Pol-LI9/H-2D(d) specificity. Higher proportions of central memory-like cells were present after low-dose vaccination and at later time points. However, there were no noteworthy phenotypic differences between epitope-specific CD8 T cell populations across vaccine doses or time points. Collectively, these data indicate that the functional and phenotypic properties of vaccine-induced CD8 T cell populations are sensitive to dose manipulation, yet constrained by epitope specificity in a clonotype-dependent manner. C1 [Hill, Brenna J.; Darrah, Patricia A.; Ende, Zachary; Ambrozak, David R.; Quinn, Kylie M.; Darko, Sam; Seder, Robert A.; Price, David A.; Douek, Daniel C.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Gostick, Emma; Price, David A.] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [Wooldridge, Linda] Univ Bristol, Fac Med & Vet Sci, Bristol BS8 1TD, Avon, England. [van den Berg, Hugo A.] Univ Warwick, Math Inst, Coventry CV4 7AL, W Midlands, England. [Venturi, Vanessa; Davenport, Miles P.] Univ New S Wales, Ctr Vasc Res, Computat Biol Grp, Kensington, NSW 2052, Australia. [Larsen, Martin] INSERM, U1135, Ctr Immunol & Malad Infect, F-75013 Paris, France. [Larsen, Martin] Univ Paris 06, Sorbonne Univ, Ctr Immunol & Malad Infect, F-75013 Paris, France. RP Douek, DC (reprint author), NIH, Vaccine Res Ctr, 40 Convent Dr,Room 3509, Bethesda, MD 20892 USA. EM priced6@cardiff.ac.uk; ddouek@mail.nih.gov RI Price, David/C-7876-2013; Larsen, Martin/A-7316-2014 OI Price, David/0000-0001-9416-2737; Larsen, Martin/0000-0003-1375-4816 FU Intramural Research Program of the Vaccine Research Center; National Institute of Allergy and Infectious Diseases; National Institutes of Health; University Pierre et Marie Curie EMERGENCE Program; Fondation pour l' Aide a la Recherche sur la Sclerose En Plaques; Arthritis Fondation Courtin FX This work was supported by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health. D.A.P. is a Wellcome Trust Senior Investigator. M.L. was funded by the University Pierre et Marie Curie EMERGENCE Program, Fondation pour l' Aide a la Recherche sur la Sclerose En Plaques, and Arthritis Fondation Courtin. NR 80 TC 2 Z9 2 U1 1 U2 6 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 DEC 1 PY 2014 VL 193 IS 11 BP 5626 EP 5636 DI 10.4049/jimmunol.1401017 PG 11 WC Immunology SC Immunology GA AU2JC UT WOS:000345443000030 PM 25348625 ER PT J AU Alexaki, A Gupta, SD Majumder, S Kono, M Tuymetova, G Harmon, JM Dunn, TM Proia, RL AF Alexaki, Aikaterini Gupta, Sita D. Majumder, Saurav Kono, Mari Tuymetova, Galina Harmon, Jeffrey M. Dunn, Teresa M. Proia, Richard L. TI Autophagy regulates sphingolipid levels in the liver SO JOURNAL OF LIPID RESEARCH LA English DT Article DE ceramide; lipids; endoplasmic reticulum; triglycerides; lipophagy ID CERAMIDE SYNTHASE 2; INDUCED INSULIN-RESISTANCE; SERINE PALMITOYLTRANSFERASE; ALZHEIMERS-DISEASE; MEDIATED AUTOPHAGY; METABOLIC-PATHWAYS; TRANSGENIC MICE; CELL-DEATH; ER STRESS; CANCER AB Sphingolipid levels are tightly regulated to maintain cellular homeostasis. During pathologic conditions such as in aging, inflammation, and metabolic and neurodegenerative diseases, levels of some sphingolipids, including the bioactive metabolite ceramide, are elevated. Sphingolipid metabolism has been linked to autophagy, a critical catabolic process in both normal cell function and disease; however, the in vivo relevance of the interaction is not well-understood. Here, we show that blocking autophagy in the liver by deletion of the Atg7 gene, which is essential for autophagosome formation, causes an increase in sphingolipid metabolites including ceramide. We also show that overexpression of serine palmitoyltransferase to elevate de novo sphingolipid biosynthesis induces autophagy in the liver. The results reveal autophagy as a process that limits excessive ceramide levels and that is induced by excessive elevation of de novo sphingolipid synthesis in the liver. Dysfunctional autophagy may be an underlying mechanism causing elevations in ceramide that may contribute to pathogenesis in diseases. C1 [Alexaki, Aikaterini; Majumder, Saurav; Kono, Mari; Tuymetova, Galina; Proia, Richard L.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Gupta, Sita D.; Dunn, Teresa M.] Uniformed Serv Univ Hlth Sci, Dept Biochem, Bethesda, MD 20184 USA. [Harmon, Jeffrey M.] Uniformed Serv Univ Hlth Sci, Dept Mol Biol & Pharmacol, Bethesda, MD 20184 USA. RP Proia, RL (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. EM richardp@intra.niddk.nih.gov OI Harmon, Jeffrey/0000-0001-7833-931X FU Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; USU [CO75PI]; National Institutes of Health [R01NS072446, R21HD080181]; Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina [P30 CA138313]; Lipidomics Core in the South Carolina Lipidomics and Pathobiology COBRE [P20 RR017677] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, the USU Grant CO75PI and National Institutes of Health Grants R01NS072446 and R21HD080181, the Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313), and the Lipidomics Core in the South Carolina Lipidomics and Pathobiology COBRE (P20 RR017677). NR 67 TC 13 Z9 13 U1 1 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD DEC PY 2014 VL 55 IS 12 BP 2521 EP 2531 DI 10.1194/jlr.M051862 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU3NH UT WOS:000345519900009 PM 25332431 ER PT J AU Nakrani, RN Ghosh, A Lee, CCR Agarwal, PK Apolo, AB Cowen, EW AF Nakrani, Radhika N. Ghosh, Arunima Lee, Chyi-Chia Richard Agarwal, Piyush K. Apolo, Andrea B. Cowen, Edward W. TI New facial papules in a 66-year-old woman with bladder cancer SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE colon cancer; endometrial cancer; hereditary cancer; Lynch syndrome; microsatellite instability; mismatch repair; MutS homolog 2; MutS homolog 6; sebaceous epithelioma; sebaceous neoplasm; urothelial cancer ID MUIR-TORRE-SYNDROME; MSH2 MUTATION CARRIERS; LYNCH SYNDROME; MICROSATELLITE INSTABILITY; GERMLINE MUTATIONS; SEBACEOUS TUMORS; HNPCC; COLON; RISK; IMMUNOHISTOCHEMISTRY C1 [Nakrani, Radhika N.; Cowen, Edward W.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ghosh, Arunima; Lee, Chyi-Chia Richard] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Agarwal, Piyush K.] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Apolo, Andrea B.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Branch, Ctr Canc Res, Bldg 10 Room 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov RI Lee, Chyi-Chia/I-1938-2013 OI Lee, Chyi-Chia/0000-0002-5306-7781 FU Intramural Program of National Institutes of Health (NIH); Center for Cancer Research, National Cancer Institute; NIH Medical Research Scholars Program; National Institutes of Health; Pfizer Inc; Doris Duke Charitable Foundation; Alexandria Real Estate Equities Inc; Howard Hughes Medical Institute FX This research was supported by the Intramural Program of National Institutes of Health (NIH), Center for Cancer Research, National Cancer Institute, and the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the National Institutes of Health and generous contributions to the Foundation for the NIH from Pfizer Inc, the Doris Duke Charitable Foundation, the Alexandria Real Estate Equities Inc and Mr and Mrs Joel S. Marcus, and the Howard Hughes Medical Institute, as well as other private donors. NR 24 TC 2 Z9 2 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD DEC PY 2014 VL 71 IS 6 BP 1250 EP 1255 DI 10.1016/j.jaad.2014.07.012 PG 6 WC Dermatology SC Dermatology GA AT9FD UT WOS:000345232400037 PM 25108634 ER PT J AU Fargnoli, MC Sera, F Suppa, M Piccolo, D Landi, MT Chiarugi, A Pellegrini, C Seidenari, S Peris, K AF Fargnoli, M. C. Sera, F. Suppa, M. Piccolo, D. Landi, M. T. Chiarugi, A. Pellegrini, C. Seidenari, S. Peris, K. TI Dermoscopic features of cutaneous melanoma are associated with clinical characteristics of patients and tumours and with MC1R genotype SO JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY LA English DT Article ID MELANOCORTIN 1 RECEPTOR; PIGMENTED SKIN-LESIONS; NAKED-EYE EXAMINATION; BRAF-MUTANT MELANOMA; EPILUMINESCENCE MICROSCOPY; PATTERN-ANALYSIS; ABCD RULE; VARIANTS; RISK; MUTATIONS AB BackgroundSeveral algorithms are available for the dermoscopic diagnosis of pigmented skin lesions. The MC1R gene is a key determinant of pigmentation characteristics that are established host-related melanoma risk factors. ObjectivesTo investigate the association of dermoscopic features of sporadic cutaneous melanomas with clinical characteristics of patients and corresponding tumours and with genetic changes in the MC1R and BRAF genes. MethodsA total of 64 dermoscopic images of 62 patients were scored by ABCD rule and modified pattern analysis. Detailed patients' and melanomas' characteristics were collected. Patients were screened for germline MC1R variants and related melanomas for somatic V600 BRAF mutations. ResultsA lower total dermoscopic score (TDS) was observed in melanomas of patients with red hair (P=0.019), due to reduced dermoscopic structures (P<0.0001). Thicker melanomas showed higher TDS values (P=0.021) due to sharper borders (P<0.0001) and higher number of colors (P=0.004). An atypical pigment network was prevalent in superficial spreading melanomas (P=0.010), in individuals with dark skin (P=0.043) and hair color (P=0.001). An atypical vascular pattern was more frequent in nodular (P<0.0001) and thick (P<0.0001) melanomas, in individuals with skin type I-II (P=0.037), blond or red hair color (P=0.032) and blue or green eyes (P=0.014). Melanomas of MC1R R carriers showed lower TDS value (P=0.037), reduced dermoscopic structures (P=0.001) and lower prevalence of atypical pigment network (P=0.001). No differences were identified between BRAF-mutated or wild-type melanomas. ConclusionsWe suggest a phenotypic/MC1R profile for melanoma patients and their tumours. Melanomas of MC1R R carriers show a significant lower TDS value, with reduced dermoscopic structures, and a lower prevalence of an atypical pigment network. Non-carriers of MC1R R variants develop melanomas dermoscopically characterized by an atypical pigment network which is prevalent in superficial spreading melanomas, in patients with dark complexion and less frequent in red-haired individuals. C1 [Fargnoli, M. C.; Suppa, M.; Piccolo, D.; Pellegrini, C.; Peris, K.] Univ Aquila, Dept Dermatol, I-67100 Laquila, Italy. [Sera, F.] UCL Inst Child Hlth, MRC Ctr Epidemiol Child Hlth, London, England. [Landi, M. T.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chiarugi, A.] Inst Canc Study & Prevent ISPO, Melanoma Early Diag Serv, Florence, Italy. [Seidenari, S.] Univ Modena & Reggio Emilia, Dept Dermatol, Modena, Italy. RP Fargnoli, MC (reprint author), Univ Aquila, Dept Dermatol, I-67100 Laquila, Italy. EM mariaconcetta.fargnoli@univaq.it RI Sera, Francesco/C-8176-2011; OI Peris, Ketty/0000-0002-5237-0463; Fargnoli, Maria Concetta/0000-0002-7249-2556 NR 34 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0926-9959 EI 1468-3083 J9 J EUR ACAD DERMATOL JI J. Eur. Acad. Dermatol. Venereol. PD DEC PY 2014 VL 28 IS 12 BP 1768 EP 1775 DI 10.1111/jdv.12411 PG 8 WC Dermatology SC Dermatology GA AU0YS UT WOS:000345348800024 PM 24588892 ER PT J AU Ingale, J Tran, K Kong, L Dey, B McKee, K Schief, W Kwong, PD Mascola, JR Wyatt, RT AF Ingale, Jidnyasa Karen Tran Kong, Leopold Dey, Barna McKee, Krisha Schief, William Kwong, Peter D. Mascola, John R. Wyatt, Richard T. TI Hyperglycosylated Stable Core Immunogens Designed To Present the CD4 Binding Site Are Preferentially Recognized by Broadly Neutralizing Antibodies SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODY; TYPE-1 ENVELOPE GLYCOPROTEINS; HIV-1 GP120 CORE; STRUCTURAL-ANALYSIS; RATIONAL DESIGN; CD4-BOUND STATE; POTENT; EPITOPE; RECEPTOR AB The HIV-1 surface envelope glycoprotein (Env) trimer mediates entry into CD4(+) CCR5(+) host cells. Env possesses conserved antigenic determinants, such as the gp120 primary receptor CD4 binding site (CD4bs), a known neutralization target. Env also contains variable regions and protein surfaces occluded within the trimer that elicit nonneutralizing antibodies. Here we engineered additional N-linked glycans onto a cysteine-stabilized gp120 core (0G) deleted of its major variable regions to preferentially expose the conformationally fixed CD4bs. Three, 6, 7, and 10 new NXT/S glycan (G) motifs were engineered into 0G to encode 3G, 6G, 7G, and 10G cores. Following purification, most glycoproteins, except for 10G, were recognized by broadly neutralizing CD4bs-directed antibodies. Gel and glycan mass spectrometry confirmed that additional N-glycans were posttranslationally added to the redesigned cores. Binding kinetics revealed high-affinity recognition by seven broadly neutralizing CD4bs-directed antibodies and low to no binding by non-broadly neutralizing CD4bs-directed antibodies. Rabbits inoculated with the hyperglycosylated cores elicited IgM and IgG responses to each given protein that were similar in their neutralization characteristics to those elicited by parental 0G. Site-specific glycan masking effects were detected in the elicited sera, and the antisera competed with b12 for CD4bs-directed binding specificity. However, the core-elicited sera showed limited neutralization activity. Trimer priming or boosting of the core immunogens elicited tier 1-level neutralization that mapped to both the CD4bs and V3 and appeared to be trimer dependent. Fine mapping at the CD4bs indicated that conformational stabilization of the cores and addition of N-glycans altered the molecular surface of Env sites of vulnerability to neutralizing antibody, suggesting an explanation for why the elicited neutralization was not improved by this rational design strategy. IMPORTANCE Major obstacles to developing an effective HIV-1 vaccine include the variability of the envelope surface glycoproteins and its high-density glycan shield, generated by incorporation of host (human) glycosylation. HIV-1 does harbor highly conserved sites on the exposed envelope protein surface of gp120, one of which is the virus receptor (CD4) binding site. Several broadly neutralizing antibodies elicited from HIV patients do target this gp120 CD4 binding site (CD4bs); however, gp120 immunogens do not elicit broadly neutralizing antibodies. In this study, we targeted the CD4bs by conformational stabilization and additional glycan masking. We used the atomic-level structure to reengineer gp120 cores to preferentially present the cysteine-stabilized CD4bs and to mask (by glycan) nonneutralizing determinants. Importantly, glycan masking did successfully focus antibody responses to the CD4bs; however, the elicited CD4bs-directed antibodies did not neutralize HIV or bind to unmodified gp120, presumably due to the structure-guided modifications of the modified gp120 core. C1 [Ingale, Jidnyasa; Schief, William; Wyatt, Richard T.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Karen Tran; Schief, William; Wyatt, Richard T.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Kong, Leopold] Scripps Res Inst, La Jolla, CA 92037 USA. [Dey, Barna] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [McKee, Krisha; Kwong, Peter D.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Wyatt, RT (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. EM wyatt@scripps.edu FU NIH intramural research program (NIH) [P01 AI10472, AI100663]; NIH/NCRR [1 P41 RR018502-01]; Vaccine Research Center FX We thank the International AIDS Vaccine Initiative (IAVI) and the NIH intramural research program (NIH grants P01 AI10472 and AI100663). IAVI's funding is made possible by generous support from many donors, with the full list of IAVI donors available at www.iavi.org. This research was also supported in part by an NIH/NCRR-funded grant, entitled "Integrated Technology Resource for Biomedical Glycomics" (grant 1 P41 RR018502-01), to the Complex Carbohydrate Research Center and by intramural funding of the Vaccine Research Center. NR 50 TC 7 Z9 7 U1 0 U2 7 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 DEC PY 2014 VL 88 IS 24 BP 14002 EP 14016 DI 10.1128/JVI.02614-14 PG 15 WC Virology SC Virology GA AU0CZ UT WOS:000345292100008 PM 25253346 ER PT J AU Malone, AF Phelan, PJ Hall, G Cetincelik, U Homstad, A Alonso, AS Jiang, RJ Lindsey, TB Wu, GH Sparks, MA Smith, SR Webb, NJA Kalra, PA Adeyemo, AA Shaw, AS Conlon, PJ Jennette, JC Howell, DN Winn, MP Gbadegesin, RA AF Malone, Andrew F. Phelan, Paul J. Hall, Gentzon Cetincelik, Umran Homstad, Alison Alonso, Andrea S. Jiang, Ruiji Lindsey, Thomas B. Wu, Guanghong Sparks, Matthew A. Smith, Stephen R. Webb, Nicholas J. A. Kalra, Philip A. Adeyemo, Adebowale A. Shaw, Andrey S. Conlon, Peter J. Jennette, J. Charles Howell, David N. Winn, Michelle P. Gbadegesin, Rasheed A. TI Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis SO KIDNEY INTERNATIONAL LA English DT Article DE Alport syndrome; focal segmental glomerulosclerosis; podocyte; proteinuria ID BASEMENT-MEMBRANE NEPHROPATHY; DOMINANT ALPORT-SYNDROME; NEPHROTIC SYNDROME; NATURAL-HISTORY; LAMININ BETA-2; COL4A4 GENE; MUTATIONS; DISEASE; FEATURES; ADULTS AB Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes, including inherited genetic defects, with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome (AS), thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane (GBM) findings. Secondary FSGS is known to develop in classic AS at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical finding at diagnosis was proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic-range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin GBM, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes. C1 [Malone, Andrew F.; Phelan, Paul J.; Hall, Gentzon; Homstad, Alison; Alonso, Andrea S.; Jiang, Ruiji; Lindsey, Thomas B.; Wu, Guanghong; Winn, Michelle P.; Gbadegesin, Rasheed A.] Duke Mol Physiol Inst, Durham, NC USA. [Malone, Andrew F.; Phelan, Paul J.; Hall, Gentzon; Sparks, Matthew A.; Smith, Stephen R.; Winn, Michelle P.] Duke Univ, Div Nephrol, Dept Pediat, Med Ctr, Durham, NC 27710 USA. [Cetincelik, Umran] Sisli Etfal Training & Res Hosp, Dept Genet, Istanbul, Turkey. [Homstad, Alison; Alonso, Andrea S.; Jiang, Ruiji; Gbadegesin, Rasheed A.] Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. [Webb, Nicholas J. A.] Univ Manchester, Royal Manchester Childrens Hosp, Dept Pediat Nephrol, Manchester, Lancs, England. [Webb, Nicholas J. A.] Univ Manchester, NIHR Wellcome Trust Childrens Clin Res Facil, Manchester Acad Hlth Sci Ctr, Royal Manchester Childrens Hosp, Manchester, Lancs, England. [Kalra, Philip A.] Hope Hosp, Salford M6 8HD, Lancs, England. [Adeyemo, Adebowale A.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Shaw, Andrey S.] Washington Univ, Dept Pathol & Immunol, St Louis, MO USA. [Conlon, Peter J.] Beaumont Hosp, Beaumont Kidney Ctr, Royal Coll Surg, Dublin 9, Ireland. [Jennette, J. Charles] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC USA. [Howell, David N.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. RP Gbadegesin, RA (reprint author), Duke Univ, Div Nephrol, Dept Pediat, Med Ctr, Durham, NC 27710 USA. EM rasheed.gbadegesin@duke.edu OI Sparks, Matthew/0000-0003-2075-2691; Adeyemo, Adebowale/0000-0002-3105-3231 FU NIH NIDDK [K08DK082495, 1R56DK098135-01, P30DK096493, 5R01DK094987]; Nephcure foundation; Doris Duke Clinical Scientist Development Award; Doris Duke Charitable Foundation [2009033]; Duke O'Brien Center for Kidney research (DOCK); NIH/NIDDK Duke Training Grant in Nephrology [5T32DK0007731]; ARRA [1RC2NS070342-01]; Bryan ADRC NIA [P30 AG028377]; NIMH [RC2MH089915]; NIAID/NIH [1R56AI098588-01A1] FX This project was funded by NIH NIDDK K08DK082495, 1R56DK098135-01, and grants from Nephcure foundation to RAG. RAG is the recipient of a Doris Duke Clinical Scientist Development Award and acknowledges that part of this work was supported by the Doris Duke Charitable Foundation Grant #: 2009033. RAG is the recipient of P&F grant from Duke O'Brien Center for Kidney research (DOCK) supported by NIH NIDDK P30DK096493 award. NIH NIDDK 5R01DK094987 to MPW. GH receives salary support from the NIH/NIDDK Duke Training Grant in Nephrology 5T32DK0007731. The sequenced controls used for this study were funded in part by ARRA 1RC2NS070342-01, Bryan ADRC NIA P30 AG028377, NIMH Grant RC2MH089915, and NIAID/NIH Grant# 1R56AI098588-01A1. We thank Dr Elizabeth T. Cirulli, Dr David B. Goldstein, Dr Erin Heinzen, and Dr Nanye Long and the personnel of the Center for Human Genome Variation for assistance with sequencing. We acknowledge the following individuals for the contributions of control samples: Dr James Burke, Dr Christine Hulette, and Dr Kathleen Welsh-Bohmer; Dr Francis J. McMahon and Nirmala Akula; Dr Julie Hoover-Fong, Dr Nara L. Sobreira, and Dr David Valle; Dr M. Chiara Manzini; Dr Annapurna Poduri; Dr Nicole Calakos; Mr. David H. Murdock and The MURDOCK Study Community Registry and Biorepository; Dr Joseph McEvoy, Dr Anna Need, Mr. Jordan Silver, and Ms. Marlyne Silver; Dr Eli J. Holtzman; Dr Gianpiero Cavalleri, Dr Norman Delanty, Dr Chantal Depondt, and Dr Sanjay Sisodiya; Dr William B. Gallentine, Dr Erin L. Heinzen, Dr Aatif M. Husain, Ms. Kristen N Linney, Dr Mohamad A. Mikati, Dr Rodney A. Radtke, Dr Saurabh R. Sinha, and Ms. Nicole M. Walley; Dr Deborah Koltai Attix; Ms. Vicki Dixon and Ms. Jill McEvoy; Dr Vandana Shashi; Dr Patricia Lugar; Dr William L. Lowe; Dr Scott M. Palmer; Dr Doug Marchuk; Dr Deborah Levy; Dr Zvi Farfel, Dr Doron Lancet, and Dr Elon Pras; Dr Yong-Hui Jiang; Dr Qian Zhao; Dr Joshua Milner; Dr Demetre Daskalakis; Mr. Arthur Holden and Dr Elijah Behr; Dr Robert H. Brown, Jr.; Dr Sarah Kerns and Dr Harriet Oster. We thank the personnel of the Center for Human Genetics core facilities and most importantly the family members of the Duke FSGS project. NR 28 TC 23 Z9 24 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD DEC PY 2014 VL 86 IS 6 BP 1253 EP 1259 DI 10.1038/ki.2014.305 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AU4ZN UT WOS:000345616900024 PM 25229338 ER PT J AU Ishman, SL Benke, JR Cohen, AP Stephen, MJ Ishii, LE Gourin, CG AF Ishman, Stacey L. Benke, James R. Cohen, Aliza P. Stephen, Matthew J. Ishii, Lisa E. Gourin, Christine G. TI Does Surgery for Obstructive Sleep Apnea Improve Depression and Sleepiness? SO LARYNGOSCOPE LA English DT Article DE Epworth Sleepiness scale; obstructive sleep apnea; depression; sleepiness; Beck Depression Inventory; surgery ID POSITIVE AIRWAY PRESSURE; APNOEA/HYPOPNOEA SYNDROME; DAYTIME FUNCTION; MAJOR DEPRESSION; CONTROLLED TRIAL; CPAP THERAPY; SYMPTOMS; EPIDEMIOLOGY; POPULATION; PREDICTORS AB Objectives/HypothesisTo determine if surgical intervention for OSA (obstructive sleep apnea), particularly multilevel surgery, decreases depression and sleepiness. Study DesignProspective cohort study. MethodsChart and prospective outcome database review of patients who underwent surgery from August 2008 through November 2012. Patients were evaluated before and after surgery using the Epworth Sleepiness Scale (ESS), the Beck Depression Index (BDI), and overnight polysomnography. ResultsForty-four patients (12 females; 32 males) met inclusion criteria. Mean age of participants was 44.0 years (SD, 10.2); mean body mass index was 31.9 (SD, 9.3). The mean preoperative obstructive respiratory disturbance index (RDI) was 35.8 events/hour (SD, 21.9; range, 6.6-94.2), which decreased to 17.1 (SD, 19.5; range, 0.8-78.1; P<0.0001). Mean ESS improved from 10.8 (SD, 4.7) to 6.3 (SD, 3.7; P=0.0001); whereas BDI scores improved from 8.4 (SD, 8.2) to 4.9 (SD, 6.0; P=0.0051). There were 22 (50.0%) patients with excessive daytime sleepiness and 12 (27.3%) patients with depression before surgery. Surgery was associated with resolution of sleepiness in 17 patients (77.3%) and depression in 9 patients (75.0%). In multivariable regression analysis, only change in ESS (P=0.003) and baseline BDI (P<0.001) were associated with improvement in depression. RDI was not significant (P=0.15). ConclusionsSurgical treatment of OSA, especially multilevel surgery, resulted in significantly reduced depression, with resolution in 75% of patients. Similarly, surgery resulted in significantly reduced sleepiness, with resolution in 77% of patients. Reduction in sleepiness scores, but not OSA severity, was predictive of improvement in depression scores. Further evaluation with a larger sample size and a control group is warranted. Level of Evidence4. Laryngoscope, 124:2829-2836, 2014 C1 [Ishman, Stacey L.; Cohen, Aliza P.] Univ Cincinnati, Coll Med, Dept Otolaryngol Head & Neck Surg, Cincinnati, OH USA. [Ishman, Stacey L.] Cincinnati Childrens Hosp Med Ctr, Div Pediat Otolaryngol, Cincinnati, OH 45229 USA. [Ishman, Stacey L.] Cincinnati Childrens Hosp Med Ctr, Div Pulm Med, Cincinnati, OH 45229 USA. [Benke, James R.; Ishii, Lisa E.; Gourin, Christine G.] Johns Hopkins Med Inst, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. [Stephen, Matthew J.] NIH, Bethesda, MD 20892 USA. RP Ishman, SL (reprint author), Cincinnati Childrens Hosp Med Ctr, Upper Airway Ctr, Div Pediat Otolaryngol, 3333 Burnet Ave,MLC 2018, Cincinnati, OH 45229 USA. EM stacey.ishman@cchmc.org NR 36 TC 4 Z9 4 U1 0 U2 1 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 DEC PY 2014 VL 124 IS 12 BP 2829 EP 2836 DI 10.1002/lary.24729 PG 8 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA AU0WZ UT WOS:000345344200037 PM 24764127 ER PT J AU Zaitlen, N Pasaniuc, B Sankararaman, S Bhatia, G Zhang, JQ Gusev, A Young, T Tandon, A Pollack, S Vilhjalmsson, BJ Assimes, TL Berndt, SI Blot, WJ Chanock, S Franceschini, N Goodman, PG He, J Hennis, AJM Hsing, A Ingles, SA Isaacs, W Kittles, RA Klein, EA Lange, LA Nemesure, B Patterson, N Reich, D Rybicki, BA Stanford, JL Stevens, VL Strom, SS Whitse, EA Witte, JS Xu, JF Haiman, C Wilson, JG Kooperberg, C Stram, D Reiner, AP Tang, H Price, AL AF Zaitlen, Noah Pasaniuc, Bogdan Sankararaman, Sriram Bhatia, Gaurav Zhang, Jianqi Gusev, Alexander Young, Taylor Tandon, Arti Pollack, Samuela Vilhjalmsson, Bjarni J. Assimes, Themistocles L. Berndt, Sonja I. Blot, William J. Chanock, Stephen Franceschini, Nora Goodman, Phyllis G. He, Jing Hennis, Anselm J. M. Hsing, Ann Ingles, Sue A. Isaacs, William Kittles, Rick A. Klein, Eric A. Lange, Leslie A. Nemesure, Barbara Patterson, Nick Reich, David Rybicki, Benjamin A. Stanford, Janet L. Stevens, Victoria L. Strom, Sara S. Whitse, Eric A. Witte, John S. Xu, Jianfeng Haiman, Christopher Wilson, James G. Kooperberg, Charles Stram, Daniel Reiner, Alex P. Tang, Hua Price, Alkes L. TI Leveraging population admixture to characterize the heritability of complex traits SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; MISSING HERITABILITY; COMMON SNPS; LATINO POPULATIONS; NATURAL-SELECTION; GENETIC-VARIATION; SIBLING PAIRS; ANCESTRY; HEIGHT; PROPORTION AB Despite recent progress on estimating the heritability explained by genotyped SNPs (h(g)())(2), a large gap between h(g)(2) estimates of total narrow-sense heritability (h(2)) remains. Explanations for this gap include rare variants or upward bias in family-based estimates of h(2) due to shared environment or epistasis. We estimate h(2) from unrelated individuals in admixed populations by first estimating the heritability explained by local ancestry (h(gamma)(2)). We show that h(gamma)(2) = 2F(STC)theta(1 - theta)h(2), where F-STC measures frequency differences between populations at causal loci and theta is the genome-wide ancestry proportion. Our approach is not susceptible to biases caused by epistasis or shared environment. We applied this approach to the analysis of 13 phenotypes in 21,497 African-American individuals from 3 cohorts. For height and body mass index (BMI), we obtained h(2) estimates of 0.55 +/- 0.09 and 0.23 +/- 0.06, respectively, which are larger than estimates of h(g)(2) these and other data but smaller than family-based estimates of h(2). C1 [Zaitlen, Noah] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Pasaniuc, Bogdan] Univ Calif San Francisco, Dept Pathol & Lab Med, San Francisco, CA 94143 USA. [Sankararaman, Sriram; Bhatia, Gaurav; Gusev, Alexander; Young, Taylor; Tandon, Arti; Pollack, Samuela; Vilhjalmsson, Bjarni J.; Patterson, Nick; Reich, David; Price, Alkes L.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Sankararaman, Sriram; Tandon, Arti; Reich, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Bhatia, Gaurav; Gusev, Alexander; Pollack, Samuela; Vilhjalmsson, Bjarni J.; Price, Alkes L.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Bhatia, Gaurav; Gusev, Alexander; Pollack, Samuela; Vilhjalmsson, Bjarni J.; Price, Alkes L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Zhang, Jianqi; He, Jing; Ingles, Sue A.; Haiman, Christopher; Stram, Daniel] Univ Calif San Francisco, Dept Prevent Med, San Francisco, CA 94143 USA. [Assimes, Themistocles L.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Berndt, Sonja I.; Chanock, Stephen] NCI, Div Canc Epidemiol & Genet, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Blot, William J.] Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37212 USA. [Blot, William J.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Blot, William J.] Int Epidemiol Inst, Rockville, MD USA. [Franceschini, Nora; Whitse, Eric A.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Goodman, Phyllis G.] SWOG Stat Ctr, Seattle, WA USA. SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. [Hennis, Anselm J. M.] Univ W Indies, Chron Dis Res Ctr, Bridgetown, Barbados. Univ W Indies, Fac Med Sci, Bridgetown, Barbados. [Hennis, Anselm J. M.] Minist Hlth, Bridgetown, Barbados. [Hsing, Ann] Canc Prevent Inst Calif, Fremont, CA USA. [Hsing, Ann] Stanford Univ, Sch Med, Div Epidemiol, Stanford, CA 94305 USA. [Isaacs, William] Johns Hopkins Hosp & Med Inst, James Buchanan Brady Urol, Baltimore, MD USA. [Kittles, Rick A.] Univ Illinois, Dept Med, Chicago, IL USA. [Klein, Eric A.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. [Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Reich, David] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Rybicki, Benjamin A.] Henry Ford Hosp, Dept Publ Hlth Sci, Detroit, MI 48202 USA. [Stanford, Janet L.; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Stevens, Victoria L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Strom, Sara S.] Univ Texas MD Anderson Canc Ctr, Div Canc Prevent & Populat Sci, Dept Epidemiol, Houston, TX 77030 USA. [Witte, John S.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Winston Salem, NC USA. [Haiman, Christopher] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Reiner, Alex P.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Tang, Hua] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. RP Zaitlen, N (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. EM noah.zaitlen@ucsf.edu; huatang@stanford.edu; aprice@hsph.harvard.edu RI Vilhjalmsson, Bjarni/K-3971-2014; OI Vilhjalmsson, Bjarni/0000-0003-2277-9249; Assimes, Themistocles/0000-0003-2349-0009 FU US National Institutes of Health [R01 HG006399, R01 GM073059, 1K25HL121295-01A1, R21 ES020754]; National Heart, Lung, and Blood Institute; US National Institutes of Health; US Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C] FX This research was supported by US National Institutes of Health grants R01 HG006399, R01 GM073059, 1K25HL121295-01A1 and R21 ES020754. The WHI program is funded by the National Heart, Lung, and Blood Institute, US National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C. NR 44 TC 14 Z9 14 U1 0 U2 21 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 DEC PY 2014 VL 46 IS 12 BP 1356 EP 1362 DI 10.1038/ng.3139 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA AU3YU UT WOS:000345547300019 PM 25383972 ER PT J AU Byrareddy, SN Kallam, B Arthos, J Cicala, C Nawaz, F Hiatt, J Kersh, EN McNicholl, JM Hanson, D Reimann, KA Brameier, M Walter, L Rogers, K Mayne, AE Dunbar, P Villinger, T Little, D Parslow, TG Santangelo, PJ Villinger, F Fauci, AS Ansari, AA AF Byrareddy, Siddappa N. Kallam, Brianne Arthos, James Cicala, Claudia Nawaz, Fatima Hiatt, Joseph Kersh, Ellen N. McNicholl, Janet M. Hanson, Debra Reimann, Keith A. Brameier, Markus Walter, Lutz Rogers, Kenneth Mayne, Ann E. Dunbar, Paul Villinger, Tara Little, Dawn Parslow, Tristram G. Santangelo, Philip J. Villinger, Francois Fauci, Anthony S. Ansari, Aftab A. TI Targeting alpha(4)beta(7) integrin reduces mucosal transmission of simian immunodeficiency virus and protects gut-associated lymphoid tissue from infection SO NATURE MEDICINE LA English DT Article ID T-CELL SUBSET; SIV INFECTION; GASTROINTESTINAL-TRACT; MAINTENANCE THERAPY; ULCERATIVE-COLITIS; IMMUNE ACTIVATION; RHESUS MACAQUES; ALPHA-4-BETA-7; VEDOLIZUMAB; HIV-1 AB alpha(4)beta(7) integrin expressing CD4(+) T cells preferentially traffic to gut-associated lymphoid tissue (GALT) and have a key role in HIV and simian immunodeficiency virus (SIV) pathogenesis. We show here that the administration of an anti-alpha(4)beta(7) monoclonal antibody just prior to and during acute infection protects rhesus macaques from transmission following repeated low-dose intravaginal challenges with SIVmac251. In treated animals that became infected, the GALT was significantly protected from infection and CD4(+) T cell numbers were maintained in both the blood and the GALT. Thus, targeting alpha(4)beta(7) reduces mucosal transmission of Sly in macaques. C1 [Byrareddy, Siddappa N.; Kallam, Brianne; Mayne, Ann E.; Dunbar, Paul; Villinger, Tara; Little, Dawn; Parslow, Tristram G.; Villinger, Francois; Ansari, Aftab A.] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Arthos, James; Cicala, Claudia; Nawaz, Fatima; Hiatt, Joseph; Fauci, Anthony S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Kersh, Ellen N.; McNicholl, Janet M.; Hanson, Debra] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Atlanta, GA USA. [Reimann, Keith A.] Univ Massachusetts, Sch Med, Mass Biol, Boston, MA 02125 USA. [Brameier, Markus; Walter, Lutz] German Primate Ctr, Leibniz Inst Primate Res, Primate Genet Lab, Gottingen, Germany. [Rogers, Kenneth; Villinger, Francois] Emory Univ, Yerkes Natl Primate Res Ctr, Div Microbiol & Immunol, Atlanta, GA 30322 USA. [Santangelo, Philip J.] Georgia Inst Technol, Wallace H Coulter Dept Biomed Engn, Atlanta, GA 30332 USA. [Santangelo, Philip J.] Emory Univ, Atlanta, GA 30322 USA. RP Ansari, AA (reprint author), Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. EM pathaaa@emory.edu OI Hiatt, Joseph/0000-0002-8015-9614 FU NIH-NIAID [AI-098628-01]; NIAID NIH Intramural Research Program; Nonhuman Primate Reagent Resource (NIAID, NIH) [HHSN272200900037C]; [OD 51POD1113] FX This work was supported by a grant from the NIH-NIAID AI-098628-01 (to A.A.A.), the NIAID NIH Intramural Research Program and OD 51POD1113 to the Yerkes National Primate Research Center. We are grateful to F. Connor-Stroud for help with the cytobrush studies and to the veterinary staff and animal caretakers of the Yerkes National Primate Center of Emory University, specially S. Ehnert and her team. The authors also acknowledge the assistance of M. Piatak for performing the ultrasensitive PCR analysis and R. Kaul and L.R. McKinnon for sharing with us their finding on cervical brush analyses in Africa and advising us on how to proceed in adapting their human findings to our nonhuman primates. Recombinant mAbs were produced by the Nonhuman Primate Reagent Resource (NIAID, NIH contract # HHSN272200900037C). The virus stock of SIVmac251 was obtained courtesy of N. Miller (NIAID, NIH). We apologize to all the authors whose publications we failed to cite. The findings in this report are those of the authors and do not necessarily reflect the views of the US Centers for Disease Control and Prevention. NR 20 TC 30 Z9 30 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD DEC PY 2014 VL 20 IS 12 BP 1397 EP 1400 DI 10.1038/nm.3715 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA AU7ZZ UT WOS:000345817900014 PM 25419708 ER PT J AU Schubert, D Bode, C Kenefeck, R Hou, TZ Wing, JB Kennedy, A Bulashevska, A Petersen, BS Schaffer, AA Gruning, BA Unger, S Frede, N Baumann, U Witte, T Schmidt, RE Dueckers, G Niehues, T Seneviratne, S Kanariou, M Speckmann, C Ehl, S Rensing-Ehl, A Warnatz, K Rakhmanov, M Thimme, R Hasselblatt, P Emmerich, F Cathomen, T Backofen, R Fisch, P Seidl, M May, A Schmitt-Graeff, A Ikemizu, S Salzer, U Franke, A Sakaguchi, S Walker, LSK Sansom, DM Grimbacher, B AF Schubert, Desiree Bode, Claudia Kenefeck, Rupert Hou, Tie Zheng Wing, James B. Kennedy, Alan Bulashevska, Alla Petersen, Britt-Sabina Schaeffer, Alejandro A. Gruening, Bjoern A. Unger, Susanne Frede, Natalie Baumann, Ulrich Witte, Torsten Schmidt, Reinhold E. Dueckers, Gregor Niehues, Tim Seneviratne, Suranjith Kanariou, Maria Speckmann, Carsten Ehl, Stephan Rensing-Ehl, Anne Warnatz, Klaus Rakhmanov, Mirzokhid Thimme, Robert Hasselblatt, Peter Emmerich, Florian Cathomen, Toni Backofen, Rolf Fisch, Paul Seidl, Maximilian May, Annette Schmitt-Graeff, Annette Ikemizu, Shinji Salzer, Ulrich Franke, Andre Sakaguchi, Shimon Walker, Lucy S. K. Sansom, David M. Grimbacher, Bodo TI Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations SO NATURE MEDICINE LA English DT Article ID REGULATORY T-CELLS; COMMON VARIABLE IMMUNODEFICIENCY; GERMLINE MUTATIONS; CLINICAL-PICTURE; ANTIGEN 4; AUTOIMMUNITY; TOLERANCE; FOXP3; MICE; HOMEOSTASIS AB The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses, and its loss causes fatal autoimmunity in mice. We studied a large family in which five individuals presented with a complex, autosomal dominant immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune clinical features. We identified a heterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparable clinical phenotypes identified five additional families (nine individuals) with previously undescribed splice site and missense mutations in CTLA4. Clinical penetrance was incomplete (eight adults of a total of 19 genetically proven CTLA4 mutation carriers were considered unaffected). However, CTLA-4 protein expression was decreased in regulatory T cells (T-reg cells) in both patients and carriers with CTLA4 mutations. Whereas T-reg cells were generally present at elevated numbers in these individuals, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations in CTLA4 were also associated with decreased circulating B cell numbers. Taken together, mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome. C1 [Schubert, Desiree; Bode, Claudia; Bulashevska, Alla; Unger, Susanne; Frede, Natalie; Speckmann, Carsten; Ehl, Stephan; Rensing-Ehl, Anne; Warnatz, Klaus; Rakhmanov, Mirzokhid; Cathomen, Toni; Salzer, Ulrich; Grimbacher, Bodo] Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, Freiburg, Germany. [Schubert, Desiree] Univ Freiburg, Spemann Grad Sch Biol & Med, D-79106 Freiburg, Germany. [Kenefeck, Rupert; Hou, Tie Zheng; Kennedy, Alan; Seneviratne, Suranjith; Walker, Lucy S. K.; Sansom, David M.; Grimbacher, Bodo] UCL, Inst Immun & Transplantat, London, England. [Wing, James B.; Sakaguchi, Shimon] Osaka Univ, World Premier Int Immunol Frontier Res Ctr, Osaka, Japan. [Petersen, Britt-Sabina; Franke, Andre] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany. [Schaeffer, Alejandro A.] NIH, Natl Lib Med, Bethesda, MD 20892 USA. [Gruening, Bjoern A.; Backofen, Rolf] Univ Freiburg, Dept Comp Sci, D-79106 Freiburg, Germany. [Baumann, Ulrich; Witte, Torsten; Schmidt, Reinhold E.] Hannover Med Sch, Dept Pediat Pulmonol Allergy & Neonatol, Hannover, Germany. [Dueckers, Gregor; Niehues, Tim] HELIOS Childrens Hosp, Krefeld, Germany. [Kanariou, Maria] Aghia Sophia Childrens Hosp, Dept Immunol & Histocompatibil, Athens, Greece. [Thimme, Robert; Hasselblatt, Peter] Univ Med Ctr Freiburg, Clin Internal Med 2, Freiburg, Germany. [Emmerich, Florian; Cathomen, Toni] Univ Med Ctr Freiburg, Inst Cell & Gene Therapy, Freiburg, Germany. [Fisch, Paul; Seidl, Maximilian; May, Annette; Schmitt-Graeff, Annette] Univ Med Ctr Freiburg, Dept Pathol, Freiburg, Germany. [Ikemizu, Shinji] Kumamoto Univ, Div Struct Biol, Kumamoto, Japan. RP Grimbacher, B (reprint author), Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, Freiburg, Germany. EM bodo.grimbacher@uniklinik-freiburg.de RI HOU, TIEZHENG/B-4848-2015; Sakaguchi, Shimon/C-9535-2009; Petersen, Britt-Sabina/I-1671-2012; Witte, Torsten/B-5783-2016; Franke, Andre/B-2151-2010; OI Petersen, Britt-Sabina/0000-0001-9022-9017; Franke, Andre/0000-0003-1530-5811; Sansom, David/0000-0001-6506-3115; Ehl, Stephan/0000-0002-9265-2721; Walker, Lucy/0000-0001-5986-5015; Gruning, Bjorn/0000-0002-3079-6586; Wing, James/0000-0002-3462-1003; Cathomen, Toni/0000-0002-7757-4630 FU Bundesministerium fur Bildung und Forschung, grant: Integriertes Forschungs und Behandlungszentrum/Center for Chronic Immunodeficiencies [01EO1303]; Bildung und Forschung, grant Systems Biology E:med/SysInflame [012X1306F]; Deutsches Zentrum fur Infelctionsforschung [8000805-3]; Excellence Initiative of the German Research Foundation [GSC-4]; Intramural Research Program of the US National Institutes of Health, National Library of Medicine; DFG [CRC 992]; UK Medical Research Council; Wellcome Trust; Diabetes UK; Japan Society for the Promotion of ScienceYoung Scientist B grant; Ministry of Education, Culture, Sports, Science and Technology of Japan; Japan Science and Technology Agency FX We thank the patients and their relatives for their participation in this study. We thank F. Atschekzei, S. Kock, A. Gaa, S. Glatzel and M. Stenzel for technical assistance, and D. Comtesse, R. Weinert, R. Wieland, M. Schuler and N. Verma for their excellent and dedicated patient care. This research was funded by the Bundesministerium fur Bildung und Forschung with the following grants: Integriertes Forschungs und Behandlungszentrum/Center for Chronic Immunodeficiencies 01EO1303, Systems Biology E:med/SysInflame: 012X1306F; the Deutsches Zentrum fur Infelctionsforschung #8000805-3 and in part by the Excellence Initiative of the German Research Foundation (GSC-4, Spemann Graduate School) and by the Intramural Research Program of the US National Institutes of Health, National Library of Medicine. We also thank the German Crohn's and Colitis Foundation for support of the exome sequencing and the Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence "Inflammation at Interfaces' B.A.G. is funded by the DFG CRC 992 Medical Epigenetics, L.S.K.W. by a UK Medical Research Council Senior Fellowship, T.Z.H. by the Wellcome Trust, R.K. by Diabetes UK, J.B.W. by a Japan Society for the Promotion of ScienceYoung Scientist B grant and S.S. by the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Japan Science and Technology Agency. NR 45 TC 108 Z9 110 U1 3 U2 32 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD DEC PY 2014 VL 20 IS 12 BP 1410 EP 1416 DI 10.1038/nm.3746 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA AU7ZZ UT WOS:000345817900016 PM 25329329 ER PT J AU Clatworthy, MR Aronin, CEP Mathews, RJ Morgan, NY Smith, KGC Germain, RN AF Clatworthy, Menna R. Aronin, Caren E. Petrie Mathews, Rebeccah J. Morgan, Nicole Y. Smith, Kenneth G. C. Germain, Ronald N. TI Immune complexes stimulate CCR7-dependent dendritic cell migration to lymph nodes SO NATURE MEDICINE LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; FC-GAMMA-RIIB; SELECTIVE BLOCKADE; LANGERHANS CELLS; LIPID RAFTS; RECEPTOR; POLYMORPHISM; MATURATION; IGG; METALLOPROTEINASE-9 AB Antibodies are critical for defense against a variety of microbes, but they may also be pathogenic in some autoimmune diseases. Many effector functions of antibodies are mediated by Fc gamma receptors (Fc gamma Rs), which are found on most immune cells, including dendritic cells (DCs)-important antigen-presenting cells that play a central role in inducing antigen-specific tolerance or immunity(1,2). Following antigen acquisition in peripheral tissues, DCs migrate to draining lymph nodes via the lymphatics to present antigen to T cells. Here we demonstrate that Fc-gamma R engagement by IgG immune complexes (ICs) stimulates DC migration from peripheral tissues to the paracortex of draining lymph nodes. In vitro, IC-stimulated mouse and human DCs showed greater directional migration in a chemokine (C-C) ligand 19 (CCL19) gradient and increased chemokine (C-C) receptor 7 (CCR7) expression. Using intravital two-photon microscopy, we observed that local administration of IC resulted in dermal DC mobilization. We confirmed that dermal DC migration to lymph nodes depended on CCR7 and increased in the absence of the inhibitory receptor Fc gamma RIIB. These observations have relevance to autoimmunity because autoantibody-containing serum from humans with systemic lupus erythematosus (SLE) and from a mouse model of SLE also increased dermal DC migration in vivo, suggesting that this process may occur in lupus, potentially driving the inappropriate localization of autoantigen-bearing DCs. C1 [Clatworthy, Menna R.; Mathews, Rebeccah J.] Univ Cambridge, Dept Med, MRC Lab Mol Biol, Cambridge CB2 2QQ, England. [Clatworthy, Menna R.; Aronin, Caren E. Petrie; Germain, Ronald N.] NIAID, Lab Syst Biol, Lymphocyte Biol Sect, NIH, Bethesda, MD 20892 USA. [Morgan, Nicole Y.] Natl Inst Biomed Imaging & Bioengn, Microfabricat & Microfluid Unit, NIH, Bethesda, MD USA. [Smith, Kenneth G. C.] Cambridge Inst Med Res, Cambridge, England. [Smith, Kenneth G. C.] Univ Cambridge, Sch Clin Med, Dept Med, Cambridge, England. RP Clatworthy, MR (reprint author), Univ Cambridge, Dept Med, MRC Lab Mol Biol, Cambridge CB2 2QQ, England. EM mrc38@cam.ac.uk; rgermain@nih.gov FU Wellcome Trust [WT081020]; National Institute for Health Research Cambridge Biomedical Research Centre; Intramural Research Program of the US National Institute of Allergy and Infectious Diseases of the US National Institutes of Health FX This work was supported by a Wellcome Trust Intermediate Fellowship (WT081020) to M.R.C. and by the National Institute for Health Research Cambridge Biomedical Research Centre and the Intramural Research Program of the US National Institute of Allergy and Infectious Diseases, part of the US National Institutes of Health. We thank J. Yoon for technical advice and M. Espeli for helpful discussions. NR 37 TC 27 Z9 29 U1 4 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD DEC PY 2014 VL 20 IS 12 BP 1458 EP 1463 DI 10.1038/nm.3709 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA AU7ZZ UT WOS:000345817900022 PM 25384086 ER PT J AU Kikuchi, R Nakamura, K MacLauchlan, S Ngo, DTM Shimizu, I Fuster, JJ Katanasaka, Y Yoshida, S Qiu, Y Yamaguchi, TP Matsushita, T Murohara, T Gokce, N Bates, DO Hamburg, NM Walsh, K AF Kikuchi, Ryosuke Nakamura, Kazuto MacLauchlan, Susan Doan Thi-Minh Ngo Shimizu, Ippei Fuster, Jose Javier Katanasaka, Yasufumi Yoshida, Sumiko Qiu, Yan Yamaguchi, Terry P. Matsushita, Tadashi Murohara, Toyoaki Gokce, Noyan Bates, David O. Hamburg, Naomi M. Walsh, Kenneth TI An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease SO NATURE MEDICINE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; INTERMITTENT CLAUDICATION; SKELETAL-MUSCLE; SPLICE VARIANT; PHASE-II; ANGIOGENESIS; INFLAMMATION; ASSOCIATION; MECHANISMS; VEGF(165)B AB Peripheral artery disease (PAD) generates tissue ischemia through arterial occlusions and insufficient collateral vessel formation. Vascular insufficiency in PAD occurs despite higher circulating levels of vascular endothelial growth factor A (VEGF-A)1,2, a key regulator of angiogenesis. Here we show that clinical PAD is associated with elevated levels of an antiangiogenic VEGF-A splice isoform (VEGF-A(165)b) and a corresponding reduction in levels of the proangiogenic VEGF-A(165)a splice isoform. In mice, VEGF-A(165)b expression was upregulated by conditions associated with impaired limb revascularization, including leptin deficiency, diet-induced obesity, genetic ablation of the secreted frizzled-related protein 5 (Sfrp5) adipokine and transgenic overexpression of Wnt5a in myeloid cells. In a mouse model of PAD, delivery of VEGF-A(165)b inhibited revascularization of ischemic hind limbs, Whereas treatment with an isoform-specific neutralizing antibody reversed impaired revascularization caused by metabolic dysfunction or perturbations in the Wnt5a-Sfrp5 regulatory system. These results indicate that inflammation-driven expression of the antiangiogenic VEGF-A isoform can contribute to impaired collateralization in ischemic cardiovascular disease. C1 [Kikuchi, Ryosuke; Nakamura, Kazuto; MacLauchlan, Susan; Shimizu, Ippei; Fuster, Jose Javier; Katanasaka, Yasufumi; Yoshida, Sumiko; Hamburg, Naomi M.; Walsh, Kenneth] Boston Univ, Sch Med, Boston, MA 02118 USA. [Kikuchi, Ryosuke; Nakamura, Kazuto; MacLauchlan, Susan; Doan Thi-Minh Ngo; Shimizu, Ippei; Fuster, Jose Javier; Katanasaka, Yasufumi; Yoshida, Sumiko; Gokce, Noyan; Hamburg, Naomi M.; Walsh, Kenneth] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Kikuchi, Ryosuke] Nagoya Univ Hosp, Dept Med Tech, Nagoya, Aichi, Japan. [Doan Thi-Minh Ngo; Gokce, Noyan] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Qiu, Yan; Bates, David O.] Univ Bristol, Sch Physiol & Pharmacol, Microvasc Res Labs, Bristol, Avon, England. [Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, NIH, Frederick, MD 21701 USA. [Matsushita, Tadashi] Nagoya Univ Hosp, Dept Clin Lab, Nagoya, Aichi, Japan. [Murohara, Toyoaki] Nagoya Univ, Grad Sch Med, Dept Cardiol, Nagoya, Aichi 4648601, Japan. [Bates, David O.] Univ Nottingham, Sch Med, Queens Med Ctr, Div Canc & Stem Cells, Nottingham, England. [Hamburg, Naomi M.] Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02118 USA. RP Walsh, K (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA. EM kxwalsh@bu.edu RI Murohara, Toyoaki/M-4958-2014; Matsushita, Tadadshi/I-7349-2014; Fuster, Jose/A-2117-2017; OI Fuster, Jose/0000-0002-5970-629X; Maclauchlan, Susan/0000-0001-9689-0826 FU US National Institutes of Health (NIH) [HL102874, AG34972, HL68758, HL126141]; Uehara Memorial Foundation; NIH [HL102299, HL109790, HL081587, HL1145675]; British Heart Foundation [PG/13/47130337, PG/08/054/25272]; Wellcome Trust; Cancer Research UK; Medical Research Council FX This work was supported by US National Institutes of Health (NIH) grants HL102874, AG34972, HL68758 and HL126141 to K.W. R.K. is supported by the Uehara Memorial Foundation and the Grant-in-Aid for Young Scientists B. N.M.H. is supported by NIH grants HL102299 and HL109790, and N.G. is supported by NIH grants HL081587 and HL1145675. D.O.B. is supported by the British Heart Foundation PG/13/47130337 and PG/08/054/25272, the Wellcome Trust, Cancer Research UK and the Medical Research Council. We are grateful to S.M. Eswarappa and P.L. Fox, Department of Cellular and Molecular Medicine, The Lerner Research Institute, Cleveland Clinic, for providing Ax-specific antibody and recombinant VEGF-Ax protein. NR 29 TC 31 Z9 31 U1 5 U2 31 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD DEC PY 2014 VL 20 IS 12 BP 1464 EP 1471 DI 10.1038/nm.3703 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA AU7ZZ UT WOS:000345817900023 PM 25362254 ER PT J AU Heller, EA Cates, HM Pena, CJ Sun, HS Shao, NY Feng, J Golden, SA Herman, JP Walsh, JJ Mazei-Robison, M Ferguson, D Knight, S Gerber, MA Nievera, C Han, MH Russo, SJ Tamminga, CS Neve, RL Shen, L Zhang, HS Zhang, F Nestler, EJ AF Heller, Elizabeth A. Cates, Hannah M. Pena, Catherine J. Sun, Haosheng Shao, Ningyi Feng, Jian Golden, Sam A. Herman, James P. Walsh, Jessica J. Mazei-Robison, Michelle Ferguson, Deveroux Knight, Scott Gerber, Mark A. Nievera, Christian Han, Ming-Hu Russo, Scott J. Tamminga, Carol S. Neve, Rachael L. Shen, Li Zhang, H. Steve Zhang, Feng Nestler, Eric J. TI Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors SO NATURE NEUROSCIENCE LA English DT Article ID COCAINE-INDUCED PLASTICITY; NUCLEUS-ACCUMBENS; DELTA-FOSB; HISTONE ACETYLATION; MEMORY FORMATION; BINDING PROTEIN; TRANSCRIPTION; METHYLATION; EXPRESSION; BRAIN AB Chronic exposure to drugs of abuse or stress regulates transcription factors, chromatin-modifying enzymes and histone post-translational modifications in discrete brain regions. Given the promiscuity of the enzymes involved, it has not yet been possible to obtain direct causal evidence to implicate the regulation of transcription and consequent behavioral plasticity by chromatin remodeling that occurs at a single gene. We investigated the mechanism linking chromatin dynamics to neurobiological phenomena by applying engineered transcription factors to selectively modify chromatin at a specific mouse gene in vivo. We found that histone methylation or acetylation at the Fosb locus in nucleus accumbens, a brain reward region, was sufficient to control drug- and stress-evoked transcriptional and behavioral responses via interactions with the endogenous transcriptional machinery. This approach allowed us to relate the epigenetic landscape at a given gene directly to regulation of its expression and to its subsequent effects on reward behavior. C1 [Heller, Elizabeth A.; Cates, Hannah M.; Pena, Catherine J.; Sun, Haosheng; Shao, Ningyi; Feng, Jian; Golden, Sam A.; Walsh, Jessica J.; Mazei-Robison, Michelle; Ferguson, Deveroux; Russo, Scott J.; Shen, Li; Nestler, Eric J.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. [Heller, Elizabeth A.; Cates, Hannah M.; Pena, Catherine J.; Sun, Haosheng; Shao, Ningyi; Feng, Jian; Golden, Sam A.; Walsh, Jessica J.; Mazei-Robison, Michelle; Ferguson, Deveroux; Russo, Scott J.; Shen, Li; Nestler, Eric J.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Herman, James P.] NEI, NIH, Bethesda, MD 20892 USA. [Walsh, Jessica J.; Han, Ming-Hu] Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA. [Knight, Scott; Gerber, Mark A.; Nievera, Christian] Sigma Aldrich, St Louis, MO USA. [Tamminga, Carol S.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Neve, Rachael L.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Zhang, H. Steve] Sangamo Biosci Inc, Richmond, CA USA. [Ferguson, Deveroux; Zhang, Feng] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. RP Nestler, EJ (reprint author), Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. EM eric.nestler@mssm.edu RI SHAO, Ning-Yi/N-4947-2015; OI SHAO, Ning-Yi/0000-0003-4231-828X; Ferguson, Deveroux/0000-0001-9302-5992; Golden, Sam/0000-0002-2104-2272; Herman, James/0000-0001-6916-2807; Cates, Hannah/0000-0002-9413-0847 FU National Institute on Drug Abuse; National Institute of Mental Health; Hope for Depression Research Foundation FX The authors wish to thank G. Stuber and R. Ung for their help in generating social interaction heat maps. This work was supported by grants from the National Institute on Drug Abuse (E.A.H. and E.J.N.), the National Institute of Mental Health and the Hope for Depression Research Foundation (E.J.N.). NR 40 TC 41 Z9 43 U1 2 U2 35 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 DEC PY 2014 VL 17 IS 12 BP 1720 EP 1727 DI 10.1038/nn.3871 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AU2ZY UT WOS:000345484000019 PM 25347353 ER PT J AU Grieder, TE Herman, MA Contet, C Tan, LA Vargas-Perez, H Cohen, A Chwalek, M Maal-Bared, G Freiling, J Schlosburg, JE Clarke, L Crawford, E Koebel, P Repunte-Canonigo, V Sanna, PP Tapper, AR Roberto, M Kieffer, BL Sawchenko, PE Koob, GF van der Kooy, D George, O AF Grieder, Taryn E. Herman, Melissa A. Contet, Candice Tan, Laura A. Vargas-Perez, Hector Cohen, Ami Chwalek, Michal Maal-Bared, Geith Freiling, John Schlosburg, Joel E. Clarke, Laura Crawford, Elena Koebel, Pascale Repunte-Canonigo, Vez Sanna, Pietro P. Tapper, Andrew R. Roberto, Marisa Kieffer, Brigitte L. Sawchenko, Paul E. Koob, George F. van der Kooy, Derek George, Olivier TI VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation SO NATURE NEUROSCIENCE LA English DT Article ID VENTRAL TEGMENTAL AREA; CORTICOTROPIN-RELEASING-FACTOR; DENDRITIC PEPTIDE RELEASE; STRESS-INDUCED RELAPSE; DOPAMINERGIC-NEURONS; GABA NEURONS; COCAINE SEEKING; CENTRAL NUCLEUS; BINDING-PROTEIN; DEPENDENT RATS AB Dopaminergic neurons in the ventral tegmental area (VIA) are well known for mediating the positive reinforcing effects of drugs of abuse. Here we identify in rodents and humans a population of VIA dopaminergic neurons expressing corticotropin-releasing factor (CRF). We provide further evidence in rodents that chronic nicotine exposure upregulates Crh mRNA (encoding CRF) in dopaminergic neurons of the posterior VIA, activates local CRF1 receptors and blocks nicotine-induced activation of transient GABAergic input to dopaminergic neurons. Local downregulation of Crh mRNA and specific pharmacological blockade of CRF1 receptors in the VIA reversed the effect of nicotine on GABAergic input to dopaminergic neurons, prevented the aversive effects of nicotine withdrawal and limited the escalation of nicotine intake. These results link the brain reward and stress systems in the same brain region to signaling of the negative motivational effects of nicotine withdrawal. C1 [Grieder, Taryn E.; Vargas-Perez, Hector; Chwalek, Michal; Maal-Bared, Geith; Clarke, Laura; van der Kooy, Derek] Univ Toronto, Inst Med Sci, Toronto, ON, Canada. [Grieder, Taryn E.; Vargas-Perez, Hector; Chwalek, Michal; Maal-Bared, Geith; Clarke, Laura; van der Kooy, Derek] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Herman, Melissa A.; Contet, Candice; Cohen, Ami; Freiling, John; Schlosburg, Joel E.; Crawford, Elena; Roberto, Marisa; George, Olivier] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Tan, Laura A.; Sawchenko, Paul E.] Salk Inst Biol Studies, La Jolla, CA USA. [Koebel, Pascale; Kieffer, Brigitte L.] Univ Strasbourg, INSERM, CNRS, Inst Genet & Biol Mol & Cellulaire, Illkirch Graffenstaden, France. [Repunte-Canonigo, Vez; Sanna, Pietro P.] Scripps Res Inst, La Jolla, CA 92037 USA. [Tapper, Andrew R.] Univ Massachusetts, Sch Med, Brudnick Neuropsychiat Res Inst, Worcester, MA USA. [Kieffer, Brigitte L.] McGill Univ, Douglas Hosp, Dept Psychiat, Res Ctr, Montreal, PQ, Canada. [Koob, George F.] NIAAA, Rockville, MD 20852 USA. RP George, O (reprint author), Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. EM ogeorge@scripps.edu RI Vargas Perez, Hector/F-3176-2015; koob, george/P-8791-2016; OI george, olivier/0000-0002-3700-5003 FU Canadian Institutes of Health Research; US National Institute on Drug Abuse [DA023597, DA035371, DA031566]; US National Institute on Alcohol Abuse and Alcoholism [AA021491, AA015566, F32 AA020430, AA006420, AA016658, AA021667, INIA AA013498]; Tobacco-Related Disease Research Program [12RT-0099]; US National Institute of Diabetes and Digestive and Kidney Diseases [DK026741]; Clayton Medical Research Foundation FX The authors thank M. Brennan, B. Takabe, C. Arias and the University of Toronto Division of Comparative Medicine staff for technical assistance and M. Arends for editorial assistance. The authors would also like to thank R. Nagra and J. Riehl and the UCLA Brain Bank (The Human Brain and Spinal Fluid Resource Center) for providing the human samples. This work was supported by the Canadian Institutes of Health Research, US National Institute on Drug Abuse (DA023597, DA035371 and DA031566), US National Institute on Alcohol Abuse and Alcoholism (AA021491, AA015566, F32 AA020430, AA006420, AA016658, AA021667 and INIA AA013498), Tobacco-Related Disease Research Program (12RT-0099), US National Institute of Diabetes and Digestive and Kidney Diseases (DK026741) and the Clayton Medical Research Foundation. NR 50 TC 25 Z9 25 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 DEC PY 2014 VL 17 IS 12 BP 1751 EP 1758 DI 10.1038/nn.3872 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AU2ZY UT WOS:000345484000023 PM 25402857 ER PT J AU Mackall, CL Merchant, MS Fry, TJ AF Mackall, Crystal L. Merchant, Melinda S. Fry, Terry J. TI Immune-based therapies for childhood cancer SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Review ID STEM-CELL TRANSPLANTATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; NATURAL-KILLER-CELLS; EPSTEIN-BARR-VIRUS; ANTI-GD2 MONOCLONAL-ANTIBODY; RESISTANT PROSTATE-CANCER; CYTOKINE RELEASE SYNDROME; COLONY-STIMULATING FACTOR; MODIFIED T-CELLS; PHASE-I TRIAL AB After decades of research, immunotherapies for cancer are demonstrating increasing success. These agents can amplify existent antitumour immunity or induce durable antitumour immune responses in a wide array of cancers. The spectrum of immunotherapeutics is broad, spanning monoclonal antibodies and their derivatives, tumour vaccines, and adoptive therapies using T cells and natural killer cells. Only a small number of immunotherapies have been tested in paediatric cancers, but impressive antitumour effects have already been observed. Mononclonal antibodies targeting GD2 that induce antibody-dependent cell-mediated cytotoxicity improve survival in high-risk neuroblastoma. Bi-specific monoclonal antibodies that simultaneously target CD19 and activate T cells can induce remission in acute B-cell lymphoblastic leukaemia (B-ALL) and adoptive immunotherapy using T cells genetically engineered to express chimeric antigen receptors targeting CD19 induce impressive responses in B-ALL. Efforts are underway to generate and test new immunotherapies in a wider array of paediatric cancers. Major challenges include a need to identify immunotherapy targets on the most lethal childhood cancers, to expand availability of technology-intense platforms, such as adoptive cell therapy, to optimize management of novel toxicities associated with this new class of cancer therapies and to determine how best to incorporate these therapies into standard treatment paradigms. C1 [Mackall, Crystal L.; Merchant, Melinda S.; Fry, Terry J.] NCI, Ctr Canc Res, Paediat Oncol Branch, Bethesda, MD 20892 USA. RP Mackall, CL (reprint author), NCI, Ctr Canc Res, Paediat Oncol Branch, 10 Ctr Dr,MSC 1104, Bethesda, MD 20892 USA. EM mackallc@mail.nih.gov FU Intramural Research Program of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institutes of Health. NR 93 TC 27 Z9 30 U1 0 U2 23 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD DEC PY 2014 VL 11 IS 12 BP 693 EP 703 DI 10.1038/nrclinonc.2014.177 PG 11 WC Oncology SC Oncology GA AU4FT UT WOS:000345566100005 PM 25348789 ER PT J AU Roychowdhury, S Zwierzchowski, AN Garcia-Oscos, F Olguin, RC Delgado, RS Atzori, M AF Roychowdhury, Swagata Zwierzchowski, Amy N. Garcia-Oscos, Francisco Cuevas Olguin, Roberto Salgado Delgado, Roberto Atzori, Marco TI Layer- and Area-Specificity of the Adrenergic Modulation of Synaptic Transmission in the Rat Neocortex SO NEUROCHEMICAL RESEARCH LA English DT Article DE Prefrontal cortex; Temporal cortex; GABA; AMPA; Patch-clamp; Norepinephrine ID AUDITORY-CORTEX NEURONS; MEDIAL PREFRONTAL CORTEX; COERULEUS-NOREPINEPHRINE SYSTEM; LOCUS-COERULEUS; GABAERGIC INTERNEURONS; OPTIMAL PERFORMANCE; DECISION-MAKING; ADAPTIVE GAIN; NMDA-RECEPTOR; IN-VITRO AB The mammalian neocortex is a multilayered structure receiving extensive adrenergic projections both in rostral and caudal areas. The cellular mechanisms of norepinephrine (NE) in the neocortex are incompletely understood. We used electrophysiology to determine whether NE modulation of synaptic transmission were similar in rostral versus caudal cortical areas, and in infra- versus supra-granular cortical layers. To address these questions we used bath applications of NE (20 A mu M) to determine its effects on pharmacologically isolated electrically-evoked 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propionic acid receptor (AMPAR)-mediated excitatory synaptic currents (eEPSCs), or gamma-amino butyric acid A receptor (GABA(A)R)-mediated inhibitory synaptic currents (eIPSCs). We monitored synaptic currents in pyramidal neurons using whole-cell patch-clamp recordings from supragranular layer 2/3 (L2/3) and infragranular layer 5 (L5) neurons in a thin-slice preparation of rat medial prefrontal cortex (mPFC). These results were compared with the effects in the temporal cortex (TC) under similar experimental conditions. We found that NE uniformly and transiently depressed eEPSCs from supragranular to infragranular layers in both the PFC and the TC. On the contrary, the effects of NE on eIPSC were area- and layer-dependent, as NE enhanced the mean amplitude in TC L2/3 and PFC L5 eIPSCs (which displayed the largest saturation currents in the areas studied) but depressed PFC L2/3 eIPSCs, without affecting TC L5 eIPSCs. While the precise physiological meaning of these results is still unclear, our data are consistent with the existence of a dense noradrenergic-controlled GABAergic cortical network in the PFC, in which L5 may act as a decisional bottleneck for behavioral inhibition. C1 [Roychowdhury, Swagata; Zwierzchowski, Amy N.; Atzori, Marco] Univ Texas Dallas, Sch Behav & Brain Sci, Richardson, TX 75080 USA. [Roychowdhury, Swagata] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Garcia-Oscos, Francisco] UT Southwestern, Dept Psychiat, Dallas, TX USA. [Cuevas Olguin, Roberto; Atzori, Marco] Univ Autonoma San Luis Potosi, Lab Neurofisiol Conductual & Sinapt, Programa Biol, Fac Ciencias, San Luis Potosi 78290, Mexico. [Salgado Delgado, Roberto] Univ Autonoma San Luis Potosi, Lab Neurobiol Ritmos Circadianos, Programa Biol, Fac Ciencias, San Luis Potosi 78290, Mexico. RP Atzori, M (reprint author), Univ Autonoma San Luis Potosi, Lab Neurofisiol Conductual & Sinapt, Programa Biol, Fac Ciencias, Av Manuel Nava, San Luis Potosi 78290, Mexico. EM marco.atzori@utdallas.edu OI Roychowdhury, Sagorika/0000-0001-9376-3928 FU PROMEP/PRODEP; Basic Science/CONACyT FX The work was funded with a PROMEP/PRODEP and a Basic Science/CONACyT grant to MA. NR 45 TC 3 Z9 4 U1 0 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 EI 1573-6903 J9 NEUROCHEM RES JI Neurochem. Res. PD DEC PY 2014 VL 39 IS 12 BP 2377 EP 2384 DI 10.1007/s11064-014-1440-x PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AU5KL UT WOS:000345645700011 PM 25266551 ER PT J AU Xu, YS Tong, YX Liu, SY Chow, H AbdulSabur, NY Mattay, GS Braun, AR AF Xu, Yisheng Tong, Yunxia Liu, Siyuan Chow, HoMing AbdulSabur, Nuria Y. Mattay, Govind S. Braun, Allen R. TI Denoising the speaking brain: Toward a robust technique for correcting artifact-contaminated fMRI data under severe motion SO NEUROIMAGE LA English DT Article DE fMRI; Motion artifacts; Independent component analysis; Speech production; Resting-state functional connectivity ID INDEPENDENT-COMPONENT ANALYSIS; RESTING-STATE FMRI; FUNCTIONAL CONNECTIVITY MRI; EVENT-RELATED FMRI; TIME-SERIES; IMAGE REGISTRATION; BLIND SEPARATION; SUBJECT MOTION; HEAD MOTION; SPEECH AB A comprehensive set of methods based on spatial independent component analysis (sICA) is presented as a robust technique for artifact removal, applicable to a broad range of functional magnetic resonance imaging (fMRI) experiments that have been plagued by motion-related artifacts. Although the applications of sICA for fMRI denoising have been studied previously, three fundamental elements of this approach have not been established as follows: 1) a mechanistically-based ground truth for component classification; 2) a general framework for evaluating the performance and generalizability of automated classifiers; and 3) a reliable method for validating the effectiveness of denoising. Here we perform a thorough investigation of these issues and demonstrate the power of our technique by resolving the problem of severe imaging artifacts associated with continuous overt speech production. As a key methodological feature, a dual-mask sICA method is proposed to isolate a variety of imaging artifacts by directly revealing their extracerebral spatial origins. It also plays an important role for understanding the mechanistic properties of noise components in conjunction with temporal measures of physical or physiological motion. The potentials of a spatially-based machine learning classifier and the general criteria for feature selection have both been examined, in order to maximize the performance and generalizability of automated component classification. The effectiveness of denoising is quantitatively validated by comparing the activation maps of fMRI with those of positron emission tomography acquired under the same task conditions. The general applicability of this technique is further demonstrated by the successful reduction of distance-dependent effect of head motion on resting-state functional connectivity. (C) 2014 Elsevier Inc. All rights reserved. C1 [Xu, Yisheng; Liu, Siyuan; Chow, HoMing; AbdulSabur, Nuria Y.; Braun, Allen R.] NIDCD, Language Sect, Voice Speech & Language Branch, NIH, Bethesda, MD 20892 USA. [Tong, Yunxia] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [AbdulSabur, Nuria Y.] Univ Maryland, Dept Linguist, College Pk, MD 20742 USA. [Mattay, Govind S.] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. RP Xu, YS (reprint author), NIDCD, Language Sect, Voice Speech & Language Branch, NIH, Bethesda, MD 20892 USA. EM xuyi@nidcd.nih.gov FU NIH [92-DC-0178] FX This study was supported by the NIH Intramural Research Program (Protocol 92-DC-0178). We thank Venkata S. Mattay, S. Lalith Talagala and Souheil J. Inati for valuable comments on the manuscript; and Caroline F. Zink for helpful discussions. We are also particularly grateful to Jonathon D. Power for kindly sharing the resting-state fcMRI data. NR 62 TC 8 Z9 8 U1 4 U2 11 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 DEC PY 2014 VL 103 BP 33 EP 47 DI 10.1016/j.neuroimage.2014.09.013 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AU1PR UT WOS:000345393100004 PM 25225001 ER PT J AU Pan, YT You, J Volkow, ND Park, K Du, CW AF Pan, Yingtian You, Jiang Volkow, Nora D. Park, Kicheon Du, Congwu TI Ultrasensitive detection of 3D cerebral microvascular network dynamics in vivo SO NEUROIMAGE LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; BLOOD-FLOW; BRAIN; ANGIOGRAPHY; STROKE; ANGIOGENESIS; GLIOBLASTOMA; POPULATION; MICROSCOPY; VESSELS AB Despite widespread applications of multiphoton microscopy in microcirculation, its small field of view and inability to instantaneously quantify cerebral blood flow velocity (CBFv) in vascular networks limit its utility in investigating the heterogeneous responses to brain stimulations. Optical Doppler tomography (ODT) provides 3D images of CBFv networks, but it suffers poor sensitivity for measuring capillary flows. Here we report on a new method, contrast-enhanced ODT with Intralipid that significantly improves quantitative CBFv imaging of capillary networks by obviating the errors from long latency between flowing red blood cells (low hematocrit similar to 20% in capillaries). This enhanced sensitivity allowed us to measure the ultraslow microcirculation surrounding a brain tumor and the abnormal ingrowth of capillary flows in the tumor as well as in ischemia triggered by chronic cocaine in the mouse brain that could not be detected by regular ODT. It also enabled significantly enhanced sensitivity for quantifying the heterogeneous CBFv responses of vascular networks to acute cocaine exposure. Inasmuch as lipid emulsions are widely used for parenteral nutrition the Intralipid contrast method has translational potential for clinical applications. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/). C1 [Pan, Yingtian; You, Jiang; Park, Kicheon; Du, Congwu] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. [Volkow, Nora D.] NIAAA, NIH, Bethesda, MD 20857 USA. RP Pan, YT (reprint author), SUNY Stony Brook, Dept Biomed Engn, Bioengn Bldg G17, Stony Brook, NY 11794 USA. EM yingtian.pan@stonybrook.edu FU National Institutes of Health (NIH) [R21DA032228, 1R01DA029718, K25 DA021200]; NIH's Intramural Program FX This work was supported in part by the National Institutes of Health (NIH) grants R21DA032228 (YP/CD), 1R01DA029718 (CD/YP), K25 DA021200 (CD) and NIH's Intramural Program (NV). NR 36 TC 10 Z9 10 U1 4 U2 17 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 DEC PY 2014 VL 103 BP 492 EP 501 DI 10.1016/j.neuroimage.2014.08.051 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AU1PR UT WOS:000345393100049 PM 25192654 ER PT J AU Vannest, J Rajagopal, A Cicchino, ND Franks-Henry, J Simpson, SM Lee, G Altaye, M Sroka, C Holland, SK AF Vannest, Jennifer Rajagopal, Akila Cicchino, Nicole D. Franks-Henry, Julie Simpson, Sarah M. Lee, Gregory Altaye, Mekibib Sroka, Claire Holland, Scott K. CA CMIND Authorship Consortium TI Factors Determining Success of Awake and Asleep Magnetic Resonance Imaging Scans in Nonsedated Children SO NEUROPEDIATRICS LA English DT Article DE neuroimaging; behavioral methods; infant imaging ID PREPARING CHILDREN; MRI AB Effective techniques that allow children to complete magnetic resonance imaging (MRI) scans without sedation are high priority for the imaging community. We used behavioral approaches to scan 64 sleeping infants and toddlers younger than 4 years, and 156 awake children aged 2.5 to 18 years, for a neuroimaging research protocol. Infants and their families participated in a desensitization protocol for several days, then scanning was performed at the child's bedtime during natural sleep. For awake young children, a behavioral protocol was used that included tangible reinforcers, exploration of the scanner environment and a brief practice session. Two scan sessions were targeted for awake children. Success rates by participant were quantified in terms of the proportion of requisite scans in each session that were successfully acquired. The average success rate in sleeping infants and toddlers was 0.461. For awake children aged 2.5 to 6 years, success rates for each session were 0.739 and 0.847. For children aged 7 years and older, success rates were over 0.900 for both the sessions. Overall, though success was lower later in a scan session for both sleeping infants and awake young children, our results demonstrate that it is feasible to collect high-quality imaging data using standard imaging sequences in infants and children without sedation. C1 [Vannest, Jennifer; Rajagopal, Akila; Cicchino, Nicole D.; Franks-Henry, Julie; Simpson, Sarah M.; Lee, Gregory; Altaye, Mekibib; Sroka, Claire; Holland, Scott K.] Cincinnati Childrens Hosp Med Ctr, Pediat Neuroimaging Res Consortium, Cincinnati, OH 45229 USA. UPMC, Pediat Imaging Res Ctr, Dept Radiol, Childrens Hosp Pittsburgh, Pittsburgh, PA USA. Univ Michigan, Dept Biomed Engn, Funct MRI Lab, Ann Arbor, MI 48109 USA. Univ Arizona, Dept Speech Language & Hearing Sci, Tucson, AZ USA. Univ Cincinnati, Dept Pediat, Div Neurol, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. Univ Cincinnati, Dept Radiol, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. Univ Cincinnati, Dept Pediat, Cincinnati Childrens Hosp Med Ctr, Div Biostat & Epidemiol, Cincinnati, OH USA. Univ Cincinnati, Dept Pediat, Cincinnati Childrens Hosp Med Ctr, Div Biomed Informat, Cincinnati, OH USA. Univ Cincinnati, Dept Otolaryngol, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. Univ Cincinnati, Commun Sci Res Ctr, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. Univ So Calif, Keck Sch Med, Lab Neuroimaging, Los Angeles, CA 90033 USA. Univ So Calif, Keck Sch Med, Dept Ophthalmol, Los Angeles, CA 90033 USA. Univ So Calif, Keck Sch Med, Dept Neurol, Los Angeles, CA 90033 USA. Univ So Calif, Keck Sch Med, Dept Psychiat, Los Angeles, CA 90033 USA. [CMIND Authorship Consortium] Univ So Calif, Keck Sch Med, Dept Behav Sci, Los Angeles, CA 90033 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Vannest, J (reprint author), Cincinnati Childrens Hosp Med Ctr, Pediat Neuroimaging Res Consortium, 3333 Burnet Ave ML 5033, Cincinnati, OH 45229 USA. EM Jennifer.Vannest@cchmc.org RI Altaye, Mekibib/N-5274-2015; Wagner, Michael/E-6273-2016; OI Wagner, Michael/0000-0003-3421-4763; Freund, Lisa/0000-0003-2095-4023 NR 12 TC 8 Z9 8 U1 0 U2 4 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0174-304X EI 1439-1899 J9 NEUROPEDIATRICS JI Neuropediatrics PD DEC PY 2014 VL 45 IS 6 BP 370 EP 377 DI 10.1055/s-0034-1387816 PG 8 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA AU2NU UT WOS:000345456100005 PM 25144603 ER PT J AU Phillips, KA Epstein, DH Preston, KL AF Phillips, Karran A. Epstein, David H. Preston, Kenzie L. TI Psychostimulant addiction treatment SO NEUROPHARMACOLOGY LA English DT Review DE Psychostimulant; Addiction; Treatment ID PLACEBO-CONTROLLED TRIAL; COCAINE-DEPENDENT OUTPATIENTS; METHADONE-MAINTAINED PATIENTS; COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; SUBSTANCE USE DISORDERS; DOUBLE-BLIND; METHAMPHETAMINE DEPENDENCE; CONTINGENCY MANAGEMENT; ALCOHOL DEPENDENCE AB Treatment of psychostimulant addiction has been a major, and not fully met, challenge. For opioid addiction, there is strong evidence for the effectiveness of several medications. For psychostimulants, there is no corresponding form of agonist maintenance that has met criteria for regulatory approval or generally accepted use. Stimulant-use disorders remain prevalent and can result in both short-term and long-term adverse consequences. The mainstay of treatment remains behavioral interventions. In this paper, we discuss those interventions and some promising candidates in the search for pharmacological interventions. This article is part of the Special Issue entitled 'CNS Stimulants'. Published by Elsevier Ltd. C1 [Phillips, Karran A.; Epstein, David H.; Preston, Kenzie L.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Phillips, KA (reprint author), NIDA, Archway Clin, Treatment Sect, Intramural Res Program,NIH, Baltimore, MD 21224 USA. EM phillipsk@nida.nih.gov FU National Institute on Drug Abuse, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 122 TC 11 Z9 11 U1 6 U2 28 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD DEC PY 2014 VL 87 SI SI BP 150 EP 160 DI 10.1016/j.neuropharm.2014.04.002 PG 11 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA AU2XR UT WOS:000345478400016 PM 24727297 ER PT J AU Gonzalez, B Raineri, M Cadet, JL Garcia-Rill, E Urbano, FJ Bisagno, V AF Gonzalez, Betina Raineri, Mariana Cadet, Jean Lud Garcia-Rill, Edgar Urbano, Francisco J. Bisagno, Veronica TI Modafinil improves methamphetamine-induced object recognition deficits and restores prefrontal cortex ERK signaling in mice SO NEUROPHARMACOLOGY LA English DT Article DE Modafinil; Methamphetamine; Novelty; ERK; Prefrontal cortex ID PLACEBO-CONTROLLED TRIAL; REGULATED KINASE; DOUBLE-BLIND; DEPENDENT INDIVIDUALS; RESPONSE-INHIBITION; COCAINE DEPENDENCE; DOPAMINE-RECEPTORS; NUCLEUS-ACCUMBENS; WORKING-MEMORY; D1 RECEPTORS AB Chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans and in animal models. Modafinil is a wake-promoting compound approved for the treatment of sleeping disorders. It is also prescribed off label to treat METH dependence. In the present study, we investigated whether modafinil could improve cognitive deficits induced by sub-chronic METH treatment in mice by measuring visual retention in a Novel Object Recognition (NOR) task. After sub-chronic METH treatment (1 mg/kg, once a day for 7 days), mice performed the NOR task, which consisted of habituation to the object recognition arena (5 min a day, 3 consecutive days), training session (2 equal objects, 10 min, day 4), and a retention session (1 novel object, 5 min, day 5). One hour before the training session, mice were given a single dose of modafinil (30 or 90 mg/kg). METH-treated mice showed impairments in visual memory retention, evidenced by equal preference of familiar and novel objects during the retention session. The lower dose of modafinil (30 mg/kg) had no effect on visual retention scores in METH-treated mice, while the higher dose (90 mg/kg) rescued visual memory retention to control values. We also measured extracellular signal-regulated kinase (ERK) phosphorylation in medial prefrontal cortex (mPFC), hippocampus, and nucleus accumbens (NAc) of METH- and vehicle-treated mice that received modafinil 1 h before exposure to novel objects in the training session, compared to mice placed in the arena without objects. Elevated ERK phosphorylation was found in the mPFC of vehicle-treated mice, but not in METH-treated mice, exposed to objects. The lower dose of modafinil had no effect on ERK phosphorylation in METH-treated mice, while 90 mg/kg modafinil treatment restored the ERK phosphorylation induced by novelty in METH-treated mice to values comparable to controls. We found neither a novelty nor treatment effect on ERK phosphorylation in hippocampus or NAc of vehicle- and METH-treated mice receiving acute 90 mg/kg modafinil treatment. Our results showed a palliative role of modafinil against METH-induced visual cognitive impairments, possibly by normalizing ERK signaling pathways in mPFC. Modafinil may be a valuable pharmacological tool for the treatment of cognitive deficits observed in human METH abusers as well as in other neuropsychiatric conditions. This article is part of the Special Issue entitled 'CNS Stimulants'. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Gonzalez, Betina; Raineri, Mariana; Bisagno, Veronica] Univ Buenos Aires, CONICET, Inst lnvest Farrnacol, Buenos Aires, DF, Argentina. [Urbano, Francisco J.] Univ Buenos Aires, CONICET, Inst Fisiol Biol Mol & Neurociencias, Lab Fisiol & Biol Mol, Buenos Aires, DF, Argentina. [Cadet, Jean Lud] NIDA, Mol Neuropsychiat Res Branch, NIH, Intramural Res Program, Baltimore, MD USA. [Garcia-Rill, Edgar] Univ Arkansas Med Sci, Dept Neurobiol & Dev Sci, Ctr Translat Neurosci, Little Rock, AR 72205 USA. RP Bisagno, V (reprint author), ININFA CONICET UBA, Inst Invest Farmacol, Junin 956,5,Ciudad Buenos Aires C1113AAD, Caba, Argentina. EM vbisagno@ffyb.uba.ar OI Garcia-Rill, Edgar/0000-0003-1367-3071 FU Fundacion Bunge y Born; grant PIP, Argentina [11420100100072]; grant PICT, Argentina [2012-0924]; NIH [P20 GM103425] FX Dr. Bisagno has been authorized to study drug abuse substances in animal models by A.N.M.A.T. (National Board of Medicine Food and Medical Technology, Ministerio de Salud, Argentina). Dr. Betina Gonzalez is a recipient of a Postdoctoral Award from Fundacion Bunge y Born. This work is supported by grants PIP 11420100100072 and PICT 2012-0924, Argentina, and by NIH award P20 GM103425 to the Center for Translational Neuroscience. NR 64 TC 14 Z9 15 U1 3 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD DEC PY 2014 VL 87 SI SI BP 188 EP 197 DI 10.1016/j.neuropharm.2014.02.002 PG 10 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA AU2XR UT WOS:000345478400020 PM 24530829 ER PT J AU Marusich, JA Antonazzo, KR Wiley, JL Blough, BE Partilla, JS Baumann, MH AF Marusich, Julie A. Antonazzo, Kateland R. Wiley, Jenny L. Blough, Bruce E. Partilla, John S. Baumann, Michael H. TI Pharmacology of novel synthetic stimulants structurally related to the "bath salts" constituent 3,4-methylenedioxypyrovalerone (MDPV) SO NEUROPHARMACOLOGY LA English DT Article DE 3,4-Methylenedioxypyrovalerone; alpha-PVP; Functional observational battery; Locomotor activity; Monoamine transporter; Synthetic cathinones ID 2ND-GENERATION LEGAL HIGHS; CATHINONE DERIVATIVES; MONOAMINE TRANSPORTERS; LOCOMOTOR-ACTIVITY; IN-VITRO; MEPHEDRONE; RATS; DOPAMINE; INTOXICATION; ANALOGS AB There has been a dramatic rise in the abuse of synthetic cathinones known as "bath salts," including 3,4-methylenedioxypyrovalerone (MDPV), an analog linked to many adverse events. MDPV differs from other synthetic cathinones because it contains a pyrrolidine ring which gives the drug potent actions as an uptake blocker at dopamine and norepinephrine transporters. While MDPV is now illegal, a wave of "second generation" pyrrolidinophenones has appeared on the market, with alpha-pyrrolidinovalerophenone (alpha-PVP) being most popular. Here, we sought to compare the in vitro and in vivo pharmacological effects of MDPV and its congeners: alpha-PVP, alpha-pyrrolidinobutiophenone (alpha-PBP), and alpha-pyrrolidinopropiophenone (alpha-PPP). We examined effects of test drugs in transporter uptake and release assays using rat brain synaptosomes, then assessed behavioral stimulant effects in mice. We found that alpha-PVP is a potent uptake blocker at dopamine and norepinephrine transporters, similar to MDPV. alpha-PBP and alpha-PPP are also catecholamine transporter blockers but display reduced potency. All of the test drugs are locomotor stimulants, and the rank order of in vivo potency parallels dopamine transporter activity, with MDPV > alpha-PVP > alpha-PBP > alpha-PPP. Motor activation produced by all drugs is reversed by the dopamine receptor antagonist SCH23390. Furthermore, results of a functional observational battery show that all test drugs produce typical stimulant effects at lower doses and some drugs produce bizarre behaviors at higher doses. Taken together, our findings represent the first evidence that second generation analogs of MDPV are catecholamine-selective uptake blockers which may pose risk for addiction and adverse effects in human users. This article is part of the Special Issue entitled 'CNS Stimulants'. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Marusich, Julie A.; Antonazzo, Kateland R.; Wiley, Jenny L.; Blough, Bruce E.] RTI Int, Res Triangle Pk, NC 27709 USA. [Partilla, John S.; Baumann, Michael H.] NIDA, Designer Drug Res Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Marusich, JA (reprint author), RTI Int, 3040 Cornwallis Rd,138 Hermann, Res Triangle Pk, NC 27709 USA. EM jmarusich@rti.org FU NIDA; RTI International Internal Research And Development Funds; NIH/NIDA [DA12970] FX The authors thank Tim Lefever and Tony Landavazo for technical assistance. Research was generously supported by the Intramural Research Program at NIDA, RTI International Internal Research And Development Funds, and NIH/NIDA Grant DA12970. These sources of funding did not play any role in study design, data collection, analysis, and interpretation, in writing the report, or in the decision to submit the article for publication. NR 55 TC 39 Z9 40 U1 2 U2 26 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD DEC PY 2014 VL 87 SI SI BP 206 EP 213 DI 10.1016/j.neuropharm.2014.02.016 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA AU2XR UT WOS:000345478400022 PM 24594476 ER PT J AU Knuth, ND Johannsen, DL Tamboli, RA Marks-Shulman, PA Huizenga, R Chen, KY Abumrad, NN Ravussin, E Hall, KD AF Knuth, Nicolas D. Johannsen, Darcy L. Tamboli, Robyn A. Marks-Shulman, Pamela A. Huizenga, Robert Chen, Kong Y. Abumrad, Naji N. Ravussin, Eric Hall, Kevin D. TI Metabolic Adaptation Following Massive Weight Loss is Related to the Degree of Energy Imbalance and Changes in Circulating Leptin SO OBESITY LA English DT Article ID FAT-FREE MASS; Y GASTRIC BYPASS; BARIATRIC SURGERY; SKELETAL-MUSCLE; BODY-WEIGHT; EXPENDITURE; EXERCISE; MAINTENANCE; OBESITY; CHOLESTEROL AB ObjectiveTo measure changes in resting metabolic rate (RMR) and body composition in obese subjects following massive weight loss achieved via bariatric surgery or calorie restriction plus vigorous exercise. MethodsBody composition and RMR were measured in 13 pairs of obese subjects retrospectively matched for sex, body mass index, weight, and age who underwent either Roux-en-Y gastric bypass surgery (RYGB) or participated in The Biggest Loser weight loss competition (BLC). ResultsBoth groups had similar final weight loss (RYGB: 40.212.7 kg, BLC: 48.8 +/- 14.9 kg; P=0.14); however, RYGB lost a larger proportion of their weight as fat-free mass (FFM) (RYGB: 30 +/- 12%, BLC: 16 +/- 8% [P<0.01]). In both groups, RMR decreased significantly more than expected based on measured body composition changes. The magnitude of this metabolic adaptation was correlated with the degree of energy imbalance (r=0.55, P=0.004) and the decrease in circulating leptin (r=0.47, P=0.02). ConclusionsCalorie restriction along with vigorous exercise in BLC participants resulted in preservation of FFM and greater metabolic adaption compared to RYGB subjects despite comparable weight loss. Metabolic adaptation was related to the degree of energy imbalance and the changes in circulating leptin. C1 [Knuth, Nicolas D.; Chen, Kong Y.; Hall, Kevin D.] NIDDK, NIH, Bethesda, MD 20892 USA. [Johannsen, Darcy L.; Ravussin, Eric] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Tamboli, Robyn A.; Marks-Shulman, Pamela A.; Abumrad, Naji N.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Huizenga, Robert] Univ Calif Los Angeles, Los Angeles, CA USA. RP Hall, KD (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov OI Chen, Kong/0000-0002-0306-1904 FU Intramural Research Program of the NIH, National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); Pennington NORC Center Grant [P30 DK072476]; NIDDK [R01-DK070860, DK20593, DK058404, K01DK89005]; Vanderbilt CTSA from NCRR [1 UL1 RR024975] FX Funding agencies: This research was supported in part by the Intramural Research Program of the NIH, National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) (NDK and KDH), the Pennington NORC Center Grant P30 DK072476 (to ER), NIDDK grants R01-DK070860 (to NNA), DK20593 to the Vanderbilt Diabetes Research and Training Center, DK058404 to the Vanderbilt Digestive Disease Research Center, K01DK89005 (to DLJ), and the Vanderbilt CTSA grant 1 UL1 RR024975 from the NCRR. NR 40 TC 19 Z9 19 U1 2 U2 16 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 DEC PY 2014 VL 22 IS 12 BP 2563 EP 2569 DI 10.1002/oby.20900 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AU1XA UT WOS:000345409500016 PM 25236175 ER PT J AU Nicholson, BP Zhou, M Rostamizadeh, M Mehta, P Agron, E Wong, W Wiley, H Nussenblatt, R Sen, HN AF Nicholson, Benjamin P. Zhou, Mei Rostamizadeh, Mahdi Mehta, Preema Agron, Elvira Wong, Wai Wiley, Henry Nussenblatt, Robert Sen, H. Nida TI Epidemiology of Epiretinal Membrane in a Large Cohort of Patients with Uveitis SO OPHTHALMOLOGY LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; RISK-FACTORS; PREVALENCE; ASSOCIATIONS; POPULATION; FEATURES; EYE AB Objective: To identify clinical characteristics associated with the presence of epiretinal membrane (ERM) in patients with uveitis. Design: Case-control study. Participants andControls: Five hundred ninety- eight subjects seen in a single tertiary referral clinic between January 1, 2008, and December 31, 2011, who were diagnosed with uveitis. Methods: Spectral- domain optical coherence tomography (SD OCT) images of all subjects were reviewed to assess for ERM. A multivariate logistic regression analysis was performed to compare characteristics of subjects with ERM (cases) with characteristics of subjects without ERM (controls). A second multivariate analysis assessed the relationship between ERM and visual acuity. Fundus photographs were reviewed to compare SD OCT ascertainment of ERM with photographic ascertainment. Main Outcome Measures: Presence or absence of ERM on OCT imaging. Results: Of 598 uveitic participants, 246 (41%) were found to have ERM in at least 1 eye on SD OCT imaging. The prevalence of ERM by Standardization of Uveitis Nomenclature anatomic subtype was 28.1% for anterior uveitis, 57.0% for intermediate uveitis, and 43.4% for posterior uveitis and panuveitis. Multivariate analysis showed that the following clinical factors were associated significantly with ERM: older age (3% increased risk per year of age; 95% confidence interval [ CI], 1.02=1.05), intermediate uveitis (odds ratio [OR], 3.41; 95% CI, 1.67=6.96), posterior uveitis and panuveitis (OR, 1.81; 95% CI, 1.09-3.01), male sex (OR, 1.59; 95% CI, 1.05-2.42), and history of cataract surgery (OR, 1.78; 95% CI, 1.13-2.79). When adjusted for covariates, eyes with ERM had a mean logarithm of the minimum angle of resolution visual acuity of 0.58 (20/76) versus 0.48 (20/ 60) in non-ERM eyes (P = 0.039). Of OCT-defined ERMs in this cohort, 38% were not detectable on fundus photographs. Conclusions: Epiretinal membrane is a common complication of uveitis that is associated with patient age, intermediate uveitis, posterior uveitis, panuveitis, male sex, and previous cataract surgery. It can contribute independently to vision loss in uveitic eyes. In uveitis, OCT is more sensitive than fundus photography for identification of ERM. (C) 2014 by the American Academy of Ophthalmology C1 [Nicholson, Benjamin P.; Zhou, Mei; Rostamizadeh, Mahdi; Mehta, Preema; Agron, Elvira; Wong, Wai; Wiley, Henry; Nussenblatt, Robert; Sen, H. Nida] NEI, NIH, Bethesda, MD 20892 USA. RP Sen, HN (reprint author), NEI, NIH, Bldg 10,Magnuson Room 10D40,10 Ctr Dr, Bethesda, MD 20892 USA. EM senh@nei.nih.gov OI Wong, Wai/0000-0003-0681-4016 FU National Eye Institute Intramural Research Program, National Institutes of Health, Bethesda, Maryland FX Supported by the National Eye Institute Intramural Research Program, National Institutes of Health, Bethesda, Maryland. NR 16 TC 5 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD DEC PY 2014 VL 121 IS 12 BP 2393 EP 2398 DI 10.1016/j.ophtha.2014.06.015 PG 6 WC Ophthalmology SC Ophthalmology GA AU3JR UT WOS:000345509500023 PM 25064724 ER PT J AU Chew, EY Davis, MD Danis, RP Lovato, JF Perdue, LH Greven, C Genuth, S Goff, DC Leiter, LA Ismail-Beigi, F Ambrosius, WT AF Chew, Emily Y. Davis, Matthew D. Danis, Ronald P. Lovato, James F. Perdue, Letitia H. Greven, Craig Genuth, Saul Goff, David C. Leiter, Lawrence A. Ismail-Beigi, Faramarz Ambrosius, Walter T. CA Action Control Cardiovasc Risk TI The Effects of Medical Management on the Progression of Diabetic Retinopathy in Persons with Type 2 Diabetes The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study SO OPHTHALMOLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; MICROVASCULAR COMPLICATIONS; GLUCOSE CONTROL; MACULAR EDEMA; MELLITUS; THERAPY; FENOFIBRATE; DIAGNOSIS; OUTCOMES; AGE AB Purpose: To report additional ocular outcomes of intensive treatment of hyperglycemia, blood pressure, and dyslipidemia in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. Design: Double 2x2 factorial, multicenter, randomized clinical trials in people with type 2 diabetes who had cardiovascular disease or cardiovascular risk factors. In the glycemia trial, targets of intensive and standard treatment were: hemoglobin A1c < 6.0% and 7.0% to 7.9%, respectively, and in the blood pressure trial: systolic blood pressures of < 120 and < 140 mmHg, respectively. The dyslipidemia trial compared fenofibrate plus simvastatin with placebo plus simvastatin. Participants: Of the 3472 ACCORD Eye Study participants enrolled, 2856 had 4-year data (85% of survivors). Methods: Eye examinations and fundus photographs were taken at baseline and year 4. Photographs were graded centrally for retinopathy severity and macular edema using the Early Treatment Diabetic Retinopathy Study (ETDRS) methods. Main Outcome Measures: Three or more steps of progression on the ETDRS person scale or treatment of retinopathy with photocoagulation or vitrectomy. Results: As previously reported, there were significant reductions in the primary outcome in the glycemia and dyslipidemia trials, but no significant effect in the blood pressure trial. Results were similar for retinopathy progression by 1, 2, and 4 or more steps on the person scale and for >= 2 steps on the eye scale. In the subgroup of patients with mild retinopathy at baseline, effect estimates were large (odds ratios, similar to 0.30; P < 0.001), but did not reach nominal significance for participants with no retinopathy or for those with moderate to severe retinopathy at baseline. Conclusions: Slowing of progression of retinopathy by intensive treatment of glycemia was observed in ACCORD participants, whose average age and diabetes duration were 62 and 10 years, respectively, and who had cardiovascular disease or cardiovascular risk factors. The effect seemed stronger in patients with mild retinopathy. Similar slowing of progression was observed in patients treated with fenofibrate, with no effect observed with intensive blood pressure treatment. This is the second study to confirm the benefits of fenofibrate in reducing diabetic retinopathy progression, and fenofibrate should be considered for treatment of diabetic retinopathy. (C) 2014 by the American Academy of Ophthalmology. C1 [Chew, Emily Y.] NEI, NIH, Bethesda, MD 20892 USA. [Davis, Matthew D.; Danis, Ronald P.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Lovato, James F.; Perdue, Letitia H.; Greven, Craig; Ambrosius, Walter T.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Genuth, Saul; Ismail-Beigi, Faramarz] Case Western Reserve Univ, Dept Med, Univ Hosp, Cleveland, OH 44106 USA. [Genuth, Saul; Ismail-Beigi, Faramarz] Case Western Reserve Univ, Cleveland VA Med Ctr, Cleveland, OH 44106 USA. [Goff, David C.] Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA. [Leiter, Lawrence A.] Univ Toronto, Li Ka Shing Knowledge Inst, St Michaels Hosp, Toronto, ON M5S 1A1, Canada. [Leiter, Lawrence A.] Univ Toronto, Keenan Res Ctr Biomed Sci, St Michaels Hosp, Toronto, ON M5S 1A1, Canada. [Leiter, Lawrence A.] Univ Toronto, Div Endocrinol, Toronto, ON M5S 1A1, Canada. RP Chew, EY (reprint author), NEI, NIH, CRC, 10 Ctr Dr,MSC 1204,Bldg 10,Room 3-2531, Bethesda, MD 20892 USA. EM echew@nei.nih.gov FU National Heart, Lung, and Blood Institute and the National Institutes of Health (NIH) [N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, IAA-Y1-HC-1010]; National Heart, Lung, and Blood Institute, NIH; Novo-Nordisk; National Institute of Diabetes and Digestive and Kidney Diseases; National Eye Institute; National Institute on Aging; Centers for Disease Control and Prevention FX The author(s) have made the following disclosure(s): R. P. D.: Board member - EyeKor, LLC; Consultant - Allergan, GlaxoSmithKline, Thrombogenics (Data and Safety Monitoring Board [DSMB]), Oraya, Eli Lilly. L. H. P.: Grants - National Heart, Lung, and Blood Institute, NIH. D. C. G.: Consultant to and receives payment for lectures, Speakers bureaus - Merck; DSMB - Takeda. L. A. L,: Consultant - AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novo Nordisk, Roche, Sanofi, Servier, Takeda; Research grants - AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novo Nordisk, Roche, and Sanofi; Speakers bureaus-AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, Takeda. C. G.: Consultant - Thrombogenics. W. T. A.: Consultant-NIH/Office of Behavioral and Social Sciences Research and several DSMBs; Receives payment for the development of educational presentations, has a salary covered by NIH grants; Employed -Wake Forest School of Medicine. F. I.-. B.: Research grant - Novo-Nordisk for Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER), and Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN); Shares -Thermalin Diabetes.; Supported by contracts (N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, and IAA-Y1-HC-1010) from the National Heart, Lung, and Blood Institute and the National Institutes of Health (NIH), with additional support from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Eye Institute, the National Institute on Aging, and the Centers for Disease Control and Prevention. General clinical research centers provided support at many sites. The following companies donated study medications, equipment, or supplies: Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca Pharmaceuticals, Bayer HealthCare, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis Pharmaceuticals, Novo Nordisk, Omron Healthcare, Sanofi-Aventis U. S., and Takeda Pharmaceuticals. NR 23 TC 46 Z9 46 U1 1 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD DEC PY 2014 VL 121 IS 12 BP 2443 EP 2451 DI 10.1016/j.ophtha.2014.07.019 PG 9 WC Ophthalmology SC Ophthalmology GA AU3JR UT WOS:000345509500029 PM 25172198 ER PT J AU Janes, K Esposito, E Doyle, T Cuzzocrea, S Tosh, DK Jacobson, KA Salvemini, D AF Janes, Kali Esposito, Emanuela Doyle, Timothy Cuzzocrea, Salvatore Tosh, Dillip K. Jacobson, Kenneth A. Salvemini, Daniela TI A(3) adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways SO PAIN LA English DT Article DE A3; Adenosine; Chemotherapy-induced peripheral neuropathy; Neuroinflammation; Neuropathic pain; Paclitaxel; Spinal cord ID PROTEIN-KINASE-C; MANGANESE SUPEROXIDE-DISMUTASE; INDUCED PERIPHERAL NEUROPATHY; RETINAL GANGLION-CELLS; REACTIVE OXYGEN; GLUTAMATE TRANSPORTER; NITRIC-OXIDE; PHOSPHOLIPASE-D; NADPH OXIDASES; ACTIVATION AB Chemotherapy-induced peripheral neuropathy accompanied by chronic neuropathic pain is the major dose-limiting toxicity of several anticancer agents including the taxane paclitaxel (Taxol). A critical mechanism underlying paclitaxel-induced neuropathic pain is the increased production of peroxynitrite in spinal cord generated in response to activation of the superoxide-generating enzyme, NADPH oxidase. Peroxynitrite in turn contributes to the development of neuropathic pain by modulating several redox-dependent events in spinal cord. We recently reported that activation of the G(i)/G(q)-coupled A(3) adenosine receptor (A(3)AR) with selective A(3)AR agonists (ie, IB-MECA) blocked the development of chemotherapy induced-neuropathic pain evoked by distinct agents, including paclitaxel, without interfering with anticancer effects. The mechanism or mechanisms of action underlying these beneficial effects has yet to be explored. We now demonstrate that IB-MECA attenuates the development of paclitaxel-induced neuropathic pain by inhibiting the activation of spinal NADPH oxidase and two downstream redox-dependent systems. The first relies on inhibition of the redox-sensitive transcription factor (NF kappa B) and mitogen activated protein kinases (ERK and p38) resulting in decreased production of neuroexcitatory/proinflammatory cytokines (TNF-alpha, IL-1 beta) and increased formation of the neuroprotective/anti-inflammatory IL-10. The second involves inhibition of redox-mediated posttranslational tyrosine nitration and modification (inactivation) of glia-restricted proteins known to play key roles in regulating synaptic glutamate homeostasis: the glutamate transporter GLT-1 and glutamine synthetase. Our results unravel a mechanistic link into biomolecular signaling pathways employed by A(3)AR activation in neuropathic pain while providing the foundation to consider use of A(3)AR agonists as therapeutic agents in patients with chemotherapy-induced peripheral neuropathy. (c) 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. C1 [Janes, Kali; Doyle, Timothy; Salvemini, Daniela] St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, St Louis, MO 63104 USA. [Esposito, Emanuela; Cuzzocrea, Salvatore] Univ Messina, Dept Clin & Expt Med & Pharmacol, I-98122 Messina, Italy. [Tosh, Dillip K.; Jacobson, Kenneth A.] Natl Inst Diabet & Digest & Kidney Dis, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Salvemini, D (reprint author), St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, 1402 South Grand Blvd, St Louis, MO 63104 USA. EM salvemd@slu.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU National Cancer Institute [RO1CA169519]; St Louis University; St Louis Cancer Center; NIDDK FX We thank Leesa Bryant for her technical assistance in performing some of the animal experiments. This study was funded by grants from National Cancer Institute (RO1CA169519) and the St Louis University President Research Fund with additional support from the St Louis Cancer Center. KAJ and DKT acknowledge support from the NIDDK Intramural Research Program. NR 62 TC 15 Z9 16 U1 1 U2 14 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 DEC PY 2014 VL 155 IS 12 BP 2560 EP 2567 DI 10.1016/j.pain.2014.09.016 PG 8 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA AU1YZ UT WOS:000345414700018 PM 25242567 ER PT J AU To, TM Soldatos, A Sheriff, H Schmid, DS Espinosa, N Cosentino, G Preas, CP Glaser, CA AF To, Tu M. Soldatos, Ariane Sheriff, Heather Schmid, D. Scott Espinosa, Natasha Cosentino, Giorgio Preas, Christopher P. Glaser, Carol A. TI INSIGHTS INTO PEDIATRIC HERPES SIMPLEX ENCEPHALITIS FROM A COHORT OF 21 CHILDREN FROM THE CALIFORNIA ENCEPHALITIS PROJECT, 1998-2011 SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE herpes simplex encephalitis; California Encephalitis Project; pediatric encephalitis ID DIAGNOSIS AB Twenty-one children with confirmed herpes simplex encephalitis were identified in the California Encephalitis Project. Noteworthy features included 6 (29%) patients with an initial negative herpes simplex virus cerebrospinal fluid polymerase chain reaction test and 13 (59%) patients with extratemporal lobe involvement identified by neuroimaging. Eleven cases were <4 years of age, but all 4 fatal cases occurred in adolescents. C1 [To, Tu M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94107 USA. [To, Tu M.; Glaser, Carol A.] Calif Dept Publ Hlth, Ctr Infect Dis, Div Communicable Dis Control, Communicable Dis & Emergency Response Branch, Richmond, CA USA. [To, Tu M.] Calif Dept Publ Hlth, Calif Epidemiol Investigat Serv Cal EIS, Sacramento, CA USA. [Soldatos, Ariane] NINDS, NIH, Bethesda, MD 20892 USA. [Sheriff, Heather; Espinosa, Natasha; Cosentino, Giorgio; Preas, Christopher P.] Calif Dept Publ Hlth, Ctr Infect Dis, Div Communicable Dis Control, Viral & Rickettsial Dis Lab, Richmond, CA USA. [Schmid, D. Scott] Ctr Dis Control & Prevent, Measles Mumps Rubella & Herpesvirus Lab Branch, Div Viral Dis, Off Infect Dis,Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. RP To, TM (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, 185 Berry St,Lobby 5,Suite 5700, San Francisco, CA 94107 USA. EM tumy.to@ucsf.edu FU Centers for Disease Control and Prevention Emerging Infections Program [U50/CCU915546-09] FX Financial support was by Centers for Disease Control and Prevention Emerging Infections Program (U50/CCU915546-09). NR 10 TC 9 Z9 9 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 DEC PY 2014 VL 33 IS 12 BP 1287 EP 1288 DI 10.1097/INF.0000000000000422 PG 3 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA AU2ND UT WOS:000345454300018 PM 24911898 ER PT J AU Krishnan, A Samtani, R Dhanantwari, P Lee, E Yamada, S Shiota, K Donofrio, MT Leatherbury, L Lo, CW AF Krishnan, Anita Samtani, Rajeev Dhanantwari, Preeta Lee, Elaine Yamada, Shigehito Shiota, Kohei Donofrio, Mary T. Leatherbury, Linda Lo, Cecilia W. TI A detailed comparison of mouse and human cardiac development SO PEDIATRIC RESEARCH LA English DT Article ID CONGENITAL HEART-DISEASE; OUTFLOW TRACT; ARTERIAL TRUNKS; SEPTATION; MICE; ORGANOGENESIS; TRUNCUS; EMBRYOS; CHICK AB BACKGROUND: Mouse mutants are used to model human congenital cardiovascular disease. Few studies exist comparing normal cardiovascular development in mice vs. humans. We carried out a systematic comparative analysis of mouse and human fetal cardiovascular development. METHODS: Episcopic fluorescence image capture (EFIC) was performed on 66 wild-type mouse embryos from embryonic day (E) 9.5 to birth; 2-dimensional and 3-dimensional datasets were compared with EFIC and magnetic resonance images from a study of 52 human fetuses (Carnegie stage 13-23). RESULTS: Time course of atrial, ventricular, and outflow septation were outlined and followed a similar sequence in both species. Bilateral venae cavae and prominent atrial appendages were seen in the mouse fetus; in human fetuses, atrial appendages were small, and a single right superior vena cava was present. In contrast to humans with separate pulmonary vein orifices, a pulmonary venous confluence with one orifice enters the left atrium in mice. CONCLUSION: The cardiac developmental sequences observed in mouse and human fetuses are comparable, with minor differences in atrial and venous morphology. These comparisons of mouse and human cardiac development strongly support that mouse morphogenesis is a good model for human development. C1 [Krishnan, Anita; Samtani, Rajeev; Lee, Elaine; Leatherbury, Linda; Lo, Cecilia W.] NHLBI, Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Krishnan, Anita; Donofrio, Mary T.; Leatherbury, Linda] Childrens Natl Med Ctr, Childrens Natl Heart Inst, Washington, DC 20010 USA. [Samtani, Rajeev] George Washington Univ, Sch Med, Washington, DC USA. [Dhanantwari, Preeta] Schneider Childrens Hosp, Div Pediat Cardiol, New Hyde Pk, NY USA. [Lee, Elaine] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Yamada, Shigehito; Shiota, Kohei] Kyoto Univ, Grad Sch Med, Congenital Anomaly Res Ctr, Kyoto, Japan. [Lo, Cecilia W.] Univ Pittsburgh, Sch Med, Dept Dev Biol, Pittsburgh, PA USA. RP Krishnan, A (reprint author), NHLBI, Dev Biol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM akrishna@childrensnational.org RI Yamada, Shigehito/G-2061-2010 OI Yamada, Shigehito/0000-0002-8194-6927 FU United States National Institutes of Health [ZO1-HL005701]; Japanese Ministry of Education, Culture, Sports, Science, and Technology [19390050]; Japanese Ministry of Health, Labor, and Welfare [17A-6]; Japan Science Technology Agency (BIRD grant); Kyoto University Foundation; intramural Center of Genetics and Developmental Biology, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD FX This work was supported by United States National Institutes of Health grant ZO1-HL005701. The Kyoto collection was supported by the Japanese Ministry of Education, Culture, Sports, Science, and Technology (grant 19390050); Japanese Ministry of Health, Labor, and Welfare (grant 17A-6); and Japan Science Technology Agency (BIRD grant). S.Y. was supported by Kyoto University Foundation. L.L. had a subgrant from the intramural Center of Genetics and Developmental Biology, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD. NR 31 TC 4 Z9 4 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0031-3998 EI 1530-0447 J9 PEDIATR RES JI Pediatr. Res. PD DEC PY 2014 VL 76 IS 6 BP 500 EP 507 DI 10.1038/pr.2014.128 PG 8 WC Pediatrics SC Pediatrics GA AU3XZ UT WOS:000345545200001 PM 25167202 ER PT J AU Qi, SQ O'Hayre, M Gutkind, JS Hurley, JH AF Qi, Shiqian O'Hayre, Morgan Gutkind, J. Silvio Hurley, James H. TI Insights into beta 2-adrenergic receptor binding from structures of the N-terminal lobe of ARRDC3 SO PROTEIN SCIENCE LA English DT Article DE protein crystallography; ubiquitin ligase; arrestin; coimmunoprecipitation; asthma ID DOMAIN-CONTAINING PROTEINS; CRYSTAL-STRUCTURE; BETA-ARRESTINS; TRAFFICKING; LIGASE; UBIQUITINATION; RECRUITMENT; ENDOCYTOSIS; RETROMER; FAMILY AB ARRDC3 is one of six known human -arrestins, and has been implicated in the downregulation of the 2-adrenergic receptor (2AR). ARRDC3 consists of a two-lobed arrestin fold and a C-terminal tail containing two PPYX motifs. In the current model for receptor downregulation by ARRDC3, the arrestin fold portion is thought to bind the receptor, while the PPXY motifs recruit ubiquitin ligases of the NEDD4 family. Here we report the crystal structures of the N-terminal lobe of human ARRDC3 in two conformations, at 1.73 and 2.8 angstrom resolution, respectively. The structures reveal a large electropositive region that is capable of binding phosphate ions of crystallization. Residues within the basic patch were shown to be important for binding to 2AR, similar to the situation with -arrestins. This highlights potential parallels in receptor recognition between - and -arrestins. C1 [Qi, Shiqian; Hurley, James H.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Qi, Shiqian; Hurley, James H.] Univ Calif Berkeley, Calif Inst Quantitat Biosci, Berkeley, CA 94720 USA. [O'Hayre, Morgan; Gutkind, J. Silvio] NIDR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Hurley, James H.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA. RP Hurley, JH (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA. EM jimhurley@berkeley.edu RI Qi, Shiqian/P-9177-2014 FU American Asthma Foundation [AAF 2011-0228]; NIH Intramural program, NIDCR FX Grant sponsor: American Asthma Foundation AAF 2011-0228 and NIH Intramural program, NIDCR. NR 31 TC 5 Z9 6 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD DEC PY 2014 VL 23 IS 12 BP 1708 EP 1716 DI 10.1002/pro.2549 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU0QW UT WOS:000345329800006 PM 25220262 ER PT J AU Imai, M Venkatesh, BA Samiei, S Donekal, S Habibi, M Armstrong, AC Heckbert, SR Wu, CLO Bluemke, DA Lima, JAC AF Imai, Masamichi Venkatesh, Bharath Ambale Samiei, Sanaz Donekal, Sirisha Habibi, Mohammadali Armstrong, Anderson C. Heckbert, Susan R. Wu, Colin O. Bluemke, David A. Lima, Joao A. C. TI Multi-Ethnic Study of Atherosclerosis: Association between Left Atrial Function Using Tissue Tracking from Cine MR Imaging and Myocardial Fibrosis SO RADIOLOGY LA English DT Article ID CARDIOVASCULAR MAGNETIC-RESONANCE; HEART-FAILURE; DELAYED ENHANCEMENT; IRREVERSIBLE INJURY; SPECKLE TRACKING; INFARCTION; STRAIN; VOLUME; RISK; SIZE AB Purpose: To investigate the association between left atrial (LA) function and left ventricular myocardial fibrosis using cardiac magnetic resonance (MR) imaging in a multi-ethnic population. Materials and Methods: For this HIPAA-compliant study, the institutional review board at each participating center approved the study protocol, and all participants provided informed consent. Of 2839 participants who had undergone cardiac MR in 2010-2012, 143 participants with myocardial scar determined with late gadolinium enhancement and 286 age, sex-, and ethnicity-matched control participants were identified. LA volume, strain, and strain rate were analyzed by using multimodality tissue tracking from cine MR imaging. T1 mapping was applied to assess diffuse myocardial fibrosis. The association between LA parameters and myocardial fibrosis was evaluated with the Student t test and multivariable regression analysis. Results: The scar group had significantly higher minimum LA volume than the control group (mean, 22.0 +/- 10.5 [standard deviation] vs 19.0 +/- 7.8, P = .002) and lower LA ejection fraction (45.9 +/- 10.7 vs 51.3 +/- 8.7, P < .001), maximal LA strain (S-max) (25.4 +/- 10.7 vs 30.6 +/- 10.6, P < .001) and maximum LA strain rate (SRmax) (1.08 +/- 0.45 vs 1.29 +/- 0.51, P < .001), and lower absolute LA strain rate at early diastolic peak (SRE) (-0.77 +/- 0.42 vs -1.01 +/- 0.48, P < .001) and LA strain rate at atrial contraction peak (SRA) (-1.50 +/- 0.62 vs -1.78 +/- 0.69, P < .001) than the control group. T1 time 12 minutes after contrast material injection was significantly associated with S-max (beta coefficient = 0.043, P = .013), SRmax (beta coefficient = 0.0025, P = .001), SRE (beta coefficient = -0.0016, P = .027), and SRA (beta coefficient -0.0028, P = .01) in the regression model. T1 time 25 minutes after contrast material injection was significantly associated with SRmax (beta coefficient = 0.0019, P = .016) and SRA (beta coefficient = -0.0022, P = .034). Conclusion: Reduced LA regional and global function are related to both replacement and diffuse myocardial fibrosis processes. (C) RSNA, 2014 C1 [Imai, Masamichi; Venkatesh, Bharath Ambale; Samiei, Sanaz; Donekal, Sirisha; Armstrong, Anderson C.; Lima, Joao A. C.] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD 21287 USA. [Habibi, Mohammadali] Johns Hopkins Univ Hosp, Dept Cardiol, Baltimore, MD 21287 USA. [Heckbert, Susan R.] Washington Univ, Cardiovasc Hlth Res Unit, St Louis, MO USA. [Wu, Colin O.; Bluemke, David A.] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Lima, JAC (reprint author), Johns Hopkins Univ, Dept Med, Div Cardiol, 600 N Wolfe St,Blalock 524, Baltimore, MD 21287 USA. EM jlima1@jhmi.edu RI Armstrong, Anderson/G-8407-2012; Ambale Venkatesh, Bharath/F-4941-2016; OI Armstrong, Anderson/0000-0003-3161-8922; Ambale Venkatesh, Bharath/0000-0002-2330-2373; Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [N01-HC-95159-N01-HC-95166, N01-HC-95168]; National Center for Research Resources, National Institutes of Health [UL1-RR-024156, UL1-RR-025005] FX This research was supported by the National Heart, Lung, and Blood Institute (grants N01-HC-95159-N01-HC-95166, N01-HC-95168) and by the National Center for Research Resources (grants UL1-RR-024156 and UL1-RR-025005), National Institutes of Health. C.O.W. and D.A.B. are employees of the National Institutes of Health. NR 33 TC 10 Z9 10 U1 1 U2 3 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 DEC PY 2014 VL 273 IS 3 BP 703 EP 713 DI 10.1148/radiol.14131971 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AU3LQ UT WOS:000345515100009 PM 25019562 ER PT J AU Ren, ZX Haneline, LS AF Ren, Zhaoxia Haneline, Laura S. TI Common Drugs in Pregnancy: an Update from the Obstetric-Fetal Pharmacology Research Unit Network Introduction SO SEMINARS IN PERINATOLOGY LA English DT Editorial Material C1 [Ren, Zhaoxia] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Obstet & Pediat Pharmacol & Therapeut Branch, Bethesda, MD 20892 USA. [Haneline, Laura S.] Indiana Univ Sch Med, Dept Pediat, Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA. [Haneline, Laura S.] Indiana Univ Sch Med, Dept Cellular & Integrat Physiol, Indianapolis, IN 46202 USA. [Haneline, Laura S.] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. RP Ren, ZX (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Obstet & Pediat Pharmacol & Therapeut Branch, Bethesda, MD 20892 USA. EM lhanelin@iu.edu NR 13 TC 0 Z9 0 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0146-0005 EI 1558-075X J9 SEMIN PERINATOL JI Semin. Perinatol. PD DEC PY 2014 VL 38 IS 8 BP 473 EP 474 DI 10.1053/j.semperi.2014.08.010 PG 2 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA AU3UW UT WOS:000345539900001 PM 25267278 ER PT J AU Bodhak, S Diaz, LF Kuznetsov, SA Kilts, T Young, MF Lin-Gibson, S Robey, PG Simon, CG AF Bodhak, S. Diaz, L. F. Kuznetsov, S. A. Kilts, T. Young, M. F. Lin-Gibson, S. Robey, P. G. Simon, C. G., Jr. TI Combinatorial Cassette For High-throughput Screening Of Osteogenesis SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS-AM Conference CY DEC 13-16, 2014 CL Washington, DC SP TERMIS AM C1 [Bodhak, S.; Lin-Gibson, S.; Simon, C. G., Jr.] NIST, Biomat Grp, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. [Diaz, L. F.; Kuznetsov, S. A.; Kilts, T.; Young, M. F.; Robey, P. G.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC 1 PY 2014 VL 20 SU 1 MA P-739 BP S132 EP S133 PG 2 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AU6AK UT WOS:000345684300523 ER PT J AU Burks, S Nguyen, B Kim, S Frank, J AF Burks, S. Nguyen, B. Kim, S. Frank, J. TI Mesenchymal Stem Cell Homing to Kidneys Is Inhibited by Disrupting Interleukin 1 Alpha, Tumor Necrosis Factor Alpha, or Cyclooxygenase-2 Signaling SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS-AM Conference CY DEC 13-16, 2014 CL Washington, DC SP TERMIS AM C1 [Burks, S.; Nguyen, B.; Kim, S.; Frank, J.] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC 1 PY 2014 VL 20 SU 1 MA P-327 BP S86 EP S87 PG 2 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AU6AK UT WOS:000345684300337 ER PT J AU Burks, S Nguyen, B Kim, S Tebebi, P Street, J Yuen, P Star, R Frank, J AF Burks, S. Nguyen, B. Kim, S. Tebebi, P. Street, J. Yuen, P. Star, R. Frank, J. TI Targeted Homing of Mesenchymal Stem Cells by Pulsed Focused Ultrasound Improves Survival and Renal Function During Established Acute Kidney Injury SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS-AM Conference CY DEC 13-16, 2014 CL Washington, DC SP TERMIS AM C1 [Burks, S.; Nguyen, B.; Kim, S.; Tebebi, P.; Frank, J.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Street, J.; Yuen, P.; Star, R.] NIDDK, Bethesda, MD 20892 USA. RI Yuen, Peter/B-1954-2008 OI Yuen, Peter/0000-0001-9557-3909 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC 1 PY 2014 VL 20 SU 1 MA P-133 BP S61 EP S61 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AU6AK UT WOS:000345684300235 ER PT J AU Frieden, L King, LM AF Frieden, L. King, L. Mertens TI NIDCR Research Training and Career Development Opportunities SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS-AM Conference CY DEC 13-16, 2014 CL Washington, DC SP TERMIS AM C1 [Frieden, L.; King, L. Mertens] Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC 1 PY 2014 VL 20 SU 1 MA P-113 BP S58 EP S59 PG 2 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AU6AK UT WOS:000345684300224 ER PT J AU Hassan, S Burns, J Oliver, E Kiell, E Yoo, J Jackson, J Atala, A AF Hassan, S. Burns, J. Oliver, E. Kiell, E. Yoo, J. Jackson, J. Atala, A. TI In Vivo Delivery of MYC Gene to Regenerate Hair Cells for Restoring Hearing and Balance SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS-AM Conference CY DEC 13-16, 2014 CL Washington, DC SP TERMIS AM C1 [Hassan, S.; Yoo, J.; Jackson, J.; Atala, A.] Wake Forest Univ, Bowman Gray Sch Med, WFIRM, Winston Salem, NC USA. [Burns, J.] Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. [Oliver, E.; Kiell, E.] Wake Forest Univ, Bowman Gray Sch Med, Dept Otolaryngol Head & Neck Surg, Winston Salem, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC 1 PY 2014 VL 20 SU 1 MA O-277 BP S22 EP S22 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AU6AK UT WOS:000345684300078 ER PT J AU Hotaling, NA Bharti, K Kriel, H Simon, CG AF Hotaling, N. A. Bharti, K. Kriel, H. Simon, C. G., Jr. TI DiameterJ: An Open Source Nanofiber Diameter Measurement Tool SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS-AM Conference CY DEC 13-16, 2014 CL Washington, DC SP TERMIS AM C1 [Hotaling, N. A.; Simon, C. G., Jr.] Natl Inst Stand & Technol, Gaithersburg, MD 20899 USA. [Bharti, K.] NIH, Bethesda, MD 20892 USA. [Kriel, H.] Stellenbosch Nanofiber Co Pty Ltd, Cape Town, South Africa. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC 1 PY 2014 VL 20 SU 1 MA P-702 BP S126 EP S127 PG 2 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AU6AK UT WOS:000345684300498 ER PT J AU Kim, SJ Tebebi, PA Burks, SR Williams, R Nguyen, BA Frank, JA AF Kim, S. J. Tebebi, P. A. Burks, S. R. Williams, R. Nguyen, B. A. Frank, J. A. TI Comparison of Trypsin and Pronase Modification of Stem Cells in Cell Homing to Injured Tissue SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS-AM Conference CY DEC 13-16, 2014 CL Washington, DC SP TERMIS AM C1 [Kim, S. J.; Burks, S. R.; Williams, R.; Nguyen, B. A.; Frank, J. A.] NIH, Bethesda, MD 20892 USA. [Tebebi, P. A.] Catholic Univ Amer, Washington, DC 20064 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC 1 PY 2014 VL 20 SU 1 MA P-293 BP S83 EP S83 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AU6AK UT WOS:000345684300324 ER PT J AU Tebebi, P Burks, S Kim, S Williams, R Nguyen, B Frenkel, V Frank, J AF Tebebi, P. Burks, S. Kim, S. Williams, R. Nguyen, B. Frenkel, V. Frank, J. TI Inhibitors of Tumor Necrosis Factor Alpha or Cyclooxygenase-2 Block Mesenchymal Stem Cell Homing to Muscle SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS-AM Conference CY DEC 13-16, 2014 CL Washington, DC SP TERMIS AM C1 [Tebebi, P.; Burks, S.; Kim, S.; Williams, R.; Nguyen, B.; Frank, J.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Frenkel, V.] Catholic Univ Amer, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC 1 PY 2014 VL 20 SU 1 MA O-143 BP S12 EP S12 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AU6AK UT WOS:000345684300039 ER PT J AU Foster, PMD AF Foster, Paul M. D. TI Regulatory Forum Opinion Piece: New Testing Paradigms for Reproductive and Developmental Toxicity-The NTP Modified One Generation Study and OECD 443 SO TOXICOLOGIC PATHOLOGY LA English DT Article DE developmental pathology; endocrine disrupters; female reproduction; male reproduction; reproductive system; safety assessment ID WORKSHOP AB The National Toxicology Program (NTP) has developed a new flexible study design, termed the modified one generation (MOG) reproduction study. The MOG study will encompass measurements of developmental and reproductive toxicity parameters as well as enable the setting of appropriate dose levels for a cancer bioassay through evaluation of target organ toxicity that is based on test article exposure that starts during gestation. This study design is compared and contrasted with the new Organization for Economic Co-operation and Development (OECD) 443 test guideline, the extended one generation reproduction study. The MOG study has a number of advantages, with a focus on F-1 animals, the generation of adequately powered, robust data sets that include both pre and postnatal developmental toxicity information, and the measurement of effects on reproductive structure and function in the same animals. This new study design does not employ the use of internal triggers in the design structure for the use of animals already on test and is also consistent with the principles of the 3R's. C1 NIEHS, Div Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. RP Foster, PMD (reprint author), NIEHS, Div Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. EM foster2@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 6 TC 7 Z9 7 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD DEC PY 2014 VL 42 IS 8 BP 1165 EP 1167 DI 10.1177/0192623314534920 PG 3 WC Pathology; Toxicology SC Pathology; Toxicology GA AU4SQ UT WOS:000345602200001 PM 24862797 ER PT J AU Schweikart, KM Eldridge, SR Safgren, SL Parman, T Reid, JM Ames, MM Goetz, MP Davis, MA AF Schweikart, Karen M. Eldridge, Sandy R. Safgren, Stephanie L. Parman, Toufan Reid, Joel M. Ames, Matthew M. Goetz, Matthew P. Davis, Myrtle A. TI Comparative Uterotrophic Effects of Endoxifen and Tamoxifen in Ovariectomized Sprague-Dawley Rats SO TOXICOLOGIC PATHOLOGY LA English DT Article DE endoxifen; tamoxifen; endometrial cell proliferation ID BREAST-CANCER CELLS; OECD PROGRAM; ENDOMETRIAL CANCER; ADJUVANT TAMOXIFEN; DOSE-RESPONSE; METABOLITE; VALIDATE; BIOASSAY; CYP2D6; BIOAVAILABILITY AB Endoxifen (4-hydroxy-N-desmethyl-tamoxifen), one of the major active metabolites of tamoxifen, has substantially greater estrogen antagonist properties and antiproliferative effects in breast tumor cells than tamoxifen, a mixed estrogen agonist/antagonist. An associated risk of endometrial cancer and hyperplasia has been linked to the estrogen agonist properties of tamoxifen. We evaluated endoxifen using a classic uterotrophic effects method. Rats were given endoxifen or tamoxifen orally for 3 days. Estradiol was the positive control. Endoxifen and tamoxifen plasma levels exceeded those previously observed clinically. Uterine weight was 3-fold higher in the estradiol group than in the tamoxifen or endoxifen groups, which did not differ from vehicle controls. Tamoxifen and endoxifen caused a greater increase in luminal epithelial cell height than estradiol. Both tamoxifen and endoxifen produced an increase in the stromal BrdU labeling index (LI) that was estradiol and inversely related to dose, but did not affect luminal epithelial cell BrdU LI. As expected, estradiol increased luminal epithelial cell proliferation. These results indicate that endoxifen induces uterotrophic effects, but is less potent than estradiol in eliciting these effects. Given prior preclinical observations that endoxifen has superior antitumor activity than tamoxifen, the observations of similar uterine effects suggest that the endoxifen risk/benefit ratio may be superior to tamoxifen. C1 [Schweikart, Karen M.; Davis, Myrtle A.] NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. [Eldridge, Sandy R.] Charles River Labs Pathol Associates, Frederick, MD USA. [Parman, Toufan] SRI Int, Menlo Pk, CA 94025 USA. [Safgren, Stephanie L.; Reid, Joel M.; Ames, Matthew M.; Goetz, Matthew P.] Mayo Clin, Rochester, MN USA. RP Schweikart, KM (reprint author), NCI, 9609 Med Ctr Dr,Room 4W122, Bethesda, MD 20892 USA. EM schweikk@mail.nih.gov FU National Cancer Institute [N01-CM-42203, N01-CM-52206, N02-CM-27009]; Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Supported by National Cancer Institute contracts N01-CM-42203, N01-CM-52206, and N02-CM-27009. 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 supported [in part] by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 38 TC 3 Z9 3 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD DEC PY 2014 VL 42 IS 8 BP 1188 EP 1196 DI 10.1177/0192623314525688 PG 9 WC Pathology; Toxicology SC Pathology; Toxicology GA AU4SQ UT WOS:000345602200004 PM 24670817 ER PT J AU Thomas, MA Tuero, I Demberg, T Vargas-Inchaustegui, DA Musich, T Xiao, P Venzon, D LaBranche, C Montefiori, DC DiPasquale, J Reed, SG DeVico, A Fouts, T Lewis, GK Gallo, RC Robert-Guroff, M AF Thomas, Michael A. Tuero, Iskra Demberg, Thorsten Vargas-Inchaustegui, Diego A. Musich, Thomas Xiao, Peng Venzon, David LaBranche, Celia Montefiori, David C. DiPasquale, Janet Reed, Steven G. DeVico, Anthony Fouts, Timothy Lewis, George K. Gallo, Robert C. Robert-Guroff, Marjorie TI HIV-1 CD4-induced (CD4i) gp120 epitope vaccines promote B and T-cell responses that contribute to reduced viral loads in rhesus macaques SO VIROLOGY LA English DT Article DE HIV vaccine; HIV CD4i epitope; Rhesus macaque model; Replication-competent Ad; Systemic and mucosal adaptive immunity; Memory B and T cells; Antibody-dependent cellular cytotoxicity; Neutralizing antibody ID HUMAN-IMMUNODEFICIENCY-VIRUS; ADAPTIVE IMMUNE-RESPONSES; HIGHLY PATHOGENIC SIV; SIMIAN IMMUNODEFICIENCY; SHIV CHALLENGE; NONNEUTRALIZING ANTIBODIES; SHIV89.6P CHALLENGE; SIVMAC251 CHALLENGE; PROTECTIVE EFFICACY; NONHUMAN-PRIMATES AB To target the HIV CD4i envelope epitope, we primed rhesus macaques with replicating Ad-rhFLSC (HIV-1(BaL)gp120 linked to macaque CD4 D1 and D2), with or without Ad-SIVgag and Ad-SIVnef. Macaques were boosted with rhFLSC protein. Memory T-cells in PBMC, bronchoalveolar lavage and rectal tissue, antibodies with neutralizing and ADCC activity, and Env-specific secretory IgA in rectal secretions were elicited. Although protective neutralizing antibody levels were induced, SHIVSF162P4 acquisition following rectal challenge was not prevented. Rapid declines in serum ADCC activity, Env-specific memory B cells in PBMC and bone marrow, and systemic and mucosal memory T cells were observed immediately post-challenge together with delayed anamnestic responses. Innate immune signaling resulting from persisting Ad replication and the TLR-4 booster adjuvant may have been in conflict and reoriented adaptive immunity. A different adjuvant paired with replicating Ad, or a longer post-prime interval allowing vector clearance before boosting might foster persistent T- and B-cell memory. Published by Elsevier Inc. C1 [Thomas, Michael A.; Tuero, Iskra; Demberg, Thorsten; Vargas-Inchaustegui, Diego A.; Musich, Thomas; Xiao, Peng; DiPasquale, Janet; Robert-Guroff, Marjorie] NCI, Sect Immune Biol Retroviral Infect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [LaBranche, Celia; Montefiori, David C.] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Reed, Steven G.] Infect Dis Res Inst, Seattle, WA 98102 USA. [DeVico, Anthony; Lewis, George K.; Gallo, Robert C.] Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. [Fouts, Timothy] Profectus BioSci Inc, Baltimore, MD 21224 USA. RP Robert-Guroff, M (reprint author), NCI, Sect Immune Biol Retroviral Infect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov OI Fouts, Timothy/0000-0002-2429-2859 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX We thank Nancy Miller (DAIDS, NIAID) and Ranajit Pal (ABL, Inc.) for the titered SHIVSF162P4 challenge stock; Deborah Weiss, James Treece and the animal care staff at ABL, Inc., for care of the macaques, performance of animal procedures and collection of tissue samples; Jamie Lee Vernon for initial setup of the ICS assay system, Rachmat Hidajat for helpful discussion and David Liewehr for help with the statistical analysis. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 63 TC 7 Z9 7 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 0042-6822 J9 VIROLOGY JI Virology PD DEC PY 2014 VL 471 BP 81 EP 92 DI 10.1016/j.virol.2014.10.001 PG 12 WC Virology SC Virology GA AU3FJ UT WOS:000345497600010 PM 25461534 ER PT J AU Dashti, HS Shea, MK Smith, CE Tanaka, T Hruby, A Richardson, K Wang, TJ Nalls, MA Guo, XQ Liu, YM Yao, J Li, DL Johnson, WC Benjamin, EJ Kritchevsky, SB Siscovick, DS Ordovas, JM Booth, SL AF Dashti, Hassan S. Shea, M. Kyla Smith, Caren E. Tanaka, Toshiko Hruby, Adela Richardson, Kris Wang, Thomas J. Nalls, Mike A. Guo, Xiuqing Liu, Yongmei Yao, Jie Li, Dalin Johnson, W. Craig Benjamin, Emelia J. Kritchevsky, Stephen B. Siscovick, David S. Ordovas, Jose M. Booth, Sarah L. TI Meta-analysis of genome-wide association studies for circulating phylloquinone concentrations SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE GWAS; phylloquinone; vitamin K; CYP4F2; genetics ID BONE-MINERAL DENSITY; VITAMIN-K STATUS; SERUM UNDERCARBOXYLATED OSTEOCALCIN; FOOD-FREQUENCY QUESTIONNAIRE; COMMUNITY-DWELLING ADULTS; BIOCHEMICAL MEASURES; BODY-COMPOSITION; ATHEROSCLEROSIS MESA; COMMON VARIANTS; HIP FRACTURE AB Background: Poor vitamin K status is linked to greater risk of several chronic diseases. Age, sex, and diet are determinants of circulating vitamin K; however, there is still large unexplained interindividual variability in vitamin K status. Although a strong genetic component has been hypothesized, this has yet to be examined by a genome-wide association (GWA) study. Objective: The objective was to identify common genetic variants associated with concentrations of circulating phylloquinone, the primary circulating form of vitamin K. Design: We conducted a 2-stage GWA meta-analysis of circulating phylloquinone in 2 populations of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium Nutrition Working Group. Circulating phylloquinone was measured by using reversed-phase high-performance liquid chromatography. Results from adjusted cohort-specific discovery GWA analyses were meta-analyzed with inverse variance weights (n = 2138). Associations with circulating phylloquinone at P < 1 X 10(-6) were then evaluated in a second-stage analysis consisting of one independent cohort (n= 265). Results: No significant association was observed for circulating phylloquinone at the genome-wide significance level of 5 X 10(-8). However, from the discovery GWA, there were 11 single-nucleotide polymorphism (SNP) associations with circulating phylloquinone at P < 1 X 10(-6), including a functional variant previously associated with warfarin dose and altered phylloquinone metabolism. These SNPs are on 5 independent loci on 11q23.3, 8q24.3, 5q22.3, 2p12, and 19p13.12, and they fall within or near the candidate genes AP0A1/C3/A4/A5 cluster (involved in lipoprotein metabolism), COL22A1, CDO1, CTNAA2, and CYP4F2 (a phylloquinone oxidase), respectively. Second-stage analysis in an independent cohort further suggests the association of the 5q22.3 locus with circulating phylloquinone (P < 0.05). Conclusions: Multiple candidate genes related to lipoprotein and vitamin K metabolism were identified as potential determinants of circulating phylloquinone. Further investigation with a larger sample is warranted to verify our initial findings and identify other loci contributing to circulating phylloquinone. Trials related to this study were registered at clinicaltrials.gov as NCT00005121 (Framingham Offspring Study) and NCT00005487 (Multi-Ethnic Study of Atherosclerosis). C1 [Dashti, Hassan S.; Smith, Caren E.; Richardson, Kris; Ordovas, Jose M.] Tufts Univ, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, Nutr & Genom Lab, Boston, MA 02111 USA. [Shea, M. Kyla; Booth, Sarah L.] Tufts Univ, Vitamin K Lab, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Tanaka, Toshiko] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Nalls, Mike A.] NIA, Neurogenet Lab, Baltimore, MD 21224 USA. [Hruby, Adela] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Wang, Thomas J.] Vanderbilt Univ, Med Ctr, Div Cardiovasc Med, Nashville, TN USA. [Guo, Xiuqing; Yao, Jie] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Guo, Xiuqing; Yao, Jie] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Liu, Yongmei] Wake Forest Med Ctr, Dept Publ Hlth Sci, Winston Salem, NC USA. [Kritchevsky, Stephen B.] Wake Forest Med Ctr, Sticht Ctr Aging, Winston Salem, NC USA. [Li, Dalin] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Johnson, W. Craig] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Benjamin, Emelia J.] Boston Univ, Framingham, MA USA. [Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Siscovick, David S.] New York Acad Med, New York, NY USA. [Ordovas, Jose M.] CNIC, Dept Epidemiol, Madrid, Spain. [Ordovas, Jose M.] Inst Madrileno Estudios Avanzados Alimentac IMDEA, Madrid, Spain. RP Booth, SL (reprint author), Tufts Univ, Vitamin K Lab, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA. EM sarah.booth@tufts.edu OI Dashti, Hassan S/0000-0002-1650-679X; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung, and Blood Institute (NHLBI) [HL105756]; U.S. Department of Agriculture (Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium) [58-1950-0-014]; National Heart, Lung and Blood Institute's Framingham Heart Study Physical Examination, Testing and Surveillance [N01-HC 25195]; Affymetrix Inc. [N02-HL-6-4278]; NIH [2R01HL092577, R01 AGI4759, HHSN268200782096C]; NHLBI [K08 HL112845-01, N02-HL-64278]; Intramural Research Program of the NIH, National Institute on Aging (NIA) [N01AG62101, N01AG62103, N01AG62106]; NIA [R01AG032098]; Arthritis Foundation New Investigator grant; National Institute of Arthritis, Musculoskeletal and Skin Disease [R21AR062284]; [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]; [UL1-RR-025005]; [UL1-TR-000040] FX Supported in part by grant HL105756 from the National Heart, Lung, and Blood Institute (NHLBI) and by the U.S. Department of Agriculture, under agreement 58-1950-0-014 (Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium). The Framingham Offspring Study was supported in part by the National Heart, Lung and Blood Institute's Framingham Heart Study Physical Examination, Testing and Surveillance (contract N01-HC 25195) and its contract with Affymetrix Inc. for genotyping services (contract N02-HL-6-4278). EJB was supported by NIH grant 2R01HL092577. Funding for the plasma phylloquinone measures was provided by NIH R01 AGI4759. CES was supported by NHLBI grant K08 HL112845-01. The Health, Aging, and Body Composition study was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (NIA) contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant R01AG032098 to Wake Forest University Health Sciences, and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR was fully funded through a federal contract from the NIH to the Johns Hopkins University (contract HHSN268200782096C). Funding for the plasma phylloquinone measures was provided by an Arthritis Foundation New Investigator grant and grant R21AR062284 from the National Institute of Arthritis, Musculoskeletal and Skin Disease. The Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA SNP Health Association Resource (SHARe) project were conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA was provided 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, N01-HC-95169, UL1-RR-025005, and UL1-TR-000040. Funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, CA) and the Broad Institute of Harvard and MIT (Boston, MA) using the Affymetrix GenomeWide Human SNP Array 6.0. NR 50 TC 4 Z9 4 U1 2 U2 13 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC PY 2014 VL 100 IS 6 BP 1462 EP 1469 DI 10.3945/ajcn.114.093146 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AT9SZ UT WOS:000345267600009 PM 25411281 ER PT J AU Ouyang, FX Longnecker, MP Venners, SA Johnson, S Korrick, S Zhang, J Xu, XP Christian, P Wang, MC Wang, XB AF Ouyang, Fengxiu Longnecker, Matthew P. Venners, Scott A. Johnson, Sara Korrick, Susan Zhang, Jun Xu, Xiping Christian, Parul Wang, Mei-Cheng Wang, Xiaobin TI Preconception serum 1,1,1-trichloro-2,2,bis(p-chlorophenyl)ethane and B-vitamin status: independent and joint effects on women's reproductive outcomes SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE B vitamin; clinical pregnancy; DDT; early pregnancy loss; preconception ID EARLY-PREGNANCY LOSS; NEURAL-TUBE DEFECTS; CLINICAL PREGNANCY; MENSTRUAL-CYCLE; DDT EXPOSURE; CONCEPTION; ESTROGEN; TIME; AGE; SUPPLEMENTATION AB Background: Although preconception 1,1,1-trichloro-2,2,bis(p-chlorophenyl)ethane (DDT) exposure and B-vitamin deficiencies have each been shown to negatively affect human reproductive outcomes, little is known about their joint effect. Objective: We sought to examine whether B-vitamin sufficiency protects against adverse effects of DDT on clinical pregnancy (CP) and subclinical early pregnancy loss (EPL). Design: We measured preconception concentrations of plasma B vitamins (vitamin B-6, vitamin B-12, and folate) and serum total DDT [sum of p,p' and o,p' isomers of DDT and 1,1-dichloro-2,2-bis (p-chlorophenyl)ethylene] in 291 nulligravid women from Anhui, China, who were studied in 1996-1998. The women were followed prospectively from the time they stopped contraception until CP (gestational age >= 42 d) or 12 mo (whichever occurred first). EPL was identified by using daily urinary human chorionic gonadotropin. The women were categorized according to B-vitamin status (deficiency compared with sufficiency) and DDT concentration (high compared with low). Results: Of 291 study women, a total of 385 conceptions (31% of which ended in EPL) and 265 CPs occurred. Compared with women with adequate B-vitamins and low DDT, incidence rates of CP were reduced in women with B-vitamin deficiency and a high DDT concentration (P < 0.05 for all). Most notably, in women with sufficient vitamin B-12, DDT was not associated with the incidence of CP; in contrast, in women with vitamin B-12 deficiency, high DDT was associated with a lower incidence of CP (HR: 0.44; 95% CI: 0.23, 0.84); and the test for interaction was significant (P < 0.05). The odds of EPL decreased by 45% (95% CI: 21%, 62%) for each interquartile distance increase in folate in women with high DDT concentrations, and the test for interaction was significant (P = 0.006). Conclusions: Our results provide suggestive evidence that vitamin B-12 and folate sufficiency may help protect against adverse reproductive effects of DDT exposure. Additional studies are needed to confirm our findings. C1 [Ouyang, Fengxiu] Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Minist Educ,Key Lab Childrens Environm Hlth, Shanghai 200030, Peoples R China. [Longnecker, Matthew P.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Venners, Scott A.] Simon Fraser Univ, Fac Hlth Sci, Burnaby, BC V5A 1S6, Canada. [Johnson, Sara; Wang, Xiaobin] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Gen Pediat & Adolescent Med, Baltimore, MD 21205 USA. [Korrick, Susan] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Zhang, Jun] Shanghai Jiao Tong Univ, Sch Publ Hlth, Shanghai 200030, Peoples R China. [Xu, Xiping] Southern Med Univ, Natl Clin Res Ctr Kidney Dis, Guangzhou, Guangdong, Peoples R China. [Xu, Xiping] Southern Med Univ, State Key Lab Organ Failure Res, Guangzhou, Guangdong, Peoples R China. [Xu, Xiping] Southern Med Univ, Nanfang Hosp, Guangzhou, Guangdong, Peoples R China. [Christian, Parul] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21205 USA. [Wang, Mei-Cheng] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Wang, Xiaobin] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Ctr Early Life Origins Dis, Dept Populat Family & Reprod Hlth, Baltimore, MD 21205 USA. RP Wang, XB (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Ctr Early Life Origins Dis, 615 North Wolfe St,E4132, Baltimore, MD 21205 USA. EM xwang82@jhu.edu OI Longnecker, Matthew/0000-0001-6073-5322 FU NIH [R01 HD32505, R01 ES11682, R03 ES022790]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences; Ministry of Science and Technology of China [2014CB943300]; National Natural Science Foundation of China [81102139, 81372954, 81273091]; Shanghai Pujiang Program [12PJD026]; Canadian Institutes of Health Research [12301]; Michael Smith Foundation for Health Research [5176] FX Supported in part by grants from the NIH (R01 HD32505, R01 ES11682, and R03 ES022790) and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. FO is supported by the Ministry of Science and Technology of China (2014CB943300), grants from National Natural Science Foundation of China (81102139, 81372954, and 81273091), and the Shanghai Pujiang Program (12PJD026). SAV is supported by grants from the Canadian Institutes of Health Research (12301) and the Michael Smith Foundation for Health Research (5176). NR 37 TC 3 Z9 3 U1 1 U2 4 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC PY 2014 VL 100 IS 6 BP 1470 EP 1478 DI 10.3945/ajcn.114.088377 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AT9SZ UT WOS:000345267600010 PM 25411282 ER PT J AU Bork, KA Cournil, A Read, JS Newell, ML Cames, C Meda, N Luchters, S Mbatia, G Naidu, K Gaillard, P de Vincenzi, I AF Bork, Kirsten A. Cournil, Amandine Read, Jennifer S. Newell, Marie-Louise Cames, Cecile Meda, Nicolas Luchters, Stanley Mbatia, Grace Naidu, Kevindra Gaillard, Philippe de Vincenzi, Isabelle TI Morbidity in relation to feeding mode in African HIV-exposed, uninfected infants during the first 6 mo of life: the Kesho Bora study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE Africa; HIV/AIDS; diarrhea; infant feeding; infections ID IMMUNODEFICIENCY-VIRUS TYPE-1; ACTIVE ANTIRETROVIRAL THERAPY; TO-CHILD TRANSMISSION; INFECTED WOMEN; HUMAN-MILK; MORTALITY; MOTHER; PREGNANCY; OLIGOSACCHARIDES; GASTROENTERITIS AB Background: Refraining from breastfeeding to prevent HIV transmission has been associated with increased morbidity and mortality in HIV-exposed African infants. Objective: The objective was to assess risks of common and serious infectious morbidity by feeding mode in HIV-exposed, uninfected infants <= 6 mo of age with special attention to the issue of reverse causality. Design: HIV-infected pregnant women from 5 sites in Burkina Faso, Kenya, and South Africa were enrolled in the prevention of mother-to-child transmission Kesho Bora trial and counseled to either breastfeed exclusively and cease by 6 mo postpartum or formula feed exclusively. Maternal-reported morbidity (fever, diarrhea, and vomiting) and serious infectious events (SIEs) (gastroenteritis and lower respiratory tract infections) were investigated for 751 infants for 2 age periods (0-2.9 and 3-6 mo) by using generalized linear mixed models with breastfeeding as a time-dependent variable and adjustment for study site, maternal education, economic level, and cotrimoxazole prophylaxis. Results: Reported morbidity was not significantly higher in non-breastfed compared with breastfed infants [OR: 1.31 (95% CI: 0.97, 1.75) and 1.21 (0.90, 1.62) at 0-2.9 and 3-6 mo of age, respectively]. Between 0 and 2.9 mo of age, never-breastfed infants had increased risks of morbidity compared with those of infants who were exclusively breastfed (OR: 1.49; 95% CI: 1.01, 2.2; P = 0.042). The adjusted excess risk of SIEs in nonbreastfed infants was large between 0 and 2.9 mo (OR: 6.0; 95% CI: 2.2, 16.4; P = 0.001). Between 3 and 6 mo, the OR for SIEs was sensitive to the timing of breastfeeding status, i.e., 4.3 (95% CI: 1.2, 15.3; P = 0.02) when defined at end of monthly intervals and 2.0 (95% CI: 0.8, 5.0; P = 0.13) when defined at the beginning of intervals. Of 52 SIEs, 3 mothers reported changes in feeding mode during the SW although none of the mothers ceased breastfeeding completely. Conclusions: Not breastfeeding was associated with increased risk of serious infections especially between 0 and 2.9 mo of age. C1 [Bork, Kirsten A.; Cournil, Amandine; Cames, Cecile] Univ Montpellier I, Inst Rech Dev, UM1233, F-34394 Montpellier 5, France. [Read, Jennifer S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Newell, Marie-Louise] Univ KwaZulu Natal, Africa Ctr Hlth & Populat Studies, Somkhele, South Africa. [Meda, Nicolas] Ctr Muraz, Bobo Dioulasso, Burkina Faso. [Luchters, Stanley] Int Ctr Reprod Hlth, Mombasa, Kenya. [Mbatia, Grace] Kenyatta Natl Hosp, Nairobi, Kenya. [Mbatia, Grace] Univ Nairobi, Nairobi, Kenya. [Naidu, Kevindra] Univ KwaZulu Natal, Durban, South Africa. [Gaillard, Philippe; de Vincenzi, Isabelle] WHO, CH-1211 Geneva, Switzerland. RP Bork, KA (reprint author), Univ Montpellier I, Inst Rech Dev, UM1233, BP 64501, F-34394 Montpellier 5, France. EM kirsten.bork@ird.fr OI Bork, Kirsten/0000-0002-5909-7332; Newell, Marie-Louise/0000-0002-1074-7699; Njagi, Ephantus/0000-0002-1484-0241 FU Agence Nationale de Recherche sur le Sida et les Hepatites Virales (ANRS); Department for International Development (DFTD); European and Developing Countries Clinical Trials Partnership (EDCTP); Thrasher Research Fund; Belgian Directorate General for International Cooperation; GlaxoSmithKline Foundation; CDC; Eunice Kennedy Shriver National Institute of Child Health and Human Development; United Nations Development Program (UNDP)/United Nations Population Fund (UNFPA)/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction; ANRS; UNDP/UNFPA/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction (WHO/HRP); WHO/HRP; EDCTP; Eunice Kennedy Shriver National Institute of Child Health and Human Development through a cooperative agreement; DFID; United Nations Children's Fund FX Supported by funding from the Agence Nationale de Recherche sur le Sida et les Hepatites Virales (ANRS), the Department for International Development (DFTD), the European and Developing Countries Clinical Trials Partnership (EDCTP), the Thrasher Research Fund, the Belgian Directorate General for International Cooperation, the GlaxoSmithKline Foundation, the CDC, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the United Nations Development Program (UNDP)/United Nations Population Fund (UNFPA)/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction. The Bobo-Dioulasso site was funded by the ANRS and the UNDP/UNFPA/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction (WHO/HRP). The Mombasa site was funded by the ANRS, WHO/HRP, EDCTP, Thrasher Research Fund, and Belgian Directorate General for International Cooperation. The Nairobi site was funded by the CDC and the Eunice Kennedy Shriver National Institute of Child Health and Human Development through a cooperative agreement. South African sites were funded by the DFID, EDCTP, United Nations Children's Fund, and WHO/HRP. The nutrition and laboratory coordination were funded by the ANRS. The overall coordination and external monitoring was funded by the WHO/HRP. NR 37 TC 7 Z9 7 U1 2 U2 10 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC PY 2014 VL 100 IS 6 BP 1559 EP 1568 DI 10.3945/ajcn.113.082149 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AT9SZ UT WOS:000345267600019 PM 25411291 ER PT J AU Reuschenbach, M Wentzensen, N Dijkstra, MG Doeberitz, MV Arbyn, M AF Reuschenbach, Miriam Wentzensen, Nicolas Dijkstra, Maaike G. Doeberitz, Magnus von Knebel Arbyn, Marc TI p16(INK4a) Immunohistochemistry in Cervical Biopsy Specimens A Systematic Review and Meta-Analysis of the Interobserver Agreement SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE p16(INK4a); Cervical intraepithelial neoplasia; Histopathology; Reproducibility; Agreement ID INTRAEPITHELIAL NEOPLASIA; HUMAN-PAPILLOMAVIRUS; IMPROVED DIAGNOSIS; AMERICAN SOCIETY; CONJUNCTIVE TOOL; NATURAL-HISTORY; CANCER; BIOMARKERS; IMPROVES; LESIONS AB Objectives: The interpretation of cervical biopsy specimens guides management of women with suspected cervical cancer precursors. However, morphologic evaluation is subjective and has low interobserver agreement. Addition of p16(INK4a) immunohistochemistry may improve interpretation. Methods: We performed a systematic review and meta-analysis of published data on interobserver agreement of p16(INK4a) positivity using p16(INK4a) immunohistochemistry and of cervical intraepithelial neoplasia grade 2 (CIN2+) and GIN grade 3 (CIN3+) classification using H&E morphology in conjunction with p16(INK4a) in comparison with H&E morphology alone. Results: The literature search revealed five eligible articles. The results show strong agreement of pathologists' interpretation of cervical biopsy specimens as p16(INK4a) positive or negative (pooled kappa = 0.90; 95% confidence interval [CI], 0.88-0.92) and significantly higher agreement for a CIN2+ diagnosis with H&E morphology in conjunction with p16(INK4a) (kappa = 0.73; 95% CI, 0.67-0.79) compared with H&E morphology alone (kappa = 0.41; 95% CI, 0.17-0.65). Also, a slightly higher agreement for CIN3+ can be observed (kappa = 0.66; 95% CI, 0.39-0.94 for H&E morphology in conjunction with p16(INK4a) and kappa = 0.61; 95% CI, 0.44-0.78 for H&E morphology alone), but this difference was not statistically significant. Conclusions: The published literature indicates improved interobserver agreement of the diagnosis of CIN2+ with the conjunctive use of H&E morphology with p16(INK4a) immunohistochemistry compared with H&E morphology alone. C1 [Reuschenbach, Miriam; Doeberitz, Magnus von Knebel] Heidelberg Univ, Inst Pathol, Dept Appl Tumor Biol, D-69120 Heidelberg, Germany. [Reuschenbach, Miriam; Doeberitz, Magnus von Knebel] German Canc Res Ctr, Clin Cooperat Unit, Heidelberg, Germany. [Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Dijkstra, Maaike G.] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Amsterdam, Netherlands. [Arbyn, Marc] Sci Inst Publ Hlth, Unit Canc Epidemiol, Brussels, Belgium. RP Reuschenbach, M (reprint author), Heidelberg Univ, Inst Pathol, Dept Appl Tumor Biol, Neuenheimer Feld 224, D-69120 Heidelberg, Germany. EM miriam.reuschenbach@meduni-heidelberg.de RI von Knebel Doeberitz, Magnus/D-2372-2016 OI von Knebel Doeberitz, Magnus/0000-0002-0498-6781 FU European Commission [603019]; FNRS (Fonds national de la Recherche scientifique); Belgian Foundation against Cancer (Brussels, Belgium); European Federation of Colposcopy FX Dr Wentzensen was supported by the Intramural Research Program of the National Cancer Institute. Dr Arbyn received grants from the seventh Framework Programme of DG Research of the European Commission, through the COHEAHR Network (grant 603019); from FNRS (Fonds national de la Recherche scientifique), through TELE VIE, Brussels, Belgium (ref 7.4.628.07.F; the Belgian Foundation against Cancer (Brussels, Belgium); and the European Federation of Colposcopy. NR 30 TC 11 Z9 13 U1 0 U2 4 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD DEC PY 2014 VL 142 IS 6 BP 767 EP 772 DI 10.1309/AJCP3TPHV4TRIZEK PG 6 WC Pathology SC Pathology GA AT6MZ UT WOS:000345053900007 PM 25389329 ER PT J AU Kirton, JW Resnick, SM Davatzikos, C Kraut, MA Dotson, VM AF Kirton, Joshua W. Resnick, Susan M. Davatzikos, Christos Kraut, Michael A. Dotson, Vonetta M. TI Depressive Symptoms, Symptom Dimensions, and White Matter Lesion Volume in Older Adults: A Longitudinal Study SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Depression; WML; symptom dimensions; aging; MRI ID LATE-LIFE DEPRESSION; CEREBRAL-BLOOD-FLOW; GERIATRIC DEPRESSION; MAJOR DEPRESSION; SEX-DIFFERENCES; CEREBROVASCULAR-DISEASE; HYPERINTENSITIES; RISK; AGE; METAANALYSIS AB Objective: White matter lesions (WMLs) are associated with depressive symptoms in older adults. However, it is not clear whether different symptom dimensions of depression have distinct associations with WMLs. The authors assessed the longitudinal relationships of the Center for Epidemiologic Studies Depression Scale (CES-D) total score and subscale scores with WML volume in the Baltimore Longitudinal Study of Aging. Methods: Using a prospective observational design, the authors examined WML volume and depressive symptoms at 1- to 2-year intervals for up to 9 years in 116 dementia-free participants (mean age: 68.78 +/- 7.68). At each visit, depressive symptoms were measured with the CES-D and WML volumes were quantified from structural magnetic resonance imaging scans. Results: Higher CES-D full-scale scores were associated with greater WML volume and with a faster rate of volume increases over time in women, especially at older ages. Higher depressed mood and somatic symptoms subscale scores were associated with greater increases in WML volume over time at older ages. In men, depressed mood and somatic symptoms were associated with larger WML volume at baseline. Conclusion: Findings confirm an association between WMLs and depressive symptoms and suggest that depressed mood and somatic symptoms may be stronger predictors of depression-related brain changes than lack of well-being. Age and sex may moderate the relationships between depressive symptoms and WMLs. Understanding particular symptom dimensions of depressive symptoms has implications for treatment and may lead to targeted interventions and more precise knowledge of mechanisms underlying depression. C1 [Kirton, Joshua W.; Dotson, Vonetta M.] Univ Florida, Dept Clin & Hlth Psychol, Gainesville, FL 32610 USA. [Resnick, Susan M.] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. [Davatzikos, Christos] Univ Penn, Sch Med, Dept Radiol, Philadelphia, PA 19104 USA. [Kraut, Michael A.] Johns Hopkins Med Inst, Dept Radiol, Baltimore, MD 21205 USA. RP Dotson, VM (reprint author), Univ Florida, Dept Clin & Hlth Psychol, POB 100165, Gainesville, FL 32610 USA. EM vonetta@phhp.ufl.edu RI Dotson, Vonetta/K-6090-2015; OI Dotson, Vonetta/0000-0002-3043-3320 FU Intramural Research Program, National Institute on Aging, National Institutes of Health FX Supported in part by the Intramural Research Program, National Institute on Aging, National Institutes of Health. The authors have no potential conflicts of interest to disclose. The authors thank Yang An, M.S., for assistance with statistical analyses. NR 42 TC 6 Z9 6 U1 2 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD DEC PY 2014 VL 22 IS 12 BP 1469 EP 1477 DI 10.1016/j.jagp.2013.10.005 PG 9 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AT7LO UT WOS:000345118500012 PM 24211028 ER PT J AU Lewandowski-Romps, L Peterson, C Berglund, PA Collins, S Cox, K Hauret, K Jones, B Kessler, RC Mitchell, C Park, N Schoenbaum, M Stein, MB Ursano, RJ Heeringa, SG AF Lewandowski-Romps, Lisa Peterson, Christopher Berglund, Patricia A. Collins, Stacey Cox, Kenneth Hauret, Keith Jones, Bruce Kessler, Ronald C. Mitchell, Colter Park, Nansook Schoenbaum, Michael Stein, Murray B. Ursano, Robert J. Heeringa, Steven G. CA Army Study Assess Risk Resilience TI Risk Factors for Accident Death in the US Army, 2004-2009 SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID INJURY PREVENTION; PUBLIC-HEALTH; MILITARY; SUICIDE; DEPLOYMENT; RESILIENCE; PREDICTORS; MORTALITY; CRASHES; STARRS AB Background: Accidents are one of the leading causes of death among U.S. active-duty Army soldiers. Evidence-based approaches to injury prevention could be strengthened by adding person-level characteristics (e.g., demographics) to risk models tested on diverse soldier samples studied over time. Purpose: To identify person-level risk indicators of accident deaths in Regular Army soldiers during a time frame of intense military operations, and to discriminate risk of not-line-of-duty from line-of-duty accident deaths. Methods: Administrative data acquired from multiple Army/Department of Defense sources for active duty Army soldiers during 2004 2009 were analyzed in 2013. Logistic regression modeling was used to identify person-level sociodemographic, service-related, occupational, and mental health predictors of accident deaths. Results: Delayed rank progression or demotion and being male, unmarried, in a combat arms specialty, and of low rank/service length increased odds of accident death for enlisted soldiers. Unique to officers was high risk associated with aviation specialties. Accident death risk decreased over time for currently deployed, enlisted soldiers and increased for those never deployed. Mental health diagnosis was associated with risk only for previous and never-deployed, enlisted soldiers. Models did not discriminate not-line-of-duty from line-of-duty accident deaths. Conclusions: Adding more refined person-level and situational risk indicators to current models could enhance understanding of accident death risk specific to soldier rank and deployment status. Stable predictors could help identify high risk of accident deaths in future cohorts of Regular Army soldiers. (C) 2014 American Journal of Preventive Medicine. All rights reserved. C1 [Lewandowski-Romps, Lisa; Berglund, Patricia A.; Collins, Stacey; Mitchell, Colter; Heeringa, Steven G.] Univ Michigan, Inst Social Res, Ann Arbor, MI 48104 USA. [Peterson, Christopher; Park, Nansook] Univ Michigan, Dept Psychol, Ann Arbor, MI 48104 USA. [Cox, Kenneth; Hauret, Keith; Jones, Bruce] US Army Inst Publ Hlth, Aberdeen Proving Ground, MD USA. [Schoenbaum, Michael] NIMH, Bethesda, MD USA. [Ursano, Robert J.] Uniformed Serv Univ Sch Med, Ctr Study Traumat Stress, Dept Psychiat, Bethesda, MD USA. [Kessler, Ronald C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Stein, Murray B.] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. RP Heeringa, SG (reprint author), Univ Michigan, Inst Social Res, 426 Thompson St, Ann Arbor, MI 48104 USA. EM sheering@umich.edu FU Department of the Army; USDHHS; NIH; NIMH; [U0IMH087981] FX The Army Study to Assess Risk and Resilience in Service-members (Army STARRS) was sponsored by the Department of the Army and funded under cooperative agreement number U0IMH087981 with the USDHHS, NIH, and NIMH. The contents are solely the responsibility of the authors and do not necessarily represent the views of the USDHHS, NIMH, Department of the Army, or Department of Defense.; As a cooperative agreement, scientists employed by NIMH (Colpe and Schoenbaum) and Army liaisons/consultants (COL Steven Cersovsky, MD, MPH and Kenneth Cox, MD, MPH, U.S. Army Institute of Public Health) collaborated to develop the study protocol and data collection instruments, supervise data collection, plan and supervise data analyses, interpret results, and prepare reports. Although a draft of this manuscript was submitted to the Army and NIMH for review and comment prior to submission, this was with the understanding that comments would be no more than advisory.; In the past 5 years, Dr. Kessler has been a consultant for Eli Lilly & Company, Glaxo, Inc., Integrated Benefits Institute, Ortho-McNeil Janssen Scientific Affairs, Pfizer Inc., Sanofi-Aventis Groupe, Shire U.S. Inc., and Transcept Pharmaceuticals Inc. and served on advisory boards for Johnson & Johnson. Dr. Kessler had research support for studies during this time period from Eli Lilly & Company, EPI-Q, GlaxoSmithKline, Ortho-McNeil Janssen Scientific Affairs, Sanofi-Aventis Groupe, Shire U.S., Inc., and Walgreens Co. Dr. Kessler owns a 25% share in DataStat, Inc. Stein has in the last 3 years been a consultant for Healthcare Management Technologies and had research support for pharmacologic imaging studies from Janssen. The remaining authors report no competing interests. NR 36 TC 0 Z9 0 U1 2 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 DEC PY 2014 VL 47 IS 6 BP 745 EP 753 DI 10.1016/j.amepre.2014.07.052 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AT9RP UT WOS:000345264200006 PM 25441238 ER PT J AU Casagrande, SS Cowie, CC Genuth, SM AF Casagrande, Sarah Stark Cowie, Catherine C. Genuth, Saul M. TI Self-Reported Prevalence of Diabetes Screening in the US, 2005-2010 SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID CARDIOVASCULAR-DISEASE; MORTALITY; CRITERIA; ADULTS; INTERVENTION; ASSOCIATION; TRIAL; RISK AB Background: Early detection of type 2 diabetes has the potential to prevent complications, but the prevalence of opportunistic screening is unknown. Purpose: To describe the prevalence of diabetes screening by demographic and diabetes-related factors and to determine predictors of screening among a representative U.S. population without self-reported diabetes. Methods: Cross-sectional data were obtained from the 2005-2010 National Health and Nutrition Examination Survey (n=15,125) and 2006 National Health Interview Survey (n=21,519). Participants were aged >= 20 years and self-reported having a diabetes screening test in the past 3 years. Diabetes screening prevalence was analyzed according to risk factors recommended by the American Diabetes Association. Logistic regression was used to determine significant predictors of diabetes screening. Analysis was conducted in 2012-2013. Results: The prevalence of having a blood test for diabetes in the past 3 years was 42.1% in 20052006, 41.6% in 2007-2008, and 46.8% in 2009-2010. This prevalence increased with age and was higher for women, non-Hispanic whites, and those with more education and income (p < 0.001 for all). BMI >= 25, age >= 45 years, having a relative with diabetes, hypertension, glycosylated hemoglobin >= 5.7%, and cardiovascular disease history were significant predictors of screening. For each additional risk factor, the likelihood of screening increased by 51%. Conclusions: Nearly half of the adult population reported having a diabetes screening test. However, testing was less prevalent in minorities and those with lower socioeconomic status. Public health efforts to address these deficiencies in screening are needed. (C) 2014 American Journal of Preventive Medicine. All rights reserved. C1 [Casagrande, Sarah Stark] Social & Sci Syst Inc, Silver Spring, MD 20910 USA. [Cowie, Catherine C.] NIDDK, Div Diabet Endocrinol & Metab Dis, Bethesda, MD USA. [Genuth, Saul M.] Case Western Reserve Univ, Sch Med, Dept Med, Div Clin & Mol Endocrinol, Cleveland, OH 44106 USA. RP Casagrande, SS (reprint author), Social & Sci Syst Inc, 8757 Georgia Ave,12th Floor, Silver Spring, MD 20910 USA. EM scasagrande@s-3.com FU National Institute of Diabetes and Digestive and Kidney Diseases [GS-10F-0381L] FX This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (contract No. GS-10F-0381L). The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 19 TC 1 Z9 1 U1 3 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 DEC PY 2014 VL 47 IS 6 BP 780 EP 787 DI 10.1016/j.amepre.2014.07.039 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AT9RP UT WOS:000345264200010 PM 25241199 ER PT J AU Gill, AJ Hes, O Papathomas, T Sedivcova, M Tan, PH Agaimy, A Andresen, PA Kedziora, A Clarkson, A Toon, CW Sioson, L Watson, N Chou, A Paik, J Clifton-Bligh, RJ Robinson, BG Benn, DE Hills, K Maclean, F Niemeijer, ND Vlatkovic, L Hartmann, A Corssmit, EPM van Leenders, GJLH Przybycin, C McKenney, JK Magi-Galluzzi, C Yilmaz, A Yu, D Nicoll, KD Yong, JL Sibony, M Yakirevich, E Fleming, S Chow, CW Miettinen, M Michal, M Trpkov, K AF Gill, Anthony J. Hes, Ondrej Papathomas, Thomas Sedivcova, Monika Tan, Puay Hoon Agaimy, Abbas Andresen, Per Arne Kedziora, Andrew Clarkson, Adele Toon, Christopher W. Sioson, Loretta Watson, Nicole Chou, Angela Paik, Julie Clifton-Bligh, Roderick J. Robinson, Bruce G. Benn, Diana E. Hills, Kirsten Maclean, Fiona Niemeijer, Nicolasine D. Vlatkovic, Ljiljana Hartmann, Arndt Corssmit, Eleonora P. M. van Leenders, Geert J. L. H. Przybycin, Christopher McKenney, Jesse K. Magi-Galluzzi, Cristina Yilmaz, Asli Yu, Darryl Nicoll, Katherine D. Yong, Jim L. Sibony, Mathilde Yakirevich, Evgeny Fleming, Stewart Chow, Chung W. Miettinen, Markku Michal, Michal Trpkov, Kiril TI Succinate Dehydrogenase (SDH)-deficient Renal Carcinoma: A Morphologically Distinct Entity A Clinicopathologic Series of 36 Tumors From 27 Patients SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE SDHB; SDHA; succinate dehydrogenase; renal carcinoma ID GASTROINTESTINAL STROMAL TUMORS; SDHD GENE-MUTATIONS; CELL CARCINOMA; GERMLINE SDHB; CLINICAL-MANIFESTATIONS; DEFICIENT GISTS; B GENE; PARAGANGLIOMA; PHEOCHROMOCYTOMA; INACTIVATION AB Succinate dehydrogenase (SDH)-deficient renal carcinoma has been accepted as a provisional entity in the 2013 International Society of Urological Pathology Vancouver Classification. To further define its morphologic and clinical features, we studied a multi-institutional cohort of 36 SDH-deficient renal carcinomas from 27 patients, including 21 previously unreported cases. We estimate that 0.05% to 0.2% of all renal carcinomas are SDH deficient. Mean patient age at presentation was 37 years (range, 14 to 76 y), with a slight male predominance (M: F = 1.7:1). Bilateral tumors were observed in 26% of patients. Thirty-four (94%) tumors demonstrated the previously reported morphology at least focally, which included: solid or focally cystic growth, uniform cytology with eosinophilic flocculent cytoplasm, intracytoplasmic vacuolations and inclusions, and round to oval low-grade nuclei. All 17 patients who underwent genetic testing for mutation in the SDH subunits demonstrated germline mutations (16 in SDHB and 1 in SDHC). Nine of 27 (33%) patients developed metastatic disease, 2 of them after prolonged follow-up (5.5 and 30 y). Seven of 10 patients (70%) with high-grade nuclei metastasized as did all 4 patients with coagulative necrosis. Two of 17 (12%) patients with low-grade nuclei metastasized, and both had unbiopsied contralateral tumors, which may have been the origin of the metastatic disease. In conclusion, SDH-deficient renal carcinoma is a rare and unique type of renal carcinoma, exhibiting stereotypical morphologic features in the great majority of cases and showing a strong relationship with SDH germline mutation. Although this tumor may undergo dedifferentiation and metastasize, sometimes after a prolonged delay, metastatic disease is rare in the absence of high-grade nuclear atypia or coagulative necrosis. C1 [Gill, Anthony J.; Clarkson, Adele; Paik, Julie] Royal N Shore Hosp, Dept Anat Pathol, St Leonards, NSW 2065, Australia. [Gill, Anthony J.; Kedziora, Andrew; Clarkson, Adele; Toon, Christopher W.; Sioson, Loretta; Watson, Nicole; Chou, Angela; Paik, Julie] Royal N Shore Hosp, Canc Diag & Pathol Res Grp, St Leonards, NSW 2065, Australia. [Clifton-Bligh, Roderick J.; Robinson, Bruce G.; Benn, Diana E.] Royal N Shore Hosp, Kolling Inst Med Res, St Leonards, NSW 2065, Australia. [Gill, Anthony J.; Toon, Christopher W.; Sioson, Loretta; Clifton-Bligh, Roderick J.; Robinson, Bruce G.; Benn, Diana E.] Univ Sydney, Sydney, NSW 2006, Australia. [Toon, Christopher W.] Histopath Pathol, N Ryde, NSW, Australia. [Maclean, Fiona] Douglass Hanly Moir Pathol, N Ryde, NSW, Australia. [Chou, Angela] St Vincents Hosp, Dept Anat Pathol, Darlinghurst, NSW 2010, Australia. [Nicoll, Katherine D.; Yong, Jim L.] South Western Area Pathol Serv, Dept Anat Pathol, Liverpool, NSW, Australia. [Hills, Kirsten] Gold Coast Univ Hosp, Pathol Queensland, Southport, Qld, Australia. [Chow, Chung W.] Royal Childrens Hosp, Dept Anat Pathol, Parkville, Vic 3052, Australia. [Hes, Ondrej; Sedivcova, Monika] Fac Med, Dept Pathol, Plzen, Czech Republic. [Hes, Ondrej; Sedivcova, Monika] Charles Univ Prague, Plzen, Czech Republic. [Papathomas, Thomas; van Leenders, Geert J. L. H.] Erasmus MC, Josephine Nefkens Inst, Dept Pathol, Rotterdam, Netherlands. [Niemeijer, Nicolasine D.; Corssmit, Eleonora P. M.] Leiden Univ, Med Ctr, Dept Endocrinol, Leiden, Netherlands. [Tan, Puay Hoon] Singapore Gen Hosp, Dept Pathol, Singapore, Singapore. [Agaimy, Abbas; Hartmann, Arndt] Univ Erlangen Nurnberg, Inst Pathol, D-91054 Erlangen, Germany. [Andresen, Per Arne] Oslo Univ Hosp, Dept Pathol, Oslo, Norway. [Vlatkovic, Ljiljana] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Pathol, Oslo, Norway. [Przybycin, Christopher; McKenney, Jesse K.; Magi-Galluzzi, Cristina] Cleveland Clin, Robert J Tomsich Pathol & Lab Med Inst, Cleveland, OH 44106 USA. [Yakirevich, Evgeny] Brown Univ, Rhode Isl Hosp, Alpert Med Sch, Dept Pathol, Providence, RI 02903 USA. [Miettinen, Markku] NCI, Lab Surg Pathol, Bethesda, MD 20892 USA. [Yilmaz, Asli; Yu, Darryl; Trpkov, Kiril] Calgary Lab Serv, Dept Pathol & Lab Med, Calgary, AB, Canada. [Yilmaz, Asli; Yu, Darryl; Trpkov, Kiril] Univ Calgary, Calgary, AB, Canada. [Sibony, Mathilde] Univ Paris 05, Hop Cochin, Dept Pathol, Paris, France. [Fleming, Stewart] Univ Dundee, Ninewells Hosp, Dept Mol Pathol, Dundee, Scotland. RP Gill, AJ (reprint author), Royal N Shore Hosp, Dept Anat Pathol, Pacific Highway, St Leonards, NSW 2065, Australia. EM affgill@med.usyd.edu.au RI Gill, Anthony/D-4215-2015 OI Gill, Anthony/0000-0002-9447-1967 FU Cancer Institute New South Wales and Czech Republic Government [IGA NT 12010-4] FX Supported in part by the Cancer Institute New South Wales and Czech Republic Government grant agency (IGA NT 12010-4). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 48 TC 33 Z9 35 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD DEC PY 2014 VL 38 IS 12 BP 1588 EP 1602 PG 15 WC Pathology; Surgery SC Pathology; Surgery GA AT7QD UT WOS:000345131700002 PM 25025441 ER PT J AU Solomon, DA Brohl, AS Khan, J Miettinen, M AF Solomon, David A. Brohl, Andrew S. Khan, Javed Miettinen, Markku TI Clinicopathologic Features of a Second Patient With Ewing-like Sarcoma Harboring CIC-FOXO4 Gene Fusion SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Letter C1 [Solomon, David A.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA. [Brohl, Andrew S.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Khan, Javed] NCI, Genet Branch, Bethesda, MD 20892 USA. [Miettinen, Markku] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Solomon, DA (reprint author), Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA. RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 FU Intramural NIH HHS [ZIA SC010366-13] NR 3 TC 14 Z9 15 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD DEC PY 2014 VL 38 IS 12 BP 1724 EP 1725 PG 2 WC Pathology; Surgery SC Pathology; Surgery GA AT7QD UT WOS:000345131700018 PM 25321332 ER PT J AU Fraietta, JA Mueller, YM Lozenski, KL Ratner, D Boesteanu, AC Hancock, AS Lackman-Smith, C Zentner, IJ Chaiken, IM Chung, S LeGrice, SFJ Snyder, BA Mankowski, MK Jones, NM Hope, JL Gupta, P Anderson, SH Wigdahl, B Katsikis, PD AF Fraietta, Joseph A. Mueller, Yvonne M. Lozenski, Karissa L. Ratner, Deena Boesteanu, Alina C. Hancock, Aidan S. Lackman-Smith, Carol Zentner, Isaac J. Chaiken, Irwin M. Chung, Suhman LeGrice, Stuart F. J. Snyder, Beth A. Mankowski, Marie K. Jones, Natalie M. Hope, Jennifer L. Gupta, Phalguni Anderson, Sharon H. Wigdahl, Brian Katsikis, Peter D. TI Abasic Phosphorothioate Oligomers Inhibit HIV-1 Reverse Transcription and Block Virus Transmission across Polarized Ectocervical Organ Cultures SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID PREVENT VAGINAL TRANSMISSION; RANDOMIZED CONTROLLED-TRIAL; FEMALE GENITAL-TRACT; IMMUNODEFICIENCY-VIRUS; ANTIBODY PROTECTION; TYPE-1 HIV-1; MICROBICIDES; INFECTION; GEL; OLIGODEOXYNUCLEOTIDES AB In the absence of universally available antiretroviral (ARV) drugs or a vaccine against HIV-1, microbicides may offer the most immediate hope for controlling the AIDS pandemic. The most advanced and clinically effective microbicides are based on ARV agents that interfere with the earliest stages of HIV-1 replication. Our objective was to identify and characterize novel ARV-like inhibitors, as well as demonstrate their efficacy at blocking HIV-1 transmission. Abasic phosphorothioate 2' deoxyribose backbone (PDB) oligomers were evaluated in a variety of mechanistic assays and for their ability to inhibit HIV-1 infection and virus transmission through primary human cervical mucosa. Cellular and biochemical assays were used to elucidate the antiviral mechanisms of action of PDB oligomers against both lab-adapted and primary CCR5- and CXCR4-utilizing HIV-1 strains, including a multidrug-resistant isolate. A polarized cervical organ culture was used to test the ability of PDB compounds to block HIV-1 transmission to primary immune cell populations across ectocervical tissue. The antiviral activity and mechanisms of action of PDB-based compounds were dependent on oligomer size, with smaller molecules preventing reverse transcription and larger oligomers blocking viral entry. Importantly, irrespective of molecular size, PDBs potently inhibited virus infection and transmission within genital tissue samples. Furthermore, the PDB inhibitors exhibited excellent toxicity and stability profiles and were found to be safe for vaginal application in vivo. These results, coupled with the previously reported intrinsic anti-inflammatory properties of PDBs, support further investigations in the development of PDB-based topical microbicides for preventing the global spread of HIV-1. C1 [Fraietta, Joseph A.; Mueller, Yvonne M.; Lozenski, Karissa L.; Boesteanu, Alina C.; Hancock, Aidan S.; Hope, Jennifer L.; Wigdahl, Brian; Katsikis, Peter D.] Drexel Univ, Dept Microbiol & Immunol, Coll Med, Philadelphia, PA 19104 USA. [Fraietta, Joseph A.; Mueller, Yvonne M.; Lozenski, Karissa L.; Boesteanu, Alina C.; Hancock, Aidan S.; Hope, Jennifer L.; Wigdahl, Brian; Katsikis, Peter D.] Drexel Univ, Ctr Immunol & Vaccine Sci, Coll Med, Inst Mol Med & Infect Dis, Philadelphia, PA 19104 USA. [Ratner, Deena; Gupta, Phalguni] Univ Pittsburgh, Dept Infect Dis & Microbiol, Pittsburgh, PA USA. [Lackman-Smith, Carol; Snyder, Beth A.; Mankowski, Marie K.; Jones, Natalie M.] So Res Inst, Frederick, MD USA. [Zentner, Isaac J.; Chaiken, Irwin M.] Drexel Univ, Coll Med, Dept Biochem & Mol Biol, Philadelphia, PA 19104 USA. [Chung, Suhman; LeGrice, Stuart F. J.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. [Anderson, Sharon H.] Drexel Univ, Coll Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Anderson, Sharon H.] Main Line Fertil Ctr, Bryn Mawr, PA USA. RP Katsikis, PD (reprint author), Drexel Univ, Dept Microbiol & Immunol, Coll Med, Philadelphia, PA 19104 USA. EM peter.katsikis@drexelmed.edu OI Mueller, Yvonne/0000-0002-4654-7509 FU NIH from the National Institutes of Health [R21/33 AI082680]; Intramural Research Program of the National Cancer Institute, National Institutes of Health; National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health [N01 AI70042] FX This work was supported by NIH R21/33 AI082680 to P. D. K. from the National Institutes of Health. S.F.J.L. and S. C. were supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The project was conducted in part by the Southern Research Institute (Frederick, MD), using federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, contract N01 AI70042 "Specialized in vitro virological assays for HIV therapeutics and topical microbicides," under the direction of Roger Miller, Project Officer, Division of AIDS, NIAID. NR 58 TC 0 Z9 0 U1 2 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 DEC PY 2014 VL 58 IS 12 BP 7056 EP 7071 DI 10.1128/AAC.02991-14 PG 16 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA AT9AW UT WOS:000345221000005 PM 25224013 ER PT J AU Kulakova, L Galkin, A Chen, CZ Southall, N Marugan, JJ Zheng, W Herzberg, O AF Kulakova, Liudmila Galkin, Andrey Chen, Catherine Z. Southall, Noel Marugan, Juan J. Zheng, Wei Herzberg, Osnat TI Discovery of Novel Antigiardiasis Drug Candidates SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID GIARDIA-LAMBLIA; METHIONINE AMINOPEPTIDASES; INTESTINAL MICROSPORIDIOSIS; CRYPTOSPORIDIUM-PARVUM; STRUCTURAL BASIS; FUMAGILLIN; MICE; METRONIDAZOLE; NITAZOXANIDE; DUODENALIS AB Giardiasis is a severe intestinal parasitic disease caused by Giardia lamblia, which inflicts many people in poor regions and is the most common parasitic infection in the United States. Current standard care drugs are associated with undesirable side effects, treatment failures, and an increasing incidence of drug resistance. As follow-up to a high-throughput screening of an approved drug library, which identified compounds lethal to G. lamblia trophozoites, we have determined the minimum lethal concentrations of 28 drugs and advanced 10 of them to in vivo studies in mice. The results were compared to treatment with the standard care drug, metronidazole, in order to identify drugs with equal or better anti-Giardia activities. Three drugs, fumagillin, carbadox, and tioxidazole, were identified. These compounds were also potent against metronidazole-resistant human G. lamblia isolates (assemblages A and B), as determined in in vitro assays. Of these three compounds, fumagillin is currently an orphan drug used within the European Union to treat microsporidiosis in immunocompromised individuals, whereas carbadox and tioxidazole are used in veterinary medicine. A dose-dependent study of fumagillin in a giardiasis mouse model revealed that the effective dose of fumagillin was similar to 100-fold lower than the metronidazole dose. Therefore, fumagillin may be advanced to further studies as an alternative treatment for giardiasis when metronidazole fails. C1 [Kulakova, Liudmila; Galkin, Andrey; Herzberg, Osnat] Univ Maryland, Inst Biosci & Biotechnol Res, Rockville, MD 20850 USA. [Chen, Catherine Z.; Southall, Noel; Marugan, Juan J.; Zheng, Wei] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Herzberg, Osnat] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. RP Herzberg, O (reprint author), Univ Maryland, Inst Biosci & Biotechnol Res, Rockville, MD 20850 USA. EM osnat@umd.edu RI Southall, Noel/H-8991-2012; Zheng, Wei/J-8889-2014 OI Southall, Noel/0000-0003-4500-880X; Zheng, Wei/0000-0003-1034-0757 FU National Institutes of Health [R56AI059733]; SAIC/National Cancer Institute [11XS049]; National Center for Advancing Translational Sciences FX This work was supported by the National Institutes of Health grant R56AI059733 and SAIC/National Cancer Institute contract 11XS049 (to O.H.) and by the Intramural Research Programs of the National Center for Advancing Translational Sciences (to C.Z.C., W.Z., N.S., and J.J.M.). NR 50 TC 3 Z9 3 U1 0 U2 12 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 DEC PY 2014 VL 58 IS 12 BP 7303 EP 7311 DI 10.1128/AAC.03834-14 PG 9 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA AT9AW UT WOS:000345221000032 PM 25267663 ER PT J AU Porter, JB Walter, PB Neumayr, LD Evans, P Bansal, S Garbowski, M Weyhmiller, MG Harmatz, PR Wood, JC Miller, JL Byrnes, C Weiss, G Seifert, M Grosse, R Grabowski, D Schmidt, A Fischer, R Nielsen, P Niemeyer, C Vichinsky, E AF Porter, John B. Walter, Patrick B. Neumayr, Lynne D. Evans, Patricia Bansal, Sukhvinder Garbowski, Maciej Weyhmiller, Marcela G. Harmatz, Paul R. Wood, John C. Miller, Jeffery L. Byrnes, Colleen Weiss, Guenter Seifert, Markus Grosse, Regine Grabowski, Dagmar Schmidt, Angelica Fischer, Roland Nielsen, Peter Niemeyer, Charlotte Vichinsky, Elliott TI Mechanisms of plasma non-transferrin bound iron generation: insights from comparing transfused diamond blackfan anaemia with sickle cell and thalassaemia patients SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE iron overload; non-transferrin bound iron; NTBI; hepcidin; erythropoiesis; inflammation ID BETA-THALASSEMIA; HEPCIDIN; DISEASE; INFLAMMATION AB In transfusional iron overload, extra-hepatic iron distribution differs, depending on the underlying condition. Relative mechanisms of plasma non-transferrin bound iron (NTBI) generation may account for these differences. Markers of iron metabolism (plasma NTBI, labile iron, hepcidin, transferrin, monocyte SLC40A1 [ferroportin]), erythropoiesis (growth differentiation factor 15, soluble transferrin receptor) and tissue hypoxia (erythropoietin) were compared in patients with Thalassaemia Major (TM), Sickle Cell Disease and Diamond-Blackfan Anaemia (DBA), with matched transfusion histories. The most striking differences between these conditions were relationships of NTBI to erythropoietic markers, leading us to propose three mechanisms of NTBI generation: iron overload (all), ineffective erythropoiesis (predominantly TM) and low transferrin-iron utilization (DBA). C1 [Porter, John B.; Evans, Patricia; Garbowski, Maciej] UCL, Dept Haematol, London WC1E 6BT, England. [Walter, Patrick B.; Neumayr, Lynne D.; Weyhmiller, Marcela G.; Harmatz, Paul R.; Vichinsky, Elliott] UCSF Benioff Childrens Hosp, Oakland, CA USA. [Walter, Patrick B.] Univ Victoria, Dept Biol, Victoria, BC V8W 2Y2, Canada. [Bansal, Sukhvinder] Kings Coll London, Dept Pharm, London, England. [Wood, John C.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Miller, Jeffery L.; Byrnes, Colleen] NIDDK, Mol Genom & Therapeut Sect, Mol Med Branch, NIH, Bethesda, MD USA. [Weiss, Guenter; Seifert, Markus] Med Univ Innsbruck, Dept Internal Med 6, A-6020 Innsbruck, Austria. [Grosse, Regine; Grabowski, Dagmar; Schmidt, Angelica; Fischer, Roland; Nielsen, Peter] Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany. [Niemeyer, Charlotte] Univ Med Ctr Freiburg, Freiburg, Germany. RP Walter, PB (reprint author), UCSF Benioff Childrens Hosp Oakland, Dept Hematol Oncol, 747 West 52nd St, Oakland, CA 94609 USA. EM j.porter@cancer.ucl.ac.uk; pwalter@mail.cho.org OI Porter, John/0000-0003-3000-9359; Weiss, Guenter/0000-0003-0709-2158 FU NIH NIDDK [2R01DK057778-06A1]; NIH CTSA [UL1 RR024131]; BJH Research Fellowship; NIHR University College London Hospitals Biomedical Research Centre FX This work was funded by the NIH NIDDK grant 2R01DK057778-06A1 and also supported in part by NIH CTSA grant UL1 RR024131. MG was supported by BJH Research Fellowship Grant May 2009. JBP is supported by NIHR University College London Hospitals Biomedical Research Centre. NR 15 TC 11 Z9 12 U1 0 U2 12 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 DEC PY 2014 VL 167 IS 5 BP 692 EP 696 DI 10.1111/bjh.13081 PG 5 WC Hematology SC Hematology GA AT9BG UT WOS:000345222100012 PM 25209728 ER PT J AU Barlow, JH Nussenzweig, A AF Barlow, Jacqueline H. Nussenzweig, Andre TI Replication initiation and genome instability: a crossroads for DNA and RNA synthesis SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE DNA replication; Replication stress; Transcription; Origin licensing; R loop ID ORIGIN RECOGNITION COMPLEX; CLASS-SWITCH RECOMBINATION; S-PHASE CHECKPOINT; DOUBLE-STRAND BREAKS; B-CELL LYMPHOMAS; SACCHAROMYCES-CEREVISIAE; FRAGILE SITES; RIBONUCLEOTIDE REDUCTASE; SEQUENCING REVEALS; GLOBAL REGULATOR AB Nuclear DNA replication requires the concerted action of hundreds of proteins to efficiently unwind and duplicate the entire genome while also retaining epigenetic regulatory information. Initiation of DNA replication is tightly regulated, rapidly firing thousands of origins once the conditions to promote rapid and faithful replication are in place, and defects in replication initiation lead to proliferation defects, genome instability, and a range of developmental abnormalities. Interestingly, DNA replication in metazoans initiates in actively transcribed DNA, meaning that replication initiation occurs in DNA that is co-occupied with tens of thousands of poised and active RNA polymerase complexes. Active transcription can induce genome instability, particularly during DNA replication, as RNA polymerases can induce torsional stress, formation of secondary structures, and act as a physical barrier to other enzymes involved in DNA metabolism. Here we discuss the challenges facing mammalian DNA replication, their impact on genome instability, and the development of cancer. C1 [Barlow, Jacqueline H.; Nussenzweig, Andre] NIH, Lab Genome Integr, Bethesda, MD 20892 USA. RP Nussenzweig, A (reprint author), NIH, Lab Genome Integr, Bldg 10, Bethesda, MD 20892 USA. EM barlowjh@mail.nih.gov; andre_nussenzweig@nih.gov FU Intramural Research Program of the National Institutes of Health, the National Cancer Institute, and the Center for Cancer Research FX The authors would like to thank Sam John and Serena Tan for critical reading of the manuscript, and apologize for not being able to cite more primary literature due to space considerations. Work in the laboratory of A. N. is supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, and the Center for Cancer Research. NR 109 TC 3 Z9 3 U1 2 U2 26 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD DEC PY 2014 VL 71 IS 23 BP 4545 EP 4559 DI 10.1007/s00018-014-1721-1 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AT6ZG UT WOS:000345085000006 PM 25238783 ER PT J AU Latrofa, F Ricci, D Montanelli, L Piaggi, P Mazzi, B Bianchi, F Brozzi, F Santini, P Fiore, E Marino, M Tonacchera, M Vitti, P AF Latrofa, F. Ricci, D. Montanelli, L. Piaggi, P. Mazzi, B. Bianchi, F. Brozzi, F. Santini, P. Fiore, E. Marino, M. Tonacchera, M. Vitti, P. TI Thyroglobulin autoantibodies switch to immunoglobulin (Ig)G1 and IgG3 subclasses and preserve their restricted epitope pattern after I-131 treatment for Graves' hyperthyroidism: the activity of autoimmune disease influences subclass distribution but not epitope pattern of autoantibodies SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE B-cell epitopes; Graves' disease; IgG subclasses; intramolecular epitope spreading; thyroglobulin autoantibodies ID HASHIMOTOS-THYROIDITIS EVIDENCE; HUMAN B-CELLS; ANTIBODIES; FINGERPRINTS; INDIVIDUALS; AFFINITY; IODINE; RECOGNITION; RADIOIODINE; ANTIGEN AB The subclass distribution of thyroglobulin autoantibodies (TgAb) is debated, whereas their epitope pattern is restricted. Radioidine (I-131) treatment for Graves' disease (GD) induces a rise in TgAb levels, but it is unknown whether it modifies subclass distribution and epitope pattern of TgAb as well. We collected sera from GD patients before I-131 treatment and 3 and 6 months thereafter. We measured total TgAb, TgAb light chains and TgAb subclasses by enzyme-linked immunosorbent assay (ELISA) in 25 patients. We characterized the TgAb epitope pattern in 30 patients by inhibiting their binding to (125-I)Tg by a pool of four TgAb-Fab (recognizing Tg epitope regions A, B, C and D) and to Tg in ELISA by each TgAb-Fab. Total TgAb immunoglobulin (Ig)G rose significantly (P=0024). TgAb chains did not change (P=0052), whereas TgAb chains increased significantly (P=0001) and persistently. We observed a significant rise in IgG1 and IgG3 levels after I-131 (P=0008 and P=0006, respectively), while IgG2 and IgG4 levels did not change. The rise of IgG1 was persistent, that of IgG3 transient. The levels of inhibition of TgAb binding to Tg by the TgAb-Fab pool were comparable. A slight, non-significant reduction of the inhibition by the immune-dominant TgAb-Fab A was observed 3 and 6 months after I-131. We conclude that I-131 treatment for GD increases the levels of the complement-activating IgG1 and IgG3 subclasses and does not influence significantly the epitope pattern of TgAb. In autoimmune thyroid disease subclass distribution of autoantibodies is dynamic in spite of a stable epitope pattern. C1 [Latrofa, F.; Ricci, D.; Montanelli, L.; Mazzi, B.; Bianchi, F.; Brozzi, F.; Santini, P.; Fiore, E.; Marino, M.; Tonacchera, M.; Vitti, P.] Univ Hosp Pisa, Endocrinol Unit, I-56124 Pisa, Italy. [Piaggi, P.] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. RP Latrofa, F (reprint author), Univ Hosp Pisa, Endocrinol Unit, Via Paradisa 2, I-56124 Pisa, Italy. EM latrofaf@libero.it RI Tonacchera, Massimo/K-8523-2016; OI Latrofa, Francesco/0000-0003-0297-5904 FU MIUR [311]; University of Pisa FX These studies were supported by the grant 'Rientro dei cervelli' n. 311 from MIUR and the University of Pisa to Francesco Latrofa. We thank Sandra M. McLachlan and Basil Rapoport (Cedars-Sinai Medical Center and University of California, Los Angeles, CA, USA) for assistance with the manuscript and Andreas Bergmann (Brahms, Berlin, Germany) for the kind gift of 125-ITg. NR 53 TC 4 Z9 5 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9104 EI 1365-2249 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD DEC PY 2014 VL 178 IS 3 BP 438 EP 446 DI 10.1111/cei.12438 PG 9 WC Immunology SC Immunology GA AU0PA UT WOS:000345324300004 PM 25134846 ER PT J AU Arduc, A Dogan, BA Ozuguz, U Tuna, MM Gokay, F Tutuncu, YA Isik, S Aydin, Y Peksoy, I Berker, D Guler, S AF Arduc, Ayse Dogan, Bercem Aycicek Ozuguz, Ufuk Tuna, Mazhar Muslim Gokay, Ferhat Tutuncu, Yasemin Ates Isik, Serhat Aydin, Yusuf Peksoy, Irfan Berker, Dilek Guler, Serdar TI The Effect of Radioactive Iodine Treatment on C-14 Urea Breath Test Results in Patients with Hyperthyroidism SO CLINICAL NUCLEAR MEDICINE LA English DT Article DE radioactive iodine therapy; hyperthyroidism; Helicobacter pylori; C-14 urea breath test ID HELICOBACTER-PYLORI INFECTION; RADIOIODINE TREATMENT; THYROID-DISEASES; THERAPY; CANCER; RISK; METAANALYSIS; ERADICATION; I-131 AB Purpose: Radioactive (131)Iodine therapy (RAIT) plays a major role in the treatment of hyperthyroidism. In addition to the thyroid gland, significant amounts of radioactive iodine are maintained in the stomach. The aim of this study was to determine if RAIT has any effect on Helicobacter pylori infection, based on the C-14 urea breath test (UBT). Materials and Methods: The study included 85 patients with hyperthyroidism scheduled to undergo RAIT and 69 hyperthyroid subjects in whom methimazole treatment was planned. All subjects had pretreatment-positive UBT results, and the test was repeated on the first and third months after RAIT and methimazole treatment. Results: After a mean RAIT dose of 15 mCi (range, 10-20 mCi), UBT became negative in 13 (15.3%) of 85 patients on the first month and 18 (21.2%) of 85 patients on the third month. All subjects treated with methimazole remained UBT positive on the first and third months of methimazole treatment (100%). Reduction in the number of UBT-positive patients on both the first and the third months after RAIT was statistically significant (P < 0.001). Distribution of hyperthyroidism etiologies and thyroid autoantibody levels in subjects with UBT that became negative and in subjects with UBT that remained positive were similar in the RAIT group (P > 0.05). Urea breath test negativity rates did not differ according to the radioiodine dose. Conclusions: Our findings indirectly showed that RAIT might have an antimicrobial effect on H. pylori. Clinical applications of this beneficial effect of RAIT on H. pylori should be further evaluated. C1 [Arduc, Ayse] Minist Hlth, Ankara Numune Res & Training Hosp, Dept Endocrinol & Metab, Ankara, Turkey. [Dogan, Bercem Aycicek; Ozuguz, Ufuk; Tuna, Mazhar Muslim; Gokay, Ferhat; Tutuncu, Yasemin Ates; Isik, Serhat; Berker, Dilek] NIDDK, Endocrine & Obes Branch, NIH, Bethesda, MD 20892 USA. [Aydin, Yusuf] Duzce Univ, Fac Med, Dept Internal Med, Duzce, Turkey. [Peksoy, Irfan] Minist Hlth, Ankara Numune Res & Training Hosp, Dept Nucl Med, Ankara, Turkey. [Guler, Serdar] Hitit Univ, Dept Endocrinol & Metab, Fac Med, Corum, Turkey. RP Arduc, A (reprint author), Minist Hlth, Ankara Numune Res & Training Hosp, Dept Endocrinol & Metab, Ankara, Turkey. EM ayse_arduc@yahoo.com NR 30 TC 1 Z9 1 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD DEC PY 2014 VL 39 IS 12 BP 1022 EP 1026 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AT8AZ UT WOS:000345157400002 PM 25036019 ER PT J AU Tifft, CJ Adams, DR AF Tifft, Cynthia J. Adams, David R. TI The National Institutes of Health undiagnosed diseases program SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE genome sequencing; phenotyping; undiagnosed diseases program AB Purpose of reviewTo review the approach to undiagnosed patients and results of the National Institutes of Health (NIH) undiagnosed diseases program (UDP), and discuss its benefits to patients, academic medical centers, and the greater scientific community.Recent findingsThe NIH UDP provides comprehensive and collaborative evaluations for patients with objective findings of disease whose diagnoses have long eluded the medical community. Intensive review of patient records, careful phenotyping, and new genomic technologies have resulted in the diagnosis of new and extremely rare conditions, expanded the phenotypes of rare disorders, and determined that symptoms are caused by more than one disorder in a family.SummaryMany children and adults with complex phenotypes remain undiagnosed despite years of searching. The most common undiagnosed disorders involve a neurologic phenotype. Comprehensive phenotyping and genomic analysis utilizing nuclear families can provide a diagnosis in some cases and provide good lead' candidate genes for others. A UDP can be important for patients, academic medical centers, the scientific community, and society. C1 [Tifft, Cynthia J.; Adams, David R.] NHGRI, NIH Undiagnosed Dis Program, Off Director, NIH Common Fund, Bethesda, MD 20892 USA. [Tifft, Cynthia J.; Adams, David R.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Tifft, Cynthia J.; Adams, David R.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Tifft, CJ (reprint author), NHGRI, Off Clin Director, Bldg 10 Rm CRC3-2551,MSC 1205,10 Ctr Dr, Bethesda, MD 20892 USA. EM ctifft@nih.gov FU National Human Genome Research Institute, NIH; Office of Rare Diseases Research, National Center for Advancing Translational Sciences, NIH; NIH Common Fund; NIH Clinical Center FX Funding: The NIH Undiagnosed Diseases Program is funded by the National Human Genome Research Institute, NIH; Office of Rare Diseases Research, National Center for Advancing Translational Sciences, NIH; the NIH Common Fund; and the NIH Clinical Center. NR 12 TC 10 Z9 11 U1 1 U2 4 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 DEC PY 2014 VL 26 IS 6 BP 626 EP 633 DI 10.1097/MOP.0000000000000155 PG 8 WC Pediatrics SC Pediatrics GA AT4RB UT WOS:000344927300002 PM 25313974 ER PT J AU Biesecker, LG Biesecker, BB AF Biesecker, Leslie G. Biesecker, Barbara B. TI An approach to pediatric exome and genome sequencing SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE exome sequencing; genetic counseling; genome sequencing; informed consent ID SHARED DECISION-MAKING; PARENTAL ATTITUDES; DIAGNOSIS; CHILDREN; CARE; UNCERTAINTY AB Purpose of reviewExome and genome sequencing have recently emerged as clinical tools to resolve undiagnosed genetic conditions. Protocols are critically needed to identify proper patients for testing, select a test and laboratory, engage parents in shared decision-making, and for the return of results.Recent findingsAmong well selected patients, the likelihood for identifying the causative gene change may be as high as 30%. It is key for pediatricians to consider whether sequencing should be the primary line of pursuit of a molecular diagnosis. Parents should understand the uncertainties inherent in this sequencing and the preference-based nature of testing. Pediatricians can engage in shared decision-making for this process and work to help parents make decisions consistent with their priorities and values. Upon receipt of a pathogenic mutation, discussion of the likelihood for future treatment is paramount to parents, as are the implications for recurrence within the family. Uncertainties inherent to genomic results need to be explained in the context of the likelihood of future research and discoveries.SummaryPediatricians should make a deliberate decision with each patient whether to manage genomic testing on their own, refer the patient for such testing, or initiate the process and refer simultaneously. Regardless of which approach is taken, understanding the basics of this testing will allow the pediatrician to support the parents through the diagnostic process. C1 [Biesecker, Leslie G.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. [Biesecker, Barbara B.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), Bldg 49,Room 4A56, Bethesda, MD 20892 USA. EM lesb@mail.nih.gov FU National Human Genome Research Institute, National Institutes of Health FX The authors are supported by funding from the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 26 TC 7 Z9 8 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8703 EI 1531-698X J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD DEC PY 2014 VL 26 IS 6 BP 639 EP 645 DI 10.1097/MOP.0000000000000150 PG 7 WC Pediatrics SC Pediatrics GA AT4RB UT WOS:000344927300004 PM 25304963 ER PT J AU Kotlarz, D Zietara, N Milner, JD Klein, C AF Kotlarz, Daniel Zietara, Natalia Milner, Joshua D. Klein, Christoph TI Human IL-21 and IL-21R deficiencies: two novel entities of primary immunodeficiency SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE cryptosporidiosis; hematopoietic stem cell transplantation; inflammatory bowel disease; interleukin-21; primary immunodeficiency ID CD8(+) T-CELLS; INFLAMMATORY-BOWEL-DISEASE; SECRETING PLASMA-CELLS; COMMON GAMMA-CHAIN; B-CELLS; INTERLEUKIN-21 RECEPTOR; HUMAN NAIVE; AUTOCRINE REGULATION; NK CELLS; IN-VIVO AB Purpose of reviewThis review highlights the recent identification of human interleukin-21 (IL-21) and interleukin-21 receptor (IL-21R) deficiencies as novel entities of primary immunodeficiency.Recent findingsWe recently described the first patients with IL-21R deficiency who had cryptosporidial infections associated with chronic cholangitis and liver disease. All IL-21R-deficient patients suffered from recurrent respiratory tract infections. Immunological work-up revealed impaired B cell proliferation and immunoglobulin class-switch, reduced T cell effector functions, and variable natural killer cell dysfunctions. Recently, these findings have been extended by the discovery of one patient with a mutation in the IL21 gene. This patient predominantly manifested with very early onset inflammatory bowel disease and recurrent respiratory infections. Laboratory examination showed reduced circulating B cells and impaired B cell class-switch.SummaryHuman IL-21 and IL-21R deficiencies cause severe, primary immunodeficiency reminiscent of common variable immunodeficiency. Early diagnosis is critical to prevent life-threatening complications, such as secondary liver failure. In view of the critical role of IL-21 in controlling immune homeostasis, early hematopoietic stem cell transplantation might be considered as therapeutic intervention in affected children. C1 [Kotlarz, Daniel; Klein, Christoph] Univ Munich, Dr von Hauner Childrens Hosp, Dept Pediat, D-80337 Munich, Germany. [Zietara, Natalia] Hannover Med Sch, Inst Immunol, Hannover, Germany. [Milner, Joshua D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Klein, C (reprint author), Univ Munich, Dr von Hauner Childrens Hosp, Lindwurmstr 4, D-80337 Munich, Germany. EM christoph.klein@med.uni-muenchen.de FU DFG (Gottfried-Wilhelm-Leibniz Program) [KFO250, SFB914]; BMBF (PID-NET); Reinhard-Frank Stiftung; NIAID, NIH FX This work was partially supported by grants from the DFG (KFO250, SFB914, Gottfried-Wilhelm-Leibniz Program), BMBF (PID-NET), and Reinhard-Frank Stiftung (fellowship to D. Kotlarz). This work was sponsored in part by the intramural research program of the NIAID, NIH. NR 65 TC 12 Z9 13 U1 0 U2 9 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 DEC PY 2014 VL 26 IS 6 BP 704 EP 712 DI 10.1097/MOP.0000000000000160 PG 9 WC Pediatrics SC Pediatrics GA AT4RB UT WOS:000344927300014 PM 25321844 ER PT J AU Ravell, J Chaigne-Delalande, B Lenardo, M AF Ravell, Juan Chaigne-Delalande, Benjamin Lenardo, Michael TI X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia disease: a combined immune deficiency with magnesium defect SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE chronic Epstein-Barr virus infection; EBV-associated lymphoma; immunodeficiency; MAGT1; Mg2+ supplementation; NKG2D ID RECESSIVE MENTAL-RETARDATION; ACRODERMATITIS-ENTEROPATHICA; LYMPHOPROLIFERATIVE DISEASE; MG2+ TRANSPORTER; OVARIAN-CANCER; TUSC3 GENE; MUTATION; IDENTIFICATION; CELLS; FAMILY AB Purpose of reviewTo describe the role of the magnesium transporter 1 (MAGT1) in the pathogenesis of X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia' (XMEN) disease and its clinical implications.Recent findingsThe magnesium transporter protein MAGT1 participates in the intracellular magnesium ion (Mg2+) homeostasis and facilitates a transient Mg2+ influx induced by the activation of the T-cell receptor. Loss-of-function mutations in MAGT1 cause an immunodeficiency named XMEN syndrome', characterized by CD4 lymphopenia, chronic EBV infection, and EBV-related lymphoproliferative disorders. Patients with XMEN disease have impaired T-cell activation and decreased cytolytic function of natural killer (NK) and CD8(+) T cells because of decreased expression of the NK stimulatory receptor natural-killer group 2, member D' (NKG2D). Patients may have defective specific antibody responses secondary to T cell dysfunction, but B cells have not been shown to be directly affected by mutations in MAGT1.SummaryXMEN disease has revealed a novel role for free intracellular magnesium in the immune system. Further understanding of the MAGT1 signaling pathway may lead to new diagnostic and therapeutic approaches. C1 [Ravell, Juan; Chaigne-Delalande, Benjamin; Lenardo, Michael] NIAID, Mol cular Dev Immune Syst Sect, Lymphocyte Mol Genet Unit, Immunol Lab,NIH, Bethesda, MD 20892 USA. [Ravell, Juan; Chaigne-Delalande, Benjamin; Lenardo, Michael] NIAID, Clin Genom Program, Bethesda, MD 20892 USA. RP Lenardo, M (reprint author), NIAID, Mol Dev Sect, Immunol Lab, NIH, Bldg 10,Room 11N311,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. EM lenardo@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH; Office of Disease Prevention, NIH FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH and by co-funding through the Office of Disease Prevention, NIH. The authors thank Dr Helen Su for critically reading the manuscript; and Drs William Paul, Kathryn Zoon, and Anthony Fauci for their special support in the NIAID Clinical Genomics program. NR 47 TC 7 Z9 7 U1 2 U2 8 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 DEC PY 2014 VL 26 IS 6 BP 713 EP 719 DI 10.1097/MOP.0000000000000156 PG 7 WC Pediatrics SC Pediatrics GA AT4RB UT WOS:000344927300015 PM 25313976 ER PT J AU Ma, CS Uzel, G Tangye, SG AF Ma, Cindy S. Uzel, Gulbu Tangye, Stuart G. TI Human T follicular helper cells in primary immunodeficiencies SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE CD4(+) T cells; CXCR5; immunological memory; primary immunodeficiencies; T follicular helper cells; vaccination ID INFLAMMATORY-BOWEL-DISEASE; CLASS-SWITCH RECOMBINATION; CXC CHEMOKINE RECEPTOR-5; B-CELLS; PHOSPHOINOSITIDE 3-KINASE; ANTIBODY-RESPONSES; C-MAF; NEGATIVE REGULATOR; IMMUNE-RESPONSES; IL-21 RECEPTOR AB Purpose of reviewTo summarize our understanding of the biology of T follicular helper (Tfh) cells and how insights into this are being provided by the study of human monogenic immunological diseases.Recent findingsAntibody production is a key feature of the vertebrate immune system. Antibodies neutralize and clear pathogens, thereby protecting against infectious diseases. Long-lived humoral immunity depends on help provided by Tfh cells, which support the differentiation of antigen-specific B cells into memory and plasma cells. Tfh cells are generated from naive CD4(+) T cells following the receipt of inputs from various cell surface receptors. Although genetically modified mice have provided a great understanding of the requirements for generating Tfh cells, it is critical that the requirements for human Tfh cells are also established. This is being achieved by the systematic analysis of humans with monogenic mutations that cause primary immunodeficiencies characterized by impaired humoral immunity following infection or vaccination.SummaryThe elucidation of the mechanisms that regulate Tfh cell generation, differentiation and function should reveal targets for novel therapeutics that may offer opportunities to manipulate these cells to not only improve humoral immunity in the setting of primary immunodeficiencies but also temper their dysregulation in conditions of antibody-mediated autoimmunity. C1 [Ma, Cindy S.; Tangye, Stuart G.] St Vincents Hosp, Garvan Inst Med Res, Div Immunol, Darlinghurst, NSW 2010, Australia. [Ma, Cindy S.; Tangye, Stuart G.] Univ New S Wales, St Vincents Clin Sch, Kensington, NSW 2033, Australia. [Uzel, Gulbu] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Tangye, SG (reprint author), St Vincents Hosp, Garvan Inst Med Res, 384 Victoria St, Darlinghurst, NSW 2010, Australia. EM c.ma@garvan.org.au; g.uzel@niaid.nih.gov; s.tangye@garvan.org.au FU National Health and Medical Research Foundation of Australia; Cancer Council NSW; National Institutes of Health FX Research performed in the authors' labs is supported by grants and fellowships awarded by the National Health and Medical Research Foundation of Australia, Cancer Council NSW (C.S.M., S.G.T.) and the National Institutes of Health (G.U.). NR 65 TC 3 Z9 4 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8703 EI 1531-698X J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD DEC PY 2014 VL 26 IS 6 BP 720 EP 726 DI 10.1097/MOP.0000000000000157 PG 7 WC Pediatrics SC Pediatrics GA AT4RB UT WOS:000344927300016 PM 25268404 ER PT J AU Hoeltzel, MF Oberle, EJ Robinson, AB Agarwal, A Rider, LG AF Hoeltzel, Mark F. Oberle, Edward J. Robinson, Angela Byun Agarwal, Arunima Rider, Lisa G. TI The Presentation, Assessment, Pathogenesis, and Treatment of Calcinosis in Juvenile Dermatomyositis SO CURRENT RHEUMATOLOGY REPORTS LA English DT Article DE Juvenile dermatomyositis; Calcinosis; Dystrophic calcification; Treatment; Pathogenesis ID IDIOPATHIC INFLAMMATORY MYOPATHIES; INTRAVENOUS IMMUNOGLOBULIN THERAPY; RITUXIMAB-INDUCED REGRESSION; CONNECTIVE-TISSUE DISEASES; TOPICAL SODIUM THIOSULFATE; CREST-RELATED CALCINOSIS; NECROSIS-FACTOR-ALPHA; SYSTEMIC-SCLEROSIS; DYSTROPHIC CALCIFICATION; CLINICAL CHARACTERISTICS AB Calcinosis is one of the hallmark sequelae of juvenile dermatomyositis (JDM), and despite recent progress in the therapy of JDM, dystrophic calcification still occurs in approximately one third of patients. This review discusses our current, albeit limited, understanding of risk factors for the development of calcinosis in JDM, as well as approaches to assessment, and current views on its pathogenesis. Anecdotal approaches to treating calcinosis associated with JDM, including both anti-inflammatory therapies and agents aimed at inhibiting the deposition of calcium hydroxyapatite, are reviewed. An improved understanding of the pathogenesis of calcinosis, the establishment of standardized measurement tools to assess calcinosis, and randomized controlled trials employing more sensitive outcome measures are needed to develop efficacious therapies for this often disabling complication. C1 [Hoeltzel, Mark F.] Univ Michigan, Mott Childrens Hosp, Ann Arbor, MI 48109 USA. [Oberle, Edward J.] Med Coll Wisconsin, Childrens Hosp Wisconsin, Milwaukee, WI 53151 USA. [Robinson, Angela Byun] Rainbow Babies & Childrens Hosp, Case Med Ctr, Cleveland, OH 44106 USA. [Agarwal, Arunima] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Rider, Lisa G.] NIEHS, Environm Autoimmun Grp, Program Clin Res, NIH, Bethesda, MD 20892 USA. RP Hoeltzel, MF (reprint author), Univ Michigan, Mott Childrens Hosp, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM mhoeltze@med.umich.edu; eoberle.md@gmail.com; angela.robinson@uhhospitals.org; arunima.agarwal@gmail.com; riderl@mail.nih.gov OI Rider, Lisa/0000-0002-6912-2458 FU Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health FX This study was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. We thank Drs. Olcay Jones and James Katz for helpful comments on the manuscript. NR 116 TC 5 Z9 5 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3774 EI 1534-6307 J9 CURR RHEUMATOL REP JI Curr. Rheumatol. Rep. PD DEC PY 2014 VL 16 IS 12 AR 467 DI 10.1007/s11926-014-0467-y PG 11 WC Rheumatology SC Rheumatology GA AT0TW UT WOS:000344648600003 PM 25366934 ER PT J AU Perfetto, SP Chattopadhyay, PK Wood, J Nguyen, R Ambrozak, D Hill, JP Roederer, M AF Perfetto, Stephen P. Chattopadhyay, Pratip K. Wood, James Richard Nguyen Ambrozak, David Hill, Juliane P. Roederer, Mario TI Q and B Values are Critical Measurements Required for Inter-Instrument Standardization and Development of Multicolor Flow Cytometry Staining Panels SO CYTOMETRY PART A LA English DT Article DE inter-instrument quality control and standardization; Q and B values; panel development; panel success; panel design ID FLUORESCENCE SENSITIVITY; PERFORMANCE; CALIBRATION; RESOLUTION; QUALITY; BEADS AB Much of the complexity of multicolor flow cytometry experiments lies within the development of antibody staining panels and the standardization of instruments. In this article, we propose a theoretical metric and describe how measurements of sensitivity and resolution can be used to predict the success of panels, and ensure that performance across instruments is standardized (i.e., inter-instrument standardization). Sensitivity can be determined by summing two major contributors of background, background originating from the instrument (optical noise and electronic noise) and background due to the experimental conditions (i.e., Raman scatter, and spillover spreading arising from other fluorochromes in the panel). The former we define as B-cal and the latter we define as B-sos. The combination of instrument and experiment background is defined as B-tot. Importantly, the B-tot will affect the degree of panel separation, therefore the greater the degree of B-tot the lower the separation potential. In contrast, resolution is a measure of separation between populations. Resolution is directly proportional to the number of photoelectrons generated per molecule of excited fluorochrome and is known as the Q value. Q and B-tot values can be used to define the performance of each detector on an instrument and together they can be used to calculate a separation index. Hence, detectors with known Q and B-tot values can be used to evaluate panel success based on the detector specific separation index. However, the current technologies do not enable measurements of Q and B-tot values for all parameters, but new technology to allow these measurements will likely be introduced in the near future. Nonetheless, Q and B-tot measurements can aid in panel development, and reveal sources of instrument-to-instrument variation in panel performance. In addition, Q and B values can form the basis for a comprehensive and versatile quality assurance program. Published 2014 Wiley Periodicals Inc. C1 [Perfetto, Stephen P.; Chattopadhyay, Pratip K.; Richard Nguyen; Ambrozak, David; Hill, Juliane P.; Roederer, Mario] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20724 USA. [Wood, James] Wake Forest Sch Med, Comprehens Canc Ctr, Dept Canc Biol, Winston Salem, NC 27157 USA. RP Perfetto, SP (reprint author), NIH, Vaccine Res Ctr, Bldg 40,40 Convent Dr,Room 5507, Bethesda, MD 20892 USA. EM sperfetto@mail.nih.gov OI Chattopadhyay, Pratip/0000-0002-5457-9666 NR 17 TC 5 Z9 5 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4922 EI 1552-4930 J9 CYTOM PART A JI Cytom. Part A PD DEC PY 2014 VL 85A IS 12 BP 1037 EP 1048 DI 10.1002/cyto.a.22579 PG 12 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AU0XE UT WOS:000345344700009 PM 25346474 ER PT J AU Arnold, TD Niaudet, C Pang, MF Siegenthaler, J Gaengel, K Jung, B Ferrero, GM Mukouyama, YS Fuxe, J Akhurst, R Betsholtz, C Sheppard, D Reichardt, LF AF Arnold, Thomas D. Niaudet, Colin Pang, Mei-Fong Siegenthaler, Julie Gaengel, Konstantin Jung, Bongnam Ferrero, Gina M. Mukouyama, Yoh-suke Fuxe, Jonas Akhurst, Rosemary Betsholtz, Christer Sheppard, Dean Reichardt, Louis F. TI Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking alpha V beta 8-TGF beta signaling in the brain SO DEVELOPMENT LA English DT Article DE Angiogenesis; Brain; CNS; Hemorrhage; Sprouting; Integrin alpha V beta 8; TGF beta; Mouse ID PROTEIN-COUPLED RECEPTOR; GROWTH-FACTOR-BETA; INTEGRIN ALPHA-V-BETA-8-MEDIATED ACTIVATION; CENTRAL-NERVOUS-SYSTEM; ALPHA-V INTEGRINS; GERMINAL MATRIX; ENDOTHELIAL-CELLS; PREMATURE-INFANTS; VESSEL FORMATION; BLOOD-VESSELS AB Vascular development of the central nervous system and blood-brain barrier (BBB) induction are closely linked processes. The role of factors that promote endothelial sprouting and vascular leak, such as vascular endothelial growth factor A, are well described, but the factors that suppress angiogenic sprouting and their impact on the BBB are poorly understood. Here, we show that integrin alpha V beta 8 activates angiosuppressive TGF beta gradients in the brain, which inhibit endothelial cell sprouting. Loss of alpha V beta 8 in the brain or downstream TGF beta 1-GFBR2-ALK5-Smad3 signaling in endothelial cells increases vascular sprouting, branching and proliferation, leading to vascular dysplasia and hemorrhage. Importantly, BBB function in Itgb8 mutants is intact during early stages of vascular dysgenesis before hemorrhage. By contrast, Pdgfb(ret/ret) mice, which exhibit severe BBB disruption and vascular leak due to pericyte deficiency, have comparatively normal vascular morphogenesis and do not exhibit brain hemorrhage. Our data therefore suggest that abnormal vascular sprouting and patterning, not BBB dysfunction, underlie developmental cerebral hemorrhage. C1 [Arnold, Thomas D.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94158 USA. [Arnold, Thomas D.; Niaudet, Colin; Pang, Mei-Fong; Gaengel, Konstantin; Jung, Bongnam; Fuxe, Jonas; Betsholtz, Christer] Karolinska Inst, Dept Med Biochem & Biophys, SE-17777 Stockholm, Sweden. [Siegenthaler, Julie] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA. [Ferrero, Gina M.; Reichardt, Louis F.] Univ Calif San Francisco, Dept Physiol & Neurosci Program, San Francisco, CA 94158 USA. [Mukouyama, Yoh-suke] NHLBI, Lab Stem Cell & Neurovasc Biol, NIH, Bethesda, MD 20892 USA. [Akhurst, Rosemary] Univ Calif San Francisco, Helen Diller Canc Ctr, San Francisco, CA 94158 USA. [Akhurst, Rosemary] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94158 USA. [Sheppard, Dean] Univ Calif San Francisco, Dept Med, San Francisco, CA 94158 USA. RP Reichardt, LF (reprint author), Simons Fdn, 160 Fifth Ave, New York, NY 10010 USA. EM arnoldtd@gmail.com FU Pediatric Critical Care Scientist Development Program [K12HD047349]; Leducq Foundation Career Development Award; NIH [HL005702, K99-R00 NS070920]; Knut and Alice Wallenberg Foundation; European Research Council Advanced grant BBBARRIER [5R01 GM060514, 5R01 HL078564, R37 HL53949, R01 NS19090]; Leducq Foundation Transatlantic Network of Excellence Award FX Work was supported by Pediatric Critical Care Scientist Development Program K12HD047349 and Leducq Foundation Career Development Award (T.D.A.), NIH HL005702 (Y.M.), K99-R00 NS070920 (J.S.), Knut and Alice Wallenberg Foundation and European Research Council Advanced grant BBBARRIER (C.B.), 5R01 GM060514 and 5R01 HL078564 (R.A.), R37 HL53949 (D.S.), R01 NS19090 and Leducq Foundation Transatlantic Network of Excellence Award (L.F.R.). Deposited in PMC for release after 12 months. NR 75 TC 15 Z9 15 U1 1 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD DEC PY 2014 VL 141 IS 23 BP 4489 EP 4499 DI 10.1242/dev.107193 PG 11 WC Developmental Biology SC Developmental Biology GA AT6DP UT WOS:000345029600008 PM 25406396 ER PT J AU Yaghootkar, H Scott, RA White, CC Zhang, WH Speliotes, E Munroe, PB Ehret, GB Bis, JC Fox, CS Walker, M Borecki, IB Knowles, JW Yerges-Armstrong, L Ohlsson, C Perry, JRB Chambers, JC Kooner, JS Franceschini, N Langenberg, C Hivert, MF Dastani, Z Richards, JB Semple, RK Frayling, TM AF Yaghootkar, Hanieh Scott, Robert A. White, Charles C. Zhang, Weihua Speliotes, Elizabeth Munroe, Patricia B. Ehret, Georg B. Bis, Joshua C. Fox, Caroline S. Walker, Mark Borecki, Ingrid B. Knowles, Joshua W. Yerges-Armstrong, Laura Ohlsson, Claes Perry, John R. B. Chambers, John C. Kooner, Jaspal S. Franceschini, Nora Langenberg, Claudia Hivert, Marie-France Dastani, Zari Richards, J. Brent Semple, Robert K. Frayling, Timothy M. TI Genetic Evidence for a Normal-Weight "Metabolically Obese" Phenotype Linking Insulin Resistance, Hypertension, Coronary Artery Disease, and Type 2 Diabetes SO DIABETES LA English DT Article ID ADIPOSE-TISSUE EXPANDABILITY; GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; PPAR-GAMMA; PLASMA ADIPONECTIN; GLYCEMIC TRAITS; LOCI; VARIANTS; LIPOTOXICITY; PATHWAYS AB The mechanisms that predispose to hypertension, coronary artery disease (CAD), and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy-a reduction in subcutaneous adipose tissue-it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin-based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed genetic risk scores against disease outcomes, including 12,171 T2D cases, 40,365 CAD cases, and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (beta = 0.018; P = 4 x 10(-29)), lower HDL cholesterol (beta = -0.020; P = 7 x 10(-37)), greater hepatic steatosis (beta = 0.021; P = 3 x 10(-4)), higher alanine transaminase (beta = 0.002; P = 3 x 10(-5)), lower sex-hormone-binding globulin (beta = -0.010; P = 9 x 10(-13)), and lower adiponectin (beta = -0.015; P = 2 x 10(-26)). The same risk alleles were associated with lower BMI (per-allele beta = -0.008; P = 7 x 10(-8)) and increased visceral-to-subcutaneous adipose tissue ratio (beta = -0.015; P = 6 x 10(-7)). Individuals carrying >= 17 fasting insulin-raising alleles (5.5% population) were slimmer (0.30 kg/m(2)) but at increased risk of T2D (odds ratio [OR] 1.46; per-allele P = 5 x 10(-13)), CAD (OR 1.12; per-allele P = 1 x 10(-5)), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg [per-allele P = 2 x 10(-5)] and 0.67 mmHg [per-allele P = 2 x 10(-4)], respectively) compared with individuals carrying <= 9 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the "metabolic syndrome" and point to reduced subcutaneous adiposity as a central mechanism. C1 [Yaghootkar, Hanieh] Univ Exeter, Sch Med, Exeter, Devon, England. [Scott, Robert A.; Perry, John R. B.; Langenberg, Claudia] Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England. [White, Charles C.; Fox, Caroline S.] NHLBI, Framingham Heart Study, NIH, Framingham, MA USA. [White, Charles C.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Zhang, Weihua; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Speliotes, Elizabeth] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Speliotes, Elizabeth] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Munroe, Patricia B.] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England. [Munroe, Patricia B.] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Barts & London Genome Ctr, London, England. [Ehret, Georg B.] Univ Hosp Geneva, Ctr Cardiol, Geneva, Switzerland. [Ehret, Georg B.] Johns Hopkins Univ, Inst Med Genet, Baltimore, MD USA. [Bis, Joshua C.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Bis, Joshua C.] Univ Washington, Dept Med, Seattle, WA USA. [Fox, Caroline S.] NHLBI, Ctr Populat Studies, NIH, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Walker, Mark] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Knowles, Joshua W.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Knowles, Joshua W.] Stanford Univ, Sch Med, Cardiovasc Inst, Stanford, CA 94305 USA. [Yerges-Armstrong, Laura] Univ Maryland, Sch Med, Div Endocrinol, Baltimore, MD 21201 USA. [Ohlsson, Claes] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden. [Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Franceschini, Nora] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Langenberg, Claudia] UCL, Dept Epidemiol & Publ Hlth, London, England. [Hivert, Marie-France] Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA. [Hivert, Marie-France] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Dastani, Zari] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Dastani, Zari] McGill Univ, Dept Epidemiol & Biostat, Montreal, PQ, Canada. [Richards, J. Brent] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Richards, J. Brent] McGill Univ, Dept Med Human Genet Epidemiol & Biostat, Montreal, PQ, Canada. [Semple, Robert K.] Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England. [Semple, Robert K.] Univ Cambridge, Metab Res Labs, Inst Metab Sci, Cambridge, England. RP Frayling, TM (reprint author), Univ Exeter, Sch Med, Exeter, Devon, England. EM t.m.frayling@ex.ac.uk OI Semple, Robert/0000-0001-6539-3069 FU European Research Council [ERS: 323195]; Wellcome Trust; University of Exeter Medical School; National Institute for Health Research Barts Cardiovascular Biomedical Research Unit FX The authors thank the European Research Council (ERS: 323195), Wellcome Trust, and University of Exeter Medical School. P. B. M. acknowledges the National Institute for Health Research Barts Cardiovascular Biomedical Research Unit for supporting this work. NR 37 TC 32 Z9 32 U1 0 U2 16 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD DEC PY 2014 VL 63 IS 12 BP 4369 EP 4377 DI 10.2337/db14-0318 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AU0ST UT WOS:000345335500045 PM 25048195 ER PT J AU Murphy, RA Reinders, I Garcia, ME Eiriksdottir, G Launer, LJ Benediktsson, R Gudnason, V Jonsson, PV Harris, TB AF Murphy, Rachel A. Reinders, Ilse Garcia, Melissa E. Eiriksdottir, Gudny Launer, Lenore J. Benediktsson, Rafn Gudnason, Vilmundur Jonsson, Palmi V. Harris, Tamara B. CA Age Gene Environm Susceptibility TI Adipose Tissue, Muscle, and Function: Potential Mediators of Associations Between Body Weight and Mortality in Older Adults With Type 2 Diabetes SO DIABETES CARE LA English DT Article ID GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK; MASS INDEX; OBESITY PARADOX; INSULIN-RESISTANCE; SKELETAL-MUSCLE; COHORT; MEN; METAANALYSIS; STRENGTH; HEALTH AB OBJECTIVE Studies in type 2 diabetes report both increased mortality for normal weight and no evidence of an obesity paradox. We aimed to examine whether adipose tissue, muscle size, and physical function, which are known to vary by weight, mediate associations between BMI and mortality. RESEARCH DESIGN AND METHODS The AGES-Reykjavik cohort comprised participants aged 66-96 years with diabetes defined by fasting glucose, medications, or self-report. BMI was determined from measured height and weight and classified as normal (18.5-24.9 kg/m(2), n = 117), overweight (25.0-29.9 kg/m(2), n = 293, referent group) or obese (>= 30.0 kg/m2, n = 227). Thigh muscle area and intermuscular, visceral, and subcutaneous adipose tissues were assessed with computed tomography. Function was assessed from gait speed and knee extensor strength. Hazard ratios (HRs) and 95% CIs were estimated by Cox proportional hazards regression adjusted for demographics and diabetes-related risk factors. RESULTS The median follow-upwas 6.66 years, and there were 85, 59, and 44 deaths among normal weight, overweight, and obese participants, respectively. There was no mortality risk for obese participants and an increased risk among normal weight compared with overweight participants (HR 1.72 [95% CI 1.12-2.64]). Associations remained with adjustment for adipose tissues and knee extensor strength; however, mortality risk for normal weight was attenuated following adjustment for thigh muscle (HR 1.36 [95% CI 0.87-2.11]) and gait speed (HR 1.44 [95% CI 0.91-2.27]). Linear regression confirmed with bootstrapping indicated that thigh muscle size mediated 46% of the relationship between normal weight and mortality. CONCLUSIONS Normal weight participants had elevated mortality risk compared with overweight participants. This paradoxical association was mediated in part by muscle size. C1 [Murphy, Rachel A.; Reinders, Ilse; Garcia, Melissa E.; Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. [Benediktsson, Rafn] Landspitali Natl Univ Hosp, Reykjavik, Iceland. [Jonsson, Palmi V.] Landspitali Natl Univ Hosp, Dept Geriatr, Reykjavik, Iceland. [Jonsson, Palmi V.] Univ Iceland, Fac Med, Reykjavik, Iceland. RP Murphy, RA (reprint author), NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. EM rachel.murphy@nih.gov RI Gudnason, Vilmundur/K-6885-2015 OI Gudnason, Vilmundur/0000-0001-5696-0084 FU National Institutes of Health [N01-AG-012100]; National Institute on Aging Intramural Research Program, Hjartavernd ( the Icelandic Heart Association); Althingi ( the Icelandic Parliament); Banting Post-doctoral Fellowship FX This study was funded by National Institutes of Health contract N01-AG-012100, the National Institute on Aging Intramural Research Program, Hjartavernd ( the Icelandic Heart Association), and the Althingi ( the Icelandic Parliament). R.A.M. holds as Banting Post-doctoral Fellowship. NR 39 TC 12 Z9 12 U1 0 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD DEC PY 2014 VL 37 IS 12 BP 3213 EP 3219 DI 10.2337/dc14-0293 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AU0SQ UT WOS:000345335200029 PM 25315206 ER PT J AU Pittas, AG Dawson-Hughes, B Sheehan, PR Rosen, CJ Ware, JH Knowler, WC Staten, MA AF Pittas, Anastassios G. Dawson-Hughes, Bess Sheehan, Patricia R. Rosen, Clifford J. Ware, James H. Knowler, William C. Staten, Myrlene A. CA D2d Res Grp TI Rationale and Design of the Vitamin D and Type 2 Diabetes (D2d) Study: A Diabetes Prevention Trial SO DIABETES CARE LA English DT Article ID 25-HYDROXYVITAMIN D CONCENTRATION; PLACEBO-CONTROLLED TRIAL; D SUPPLEMENTATION; D DEFICIENCY; RANDOMIZED-TRIAL; CLINICAL-TRIALS; RISK; CALCIUM; ADULTS; WOMEN AB OBJECTIVE Observational studies suggest that vitamin D may lower the risk of type 2 diabetes. However, data from long-term trials are lacking. The Vitamin D and Type 2 Diabetes (D2d) study is a randomized clinical trial designed to examine whether a causal relationship exists between vitamin D supplementation and the development of diabetes in people at high risk for type 2 diabetes. RESEARCH DESIGN AND METHODS D2d was designed with support from a U34 planning grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The final protocol was approved by the D2d Research Group, the data and safety monitoring board, and NIDDK. Key eligibility criteria are age 30 years, BMI of 24(22.5 for Asian Americans) to 42 kg/m(2), increased risk for diabetes (defined as meeting two of three glycemic criteria for prediabetes established by the American Diabetes Association [fasting glucose 100-125 mg/dL (5.5-6.9 mmol/L), 2-h postload glucose after 75-g glucose load 140-199 mg/dL (7.7-11.0 mmol/L), hemoglobin A(1c), 5.7-6.4% (39-46 mmol/mol)]), and no hyperparathyroidism, nephrolithiasis, or hypercalcemia. D2d participants are randomized to once-daily vitamin D-3 (cholecalciferol 4,000 IU) or placebo and followed for an average of 3 years. The primary end point is time to incident diabetes as assessed by laboratory criteria during the study or by adjudication if diagnosed outside of D2d. Recruitment was initiated at the end of 2013. CONCLUSIONS D2d will test whether vitamin D supplementation is safe and effective at lowering the risk of progression to diabetes in people at high risk for type 2 diabetes. C1 [Pittas, Anastassios G.; Dawson-Hughes, Bess; Sheehan, Patricia R.] Tufts Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02111 USA. [Dawson-Hughes, Bess] Tufts Univ, Jean Mayer US Dept Agr, Bone Metab Lab, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Rosen, Clifford J.] Maine Med Ctr, Res Inst, Scarborough, ME USA. [Ware, James H.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Knowler, William C.] NIDDK, Phoenix, AZ USA. [Staten, Myrlene A.] NIDDK, Bethesda, MD 20892 USA. RP Sheehan, PR (reprint author), Tufts Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02111 USA. EM d2d@tuftsmedicalcenter.org FU NIDDK of the NIH [U34-DK-091958]; NIDDK, the Office of the Director, NIH; NIH Office of Dietary Supplements [U01-DK-098245]; American Diabetes Association [1-14-D2d-01] FX The planning phase of D2d was funded by the NIDDK of the NIH through a multicenter clinical study implementation planning grant (U34) to Tufts Medical Center in Boston, MA (U34-DK-091958). Planning was also supported in part by the Intramural Research Program of the NIDDK. The conduct of D2d is supported by a U01 multicenter clinical study corporative agreement research grant from NIDDK, the Office of the Director, NIH, and the NIH Office of Dietary Supplements (U01-DK-098245). Funding is also provided by the American Diabetes Association (1-14-D2d-01). Educational materials are provided by the National Diabetes Education Program. NR 40 TC 15 Z9 16 U1 0 U2 11 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD DEC PY 2014 VL 37 IS 12 BP 3227 EP 3234 DI 10.2337/dc14-1005 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AU0SQ UT WOS:000345335200031 PM 25205139 ER PT J AU Hugenschmidt, CE Lovato, JF Ambrosius, WT Bryan, RN Gerstein, HC Horowitz, KR Launer, LJ Lazar, RM Murray, AM Chew, EY Danis, RP Williamson, JD Miller, ME Ding, JZ AF Hugenschmidt, Christina E. Lovato, James F. Ambrosius, Walter T. Bryan, R. Nick Gerstein, Hertzel C. Horowitz, Karen R. Launer, Lenore J. Lazar, Ronald M. Murray, Anne M. Chew, Emily Y. Danis, Ronald P. Williamson, Jeff D. Miller, Michael E. Ding, Jingzhong TI The Cross-sectional and Longitudinal Associations of Diabetic Retinopathy With Cognitive Function and Brain MRI Findings: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial SO DIABETES CARE LA English DT Article ID RETINAL MICROVASCULAR ABNORMALITIES; GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK; WHITE-MATTER LESIONS; ATHEROSCLEROSIS RISK; CEREBRAL ATROPHY; FOLLOW-UP; HEALTH; COMMUNITIES; IMPAIRMENT; DECLINE AB OBJECTIVE Longitudinal evidence linking diabetic retinopathy with changes in brain structure and cognition is sparse. We used data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to determine whether diabetic retinopathy at baseline predicted changes in brain structure or cognition 40 months later. RESEARCH DESIGN AND METHODS Participants from the ACCORD-MIND and ACCORD-Eye substudies were included in analyses of cognition (n = 1,862) and MRI-derived brain variables (n = 432). Retinopathy was categorized as none, mild nonproliferative, or moderate/severe. Tests of cognition included the Mini-Mental State Examination (MMSE), Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test, and Stroop test. Primary brain outcomes were gray matter and abnormal white matter volumes. RESULTS Baseline retinopathy was associated with lower gray matter volume (adjusted means of 470, 466, and 461 cm(3) for none, mild, and moderate/severe retinopathy, respectively; P = 0.03). Baseline retinopathy also predicted a greater change in MMSE and DSST scores at 40 months in each retinopathy category (MMSE: 0.20, 0.57, and 0.42, respectively [P = 0.04]; DSST: 1.30, 1.84, and 2.89, respectively [P = 0.01]). CONCLUSIONS Diabetic retinopathy is associated with future cognitive decline in people with type 2 diabetes. Although diabetic retinopathy is not a perfect proxy for diabetes-related brain and cognitive decline, patients with type 2 diabetes and retinopathy represent a subgroup at higher risk for future cognitive decline. C1 [Hugenschmidt, Christina E.; Williamson, Jeff D.; Ding, Jingzhong] Wake Forest Sch Med, Sect Gerontol & Geriatr Med, Dept Internal Med, Winston Salem, NC 27157 USA. [Lovato, James F.; Ambrosius, Walter T.; Miller, Michael E.] Wake Forest Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC USA. [Bryan, R. Nick] Univ Penn, Sch Med, Dept Radiol, Philadelphia, PA 19104 USA. [Gerstein, Hertzel C.] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Gerstein, Hertzel C.] McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada. [Gerstein, Hertzel C.] Hamilton Hlth Sci, Hamilton, ON, Canada. [Horowitz, Karen R.] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Launer, Lenore J.] NIA, NIH, Bethesda, MD 20892 USA. [Lazar, Ronald M.] Columbia Univ Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA. [Lazar, Ronald M.] Columbia Univ Coll Phys & Surg, Dept Neurosurg, New York, NY 10032 USA. [Murray, Anne M.] Hennepin Cty Med Ctr, Dept Med, Minneapolis, MN 55415 USA. [Murray, Anne M.] Univ Minnesota, Minneapolis, MN USA. [Chew, Emily Y.] NEI, NIH, Bethesda, MD 20892 USA. [Danis, Ronald P.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. RP Hugenschmidt, CE (reprint author), Wake Forest Sch Med, Sect Gerontol & Geriatr Med, Dept Internal Med, Winston Salem, NC 27157 USA. EM chugensc@wakehealth.edu FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, Y1-HC-9035, Y1-HC-1010]; National Institute on Aging (NIA) [AG-0002]; NHLBI [AG-0002]; NIA Intramural Research Program; National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; National Eye Institute; Centers for Disease Control and Prevention FX ACCORD was funded by the National Heart, Lung, and Blood Institute (NHLBI) contracts N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA#Y1-HC-9035, and IAA#Y1-HC-1010. ACCORD-MIND was funded through an intra-agency agreement between the National Institute on Aging (NIA) and NHLBI (AG-0002) and the NIA Intramural Research Program. Other components of the National Institutes of Health, including the National Institute of Diabetes and Digestive and Kidney Diseases and the National Eye Institute, contributed funding. The Centers for Disease Control and Prevention funded ACCORD substudies of cost-effectiveness and health-related quality of life. General Clinical Research Centers provided support at many sites. The following companies provided study medications, equipment, or supplies: Abbott Laboratories (Abbott Park, IL); Amylin Pharmaceutical (San Diego, CA); AstraZeneca Pharmaceuticals LP (Wilmington, DE); Bayer HealthCare LLC (Tarrytown, NY); Closer Healthcare Inc. (Tequesta, FL); GlaxoSmithKline Pharmaceuticals (Philadelphia, PA); King Pharmaceuticals, Inc. (Bristol, TN); Merck & Co., Inc. (Whitehouse Station, NJ); Novartis Pharmaceuticals, Inc. (East Hanover, NJ); Novo Nordisk, Inc. (Princeton, NJ); Omron Healthcare, Inc. (Schaumburg, IL); Sanofi U.S. (Bridgewater, NJ); Schering-Plough Corporation (Kenilworth, NJ). The donors of medications and devices had no role in the study design, data accrual and analysis, or manuscript preparation. NR 40 TC 6 Z9 6 U1 1 U2 9 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD DEC PY 2014 VL 37 IS 12 BP 3244 EP 3252 DI 10.2337/dc14-0502 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AU0SQ UT WOS:000345335200033 PM 25193529 ER PT J AU Zhang, Z Lovato, J Battapady, H Davatzikos, C Gerstein, HC Ismail-Beigi, F Launer, LJ Murray, A Punthakee, Z Tirado, AA Williamson, J Bryan, RN Miller, ME AF Zhang, Zi Lovato, James Battapady, Harsha Davatzikos, Christos Gerstein, Hertzel C. Ismail-Beigi, Faramarz Launer, Lenore J. Murray, Anne Punthakee, Zubin Tirado, Amilcar A. Williamson, Jeff Bryan, R. Nick Miller, Michael E. TI Effect of Hypoglycemia on Brain Structure in People With Type 2 Diabetes: Epidemiological Analysis of the ACCORD-MIND MRI Trial SO DIABETES CARE LA English DT Article ID APPARENT DIFFUSION-COEFFICIENT; COGNITIVE FUNCTION; REVERSIBLE REDUCTION; INDUCED HEMIPARESIS; RISK; ASSOCIATION; MELLITUS; DECLINE; ATROPHY; DEMENTIA AB OBJECTIVE The effect of hypoglycemia related to treatment of type 2 diabetes mellitus (T2DM) on brain structure remains unclear. We aimed to assess whether symptomatic severe hypoglycemia is associated with brain atrophy and/or white matter abnormalities. RESEARCH DESIGN AND METHODS We included T2DM participants with brain MRI from the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) trial. Symptomatic severe hypoglycemia was defined as blood glucose <2.8 mmol/L or symptoms resolved with treatments that required the assistance of another person or medical assistance (hypoglycemia requiring assistance [HA]). Standardized brain MRI was performed at baseline and at 40 months. Total brain volume (TBV) and abnormal white matter (AWM) volume were calculated using an automated computer algorithm. Brain MRI scans of hypoglycemic participants were also reviewed for local disease. RESULTS Of the 503 T2DM participants (mean age, 62 years) with successful baseline and 40-month brain MRI, 28 had at least one HA episode during the 40-month follow-up. Compared with participants without HA, those with HA had marginally significant less atrophy (less decrease in TBV) from baseline to 40 months (-9.55 [95% CI - 15.21, -3.90] vs. -15.38 [95% CI -16.64, -14.12], P = 0.051), and no significant increase of AWM volume (2.06 [95% CI 1.71, 2.49] vs. 1.84 [95% CI 1.76, 1.91], P = 0.247). In addition, no unexpected local signal changes or volume loss were seen on hypoglycemic participants' brain MRI scans. CONCLUSIONS Our study suggests that hypoglycemia related to T2DM treatment may not accentuate brain pathology, specifically brain atrophy or white matter abnormalities. C1 [Zhang, Zi; Battapady, Harsha; Davatzikos, Christos; Bryan, R. Nick] Univ Penn, Philadelphia, PA 19104 USA. [Lovato, James; Williamson, Jeff; Miller, Michael E.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Gerstein, Hertzel C.; Punthakee, Zubin] McMaster Univ, Hamilton, ON, Canada. [Ismail-Beigi, Faramarz] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Launer, Lenore J.] NIA, Bethesda, MD 20892 USA. [Murray, Anne] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Tirado, Amilcar A.] Columbia Univ, New York, NY USA. RP Bryan, RN (reprint author), Univ Penn, Philadelphia, PA 19104 USA. EM nick.bryan@uphs.upenn.edu FU National Institute on Aging [AG-0002]; National Heart, Lung, and Blood Institute [AG-0002, N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184]; National Institute on Aging Intramural Research Program FX ACCORD-MIND was funded through an intra-agency agreement between the National Institute on Aging and the National Heart, Lung, and Blood Institute (AG-0002) and the National Institute on Aging Intramural Research Program. ACCORD was funded by the National Heart, Lung, and Blood Institute (N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184). NR 43 TC 8 Z9 9 U1 2 U2 11 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD DEC PY 2014 VL 37 IS 12 BP 3279 EP 3285 DI 10.2337/dc14-0973 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AU0SQ UT WOS:000345335200037 PM 25267796 ER PT J AU Hamman, RF Bell, RA Dabelea, D D'Agostino, RB Dolan, L Imperatore, G Lawrence, JM Linder, B Marcovina, SM Mayer-Davis, EJ Pihoker, C Rodriguez, BL Saydah, S AF Hamman, Richard F. Bell, Ronny A. Dabelea, Dana D'Agostino, Ralph B., Jr. Dolan, Lawrence Imperatore, Giuseppina Lawrence, Jean M. Linder, Barbara Marcovina, Santica M. Mayer-Davis, Elizabeth J. Pihoker, Catherine Rodriguez, Beatriz L. Saydah, Sharon CA SEARCH Diabet Youth Study Grp TI The SEARCH for Diabetes in Youth Study: Rationale, Findings, and Future Directions SO DIABETES CARE LA English DT Article ID CARDIOVASCULAR RISK-FACTORS; HEART-RATE-VARIABILITY; TODAY CLINICAL-TRIAL; QUALITY-OF-LIFE; INCREASED ARTERIAL STIFFNESS; HISPANIC WHITE YOUTH; BETA-CELL FUNCTION; CHILDHOOD TYPE-1; US YOUTH; NUTRITION ANCILLARY AB The SEARCH for Diabetes in Youth (SEARCH) study was initiated in 2000, with funding from the Centers for Disease Control and Prevention and support fromthe National Institute of Diabetes and Digestive and Kidney Diseases, to address major knowledge gaps in the understanding of childhood diabetes. SEARCH is being conducted at five sites across the U. S. and represents the largest, most diverse study of diabetes among U. S. youth. An active registry of youth diagnosed with diabetes at age < 20 years allows the assessment of prevalence (in 2001 and 2009), annual incidence (since 2002), and trends by age, race/ethnicity, sex, and diabetes type. Prevalence increased significantly from 2001 to 2009 for both type 1 and type 2 diabetes in most age, sex, and race/ethnic groups. SEARCH has also established a longitudinal cohort to assess the natural history and risk factors for acute and chronic diabetes-related complications as well as the quality of care and quality of life of persons with diabetes from diagnosis into young adulthood. Many youth with diabetes, particularly those from low-resourced racial/ethnic minority populations, are notmeeting recommended guidelines for diabetes care. Markers of micro-and macrovascular complications are evident in youth with either diabetes type, highlighting the seriousness of diabetes in this contemporary cohort. This review summarizes the study methods, describes key registry and cohort findings and their clinical and public health implications, and discusses future directions. C1 [Hamman, Richard F.; Dabelea, Dana] Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA. [Bell, Ronny A.] Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC 27157 USA. [D'Agostino, Ralph B., Jr.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Dolan, Lawrence] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Imperatore, Giuseppina; Saydah, Sharon] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. [Lawrence, Jean M.] Kaiser Permanente So Calif, Dept Res & Evaluat, Pasadena, CA 91101 USA. [Linder, Barbara] NIDDK, Childhood Diabet Res Div Diabet Endocrinol & Meta, Bethesda, MD 20892 USA. [Marcovina, Santica M.] Univ Washington, Northwest Lipid Res Lab, Seattle, WA 98195 USA. [Mayer-Davis, Elizabeth J.] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Mayer-Davis, Elizabeth J.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Pihoker, Catherine] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Rodriguez, Beatriz L.] Univ Hawaii, John A Burns Sch Med, Kuakini Med Ctr, Honolulu, HI 96822 USA. [Rodriguez, Beatriz L.] Inst Tecnol Monterrey, Monterrey, Mexico. RP Bell, RA (reprint author), Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC 27157 USA. EM rbell@wakehealth.edu RI Dagostino Jr, Ralph/C-4060-2017 OI Dagostino Jr, Ralph/0000-0002-3550-8395 FU Centers for Disease Control and Prevention [00097, DP-05-069, DP-10-001]; National Institute of Diabetes and Digestive and Kidney Diseases; General Clinical Research Centers at the South Carolina Clinical & Translational Research Institute, at the Medical University of South Carolina (National Institutes of Health [NIH]/National Center for Research Resources [UL1-RR-029882]; Seattle Children's Hospital (NIH Clinical and Translational Science Award of the University of Washington) [UL1-TR-000423]; University of Colorado Pediatric Clinical and Translational Research Center [UL1-TR-000154]; Barbara Davis Center at the University of Colorado at Denver (Diabetes Endocrinology Research Centers NIH) [P30-DK-057516]; National Center for Research Resources; National Center for Advancing Translational Sciences, NIH [8-UL1-TR-000077]; Kaiser Permanente Southern California [U48/CCU919219, U01-DP-000246, U18-DP-002714]; University of Colorado Denver [U48/CCU819241-3, U01-DP-000247, U18-DP-000247-06A1]; Kuakini Medical Center [U58CCU919256, U01-DP-000245]; Children's Hospital Medical Center (Cincinnati) [U48/CCU519239, U01-DP-000248, 1-U18-DP-002709]; University of North Carolina at Chapel Hill [U48/CCU419249, U01-DP-000254, U18-DP-002708]; University of Washington School of Medicine [U58/CCU019235-4, U01-DP-000244, U18-DP-002710-01]; Wake Forest University School of Medicine [U48/CCU919219, U01-DP-000250, 200-2010-35171]; Children with Medical Handicaps program FX SEARCH is funded by the Centers for Disease Control and Prevention (PA numbers 00097, DP-05-069, and DP-10-001) and supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Support was also provided by General Clinical Research Centers at the South Carolina Clinical & Translational Research Institute, at the Medical University of South Carolina (National Institutes of Health [NIH]/National Center for Research Resources grant UL1-RR-029882), Seattle Children's Hospital (NIH Clinical and Translational Science Award grant UL1-TR-000423 of the University of Washington), University of Colorado Pediatric Clinical and Translational Research Center (grant UL1-TR-000154), the Barbara Davis Center at the University of Colorado at Denver (Diabetes Endocrinology Research Centers NIH P30-DK-057516), the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH, through grant 8-UL1-TR-000077, and the Children with Medical Handicaps program managed by the Ohio Department of Health. Site contract numbers are as follows: Kaiser Permanente Southern California (U48/CCU919219, U01-DP-000246, and U18-DP-002714), University of Colorado Denver (U48/CCU819241-3, U01-DP-000247, and U18-DP-000247-06A1), Kuakini Medical Center (U58CCU919256 and U01-DP-000245), Children's Hospital Medical Center (Cincinnati) (U48/CCU519239, U01-DP-000248, and 1-U18-DP-002709), University of North Carolina at Chapel Hill (U48/CCU419249, U01-DP-000254, and U18-DP-002708), University of Washington School of Medicine (U58/CCU019235-4, U01-DP-000244, and U18-DP-002710-01), and Wake Forest University School of Medicine (U48/CCU919219, U01-DP-000250, and 200-2010-35171). NR 101 TC 40 Z9 41 U1 3 U2 18 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD DEC PY 2014 VL 37 IS 12 BP 3336 EP 3344 DI 10.2337/dc14-0574 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AU0SQ UT WOS:000345335200045 PM 25414389 ER PT J AU Fan, XM Jiang, YM Wang, Y Tan, HS Zeng, H Wang, YT Chen, P Qu, AJ Gonzalez, FJ Huang, M Bi, HC AF Fan, Xiaomei Jiang, Yiming Wang, Ying Tan, Huasen Zeng, Hang Wang, Yongtao Chen, Pan Qu, Aijuan Gonzalez, Frank J. Huang, Min Bi, Huichang TI Wuzhi Tablet (Schisandra Sphenanthera Extract) Protects against Acetaminophen-Induced Hepatotoxicity by Inhibition of CYP-Mediated Bioactivation and Regulation of NRF2-ARE and p53/p21 Pathways SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID PREGNANE-X RECEPTOR; RAW 264.7 CELLS; LIVER-REGENERATION; ANTIINFLAMMATORY ACTIVITY; SIGNALING PATHWAYS; OXIDATIVE STRESS; HEME OXYGENASE-1; CHINENSIS; MICE; INJURY AB Schisandra sphenanthera is widely used as a tonic and restorative in many countries to enhance the function of liver and other organs. Wuzhi tablet (WZ) is a preparation of an ethanol extract of Schisandra sphenanthera. Our previous study demonstrated that WZ exerted a protective effect toward acetaminophen (APAP)-induced hepatotoxicity. However, the molecular mechanisms of this protection remain unclear. This study aimed to determine what molecular pathways contributed to the hepatoprotective effects of WZ against APAP toxicity. Administration of WZ 3 days before APAP treatment significantly attenuated APAP hepatotoxicity in a dose-dependent manner and reduced APAP-induced JNK activation. Treatment with WZ resulted in potent inhibition of CYP2E1, CYP3A11, and CYP1A2 activities and then caused significant inhibition of the formation of the oxidized APAP metabolite N-acetyl-p-benzoquinone imine-reduced glutathione. The expression of NRF2 was increased after APAP and/or WZ treatment, whereas KEAP1 levels were decreased. The protein expression of NRF2 target genes including Gclc, Gclm, Ho-1, and Nqo1 was significantly increased by WZ treatment. Furthermore, APAP increased the levels of p53 and its downstream gene p21 to trigger cell cycle arrest and apoptosis, whereas WZ pretreatment could inhibit p53/p21 signaling to induce cell proliferation-associated proteins including cyclin D1, CDK4, PCNA, and ALR to promote hepatocyte proliferation. This study demonstrated that WZ prevented APAP-induced liver injury by inhibition of cytochrome P450-mediated APAP bioactivation, activation of the NRF2-antioxidant response element pathway to induce detoxification and antioxidation, and regulation of the p53, p21, cyclin D1, CDK4, PCNA, and ALR to facilitate liver regeneration after APAP-induced liver injury. C1 [Fan, Xiaomei; Jiang, Yiming; Wang, Ying; Tan, Huasen; Zeng, Hang; Wang, Yongtao; Huang, Min; Bi, Huichang] Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou, Guangdong, Peoples R China. [Chen, Pan] Sun Yat Sen Univ, Affiliated Hosp 1, Guangzhou, Guangdong, Peoples R China. [Qu, Aijuan; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bi, HC (reprint author), Sun Yat Sen Univ, Sch Pharmaceut Sci, 132 Waihuandong Rd, Guangzhou Univ City 510006, Guangdong, Peoples R China. EM bihchang@mail.sysu.edu.cn OI chen, pan/0000-0003-0271-2725 FU Natural Science Foundation of China [81373470, 81320108027]; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation [2011A060901014]; Fundamental Research Fund for the Central Universities [13ykpy08] FX This work was supported by the Natural Science Foundation of China [Grants 81373470, 81320108027], the Opening Project of Guangdong Provincial Key Laboratory of New Drug Design and Evaluation [Grant 2011A060901014], and the Fundamental Research Fund for the Central Universities [No. 13ykpy08]. NR 39 TC 11 Z9 11 U1 4 U2 31 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 EI 1521-009X J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD DEC PY 2014 VL 42 IS 12 BP 1982 EP 1990 DI 10.1124/dmd.114.059535 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AT8AP UT WOS:000345156500003 PM 25217484 ER PT J AU Zhang, LP McHale, CM Greene, N Snyder, RD Rich, IN Aardema, MJ Roy, S Pfuhler, S Venkatactahalam, S AF Zhang, Luoping McHale, Cliona M. Greene, Nigel Snyder, Ronald D. Rich, Ivan N. Aardema, Marilyn J. Roy, Shambhu Pfuhler, Stefan Venkatactahalam, Sundaresan TI Emerging Approaches in Predictive Toxicology SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Editorial Material DE predictive toxicology; model systems; in silico approaches; genotoxicity ID EMBRYONIC STEM-CELLS; MICRONUCLEUS RSMN ASSAY; METHYLTRANSFERASE 1 N6AMT1; DNA INTERCALATING AGENTS; HIGH-THROUGHPUT ASSAY; BENZENE METABOLITE; NONCOVALENT INTERACTIONS; INDUCED TOXICITY; GENETIC SCREENS; V79 CELLS AB Predictive toxicology plays an important role in the assessment of toxicity of chemicals and the drug development process. While there are several well-established in vitro and in vivo assays that are suitable for predictive toxicology, recent advances in high-throughput analytical technologies and model systems are expected to have a major impact on the field of predictive toxicology. This commentary provides an overview of the state of the current science and a brief discussion on future perspectives for the field of predictive toxicology for human toxicity. Computational models for predictive toxicology, needs for further refinement and obstacles to expand computational models to include additional classes of chemical compounds are highlighted. Functional and comparative genomics approaches in predictive toxicology are discussed with an emphasis on successful utilization of recently developed model systems for high-throughput analysis. The advantages of three-dimensional model systems and stem cells and their use in predictive toxicology testing are also described. Environ. Mol. Mutagen. 55:679-688, 2014. (c) 2014 Wiley Periodicals, Inc. C1 [Zhang, Luoping; McHale, Cliona M.] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth & Sci, Genes & Environm Lab, Berkeley, CA 94720 USA. [Greene, Nigel] Pfizer Worldwide R&D, Worldwide Med Chem, Compound Safety Predict, Groton, CT USA. [Snyder, Ronald D.] RDS Consulting Serv, Maineville, OH USA. [Rich, Ivan N.] Hemogenix, Colorado Springs, CO USA. [Aardema, Marilyn J.] Marilyn Aardema Consulting LLC, Fairfield, OH USA. [Aardema, Marilyn J.; Roy, Shambhu] BioReliance Corp, Div Toxicol, Rockville, MD USA. [Pfuhler, Stefan] Procter & Gamble Co, Cincinnati, OH USA. [Venkatactahalam, Sundaresan] NIDCR, Div Extramural Res, NIH, Bethesda, MD USA. RP Venkatactahalam, S (reprint author), NIDCR, NIH, 6701 Democracy Blvd, Bethesda, MD 20892 USA. EM sundarv@nih.gov FU NIEHS NIH HHS [P42 ES004705] NR 59 TC 2 Z9 4 U1 1 U2 24 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD DEC PY 2014 VL 55 IS 9 BP 679 EP 688 DI 10.1002/em.21885 PG 10 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AT9UX UT WOS:000345272900001 PM 25044351 ER PT J AU Momot, D Nostrand, TA John, K Ward, Y Steinberg, SM Liewehr, DJ Poirier, MC Olivero, OA AF Momot, Dariya Nostrand, Terri A. John, Kaarthik Ward, Yvona Steinberg, Seth M. Liewehr, David J. Poirier, Miriam C. Olivero, Ofelia A. TI Role of Nucleotide Excision Repair and p53 in Zidovudine (AZT)-Induced Centrosomal Deregulation SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE zidovudine; micronuclei; micronuclei with whole chromosomes; centrosomal amplification; Xpa ID GROUP-C PROTEIN; DNA-REPAIR; NUCLEOSIDE ANALOGS; DEFICIENT XPA; MICE; AMPLIFICATION; GENOTOXICITY; MECHANISMS; INTEGRITY; BINDING AB The nucleoside reverse transcriptase inhibitor zidovudine (AZT) induces genotoxic damage that includes centrosomal amplification (CA>2 centrosomes/cell) and micronucleus (MN) formation. Here we explored these end points in mice deficient in DNA repair and tumor suppressor function to evaluate their effect on AZT-induced DNA damage. We used mesenchymal-derived fibroblasts cultured from C57BL/6J mice that were null and wild type (WT) for Xpa, and WT, haploinsufficient and null for p53 (6 different genotypes). Dose-responses for CA formation, in cells exposed to 0, 10, and 100 M AZT for 24 hr, were observed in all genotypes except the Xpa((+/+))p53((+/-)) cells, which had very low levels of CA, and the Xpa((-/-))p53((-/-)) cells, which had very high levels of CA. For CA there was a significant three-way interaction between Xpa, p53, and AZT concentration, and Xpa((-/-)) cells had significantly higher levels of CA than Xpa((+/+)) cells, only for p53((+/-)) cells. In contrast, the MN and MN+chromosomes (MN+C) data showed a lack of AZT dose response. The Xpa((-/-)) cells, with p53((+/+)) or ((+/-)) genotypes, had levels of MN and MN+C higher than the corresponding Xpa((+/+)) cells. The data show that CA is a major event induced by exposure to AZT in these cells, and that there is a complicated relationship between AZT and CA formation with respect to gene dosage of Xpa and p53. The loss of both genes resulted in high levels of damage, and p53 haploinsufficicency strongly protected Xpa((+/+)) cells from AZT-induced CA damage. Environ. Mol. Mutagen. 55:719-726, 2014. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. C1 [Momot, Dariya; Nostrand, Terri A.; John, Kaarthik; Poirier, Miriam C.; Olivero, Ofelia A.] NCI, Carcinogen DNA Interact Sect, LCBG, NIH, Bethesda, MD 20892 USA. [Ward, Yvona] NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.; Liewehr, David J.] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. RP Olivero, OA (reprint author), NCI, ATS, Lab Canc Biol & Genet, Carcinogen DNA Interact Sect,NIH, 37 Convent Dr,MSC 4255,Bldg 37,Rm 4032, Bethesda, MD 20892 USA. EM oliveroo@dc37a.nci.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (CCR) FX Grant sponsors: Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (CCR). NR 33 TC 1 Z9 1 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD DEC PY 2014 VL 55 IS 9 BP 719 EP 726 DI 10.1002/em.21889 PG 8 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AT9UX UT WOS:000345272900004 PM 25073973 ER PT J AU Tsai, SYA Pokrass, MJ Klauer, NR De Credico, NE Su, TP AF Tsai, Shang-Yi A. Pokrass, Michael J. Klauer, Neal R. De Credico, Nicole E. Su, Tsung-Ping TI Sigma-1 receptor chaperones in neurodegenerative and psychiatric disorders SO EXPERT OPINION ON THERAPEUTIC TARGETS LA English DT Review DE Alzheimer's disease; amyotrophic lateral sclerosis; frontotemporal lobar degeneration; HIV-associated neurodementia; neurodegenerative diseases; Parkinson's disease; psychiatric disorders; sigma-1 receptor ID AMYOTROPHIC-LATERAL-SCLEROSIS; POSITRON-EMISSION-TOMOGRAPHY; CENTRAL-NERVOUS-SYSTEM; PROTEIN-KINASE-C; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; PC12 CELLS; NEUROPSYCHIATRIC DISORDERS; COGNITIVE IMPAIRMENT; NEURITE OUTGROWTH AB Introduction: Sigma-1 receptors (Sig-1Rs) are molecular chaperones that reside mainly in the endoplasmic reticulum (ER) but exist also in the proximity of the plasma membrane. Sig-1Rs are highly expressed in the CNS and are involved in many cellular processes including cell differentiation, neuritogenesis, microglia activation, protein quality control, calcium-mediated ER stress and ion channel modulation. Disturbance in any of the above cellular processes can accelerate the progression of many neurological disorders; therefore, the Sig-1R has been implicated in several neurological diseases. Areas covered: This review broadly covers the functions of Sig-1Rs including several neurodegenerative disorders in humans and drug addiction-associated neurological disturbance in the case of HIV infection. We discuss how several Sig-1R ligands could be utilized in therapeutic approaches to treat those disorders. Expert opinion: Emerging understanding of the cellular functions of this unique transmembrane chaperone may lead to the use of new agents or broaden the use of certain available ligands as therapeutic targets in those neurological disorders. C1 [Tsai, Shang-Yi A.; Pokrass, Michael J.; Su, Tsung-Ping] NIDA, NIH, Cellular Pathobiol Sect, Integral Neurosci Branch, Baltimore, MD 21224 USA. [Klauer, Neal R.] Univ Minnesota, Sch Med, Minneapolis, MN 55414 USA. [De Credico, Nicole E.] Rutgers, New Jersey Med Sch, Newark, NJ 07103 USA. RP Tsai, SYA (reprint author), NIDA, NIH, Cellular Pathobiol Sect, Integral Neurosci Branch, Baltimore, MD 21224 USA. EM stsai@intra.nida.nih.gov FU Intramural research program NIDA, NIH/DHHS FX The authors were supported by the Intramural research program NIDA, NIH/DHHS. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 117 TC 17 Z9 17 U1 2 U2 13 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1472-8222 EI 1744-7631 J9 EXPERT OPIN THER TAR JI Expert Opin. Ther. Targets PD DEC PY 2014 VL 18 IS 12 BP 1461 EP 1476 DI 10.1517/14728222.2014.972939 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AT8WC UT WOS:000345208800010 PM 25331742 ER PT J AU Waldmann, TA AF Waldmann, Thomas A. TI Interleukin-15 in the treatment of cancer SO EXPERT REVIEW OF CLINICAL IMMUNOLOGY LA English DT Review DE CD40; c IL-2; IL-2; IL-15R; IL-15; IL-15 receptor; malignant melanoma; renal cell cancer ID CD8(+) T-CELLS; NATURAL-KILLER-CELLS; RECEPTOR-ALPHA-CHAIN; MARROW-DERIVED CELLS; IN-VIVO; ANTITUMOR-ACTIVITY; TRANS-PRESENTATION; NK CELLS; SOLUBLE IL-15R-ALPHA; SIGNAL-TRANSDUCTION AB IL-15 is a 14-15 kDa member of the four -helix bundle of cytokines that acts through a heterotrimeric receptor involving IL-2/IL-15R , c and the IL-15 specific receptor subunit IL-15R . IL-15 stimulates the proliferation of T, B and NK cells, and induces stem, central and effector memory CD8 T cells. In rhesus macaques, continuous infusion of recombinant human IL-15 at 20 g/kg/day was associated with approximately a 10-fold increase in the numbers of circulating NK, / cells and monocytes, and an 80- to 100-fold increase in the numbers of effector memory CD8 T cells. IL-15 has shown efficacy in murine models of malignancy. Clinical trials involving recombinant human IL-15 given by bolus infusions have been completed and by subcutaneous and continuous intravenous infusions are underway in patients with metastatic malignancy. Furthermore, clinical trials are being initiated that employ the combination of IL-15 with IL-15R (+/-) IgFc. C1 NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Waldmann, TA (reprint author), NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,Room 4N115, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 98 TC 15 Z9 17 U1 1 U2 16 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1744-666X EI 1744-8409 J9 EXPERT REV CLIN IMMU JI Expert Rev. Clin. Immunol. PD DEC PY 2014 VL 10 IS 12 BP 1689 EP 1701 DI 10.1586/1744666X.2014.973856 PG 13 WC Immunology SC Immunology GA AU0QC UT WOS:000345327500013 PM 25359408 ER PT J AU Menko, FH Maher, ER Schmidt, LS Middelton, LA Aittomaki, K Tomlinson, I Richard, S Linehan, WM AF Menko, Fred H. Maher, Eamonn R. Schmidt, Laura S. Middelton, Lindsay A. Aittomaki, Kristiina Tomlinson, Ian Richard, Stephane Linehan, W. Marston TI Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment SO FAMILIAL CANCER LA English DT Article DE Hereditary leiomyomatosis and renal cell cancer; Fumarate hydratase; Type 2 papillary renal cell cancer; Tricarboxylic acid cycle; Surveillance; Nephrectomy; Targeted therapy ID FUMARATE-HYDRATASE GENE; PARENCHYMAL SPARING SURGERY; KIDNEY CANCER; UTERINE FIBROIDS; GERMLINE MUTATIONS; MISSENSE MUTATION; AGGRESSIVE FORM; TUMOR SYNDROME; FH MUTATIONS; CARCINOMA AB Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant condition in which susceptible individuals are at risk for the development of cutaneous leiomyomas, early onset multiple uterine leiomyomas and an aggressive form of type 2 papillary renal cell cancer. HLRCC is caused by germline mutations in the fumarate hydratase (FH) gene which inactivate the enzyme and alters the function of the tricarboxylic acid (Krebs) cycle. Issues surrounding surveillance and treatment for HLRCC-associated renal cell cancer were considered as part of a recent international symposium on HLRCC. The management protocol proposed in this article is based on a literature review and a consensus meeting. The lifetime renal cancer risk for FH mutation carriers is estimated to be 15 %. In view of the potential for early onset of RCC in HLRCC, periodic renal imaging and, when available, predictive testing for a FH mutation is recommended from 8 to 10 years of age. However, the small risk of renal cell cancer in the 10-20 years age range and the potential drawbacks of screening should be carefully discussed on an individual basis. Surveillance preferably consists of annual abdominal MRI. Treatment of renal tumours should be prompt and generally consist of wide-margin surgical excision and consideration of retroperitoneal lymph node dissection. The choice for systemic treatment in metastatic disease should, if possible, be part of a clinical trial. Screening procedures in HLRCC families should preferably be evaluated in large cohorts of families. C1 [Menko, Fred H.] Netherlands Canc Inst, Amsterdam, Netherlands. [Maher, Eamonn R.] Univ Cambridge, Dept Med Genet, Cambridge, England. [Schmidt, Laura S.] Frederick Natl Lab Canc Res, Basic Sci Program, Leidos Biomed Res Inc, Frederick, MD USA. [Schmidt, Laura S.; Middelton, Lindsay A.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Aittomaki, Kristiina] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Aittomaki, Kristiina] Helsinki Univ Cent Hosp HUSLAB, Helsinki, Finland. [Tomlinson, Ian] Univ Oxford, Mol & Populat Genet Lab, Oxford, England. [Tomlinson, Ian] Univ Oxford, Natl Inst Hlth Res Biomed Res Ctr, Wellcome Trust Ctr Human Genet, Oxford, England. [Richard, Stephane] Hop Bicetre, AP HP, Serv Urol, Ctr Expert Natl Canc Rares PREDIR, Le Kremlin Bicetre, France. [Richard, Stephane] Fac Med Paris Sud, INSERM U753, Genet Oncol EPHE, Villejuif, France. [Richard, Stephane] Inst Cancerol Gustave Roussy, Villejuif, France. RP Menko, FH (reprint author), Netherlands Canc Inst, Amsterdam, Netherlands. EM f.menko@nki.nl RI MAHER, EAMONN/A-9507-2008 OI MAHER, EAMONN/0000-0002-6226-6918 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research; Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E]; Wellcome Trust Centre for Human Genetics [090532/Z/09/Z]; French National Cancer Institute (INCa); French Department of Health FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research. This project has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001E. 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. The research was also supported by the Wellcome Trust Centre for Human Genetics, Grant Reference 090532/Z/09/Z. The Centre Expert National Cancers Rares PREDIR (S. Richard) is supported by grants from the French National Cancer Institute (INCa) and the French Department of Health. NR 53 TC 19 Z9 20 U1 1 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9600 EI 1573-7292 J9 FAM CANCER JI Fam. Cancer PD DEC PY 2014 VL 13 IS 4 BP 637 EP 644 DI 10.1007/s10689-014-9735-2 PG 8 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA AT7CG UT WOS:000345093500015 PM 25012257 ER PT J AU Xu, CF Yan, M Sun, Y Joo, J Wan, XY Yu, CH Wang, QY Shen, C Chen, P Li, YM Coleman, WG AF Xu, Chengfu Yan, Ming Sun, Yan Joo, Jungsoo Wan, Xingyong Yu, Chaohui Wang, Qunyan Shen, Chao Chen, Peng Li, Youming Coleman, William G., Jr. TI Prevalence of Helicobacter pylori Infection and its Relation with Body Mass Index in a Chinese Population SO HELICOBACTER LA English DT Article DE Helicobacter pylori; prevalence; body mass index ID FATTY LIVER-DISEASE; PEPTIC-ULCER DISEASE; MORBID-OBESITY; INSULIN-RESISTANCE; RISK-FACTORS; BREATH TEST; ERADICATION; GHRELIN; ASSOCIATION; MANIFESTATIONS AB BackgroundHelicobacter pylori infection is highly prevalent worldwide. The association between obesity and H.pylori infection is controversial in the literature. This study aims to investigate the prevalence of H.pylori infection and its relation with body mass index (BMI) in a Chinese population. Materials and methodsA cross-sectional study was performed among adults who underwent health checkups at the First Affiliated Hospital, College of Medicine, Zhejiang University in 2013. The prevalence of H.pylori infection was examined by C-13 urea breath tests, and the association between prevalence of H.pylori infection and BMI was analyzed. ResultsOf the 8820 participants enrolled, 3859 (43.8%) were positive for H.pylori infection. H.pylori-positive participants had a more unfavorable metabolic profile than H.pylori-negative participants. Overweight/obese participants showed a higher prevalence of H.pylori infection than that of lean participants, and a positive linear correlation between BMI and prevalence of H.pylori infection was observed. Both unadjusted and adjusted analysis revealed that BMI was significantly associated with risk factors of H.pylori infection. ConclusionsOur results showed that BMI was significantly and positively associated with H.pylori infection, and a high BMI was associated with an increased risk of the infection. C1 [Xu, Chengfu; Wan, Xingyong; Yu, Chaohui; Wang, Qunyan; Li, Youming] Zhejiang Univ, Affiliated Hosp 1, Dept Gastroenterol, Coll Med, Hangzhou 310003, Zhejiang, Peoples R China. [Xu, Chengfu; Yan, Ming; Sun, Yan; Joo, Jungsoo; Coleman, William G., Jr.] Natl Inst Minor Hlth & Hlth Dispar, Canc Cluster, NIH, Bethesda, MD USA. [Xu, Chengfu; Yan, Ming; Sun, Yan; Joo, Jungsoo] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD USA. [Shen, Chao; Chen, Peng] Zhejiang Univ, Affiliated Hosp 1, Coll Med, Int Hlth Care Ctr, Hangzhou 310003, Zhejiang, Peoples R China. RP Li, YM (reprint author), Zhejiang Univ, Affiliated Hosp 1, Dept Gastroenterol, Coll Med, 79 Qingchun Rd, Hangzhou 310003, Zhejiang, Peoples R China. EM xiaofu@zju.edu.cn; wcoleman@helix.nih.gov FU National Institutes of Health, National Institute on Minority Health and Health Disparities, National Institute of Diabetes and Digestive and Kidney Disease; National Natural Science Foundation of China [81100278, 81170378, 81230012, 81270487]; International Science and Technology Cooperation Projects of Zhejiang Province [2013C24010]; Science Foundation of Health Bureau of Zhejiang Province [2012RCA026] FX This study was supported by Intramural Research Program of the National Institutes of Health, National Institute on Minority Health and Health Disparities, National Institute of Diabetes and Digestive and Kidney Disease; National Natural Science Foundation of China (Nos. 81100278, 81170378, 81230012, and 81270487); International Science and Technology Cooperation Projects of Zhejiang Province (No.2013C24010); and Science Foundation of Health Bureau of Zhejiang Province (No.2012RCA026). The authors thank Dr. Hanqing He for his assistance in statistical analysis. NR 41 TC 11 Z9 11 U1 1 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1083-4389 EI 1523-5378 J9 HELICOBACTER JI Helicobacter PD DEC PY 2014 VL 19 IS 6 BP 437 EP 442 DI 10.1111/hel.12153 PG 6 WC Gastroenterology & Hepatology; Microbiology SC Gastroenterology & Hepatology; Microbiology GA AU0IC UT WOS:000345305700004 PM 25256639 ER PT J AU Scuteri, A Morrell, CH Orru, M Strait, JB Tarasov, KV Ferreli, LAP Loi, F Pilia, MG Delitala, A Spurgeon, H Najjar, SS AlGhatrif, M Lakatta, EG AF Scuteri, Angelo Morrell, Christopher H. Orru, Marco Strait, James B. Tarasov, Kirill V. Ferreli, Liana Anna Pina Loi, Francesco Pilia, Maria Grazia Delitala, Alessandro Spurgeon, Harold Najjar, Samer S. AlGhatrif, Majd Lakatta, Edward G. TI Longitudinal Perspective on the Conundrum of Central Arterial Stiffness, Blood Pressure, and Aging SO HYPERTENSION LA English DT Article DE aging; arteries; blood pressure; longitudinal studies; pulse wave analysis; sex ID PULSE-WAVE VELOCITY; AORTIC STIFFNESS; SYSTOLIC HYPERTENSION; CARDIOVASCULAR EVENTS; INDEPENDENT PREDICTOR; INCIDENT HYPERTENSION; HEALTHY-MEN; AGE; PROGRESSION; DIAMETER AB The age-associated increase in arterial stiffness has long been considered to parallel or to cause the age-associated increase in blood pressure (BP). Yet, the rates at which pulse wave velocity (PWV), a measure of arterial stiffness, and BP trajectories change over time within individuals who differ by age and sex have not been assessed and compared. This study determined the evolution of BP and aortic PWV trajectories during a 9.4-year follow-up in >4000 community-dwelling men and women of 20 to 100 years of age at entry into the SardiNIA Study. Linear mixed effects model analyses revealed that PWV accelerates with time during the observation period, at about the same rate over the entire age range in both men and women. In men, the longitudinal rate at which BP changed over time, however, did not generally parallel that of PWV acceleration: at ages >40 years the rates of change in systolic BP (SBP) and pulse pressure (PP) increase plateaued and then declined so that SBP, itself, also declined at older ages, whereas PP plateaued. In women, SBP, diastolic BP, and mean BP increased at constant rates across all ages, producing an increasing rate of increase in PP. Therefore, increased aortic stiffness is implicated in the age-associated increase in SBP and PP. These findings indicate that PWV is not a surrogate for BP and that arterial properties other than arterial wall stiffness that vary by age and sex also modulate the BP trajectories during aging and lead to the dissociation of PWV, PP, and SBP trajectories in men. C1 [Scuteri, Angelo] Hosp San Raffaele Pisana, IRCCS, Rome, Italy. [Morrell, Christopher H.; Strait, James B.; Tarasov, Kirill V.; Spurgeon, Harold; Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, Baltimore, MD 21224 USA. [Morrell, Christopher H.] Loyola Univ Maryland, Baltimore, MD USA. [Orru, Marco; Ferreli, Liana Anna Pina; Loi, Francesco; Pilia, Maria Grazia; Delitala, Alessandro] Cittadella Univ Monserrato, Consiglio Nazl Ric, IRGB, Cagliari, Italy. [AlGhatrif, Majd] Johns Hopkins Sch Med, Baltimore, MD USA. [Najjar, Samer S.] MedStar Heart Inst, Washington, DC USA. RP Lakatta, EG (reprint author), Biomed Res Ctr, Lab Cardiovasc Sci, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM lakattae@grc.nia.nih.gov RI Delitala, Alessandro/L-3194-2016 OI Delitala, Alessandro/0000-0003-1729-8969 FU National Institute on Aging (NIA) [NO1-AG-1-2109]; Intramural Research Program of the National Institutes of Health, NIA (USA) FX The SardiNIA team was supported by Contract NO1-AG-1-2109 from the National Institute on Aging (NIA). This research was supported in part by the Intramural Research Program of the National Institutes of Health, NIA (USA). NR 37 TC 26 Z9 26 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD DEC PY 2014 VL 64 IS 6 BP 1219 EP U150 DI 10.1161/HYPERTENSIONAHA.114.04127 PG 40 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AT7PL UT WOS:000345129900019 PM 25225210 ER PT J AU Monfredi, O Lyashkov, AE Johnsen, AB Inada, S Schneider, H Wang, RX Nirmalan, M Wisloff, U Maltsev, VA Lakatta, EG Zhang, HG Boyett, MR AF Monfredi, Oliver Lyashkov, Alexey E. Johnsen, Anne-Berit Inada, Shin Schneider, Heiko Wang, Ruoxi Nirmalan, Mahesh Wisloff, Ulrik Maltsev, Victor A. Lakatta, Edward G. Zhang, Henggui Boyett, Mark R. TI Biophysical Characterization of the Underappreciated and Important Relationship Between Heart Rate Variability and Heart Rate SO HYPERTENSION LA English DT Article DE autonomic nervous system; ion channels; physiology; sinoatrial node ID SINOATRIAL NODE; CARDIOVASCULAR CONTROL; MYOCARDIAL-INFARCTION; PACEMAKER ACTIVITY; SPECTRAL-ANALYSIS; CELLS; MORTALITY; HUMANS; RISK; MICE AB Heart rate (HR) variability (HRV; beat-to-beat changes in the R-wave to R-wave interval) has attracted considerable attention during the past 30+ years (PubMed currently lists >17 000 publications). Clinically, a decrease in HRV is correlated to higher morbidity and mortality in diverse conditions, from heart disease to fetal distress. It is usually attributed to fluctuation in cardiac autonomic nerve activity. We calculated HRV parameters from a variety of cardiac preparations (including humans, living animals, Langendorff-perfused heart, and single sinoatrial nodal cell) in diverse species, combining this with data from previously published articles. We show that regardless of conditions, there is a universal exponential decay-like relationship between HRV and HR. Using 2 biophysical models, we develop a theory for this and confirm that HRV is primarily dependent on HR and cannot be used in any simple way to assess autonomic nerve activity to the heart. We suggest that the correlation between a change in HRV and altered morbidity and mortality is substantially attributable to the concurrent change in HR. This calls for re-evaluation of the findings from many articles that have not adjusted properly or at all for HR differences when comparing HRV in multiple circumstances. C1 [Monfredi, Oliver; Schneider, Heiko; Nirmalan, Mahesh; Boyett, Mark R.] Univ Manchester, Inst Cardiovasc Sci, Manchester M13 9NT, Lancs, England. [Monfredi, Oliver; Lyashkov, Alexey E.; Maltsev, Victor A.; Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Johnsen, Anne-Berit; Wisloff, Ulrik] Norwegian Univ Sci & Technol, KG Jebsen Ctr Exercise Med, Dept Circulat & Med Imaging, N-7034 Trondheim, Norway. [Inada, Shin] Natl Cerebral & Cardiovasc Ctr, Lab Biomed Sci & Informat Management, Osaka, Japan. [Wang, Ruoxi; Zhang, Henggui] Univ Manchester, Biol Phys Grp, Manchester, Lancs, England. RP Monfredi, O (reprint author), Univ Manchester, Core Technol Facil, Inst Cardiovasc Sci, 46 Grafton St, Manchester M13 9NT, Lancs, England. EM oliver.monfredi@manchester.ac.uk OI Boyett, Mark/0000-0003-3931-2020; Monfredi, Oliver/0000-0003-1292-2902; Wisloff, Ulrik/0000-0002-7211-3587 FU British Cardiovascular Society; British Heart Foundation [RG/11/18/29257]; Intramural Research Program of the National Institutes of Health, National Institute on Aging; Engineering and Physical Science Research Council UK [EP/J00958X/1, EP/I029826/1]; K.G. Jebson Foundation FX Grants were received from British Cardiovascular Society (O. Monfredi) and British Heart Foundation (RG/11/18/29257) (M. R. Boyett). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. Other grants were received from the Engineering and Physical Science Research Council UK (EP/J00958X/1; EP/I029826/1) (H. Zhang) and the K.G. Jebson Foundation (A.-B. Johnsen and U. Wisloff). NR 50 TC 40 Z9 41 U1 0 U2 18 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 DEC PY 2014 VL 64 IS 6 BP 1334 EP U386 DI 10.1161/HYPERTENSIONAHA.114.03782 PG 26 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AT7PL UT WOS:000345129900034 PM 25225208 ER PT J AU Abraham, NG Sodhi, K Silvis, AM Vanella, L Favero, G Rezzani, R Lee, C Zeldin, DC Schwartzman, ML AF Abraham, Nader G. Sodhi, Komal Silvis, Anne M. Vanella, Luca Favero, Gaia Rezzani, Rita Lee, Craig Zeldin, Darryl C. Schwartzman, Michal L. TI CYP2J2 Targeting to Endothelial Cells Attenuates Adiposity and Vascular Dysfunction in Mice Fed a High-Fat Diet by Reprogramming Adipocyte Phenotype SO HYPERTENSION LA English DT Article DE 11,12-EET; AMP-activated protein kinases; aP2 protein, human; eNOS protein, rat; heme oxygenase-1; mesoderm-specific transcript protein ID IMPROVES INSULIN SENSITIVITY; EPOXYGENASE-DERIVED EICOSANOIDS; INCREASES ADIPONECTIN LEVELS; INDUCED RENAL INJURY; HEME OXYGENASE-1; OBESE MICE; 11,12-EPOXYEICOSATRIENOIC ACID; EPOXYEICOSATRIENOIC ACIDS; METABOLIC SYNDROME; VISCERAL OBESITY AB Obesity is a global epidemic and a common risk factor for endothelial dysfunction and the subsequent development of diabetes mellitus and vascular diseases such as hypertension. Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP)-derived metabolites of arachidonic acid that contribute to vascular protection by stimulating vasodilation and inhibiting inflammation. Heme oxygenase-1 is a stress response protein that plays an important cytoprotective role against oxidative insult in diabetes mellitus and cardiovascular disease. We recently demonstrated interplay between EETs and heme oxygenase-1 in the attenuation of adipogenesis. We examined whether adipocyte dysfunction in mice fed a high-fat diet could be prevented by endothelial-specific targeting of the human CYP epoxygenase, CYP2J2. Tie2-CYP2J2 transgenic mice, fed a high-fat diet, had a reduction in body weight gain, blood glucose, insulin levels, and inflammatory markers. Tie2-CYP2J2 gene targeting restored HF-mediated decreases in vascular heme oxygenase-1, Cyp2C44, soluble epoxide hydrolase, phosphorylated endothelial nitric oxide synthase, phosphorylated protein kinase B, and phosphorylated adenosine monophosphate protein kinase protein expression, thus improving vascular function. These changes translated into decreased inflammation and oxidative stress within adipose tissue and decreased peroxisome proliferator-activated receptor-gamma, CCAAT/enhancer binding protein alpha, mesoderm-specific transcript, and adipocyte 2 expression and increased uncoupling protein 1 and uncoupling protein 2 expression, reflecting the effect of vascular EET overproduction on adipogenesis. The current study documents a direct link between endothelial-specific EET production and adipogenesis, further implicating the EET-heme oxygenase-1 crosstalk as an important cytoprotective mechanism in the amelioration of vascular and adipocyte dysfunction resulting from diet-induced obesity. C1 [Abraham, Nader G.; Schwartzman, Michal L.] New York Med Coll, Dept Med, Valhalla, NY 10595 USA. [Abraham, Nader G.; Schwartzman, Michal L.] New York Med Coll, Dept Pharmacol, Valhalla, NY 10595 USA. [Sodhi, Komal; Silvis, Anne M.] Marshall Univ, Joan C Edwards Sch Med, Dept Med, Huntington, WV USA. [Sodhi, Komal; Silvis, Anne M.] Marshall Univ, Joan C Edwards Sch Med, Dept Obstet & Gynecol, Huntington, WV USA. [Vanella, Luca] Univ Catania, Dept Drug Sci, Biochem Sect, Catania, Italy. [Vanella, Luca] Univ Catania, Dept Drug Sci, Med Chem Sect, Catania, Italy. [Favero, Gaia; Rezzani, Rita] Univ Brescia, Dept Clin & Expt Sci, Div Anat & Physiopathol, Brescia, Italy. [Lee, Craig; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Abraham, NG (reprint author), New York Med Coll, Dept Med, Valhalla, NY 10595 USA. EM nader_abraham@nymc.edu RI Vanella, Luca/J-7354-2016; OI Vanella, Luca/0000-0002-6314-6029; Favero, Gaia/0000-0001-6895-7106; Lee, Craig/0000-0003-3595-5301 FU National Institutes of Health (NIH) [HL55601, HL34300]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES025034] FX This work was supported by National Institutes of Health (NIH) grants HL55601 (N.G. Abraham) and HL34300 (M. L. Schwartzman). This work was also supported, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES025034 to D.C. Zeldin). NR 58 TC 20 Z9 20 U1 1 U2 5 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 DEC PY 2014 VL 64 IS 6 BP 1352 EP U413 DI 10.1161/HYPERTENSIONAHA.114.03884 PG 17 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AT7PL UT WOS:000345129900036 PM 25245389 ER PT J AU Yeung, EH Liu, AY Mills, JL Zhang, CL Mannisto, T Lu, ZH Tsai, MY Mendola, P AF Yeung, Edwina H. Liu, Aiyi Mills, James L. Zhang, Cuilin Mannisto, Tuija Lu, Zhaohui Tsai, Michael Y. Mendola, Pauline TI Increased Levels of Copeptin Before Clinical Diagnosis of Preelcampsia SO HYPERTENSION LA English DT Article DE copeptin, human; diabetes, gestational; hypertension, pregnancy-induced; preeclampsia ID HEALTHY NULLIPAROUS WOMEN; PLACENTAL GROWTH-FACTOR; TYROSINE KINASE 1; ARGININE-VASOPRESSIN; SOLUBLE ENDOGLIN; NORMAL-PREGNANCY; RISK-FACTORS; PREECLAMPSIA; RECEPTORS; RATS AB Copeptin, a surrogate biomarker of vasopressin, has been associated with renal function decline and may serve as a useful early biomarker for preeclampsia. We measured serum copeptin using samples collected longitudinally during pregnancy among unaffected controls (n=136) and cases of preeclampsia (n=169), gestational diabetes mellitus (n=92), gestational hypertension (n=101), and preterm birth (n=86) in the Calcium for Preeclampsia Prevention trial (1992-1995). Preeclampsia and gestational hypertension were defined as having a diastolic blood pressure >= 90 mm Hg on 2 occasions with and without proteinuria, respectively. The risk of pregnancy complications associated with copeptin was estimated by logistic regression adjusting for maternal age, race, body mass index, insurance status, marital status, current smoking, and clinical site. Baseline copeptin levels, at mean 16 weeks of gestation, were associated with increased preeclampsia risk (adjusted odds ratios and 95% confidence interval being 1.55 per log unit; 1.03-2.31) when compared with controls (P=0.03). The association was stronger among cases diagnosed before 37 weeks (1.86; 1.08-3.20) than those diagnosed later (1.45; 0.91-2.32). Copeptin levels rose with increasing gestational age in both cases and controls but remained significantly higher among those who were diagnosed with preeclampsia. Differences in levels of copeptin between cases and controls became more apparent closer to time of diagnosis. No significant associations were found for gestational hypertension without proteinuria, gestational diabetes mellitus, or preterm birth without preeclampsia. Copeptin levels are elevated in pregnant women before diagnosis of preeclampsia with elevation specific to this pregnancy complication rather than hypertension alone. C1 [Yeung, Edwina H.; Mills, James L.; Zhang, Cuilin; Mannisto, Tuija; Mendola, Pauline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. [Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. [Lu, Zhaohui] Glotech Inc, Rockville, MD USA. [Tsai, Michael Y.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. RP Yeung, EH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, 6100 Execut Blvd,7B03, Bethesda, MD 20892 USA. EM yeungedw@mail.nih.gov RI Yeung, Edwina/F-5992-2015; OI Yeung, Edwina/0000-0002-3851-2613; Mannisto, Tuija/0000-0002-6382-9153; Mendola, Pauline/0000-0001-5330-2844; Liu, Aiyi/0000-0002-6618-5082 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health; National Institute of Child Health and Human Development [N01-HD-1-3121, N01-HD-1-3122, N01-HD-1-3123, N01-HD-1-3124, N01-HD-1-3125, N01-HD-1-3126, N01-HD-3154, N01-HD-5-3246, HHSN275201100002I-HHSN27500003]; National Heart, Lung, and Blood Institute FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health. The Calcium for Preeclampsia Prevention trial was supported by contracts (N01-HD-1-3121, -3122, -3123, -3124, -3125, and -3126; N01-HD-3154; and N01-HD-5-3246) with the National Institute of Child Health and Human Development, with cofunding from the National Heart, Lung, and Blood Institute. Recent biomarker assays including for copeptin was supported by contract (HHSN275201100002I-HHSN27500003) with the National Institute of Child Health and Human Development. NR 42 TC 18 Z9 18 U1 1 U2 5 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 DEC PY 2014 VL 64 IS 6 BP 1362 EP U424 DI 10.1161/HYPERTENSIONAHA.114.03762 PG 10 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AT7PL UT WOS:000345129900037 PM 25225209 ER PT J AU Panackal, AA Dekker, JP Proschan, M Beri, A Williamson, PR AF Panackal, Anil A. Dekker, John P. Proschan, Michael Beri, Andrea Williamson, Peter R. TI Enzyme Immunoassay versus Latex Agglutination Cryptococcal Antigen Assays in Adults with Non-HIV-Related Cryptococcosis SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article AB We compared paired enzyme immunoassay (EIA) and latex agglutination (LA) assay results with 185 blood and 164 cerebrospinal fluid (CSF) samples from 44 and 33 non-HIV cryptococcosis patients, respectively. The LA assay cutoff of 1: 256 in the blood and 1: 32 in the CSF was most highly predictive of a positive EIA result. The EIA missed 18.4% detected by the LA assay in the blood samples and 7.8% detected by the LA assay in the CSF samples. We note here the improved sensitivity of the LA assay over the EIA in non-HIV patients. C1 [Panackal, Anil A.; Williamson, Peter R.] NIAID, Translat Mycol Unit, Lab Clin Infect Dis, Div Intramural Res,NIH, Bethesda, MD 20892 USA. [Panackal, Anil A.] Uniformed Serv Univ Hlth Sci, Dept Med, Div Infect Dis, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. [Dekker, John P.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Proschan, Michael] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Beri, Andrea] NIH, Lab Informat Dev, Biomed Translat Res Informat Syst, Ctr Clin, Bethesda, MD 20892 USA. RP Panackal, AA (reprint author), NIAID, Translat Mycol Unit, Lab Clin Infect Dis, Div Intramural Res,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM anil.panackal@nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH) FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH). NR 3 TC 1 Z9 2 U1 0 U2 3 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 DEC PY 2014 VL 52 IS 12 BP 4356 EP 4358 DI 10.1128/JCM.02017-14 PG 3 WC Microbiology SC Microbiology GA AT9BM UT WOS:000345222900038 PM 25253799 ER PT J AU Sue, PK Gurda, GT Lee, R Watkins, T Green, R Memon, W Milstone, AM Zelazny, AM Fahle, GA Pham, TA Gibas, CF Sutton, DA Wickes, BL Wiederhold, NP Zhang, SX AF Sue, Paul K. Gurda, Grzegorz T. Lee, Richard Watkins, Tonya Green, Rachel Memon, Warda Milstone, Aaron M. Zelazny, Adrian M. Fahle, Gary A. Thu Anh Pham Gibas, Connie F. Sutton, Deanna A. Wickes, Brian L. Wiederhold, Nathan P. Zhang, Sean X. TI First Report of Westerdykella dispersa as a Cause of an Angioinvasive Fungal Infection in a Neutropenic Host SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID LEUKEMIA AB Angioinvasive fungal infections (AFIs) are an important cause of morbidity and mortality among immunocompromised patients. However, clinicomicrobiological characteristics and treatment of many AFI agents remain poorly defined. We report the first human case of infection with Westerdykella dispersa, an emergent cause of AFI, which was successfully treated in a neutropenic pediatric patient. C1 [Sue, Paul K.; Milstone, Aaron M.] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Pediat Infect Dis, Baltimore, MD 21205 USA. [Gurda, Grzegorz T.; Watkins, Tonya; Zhang, Sean X.] Johns Hopkins Univ, Sch Med, Dept Pathol, Div Microbiol, Baltimore, MD 21205 USA. [Lee, Richard; Green, Rachel; Memon, Warda; Zhang, Sean X.] Johns Hopkins Univ Hosp, Microbiol Lab, Baltimore, MD 21287 USA. [Zelazny, Adrian M.; Fahle, Gary A.] NIH, Microbiol Serv, Dept Lab Med, Bethesda, MD 20892 USA. [Thu Anh Pham] NIH, Mol Diagnost Unit, Pathol Lab, Bethesda, MD 20892 USA. [Gibas, Connie F.] Univ Alberta Microfungus Collect & Herbarium, Edmonton, AB, Canada. [Sutton, Deanna A.; Wickes, Brian L.; Wiederhold, Nathan P.] Univ Texas Hlth Sci Ctr San Antonio, Fungus Testing Lab, San Antonio, TX 78229 USA. RP Zhang, SX (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Div Microbiol, Baltimore, MD 21205 USA. EM szhang28@jhmi.edu OI Wiederhold, Nathan/0000-0002-2225-5122 NR 12 TC 1 Z9 1 U1 1 U2 2 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 DEC PY 2014 VL 52 IS 12 BP 4407 EP 4411 DI 10.1128/JCM.02012-14 PG 5 WC Microbiology SC Microbiology GA AT9BM UT WOS:000345222900054 PM 25232159 ER PT J AU Lau, AF Wang, HH Weingarten, RA Drake, SK Suffredini, AF 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. Chen, Yong Gucek, Marjan Youn, Jung-Ho Stock, Frida Tso, Hanna Deleo, Jim Cimino, James J. Frank, Karen M. Dekker, John P. TI Reply to "Tn4401 Carrying bla(KPC) Is Inserted within Another Insertion in pKpQIL and Related Plasmids" SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Letter 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. [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 OI Cimino, James/0000-0003-4101-1622 NR 3 TC 1 Z9 1 U1 0 U2 0 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 DEC PY 2014 VL 52 IS 12 BP 4450 EP 4450 DI 10.1128/JCM.02614-14 PG 1 WC Microbiology SC Microbiology GA AT9BM UT WOS:000345222900071 PM 25398999 ER PT J AU Tu, TW Turtzo, LC Williams, RA Lescher, JD Dean, DD Frank, JA AF Tu, Tsang-Wei Turtzo, L. Christine Williams, Rashida A. Lescher, Jacob D. Dean, Dana D. Frank, Joseph A. TI Imaging of Spontaneous Ventriculomegaly and Vascular Malformations in Wistar Rats: Implications for Preclinical Research SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE Arteriovenous malformation; Diffusion tensor MRI; Hydrocephalus; MR angiography; Ventriculomegaly; Wistar rats ID WHITE-MATTER INTEGRITY; SPINAL-CORD-INJURY; BLOOD-FLOW; NEONATAL HYDROCEPHALUS; INTRACEREBRAL HEMORRHAGE; CONGENITAL HYDROCEPHALUS; INTRACRANIAL-PRESSURE; REACTIVE ASTROCYTOSIS; OPTIC-NERVE; DIFFUSION AB Wistar rats are widely used in biomedical research and commonly serve as a model organism in neuroscience studies. In most cases when noninvasive imaging is not used, studies assume a consistent baseline condition in rats that lack visible differences. While performing a series of traumatic brain injury studies, we discovered mild spontaneous ventriculomegaly in 70 (43.2%) of 162 Wistar rats that had been obtained from 2 different vendors. Advanced magnetic resonance (MR) imaging techniques, including MR angiography and diffusion tensor imaging, were used to evaluate the rats. Multiple neuropathologic abnormalities, including presumed arteriovenous malformations, aneurysms, cysts, white matter lesions, and astrogliosis were found in association with ventriculomegaly. Postmortem microcomputed tomography and immunohistochemical staining confirmed the presence of aneurysms and arteriovenous malformations. Diffusion tensor imaging showed significant decreases in fractional anisotropy and increases in mean diffusivity, axial diffusivity, and radial diffusivity in multiple white matter tracts (p < 0.05). These results could impact the interpretation, for example, of a pseudo-increase of axon integrity and a pseudo-decrease of myelin integrity, based on characteristics intrinsic to rats with ventriculomegaly. We suggest the use of baseline imaging to prevent the inadvertent introduction of a high degree of variability in preclinical studies of neurologic disease or injury in Wistar rats. C1 [Tu, Tsang-Wei; Turtzo, L. Christine; Williams, Rashida A.; Lescher, Jacob D.; Frank, Joseph A.] NIH, Frank Lab, Ctr Clin, Bethesda, MD 20892 USA. [Dean, Dana D.] Baylor Univ, Dept Environm Sci, Waco, TX 76798 USA. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Tu, TW (reprint author), NIH, Ctr Clin, Bldg 10,Room B1N256,10 Ctr Dr MSC 1074, Bethesda, MD 20892 USA. EM tut@cc.nih.gov FU Department of Defense through the Center for Neuroscience and Regenerative Medicine (Henry M. Jackson Foundation Award) [300604-8.01-60855, 305500-8.01-60855]; Intramural Research Programs of the Clinical Center; National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health FX This work was supported by funding from the Department of Defense through the Center for Neuroscience and Regenerative Medicine (Henry M. Jackson Foundation Award 300604-8.01-60855 and 305500-8.01-60855) and from the Intramural Research Programs of the Clinical Center and of the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health. NR 53 TC 5 Z9 5 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 DEC PY 2014 VL 73 IS 12 BP 1152 EP 1165 PG 14 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA AU0DQ UT WOS:000345294200007 PM 25383642 ER PT J AU Cheng, J Fang, ZZ Nagaoka, K Okamoto, M Qu, AJ Tanaka, N Kimura, S Gonzalez, FJ AF Cheng, Jie Fang, Zhong-Ze Nagaoka, Kenjiro Okamoto, Minoru Qu, Aijuan Tanaka, Naoki Kimura, Shioko Gonzalez, Frank J. TI Activation of Intestinal Human Pregnane X Receptor Protects against Azoxymethane/Dextran Sulfate Sodium-Induced Colon Cancer SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; NF-KAPPA-B; COLORECTAL NEOPLASIA; BETA-CATENIN; MOUSE MODEL; CELLS; CARCINOGENESIS; RIFAXIMIN; COLITIS; PROLIFERATION AB The role of intestinal human pregnane X receptor (PXR) in colon cancer was determined through investigation of the chemopreventive role of rifaximin, a specific agonist of intestinal human PXR, toward azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colon cancer. Rifaximin treatment significantly decreased the number of colon tumors induced by AOM/DSS treatment in PXR-humanized mice, but not wild-type or Pxr-null mice. Additionally, rifaximin treatment markedly increased the survival rate of PXR-humanized mice, but not wild-type or Pxr-null mice. These data indicated a human PXR-dependent therapeutic chemoprevention of rifaximin toward AOM/DSS-induced colon cancer. Nuclear factor kappa-light-chain-enhancer of activated B cells-mediated inflammatory signaling was upregulated in AOM/DSS-treated mice, and inhibited by rifaximin in PXR-humanized mice. Cell proliferation and apoptosis were also modulated by rifaximin treatment in the AOM/DSS model. In vitro cell-based assays further revealed that rifaximin regulated cell apoptosis and cell cycle in a human PXR-dependent manner. These results suggested that specific activation of intestinal human PXR exhibited a chemopreventive role toward AOM/DSS-induced colon cancer by mediating anti-inflammation, antiproliferation, and proapoptotic events. C1 [Cheng, Jie; Fang, Zhong-Ze; Nagaoka, Kenjiro; Okamoto, Minoru; Qu, Aijuan; Tanaka, Naoki; Kimura, Shioko; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bldg 37,Room 3106, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov FU Intramural Research Program of the National Institutes of Health [National Cancer Institute] FX This study was supported by the Intramural Research Program of the National Institutes of Health [National Cancer Institute]. NR 24 TC 5 Z9 5 U1 3 U2 7 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 DEC PY 2014 VL 351 IS 3 BP 559 EP 567 DI 10.1124/jpet.114.215913 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AT9AK UT WOS:000345219800009 PM 25277138 ER PT J AU Djamshidian, A O'Sullivan, SS Lawrence, AD Foltynie, T Aviles-Olmos, I Magdalinou, N Tomassini, A Warner, TT Lees, AJ Averbeck, BB AF Djamshidian, Atbin O'Sullivan, Sean S. Lawrence, Andrew D. Foltynie, Thomas Aviles-Olmos, Iciar Magdalinou, Nadia Tomassini, Alessandro Warner, Thomas T. Lees, Andrew J. Averbeck, Bruno B. TI Perceptual decision-making in patients with Parkinson's disease SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Article DE Compulsivity; dopamine; impulse control disorders; impulsivity; Parkinson's disease; decision-making; reaction time ID IMPULSE CONTROL DISORDERS; CHOICE REACTION-TIME; REFLECTION-IMPULSIVITY; DOPAMINE AGONISTS; ADVANCE INFORMATION; MOVEMENT TIME; BEHAVIORS; REWARD; PHASES; TASKS AB Impulsive choice and poor information sampling have been found to be key behavioural mechanisms linked to impulse control disorders (ICDs) in Parkinson's disease (PD). Perceptual decision-making is intimately related to information sampling. Therefore, we wanted to determine whether dopaminergic medication or ICDs influence perceptual decision-making in PD. All participants performed two tasks. One was a simple reaction time task, where subjects needed to respond as quickly as possible. The second was a perceptual decision-making task, in which participants had to estimate whether a stimulus contained either more red or more blue pixels. We tested three groups of patients, one treated with levodopa monotherapy, one additionally treated with dopamine agonists, and a third group had ICDs. Results were compared to healthy controls. We found that all patients made more errors than controls. Further, patients with ICDs responded fastest on the reaction time task and also in incorrect trials on the perceptual decision-making task. Similarly, patients with dopamine agonists responded faster than those on levodopa monotherapy and controls. Our results demonstrate that all patients have deficits in perceptual decision-making. However, patients treated with dopamine agonists closely resembled patients with ICDs. C1 [Djamshidian, Atbin; Magdalinou, Nadia; Warner, Thomas T.; Lees, Andrew J.] UCL, Reta Lila Weston Inst Neurol Studies, London WC1N 1PJ, England. [Djamshidian, Atbin] Med Univ Innsbruck, Dept Neurol, A-6020 Innsbruck, Austria. [O'Sullivan, Sean S.] Natl Univ Ireland Univ Coll Cork, Dept Neurol, Cork, Ireland. [Lawrence, Andrew D.] Cardiff Univ, Sch Psychol, Cardiff CF10 3AX, S Glam, Wales. [Foltynie, Thomas; Aviles-Olmos, Iciar; Tomassini, Alessandro] Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1N 3BG, England. [Averbeck, Bruno B.] NIH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Djamshidian, A (reprint author), UCL, Reta Lila Weston Inst Neurol Studies, 1 Wakefield St, London WC1N 1PJ, England. EM a.djamshidian-tehrani@ucl.ac.uk RI Warner, Thomas/A-1454-2013 OI Warner, Thomas/0000-0001-6195-6995 NR 37 TC 3 Z9 3 U1 0 U2 9 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-8811 EI 1461-7285 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD DEC PY 2014 VL 28 IS 12 BP 1149 EP 1154 DI 10.1177/0269881114548437 PG 6 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AT9BF UT WOS:000345221900007 PM 25237123 ER PT J AU Mitchell, JA Bottai, M Park, Y Marshall, SJ Moore, SC Matthews, CE AF Mitchell, Jonathan A. Bottai, Matteo Park, Yikyung Marshall, Simon J. Moore, Steven C. Matthews, Charles E. TI A Prospective Study of Sedentary Behavior and Changes in the Body Mass Index Distribution SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE ADULT; LONGITUDINAL; OBESITY; SITTING; TELEVISION ID TELEVISION-VIEWING TIME; PHYSICAL-ACTIVITY; SITTING TIME; CARDIOMETABOLIC RISK; QUANTILE REGRESSION; UNITED-STATES; WEIGHT-GAIN; LIFE-STYLE; US ADULTS; OBESITY AB Purpose: We aimed to determine whether baseline sedentary behavior was associated with changes in body mass index (BMI) over 9 yr. Methods: Participants were enrolled into the National Institutes of Health American Association of Retired Persons (NIH-AARP) Diet and Health study in 1995-1996 (median age, 63 yr), and BMI was reported at baseline and 9 yr later (n = 158,436). Sitting time (<3 (referent), 3-4, 5-6, 7-8, or >= 9 h.d(-1)), television viewing (none, <1, 1-2, 3-4, 5-6, 7-8, or >= 9 h.d(-1)), and the covariates (age, sex, race, education, smoking, moderate-to-vigorous physical activity, caloric intake, and sleep duration) were reported at baseline. We used longitudinal quantile regression to model changes at the 10th, 25th, 50th, 75th, and 90th BMI percentiles. Results: More sitting at baseline was associated with additional increases in BMI over time, and the association was stronger at the upper BMI percentiles (e.g., <3 (referent) vs 5- 6 h.d(-1) of sitting additional increases: 50th percentile = 0.41 kg.m(-2) and 95% confidence interval (CI) = 0.34-0.48; 90th percentile = 0.85 kg.m(-2) and 95% CI = 0.72-0.98). Similar associations were observed between more television viewing at baseline and additional increases in BMI over time (e.g., no television (referent) vs 3-4 h.d(-1) of television: 50th percentile = 1.96 kg.m(-2) and 95% CI = 1.77-2.15; 90th percentile = 2.11 kg.m(-2) and 95% CI = 1.49-2.73). Conclusions: Reducing sedentary behavior could help prevent an increase in BMI in adulthood especially at the upper percentiles of the BMI distribution and thereby reduce the prevalence of obesity. C1 [Mitchell, Jonathan A.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Bottai, Matteo] Karolinska Inst, Inst Environm Med, Biostat Unit, S-10401 Stockholm, Sweden. [Park, Yikyung; Moore, Steven C.; Matthews, Charles E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Marshall, Simon J.] Univ Calif San Diego, Dept Family & Prevent Med, Div Behav Med, San Diego, CA 92103 USA. RP Mitchell, JA (reprint author), Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, 423 Guardian Dr,233 Blockley Hall, Philadelphia, PA 19104 USA. EM jmitch@mail.med.upenn.edu RI Mitchell, Jonathan/A-8723-2011; matthews, Charles/E-8073-2015; Moore, Steven/D-8760-2016; OI matthews, Charles/0000-0001-8037-3103; Moore, Steven/0000-0002-8169-1661; Mitchell, Jonathan/0000-0003-3765-2419; Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute [F32CA162847]; National Institutes of Health FX This work was supported by award number F32CA162847 from the National Cancer Institute and by the National Institutes of Health. 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 40 TC 7 Z9 7 U1 3 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD DEC PY 2014 VL 46 IS 12 BP 2244 EP 2252 DI 10.1249/MSS.0000000000000366 PG 9 WC Sport Sciences SC Sport Sciences GA AT8ZQ UT WOS:000345217900007 PM 24781893 ER PT J AU Hall, KS Morey, MC Dutta, C Manini, TM Weltman, AL Nelson, ME Morgan, AL Senior, JG Seyffarth, C Buchner, DM AF Hall, Katherine S. Morey, Miriam C. Dutta, Chhanda Manini, Todd M. Weltman, Arthur L. Nelson, Miriam E. Morgan, Amy L. Senior, Jane G. Seyffarth, Chris Buchner, David M. TI Activity-Related Energy Expenditure in Older Adults: A Call for More Research SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE PHYSICAL ACTIVITY; RESTING METABOLIC RATE; OXYGEN UPTAKE; TRANSLATION; KILOCALORIES; MET ID PHYSICAL-ACTIVITIES; METABOLIC COST; OXYGEN-CONSUMPTION; WALKING; EXERCISE; COMPENDIUM; EQUIVALENT; STANDARD; YOUNG; WOMEN AB The purposes of this article were to 1) provide an overview of the science of physical activity-related energy expenditure in older adults (>= 65 yr), 2) offer suggestions for future research and guidelines for how scientists should be reporting their results in this area, and 3) present strategies for making these data more accessible to the layperson. This article was meant to serve as a preliminary blueprint for future empirical work in the area of energy expenditure in older adults and translational efforts to make these data useful and accurate for older adults. This document was based upon deliberations of experts involved in the Strategic Health Initiative on Aging Committee of the American College of Sports Medicine. The article was designed to reach a broad audience who might not be familiar with the complexities of assessing energy expenditure, especially in older adults. C1 [Hall, Katherine S.; Morey, Miriam C.] Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Durham, NC 27705 USA. [Hall, Katherine S.; Morey, Miriam C.] Duke Univ, Med Ctr, Claude Pepper Ctr Aging, Durham, NC USA. [Hall, Katherine S.; Morey, Miriam C.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Dutta, Chhanda] NIA, Bethesda, MD 20892 USA. [Manini, Todd M.] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL USA. [Weltman, Arthur L.] Univ Virginia, Dept Kinesiol, Charlottesville, VA USA. [Nelson, Miriam E.] Tufts Univ, Friedman Sch Nutr Sci & Policy, Medford, MA 02155 USA. [Morgan, Amy L.] Bowling Green State Univ, Dept Exercise Sci, Bowling Green, OH 43403 USA. [Senior, Jane G.; Seyffarth, Chris] Amer Coll Sports Med, Indianapolis, IN USA. [Buchner, David M.] Univ Illinois, Dept Kinesiol & Community Hlth, Champaign, IL USA. RP Hall, KS (reprint author), Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, 508 Fulton St,GRECC 182, Durham, NC 27705 USA. EM katherine.hall@duke.edu OI Hall, Katherine/0000-0002-9834-2011; Weltman, Arthur/0000-0002-0125-3769 FU Charles Murcott Trust FX We thank Dr. Wendy Kohrt and Dr. Marcas Bamman for their thoughtful review of our manuscript. The authors also wish to thank the Charles Murcott Trust for providing funds to cover the publication costs of this manuscript. NR 19 TC 5 Z9 5 U1 0 U2 7 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 DEC PY 2014 VL 46 IS 12 BP 2335 EP 2340 DI 10.1249/MSS.0000000000000356 PG 6 WC Sport Sciences SC Sport Sciences GA AT8ZQ UT WOS:000345217900018 PM 24714651 ER PT J AU Kaalund, SS Newburn, EN Ye, T Tao, R Li, C Deep-Soboslay, A Herman, MM Hyde, TM Weinberger, DR Lipska, BK Kleinman, JE AF Kaalund, S. S. Newburn, E. N. Ye, T. Tao, R. Li, C. Deep-Soboslay, A. Herman, M. M. Hyde, T. M. Weinberger, D. R. Lipska, B. K. Kleinman, J. E. TI Contrasting changes in DRD1 and DRD2 splice variant expression in schizophrenia and affective disorders, and associations with SNPs in postmortem brain SO MOLECULAR PSYCHIATRY LA English DT Article DE bipolar disorder; depression; development; dopamine receptors; genotype; schizophrenia ID DOPAMINE D2 RECEPTOR; HUMAN PREFRONTAL CORTEX; WORKING-MEMORY; MESSENGER-RNA; ANTIPSYCHOTIC-DRUGS; EMISSION-TOMOGRAPHY; GENE-EXPRESSION; IN-VIVO; D-2; D1 AB Dopamine 2 receptor (DRD2) is of major interest to the pathophysiology of schizophrenia (SCZ) both as a target for antipsychotic drug action as well as a SCZ-associated risk gene. The dopamine 1 receptor (DRD1) is thought to mediate some of the cognitive deficits in SCZ, including impairment of working memory that relies on normal dorsolateral prefrontal cortex (DLPFC) function. To better understand the association of dopamine receptors with SCZ, we studied the expression of three DRD2 splice variants and the DRD1 transcript in DLPFC, hippocampus and caudate nucleus in a large cohort of subjects (similar to 700), including patients with SCZ, affective disorders and nonpsychiatric controls (from 14th gestational week to 85 years of age), and examined genotype-expression associations of 278 single-nucleotide polymorphisms (SNPs) located in or near DRD2 and DRD1 genes. Expression of D2S mRNA and D2S/D2-long (D2L) ratio were significantly increased in DLPFC of patients with SCZ relative to controls (P < 0.0001 and P < 0.0001, respectively), whereas D2L, D2Longer and DRD1 were decreased (P < 0.0001). Patients with affective disorders showed an opposite pattern: reduced expression of D2S (major depressive disorder, P < 0.0001) and increased expression of D2L and DRD1 (bipolar disorder, P < 0.0001). Moreover, SCZ-associated risk alleles at rs1079727, rs1076560 and rs2283265 predicted increased D2S/D2L expression ratio (P < 0.05) in control individuals. Our data suggest that altered splicing of DRD2 and expression of DRD1 may constitute a pathophysiological mechanism in risk for SCZ and affective disorders. The association between SCZ risk-associated polymorphism and the ratio of D2S/D2L is consistent with this possibility. C1 [Kaalund, S. S.; Newburn, E. N.; Herman, M. M.; Lipska, B. K.] NIMH, Human Brain Collect Core, IRP, Bethesda, MD 20892 USA. [Kaalund, S. S.] Bispebjerg Hosp, Res Lab Stereol & Neurosci, Copenhagen NV, Denmark. [Kaalund, S. S.] Univ Copenhagen, Fac Hlth Sci, Prot Lab, Inst Neurosci & Pharmacol, Copenhagen, Denmark. [Ye, T.; Tao, R.; Li, C.; Deep-Soboslay, A.; Hyde, T. M.; Weinberger, D. R.; Kleinman, J. E.] Lieber Inst Brain Dev, Baltimore, MD USA. RP Lipska, BK (reprint author), NIMH, Human Brain Collect Core, IRP, Bethesda, MD 20892 USA. EM lipskab@mail.nih.gov RI Lipska, Barbara/E-4569-2017; OI kaalund, sanne simone/0000-0002-8975-1825 FU National Institute of Mental Health at the National Institutes of Health; Copenhagen Graduate School of Health Science, University of Copenhagen; Julie von Muellens Foundation FX We thank Liqin Wang and Vesna Imamovic for their technical expertise, and Dr Llewellyn Bigelow for his diagnostic contributions. We thank the Offices of the Chief Medical Examiner of Washington, DC and of Northern Virginia-Northern District, and Dr Ronald Zielke, Robert Johnson and Robert Vigorito at the National Institute of Child Health and Human Brain Development Brain and Tissue Bank for Developmental Disorders, University of Maryland School of Medicine, as well as Dr Maree Webster at the Stanley Medical Institute for their collection of brains. We also thank the families of the deceased for the donations of brain tissue and their time and effort devoted to the consent process and interviews. This research was supported by the Intramural Research Program of the National Institute of Mental Health at the National Institutes of Health, and by the Copenhagen Graduate School of Health Science, University of Copenhagen and Julie von Muellens Foundation (to SSK). NR 59 TC 11 Z9 11 U1 0 U2 7 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 DEC PY 2014 VL 19 IS 12 BP 1258 EP 1266 DI 10.1038/mp.2013.165 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA AU2CL UT WOS:000345423500003 PM 24322206 ER PT J AU Mostafavi, S Battle, A Zhu, X Potash, JB Weissman, MM Shi, J Beckman, K Haudenschild, C McCormick, C Mei, R Gameroff, MJ Gindes, H Adams, P Goes, FS Mondimore, FM MacKinnon, DF Notes, L Schweizer, B Furman, D Montgomery, SB Urban, AE Koller, D Levinson, DF AF Mostafavi, S. Battle, A. Zhu, X. Potash, J. B. Weissman, M. M. Shi, J. Beckman, K. Haudenschild, C. McCormick, C. Mei, R. Gameroff, M. J. Gindes, H. Adams, P. Goes, F. S. Mondimore, F. M. MacKinnon, D. F. Notes, L. Schweizer, B. Furman, D. Montgomery, S. B. Urban, A. E. Koller, D. Levinson, D. F. TI Type I interferon signaling genes in recurrent major depression: increased expression detected by whole-blood RNA sequencing SO MOLECULAR PSYCHIATRY LA English DT Article DE interferon-I signaling; major depressive disorder; MDD; pathway expression signature; RNA-sequencing; transcriptomic ID GENOME-WIDE ASSOCIATION; MOLECULAR SIGNATURES; MONONUCLEAR-CELLS; IMMUNE-RESPONSE; ACTIVATION; DISORDER; METAANALYSIS; ALPHA; INFLAMMATION; BRAIN AB A study of genome-wide gene expression in major depressive disorder (MDD) was undertaken in a large population-based sample to determine whether altered expression levels of genes and pathways could provide insights into biological mechanisms that are relevant to this disorder. Gene expression studies have the potential to detect changes that may be because of differences in common or rare genomic sequence variation, environmental factors or their interaction. We recruited a European ancestry sample of 463 individuals with recurrent MDD and 459 controls, obtained self-report and semi-structured interview data about psychiatric and medical history and other environmental variables, sequenced RNA from whole blood and genotyped a genome-wide panel of common single-nucleotide polymorphisms. We used analytical methods to identify MDD-related genes and pathways using all of these sources of information. In analyses of association between MDD and expression levels of 13 857 single autosomal genes, accounting for multiple technical, physiological and environmental covariates, a significant excess of low P-values was observed, but there was no significant single-gene association after genome-wide correction. Pathway-based analyses of expression data detected significant association of MDD with increased expression of genes in the interferon alpha/beta signaling pathway. This finding could not be explained by potentially confounding diseases and medications (including antidepressants) or by computationally estimated proportions of white blood cell types. Although cause-effect relationships cannot be determined from these data, the results support the hypothesis that altered immune signaling has a role in the pathogenesis, manifestation, and/or the persistence and progression of MDD. C1 [Mostafavi, S.; Battle, A.; Koller, D.] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Zhu, X.; Urban, A. E.; Levinson, D. F.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Potash, J. B.; Gindes, H.] Univ Iowa Hosp & Clin, Dept Psychiat, Iowa City, IA 52242 USA. [Weissman, M. M.; Gameroff, M. J.; Adams, P.] Columbia Univ, Dept Psychiat, New York, NY USA. [Weissman, M. M.; Gameroff, M. J.; Adams, P.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Shi, J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Beckman, K.] Univ Minnesota, Biomed Genom Ctr, Minneapolis, MN USA. [Haudenschild, C.] Personalis Inc, Menlo Pk, CA USA. [McCormick, C.] Illumina Inc, La Jolla, CA USA. [Mei, R.] Centrill Biosci Inc, Palo Alto, CA USA. [Goes, F. S.; Mondimore, F. M.; MacKinnon, D. F.; Schweizer, B.] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Notes, L.] Amer Univ, Dept Clin Psychol, Washington, DC 20016 USA. [Furman, D.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Montgomery, S. B.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Montgomery, S. B.] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. RP Levinson, DF (reprint author), Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, 401 Quarry Rd,Room 3322, Stanford, CA 94305 USA. EM dflev@stanford.edu OI Weissman, Myrna/0000-0003-3490-3075 FU National Institutes of Health/National Institute of Mental Health [5RC2MH089916, 3R01MH090941] FX This work was supported by National Institutes of Health/National Institute of Mental Health Grants 5RC2MH089916 (DFL, PI; MMW, JBP, DK and AEU, Co-Investigators) and 3R01MH090941 (DK, Co-Investigator). NR 53 TC 21 Z9 21 U1 1 U2 6 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 DEC PY 2014 VL 19 IS 12 BP 1267 EP 1274 DI 10.1038/mp.2013.161 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA AU2CL UT WOS:000345423500004 PM 24296977 ER PT J AU Gerstberger, S Hafner, M Tuschl, T AF Gerstberger, Stefanie Hafner, Markus Tuschl, Thomas TI A census of human RNA-binding proteins SO NATURE REVIEWS GENETICS LA English DT Review ID POSTTRANSCRIPTIONAL GENE-REGULATION; EUKARYOTIC RIBOSOME BIOGENESIS; AICARDI-GOUTIERES-SYNDROME; SHOCK DOMAIN PROTEINS; PIWI-INTERACTING RNAS; EMBRYONIC STEM-CELLS; MESSENGER-RNA; ALTERNATIVE POLYADENYLATION; TRANSLATIONAL CONTROL; STRANDED-RNA AB Post-transcriptional gene regulation (PTGR) concerns processes involved in the maturation, transport, stability and translation of coding and non-coding RNAs. RNA-binding proteins (RBPs) and ribonucleoproteins coordinate RNA processing and PTGR. The introduction of large-scale quantitative methods, such as next-generation sequencing and modern protein mass spectrometry, has renewed interest in the investigation of PTGR and the protein factors involved at a systems-biology level. Here, we present a census of 1,542 manually curated RBPs that we have analysed for their interactions with different classes of RNA, their evolutionary conservation, their abundance and their tissue-specific expression. Our analysis is a critical step towards the comprehensive characterization of proteins involved in human RNA metabolism. C1 [Gerstberger, Stefanie; Tuschl, Thomas] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Gerstberger, Stefanie; Tuschl, Thomas] Rockefeller Univ, Lab RNA Mol Biol, New York, NY 10065 USA. [Hafner, Markus] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Tuschl, T (reprint author), Rockefeller Univ, Howard Hughes Med Inst, 1230 York Ave, New York, NY 10065 USA. EM ttuschl@rockefeller.edu OI Hafner, Markus/0000-0002-4336-6518 FU Boehringer Ingelheim Fonds; US National Institute of Arthritis and Musculoskeletal; Skin Diseases Intramural Research Program FX The body map data were kindly provided by the Gene Expression Applications research group at Illumine. The authors thank P. Morozov, M. Carty, M. Brown, R. Kim and S. Lianoglou for discussions on the computational methods, as well as Z. Ozair, A. D. Haase and all laboratory members for comments on the manuscript. S.G. was supported by a Ph.D. fellowship from the Boehringer Ingelheim Fonds. M.H. is supported by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program. T.T. is an Investigator of the Howard Hughes Medical Institute. NR 208 TC 116 Z9 117 U1 8 U2 63 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 EI 1471-0064 J9 NAT REV GENET JI Nat. Rev. Genet. PD DEC PY 2014 VL 15 IS 12 BP 829 EP 845 DI 10.1038/nrg3813 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA AT8QD UT WOS:000345196400010 PM 25365966 ER PT J AU Liu, JJ Freedman, DM Little, MP Doody, MM Alexander, BH Kitahara, CM Lee, T Rajaraman, P Miller, JS Kampa, DM Simon, SL Preston, DL Linet, MS AF Liu, Jason J. Freedman, D. Michal Little, Mark P. Doody, Michele M. Alexander, Bruce H. Kitahara, Cari M. Lee, Terrence Rajaraman, Preetha Miller, Jeremy S. Kampa, Diane M. Simon, Steven L. Preston, Dale L. Linet, Martha S. TI Work history and mortality risks in 90 268 US radiological technologists SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article DE mortality; neoplasms; circulatory system diseases; radiologic technologists; work history ID ATOMIC-BOMB SURVIVORS; BREAST-CANCER INCIDENCE; X-RAY WORKERS; UNITED-STATES; IONIZING-RADIATION; PHYSICIAN SPECIALISTS; BRITISH RADIOLOGISTS; SOLID CANCER; DISEASE; EXPOSURE AB Objectives There have been few studies of work history and mortality risks in medical radiation workers. We expanded by 11years and more outcomes our previous study of mortality risks and work history, a proxy for radiation exposure. Methods Using Cox proportional hazards models, we estimated mortality risks according to questionnaire work history responses from 1983 to 1989 through 2008 by 90268 US radiological technologists. We controlled for potential confounding by age, birth year, smoking history, body mass index, race and gender. Results There were 9566 deaths (3329 cancer and 3020 circulatory system diseases). Mortality risks increased significantly with earlier year began working for female breast (p trend=0.01) and stomach cancers (p trend=0.01), ischaemic heart (p trend=0.03) and cerebrovascular diseases (p trend=0.02). The significant trend with earlier year first worked was strongly apparent for breast cancer during baseline through 1997, but not 1998-2008. Risks were similar in the two periods for circulatory diseases. Radiological technologists working 5years before 1950 had elevated mortality from breast cancer (HR=2.05, 95% CI 1.27 to 3.32), leukaemia (HR=2.57, 95% CI 0.96 to 6.68), ischaemic heart disease (HR=1.13, 95% CI 0.96 to 1.33) and cerebrovascular disease (HR=1.28, 95% CI 0.97 to 1.69). No other work history factors were consistently associated with mortality risks from specific cancers or circulatory diseases, or other conditions. Conclusions Radiological technologists who began working in early periods and for more years before 1950 had increased mortality from a few cancers and some circulatory system diseases, likely reflecting higher occupational radiation exposures in the earlier years. C1 [Liu, Jason J.; Freedman, D. Michal; Little, Mark P.; Doody, Michele M.; Kitahara, Cari M.; Lee, Terrence; Rajaraman, Preetha; Simon, Steven L.; Linet, Martha S.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Alexander, Bruce H.; Kampa, Diane M.] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, Minneapolis, MN USA. [Miller, Jeremy S.] Informat Management Serv Inc, Rockville, MD USA. [Preston, Dale L.] Hirosoft Int, Eureka, CA USA. RP Liu, JJ (reprint author), Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, 9609 Med Ctr Dr,Room 7E520, Rockville, MD 20850 USA. EM jasonjliu.jjl@gmail.com RI Kitahara, Cari/R-8267-2016; OI Little, Mark/0000-0003-0980-7567 FU National Cancer Institute, National Institutes of Health, US Department of Health and Human Services [N01-CP-21015, N01-CP-31018, HHSN261201000139C, HHSN261201100007I] FX This study was funded in part through contracts N01-CP-21015, N01-CP-31018, HHSN261201000139C, and HHSN261201100007I with the National Cancer Institute, National Institutes of Health, US Department of Health and Human Services. NR 39 TC 4 Z9 5 U1 5 U2 12 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD DEC PY 2014 VL 71 IS 12 BP 819 EP 835 DI 10.1136/oemed-2013-101859 PG 17 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AT4UX UT WOS:000344940200004 PM 24852760 ER PT J AU Locke, SJ Colt, JS Stewart, PA Armenti, KR Baris, D Blair, A Cerhan, JR Chow, WH Cozen, W Davis, F De Roos, AJ Hartge, P Karagas, MR Johnson, A Purdue, MP Rothman, N Schwartz, K Schwenn, M Severson, R Silverman, DT Friesen, MC AF Locke, Sarah J. Colt, Joanne S. Stewart, Patricia A. Armenti, Karla R. Baris, Dalsu Blair, Aaron Cerhan, James R. Chow, Wong-Ho Cozen, Wendy Davis, Faith De Roos, Anneclaire J. Hartge, Patricia Karagas, Margaret R. Johnson, Alison Purdue, Mark P. Rothman, Nathaniel Schwartz, Kendra Schwenn, Molly Severson, Richard Silverman, Debra T. Friesen, Melissa C. TI Identifying gender differences in reported occupational information from three US population-based case-control studies SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article DE population-based studies; case-control studies; occupational exposure; occupational health ID HEALTH RESEARCH; EXPOSURE; WOMEN; WORK; RISK; OCCUPATION/INDUSTRY; EPIDEMIOLOGY; DISPARITIES; LYMPHOMA; PATTERNS AB Objectives Growing evidence suggests that gender-blind assessment of exposure may introduce exposure misclassification, but few studies have characterised gender differences across occupations and industries. We pooled control responses to job-specific, industry-specific and exposure-specific questionnaires (modules) that asked detailed questions about work activities from three US population-based case-control studies to examine gender differences in work tasks and their frequencies. Methods We calculated the ratio of female-to-male controls that completed each module. For four job modules (assembly worker, machinist, health professional, janitor/cleaner) and for subgroups of jobs that completed those modules, we evaluated gender differences in task prevalence and frequency using (2) and Mann-Whitney U tests, respectively. Results The 1360 female and 2245 male controls reported 6033 and 12083 jobs, respectively. Gender differences in female:male module completion ratios were observed for 39 of 45 modules completed by 20 controls. Gender differences in task prevalence varied in direction and magnitude. For example, female janitors were significantly more likely to polish furniture (79% vs 44%), while male janitors were more likely to strip floors (73% vs 50%). Women usually reported more time spent on tasks than men. For example, the median hours per week spent degreasing for production workers in product manufacturing industries was 6.3 for women and 3.0 for men. Conclusions Observed gender differences may reflect actual differences in tasks performed or differences in recall, reporting or perception, all of which contribute to exposure misclassification and impact relative risk estimates. Our findings reinforce the need to capture subject-specific information on work tasks. C1 [Locke, Sarah J.; Colt, Joanne S.; Baris, Dalsu; Blair, Aaron; Hartge, Patricia; Purdue, Mark P.; Rothman, Nathaniel; Silverman, Debra T.; Friesen, Melissa C.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Stewart, Patricia A.] Stewart Exposure Assessments LLC, Arlington, VA USA. [Armenti, Karla R.] Bur Publ Hlth Stat & Informat, Div Publ Hlth Serv, New Hampshire Dept Hlth & Human Serv, Concord, NH USA. [Cerhan, James R.] Mayo Clin, Coll Med, Rochester, MN USA. [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Cozen, Wendy] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Davis, Faith] Univ Alberta, Dept Publ Hlth Sci, Edmonton, AB, Canada. [De Roos, Anneclaire J.] Drexel Univ, Sch Publ Hlth, Dept Environm & Occupat Hlth, Philadelphia, PA 19104 USA. [Karagas, Margaret R.] Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH USA. [Johnson, Alison] Vermont Dept Hlth, Burlington, VT 05402 USA. [Schwartz, Kendra; Severson, Richard] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. [Schwenn, Molly] Maine Canc Registry, Augusta, ME USA. RP Locke, SJ (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 6E550,MS 9771, Bethesda, MD 20892 USA. EM lockesj@mail.nih.gov RI Purdue, Mark/C-9228-2016; Friesen, Melissa/A-5362-2009 OI Purdue, Mark/0000-0003-1177-3108; FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics [Z01 CP010122, Z01 CP010120]; National Institutes of Health; National Cancer Institute [N02-CP-11004, N02-CP-11161]; National Institutes of Health (National Cancer Institute); National Cancer Institute SEER Contract (Detroit) [N01-PC-65064]; National Cancer Institute SEER Contract (Seattle) [N01-PC-67009]; National Cancer Institute SEER Contract (Iowa) [N01-CN-67008]; National Cancer Institute SEER Contract (Los Angeles) [N01-CN-67010] FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics (Z01 CP010122; Z01 CP010120). USKCS was supported by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute with contract N02-CP-11004 (Wayne State University) and N02-CP-11161 (University of Illinois at Chicago). NCI-SEER NHL was supported in part by the Intramural Research Program of the National Institutes of Health (National Cancer Institute) and by National Cancer Institute SEER Contracts N01-PC-65064 (Detroit), N01-PC-67009 (Seattle), N01-CN-67008 (Iowa) and N01-CN-67010 (Los Angeles). NR 34 TC 3 Z9 3 U1 1 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD DEC PY 2014 VL 71 IS 12 BP 855 EP 864 DI 10.1136/oemed-2013-101801 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AT4UX UT WOS:000344940200008 PM 24683012 ER PT J AU Aschebrook-Kilfoy, B Ward, MH DellaValle, C Friesen, MC AF Aschebrook-Kilfoy, Briseis Ward, Mary H. DellaValle, Curt Friesen, Melissa C. TI Author response to "Re: occupation and thyroid cancer." SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Letter ID WORKERS; RISK C1 [Aschebrook-Kilfoy, Briseis] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Ward, Mary H.; DellaValle, Curt; Friesen, Melissa C.] NCI, Occupat & Environm Epidemiol Branch, Rockville, MD USA. RP Aschebrook-Kilfoy, B (reprint author), Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. EM brisa@uchicago.edu RI Friesen, Melissa/A-5362-2009 NR 5 TC 0 Z9 0 U1 0 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD DEC PY 2014 VL 71 IS 12 BP 878 EP 878 DI 10.1136/oemed-2014-102570 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AT4UX UT WOS:000344940200011 PM 25294859 ER PT J AU Lowe, M Gullotti, D Damjanovic, A Cheng, A Dirla, S Schleif, R AF Lowe, Mary Gullotti, David Damjanovic, Ana Cheng, Ann Dirla, Stephanie Schleif, Robert TI Computational and experimental investigation of constitutive behavior in AraC SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE allostery; gene regulation; self-guided Langevin dynamics; AraC; cluster ID GUIDED LANGEVIN DYNAMICS; L-ARABINOSE SYSTEM; DIMERIZATION DOMAIN; POSITIVE CONTROL; SUGAR-BINDING; IN-VIVO; PROTEIN; REPRESSION; MUTATIONS; CONFORMATION AB Many mutations in the N-terminal arm of AraC result in constitutive behavior in which transcription of the araBAD genes occurs even in the absence of arabinose. To begin to understand the mechanism underlying this class of mutations, we used molecular dynamics with self-guided Langevin dynamics to simulate (1) wild-type (WT) AraC, (2) known constitutive mutants resulting from alterations in the regulatory arm, particularly alanine and glycine substitutions at residue 8 because P8G is constitutive, whereas P8A behaves like wild type, and (3) selected variant AraC proteins containing alterations in the dimerization core. In all of the constitutive arm mutants, but not the WT protein, residues 37-42, which are located in the core of the dimerization domain, became restructured. This raised the question of whether or not these structural changes are an obligatory component of constitutivity. Using molecular dynamics, we identified alterations in the core that produced a similar restructuring. The corresponding mutants were constructed and their ara constitutivity status was determined experimentally. Because the core mutants were not found to be constitutive, we conclude that restructuring of core residues 37-42 does not, itself, lead to constitutivity of AraC. The available data lead to the hypothesis that the interaction of the N-terminal arm with something other than the front lip is the primary determinant of the inducing versus repressing state of AraC. Proteins 2014; 82:3385-3396. (c) 2014 Wiley Periodicals, Inc. C1 [Lowe, Mary; Gullotti, David] Loyola Univ Maryland, Dept Phys, Baltimore, MD 21210 USA. [Damjanovic, Ana] Johns Hopkins Univ, Dept Biophys, Baltimore, MD USA. [Damjanovic, Ana] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Cheng, Ann; Dirla, Stephanie; Schleif, Robert] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. RP Lowe, M (reprint author), Loyola Univ Maryland, Dept Phys, Baltimore, MD 21210 USA. EM mlowe@loyola.edu NR 33 TC 0 Z9 0 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 EI 1097-0134 J9 PROTEINS JI Proteins PD DEC PY 2014 VL 82 IS 12 BP 3385 EP 3396 DI 10.1002/prot.24693 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AU0HZ UT WOS:000345305400013 PM 25243377 ER PT J AU Dong, HX Wang, S Zeng, ZL Li, F Montalvo-Ortiz, J Tucker, C Akhtar, S Shi, JS Meltzer, HY Rice, KC Csernansky, JG AF Dong, Hongxin Wang, Shirlene Zeng, Ziling Li, Fei Montalvo-Ortiz, Janitza Tucker, Christopher Akhtar, Shahzad Shi, Jingshan Meltzer, Herbert Y. Rice, Kenner C. Csernansky, John G. TI Effects of corticotrophin-releasing factor receptor 1 antagonists on amyloid-beta and behavior in Tg2576 mice SO PSYCHOPHARMACOLOGY LA English DT Article DE Stress; Corticotrophin-releasing hormone; Antalarmin; R121919; Alzheimer disease; Tg2576 mice ID PROTEIN-COUPLED RECEPTORS; CENTRAL-NERVOUS-SYSTEM; ALZHEIMERS-DISEASE; PRECURSOR PROTEIN; PSYCHOLOGICAL DISTRESS; TAU PHOSPHORYLATION; PLASMA-CORTISOL; BINDING-PROTEIN; TRANSGENIC MICE; FACTOR CRF AB Previous studies indicate that psychosocial stressors could accelerate amyloid-beta (A beta) levels and accelerate plaque deposition in mouse models of Alzheimer disease (AD). Stressors enhanced the release of corticotrophin-releasing factor (CRF), and exogenous CRF administration mimicked the effects of stress on A beta levels in mouse models of AD. However, whether CRF receptor 1 (CRF1) antagonists could influence the stress-induced acceleration of an AD-like process in mouse models has not been well studied. We sought to examine whether CRF1 antagonists inhibit the effects of isolation stress on tissue A beta levels, A beta plaque deposition, and behaviors related to anxiety and memory in Tg2576 mice, and to investigate the molecular mechanism underlying such effects. Cohorts of Tg2576 mouse pups were isolated or group-housed at 21 days of age, and then the subgroups of these cohorts received daily intraperitoneal injections of the CRF1 antagonists, antalarmin or R121919 (5, 10, and 20 mg/kg), or vehicle for 1 week. Other cohorts of Tg2576 mouse pups were isolated or group-housed at 21 days of age, and then at 4 months of age, subgroups of these mice were administered antalarmin (20 mg/kg) or vehicle in their drinking water for 6 months. Finally, cultured primary hippocampal neurons from regular Tg2576 pups (P0) were incubated with CRF (0.1, 1, and 10 nM), antalarmin (100 nM) or H-89 (1 mu M) for 48 h. Brain tissues or cultured neurons were collected for histological and biochemical analyses, and behavioral measures were collected in the cohorts of mice that were chronically stressed. Administration of antalarmin at 20 mg/kg dose for 1 week significantly reduced A beta(1-42) levels in isolation stressed mice. Administration of antalarmin for 6 months significantly decreased plasma corticosterone levels, tissue A beta(1-42) levels, and A beta plaque deposition in the brain and blocked the effects of isolation stress on behaviors related to anxiety and memory. Finally, incubation of neurons with 100 nM antalarmin inhibited the ability of 10 nM CRF to increase A beta(1-42) levels and protein kinase A II beta expression. The effect of CRF1 on A beta(1-42) levels was also diminished by treatment with H-89, a c-AMP/PKA inhibitor. These results suggest that CRF1 antagonists can slow an AD-like process in Tg2576 mice and that the c-AMP/PKA signaling pathway may be involved in this effect. C1 [Dong, Hongxin; Wang, Shirlene; Montalvo-Ortiz, Janitza; Meltzer, Herbert Y.; Csernansky, John G.] Northwestern Univ, Feinberg Sch Med, Dept Psychiat & Behav Sci, Chicago, IL 60611 USA. [Zeng, Ziling] Shandong Univ, Shandong Prov Hosp, Dept Healthcare, Jinan 250021, Peoples R China. [Dong, Hongxin; Li, Fei; Shi, Jingshan] Zunyi Med Coll, Dept Pharmacol, Zunyi 663003, Peoples R China. [Tucker, Christopher; Akhtar, Shahzad] Astella Pharma Global Dev Inc, Drug Discovery Res, Skokie, IL 60077 USA. [Rice, Kenner C.] NIDA, Rockville, MD 20852 USA. [Rice, Kenner C.] NIAAA, Intramural Res Program, Rockville, MD 20852 USA. RP Dong, HX (reprint author), Zunyi Med Coll, Dept Pharmacol, Zunyi 663003, Peoples R China. EM h-dong@northwestern.edu RI Meltzer, Herbert/E-8131-2013 FU Alzheimer's Drug Discovery Foundation [20111208]; National Institute on Drug Abuse; National Institute of Alcohol Abuse and Alcoholism, NIH, US Department of Health and Human Services; NIMH; NIA; Genentech FX This work was supported by the Alzheimer's Drug Discovery Foundation (grant 20111208, JGC). A portion of this research was supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism, NIH, US Department of Health and Human Services (KCR). Drs. Csernansky and Dong have received research grants from the NIMH, NIA, and Dr. John G. Csernansky has served as a Data Safety and Monitoring Board (DSMB) member for Eli Lilly and Sanofi-Aventis and has received funding for his research from Genentech. The rest of the authors declare that they have no competing financial interests. NR 60 TC 6 Z9 6 U1 2 U2 7 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 DEC PY 2014 VL 231 IS 24 BP 4711 EP 4722 DI 10.1007/s00213-014-3629-8 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AT7UU UT WOS:000345143500012 PM 24862368 ER PT J AU Mehta, A Patel, D Rosenberg, A Boufraqech, M Ellis, RJ Nilubol, N Quezado, MM Marx, SJ Simonds, WF Kebebew, E AF Mehta, Amit Patel, Dhaval Rosenberg, Avi Boufraqech, Myriem Ellis, Ryan J. Nilubol, Naris Quezado, Martha M. Marx, Stephen J. Simonds, William F. Kebebew, Electron TI Hyperparathyroidism-jaw tumor syndrome: Results of operative management SO SURGERY LA English DT Article ID FAMILIAL ISOLATED HYPERPARATHYROIDISM; SPORADIC PARATHYROID TUMORS; GERMLINE HRPT2 MUTATIONS; GENETIC ANALYSES; SUPPRESSOR GENE; FOLLOW-UP; CARCINOMA; PARAFIBROMIN; DIAGNOSIS; SURVEILLANCE AB Background. Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare, autosomal-dominant disease secondary to germline-inactivating mutations of the tumor suppressor geneHRPT2/CDC73. The aim of the present study was to determine the optimal operative approach to parathyroid disease in patients with HPT-JT. Methods. A retrospective analysis of clinical and genetic features, parathyroid operative outcomes, and disease outcomes in 7 unrelated HPT-JT families. Results. Seven families had 5 distinct germline HRPT2/CDC73 mutations. Sixteen affected family members (median age, 30.7 years) were diagnosed with primary hyperparathyroidism (PHPT). Fifteen of the 16 patients underwent preoperative tumor localization studies and uncomplicated bilateral neck exploration at initial operation; all were in biochemical remission at most recent follow-up. Of these patients, 31% had multiglandular involvement; 37.5% of the patients developed parathyroid carcinoma (median overall survival, 8.9 years; median follow-up, 7.4 years). Long-term follow-up showed that 20% of patients had recurrent PHPT. Conclusion. Given the high risk of malignancy and multiglandular involvement in our cohort, we recommend bilateral neck exploration and en bloc resection of parathyroid tumors suspicious for cancer and life-long postoperative follow-up. C1 [Mehta, Amit; Patel, Dhaval; Boufraqech, Myriem; Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Mehta, Amit] Geisel Sch Med Dartmouth, Hanover, NH USA. [Rosenberg, Avi; Ellis, Ryan J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Quezado, Martha M.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Marx, Stephen J.; Simonds, William F.] NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov RI Boufraqech, Myriem/E-4823-2016; OI Rosenberg, Avi/0000-0003-2356-950X; Patel, Dhaval/0000-0002-5744-568X FU Center for Cancer Research, National Cancer Institute, National Institutes of Health; National Institute of Digestive and Diabetes and Kidney Diseases; National Institutes of Health (NIH) Medical Research Scholars Program; NIH FX Supported by the intramural research programs of the Center for Cancer Research, National Cancer Institute, National Institutes of Health and the National Institute of Digestive and Diabetes and Kidney Diseases; as well as the National Institutes of Health (NIH) Medical Research Scholars Program, 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 and Mr and Mrs Joel S. Marcus, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation website at: http://fnih.org/work/education-training-0/medical-research-scholars-prog ram. NR 45 TC 5 Z9 5 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD DEC PY 2014 VL 156 IS 6 BP 1315 EP 1325 DI 10.1016/j.surg.2014.08.004 PG 11 WC Surgery SC Surgery GA AT9OF UT WOS:000345255700005 PM 25444225 ER PT J AU Asare, EA Wang, TS Winchester, DP Mallin, K Kebebew, E Sturgeon, C AF Asare, Elliot A. Wang, Tracy S. Winchester, David P. Mallin, Katherine Kebebew, Electron Sturgeon, Cord TI A novel staging system for adrenocortical carcinoma better predicts survival in patients with stage I/II disease SO SURGERY LA English DT Article ID ADRENAL-CORTICAL CARCINOMA; NATIONAL CANCER DATABASE; PROGNOSTIC-FACTORS; UNITED-STATES; MANAGEMENT; DIAGNOSIS; FEATURES AB Background. Current American Joint Committee on Cancer/International Union against Cancer (AJCC/UICC) and European Network for the Study of Adrenal Tumors staging for adrenocortical carcinoma (ACC) have not shown a survival difference between patients with stage I/II disease. This study evaluates current staging systems for survival prediction using a larger cohort and assesses whether incorporating age into ACC staging improves survival predictions. Methods. Patients in the National Cancer Data Base (1985-2006) with a diagnosis of ACC were identified and staged using a novel TNM-A staging system: Stage I (T1/T2N0M0, age -55), stage II (T1/T2N0M0, age <= 55), stage III (T1/T2N1M0 or T3/T4N0-N1M0, any age), or stage IV (any T any NM1, any age). Differences in overall survival (OS) by stage were compared using a Cox proportional hazards model. Results. Staging was derived for 1,579 of 3,262 patients. Median age was 54 years; mean tumor size was 11.6 cm. Using current staging, differences in 5-year OS was observed only between patients with stages and III/IV ACC. With TNM-A staging, differences in 5-year OS between all stages was significant (I/II [P < .003], II/III [P < .0001], III/IV [P < .0001]). Conclusion. A staging system that incorporates patient age better predicts 5-year OS among patients with stages I/II ACC. Consideration should be given to including age in staging for ACC, because it may better inform providers about treatment and prognosis. C1 [Asare, Elliot A.] Amer Coll Surg, AJCC, Chicago, IL 60611 USA. [Asare, Elliot A.; Winchester, David P.; Mallin, Katherine] Amer Coll Surg, Canc Programs, Chicago, IL 60611 USA. [Asare, Elliot A.; Wang, Tracy S.] Med Coll Wisconsin, Dept Surg, Milwaukee, WI 53226 USA. [Kebebew, Electron] NCI, Endocrine Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Sturgeon, Cord] Northwestern Univ, Feinberg Sch Med, Dept Surg, Chicago, IL 60611 USA. RP Asare, EA (reprint author), Amer Coll Surg, Canc Programs, 633 N St Clair St,22nd Floor, Chicago, IL 60611 USA. EM easare@facs.org FU American College of Surgeons Clinical Scholars in Residence Program FX Elliot Asare is supported by the American College of Surgeons Clinical Scholars in Residence Program. NR 19 TC 5 Z9 5 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD DEC PY 2014 VL 156 IS 6 BP 1378 EP 1386 DI 10.1016/j.surg.2014.08.018 PG 9 WC Surgery SC Surgery GA AT9OF UT WOS:000345255700013 PM 25456914 ER PT J AU Gounden, V El-Maouche, D Stolze, BR Muniyappa, R Soldin, SJ AF Gounden, Verena El-Maouche, Diala Stolze, Brian R. Muniyappa, Ranganath Soldin, Steven J. TI LC-MS/MS Detection of Increased Androstenedione Levels in Patients Receiving Danazol Therapy SO THERAPEUTIC DRUG MONITORING LA English DT Letter ID STEROIDS; SERUM C1 [Gounden, Verena; Stolze, Brian R.; Soldin, Steven J.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [El-Maouche, Diala] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Muniyappa, Ranganath] NIDDKD, NIH, Bethesda, MD USA. [Soldin, Steven J.] Georgetown Univ, Dept Med, Washington, DC USA. RP Gounden, V (reprint author), NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CL999999] NR 8 TC 0 Z9 0 U1 1 U2 2 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 DEC PY 2014 VL 36 IS 6 BP 828 EP 829 PG 2 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA AT8BG UT WOS:000345158200023 PM 24819967 ER PT J AU Gourgari, E Lodish, M Keil, M Wesley, R Hill, S Xekouki, P Lyssikatos, C Belyavskaya, E De La Luz, SM Stratakis, CA AF Gourgari, Evgenia Lodish, Maya Keil, Meg Wesley, Robert Hill, Suvimol Xekouki, Paraskevi Lyssikatos, Charalampos Belyavskaya, Elena De La Luz, Sierra Maria Stratakis, Constantine A. TI Post-operative growth is different in various forms of pediatric Cushing's syndrome SO ENDOCRINE-RELATED CANCER LA English DT Letter ID SURGICAL CURE; CHILDREN; HORMONE; DISEASE; ADOLESCENTS; MUTATIONS; OBESITY C1 [Gourgari, Evgenia; Lodish, Maya; Keil, Meg; Xekouki, Paraskevi; Lyssikatos, Charalampos; Belyavskaya, Elena; De La Luz, Sierra Maria; Stratakis, Constantine A.] Program Dev Endocrinol & Genet PDEGEN, Sect Endocrinol & Genet, Bethesda, MD USA. [Gourgari, Evgenia; Lodish, Maya; Keil, Meg; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Inter Inst Training Program, NIH, Bethesda, MD 20892 USA. [Gourgari, Evgenia] Georgetown Univ, Sch Med, Dept Pediat Endocrinol, Washington, DC 20007 USA. [Wesley, Robert] Natl Inst Hlth Clin Ctr, Biostat & Clin Epidemiol Serv, Bethesda, MD 20982 USA. [Hill, Suvimol] Natl Inst Hlth Clin Ctr, Dept Radiol, Bethesda, MD 20892 USA. RP Gourgari, E (reprint author), Georgetown Univ Hosp, Div Pediat Endocrinol, 4200 Wisconsin Ave,NW,4th Floor, Washington, DC 20016 USA. EM evgenia.gourgari@gunet.georgetown.edu FU Intramural NIH HHS [Z99 HD999999] NR 14 TC 2 Z9 2 U1 0 U2 1 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD DEC PY 2014 VL 21 IS 6 BP L27 EP L31 DI 10.1530/ERC-14-0405 PG 5 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA AT2TI UT WOS:000344788600001 PM 25258026 ER PT J AU Lopez, DS Peskoe, SB Tsilidis, KK Hoffman-Bolton, J Helzlsouer, KJ Isaacs, WB Smith, MW Platz, EA AF Lopez, D. S. Peskoe, S. B. Tsilidis, K. K. Hoffman-Bolton, J. Helzlsouer, K. J. Isaacs, W. B. Smith, M. W. Platz, E. A. TI Association of variants in genes related to the immune response and obesity with BPH in CLUE II SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article ID BENIGN PROSTATIC HYPERPLASIA; CANCER PREVENTION TRIAL; URINARY-TRACT SYMPTOMS; C-REACTIVE PROTEIN; SERUM ADIPONECTIN; METABOLIC DISEASE; PPAR-GAMMA; RISK; POLYMORPHISMS; INFLAMMATION AB BACKGROUND: Chronic inflammation and obesity may contribute to the genesis or progression of BPH and BPH-associated lower urinary tract symptoms (LUTS). The influence of variants in genes related to these states on BPH has not been studied extensively. Thus, we evaluated the association of 17 single-nucleotide polymorphisms (SNPs) in immune response genes (IL18, IL6, IL8, 1L10, TNF, CRP, TLR4 and RNASEL) and genes involved in obesity, including insulin regulation (LEP, ADIPOQ, PPARG and TCF7L2), with BPH. METHODS: BPH cases (N=568) and age-frequency matched controls (N=568) were selected from among adult male CLUE II cohort participants who responded in 2000 to a mailed questionnaire. BPH was defined as BPH surgery, use of BPH medications or symptomatic BPH (American Urological Association Symptom Index Score 15). Controls were men who had not had BPH surgery, did not use BPH medications and whose symptom score was <= 7. Age-adjusted odds ratios (ORs) and 95% confidence intervals (as) were estimated using logistic regression. RESULTS: None of the candidate SNPs was statistically significantly associated with BPH. However, we could not rule out possible weak associations for CRP rs1205 (1082C>T), ADIPOQ rs1501299 (276C>A), PPARG rs1801282 (-49C>G) and TCF7L2 rs7903146 (47833T>C). After summing risk alleles, men with >= 4 had an increased BPH risk compared with those with <= 1 (OR, 1.78; 95% CI, 1.10-2.89; P-trend = 0.006). CONCLUSIONS: SNPs in genes related to immune response and obesity, especially in combination, may be associated with BPH. C1 [Lopez, D. S.; Peskoe, S. B.; Helzlsouer, K. J.; Platz, E. A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Lopez, D. S.] Univ Texas Houston, Sch Publ Hlth, Div Epidemiol, Houston, TX 77030 USA. [Lopez, D. S.] Univ Texas Houston, Sch Med, Div Urol, Houston, TX 77030 USA. [Tsilidis, K. K.] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Hoffman-Bolton, J.; Helzlsouer, K. J.] Johns Hopkins Bloomberg Sch Publ Hlth, George W Comstock Ctr Publ Hlth Res & Prevent, Hagerstown, MD USA. [Helzlsouer, K. J.] Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD USA. [Isaacs, W. B.; Platz, E. A.] James Buchanan Brady Urol Inst, Johns Hopkins Sch Med, Dept Urol, Baltimore, MD USA. [Isaacs, W. B.; Platz, E. A.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Smith, M. W.] Natl Human Genome Res Inst, Extramural Res Program, Rockville, MD USA. RP Lopez, DS (reprint author), Univ Texas Houston, Sch Publ Hlth, Div Epidemiol, 1200 Herman Pressler,Suite E-629, Houston, TX 77030 USA. EM david.s.lopez@uth.tmc.edu FU National Research Service Award from the National Cancer Institute [T32 CA009314]; American Institute for Cancer Research; National Institute of Aging [U01 AG18033]; National Cancer Institute [N01 CO12400]; National Cancer Institute Prostate Cancer Specialized Program of Research Excellence (Career Development Award) [P50 CA58236]; State of Maryland; Maryland Cigarette Restitution Fund; National Program of Cancer Registries (NPCR of the Centers for Disease Control and Prevention (CDC)) FX We appreciate the contributions of staff of the Johns Hopkins George W. Comstock Center for Public Health Research and Prevention in the conduct of the CLUE II study. Dr Lopez was supported by a National Research Service Award from the National Cancer Institute (T32 CA009314). This work was supported by the American Institute for Cancer Research, the National Institute of Aging (U01 AG18033), the National Cancer Institute (N01 CO12400) and the National Cancer Institute Prostate Cancer Specialized Program of Research Excellence (Career Development Award from P50 CA58236). Cancer incidence data have been provided by the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Department of Mental Health and Hygiene. We acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries (NPCR of the Centers for Disease Control and Prevention (CDC)) for the funds that helped support the availability of the cancer registry data. NR 32 TC 1 Z9 1 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1365-7852 EI 1476-5608 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PD DEC PY 2014 VL 17 IS 4 BP 353 EP 358 DI 10.1038/pcan.2014.36 PG 6 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AT3LC UT WOS:000344835400010 PM 25224558 ER PT J AU Stout, RL Braciszewski, JM Subbaraman, MS Kranzler, HR O'Malley, SS Falk, D AF Stout, Robert L. Braciszewski, Jordan M. Subbaraman, Meenakshi Sabina Kranzler, Henry R. O'Malley, Stephanie S. Falk, Daniel CA Grp, A TI What happens when people discontinue taking medications? Lessons from COMBINE SO ADDICTION LA English DT Article DE Alcohol treatment outcome; clinical intervention; imputation; medication compliance; medication study; missing data; research methods; statistics ID ALCOHOL CLINICAL-TRIALS; TESTING COMBINED PHARMACOTHERAPIES; BEHAVIORAL INTERVENTIONS; MISSING DATA; DEPENDENCE; ADHERENCE; NALTREXONE; OUTCOMES; DRUG AB AimsWe use intensive longitudinal data methods to illuminate processes affecting patients' drinking in relation to the discontinuation of medications within an alcohol treatment study. Although previous work has focused on broad measures of medication adherence, we focus on dynamic changes in drinking both before and after patients discontinue. DesignWe conducted secondary data analyses using the COMBINE (Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence) study, focused on participants who discontinued medications prior to the planned end of treatment. Using an interrupted time-series analysis, we analysed drinking in the weeks before and after discontinuation and also studied outcomes at the end of the COMBINE follow-up. SettingUnites States of America. ParticipantsWe describe the subsample of COMBINE participants who discontinued medications (n=450), and compare them with those who were medication-adherent (n=559) and with those who discontinued but had substantial missing data (n=217). MeasurementsThe primary outcomes were percentage of days abstinent (PDA) and percentage of heavy drinking days (PHDD). Medication adherence data were used to approximate the date of discontinuation. FindingsFor many patients, an increase in drinking began weeks before discontinuation (PDA: F-(1,F-4803)=19.07, P<0.001; PHDD: F-(1,F-4804)=8.58, P=0.003) then escalated at discontinuation (PDA: F-(1,F-446)=5.05, P=0.025; PHDD: F-(1,F-446)=4.52, P=0.034). Among other effects, the amount of change was moderated by the reason for discontinuation (e.g. adverse event; PDA: F-(2,F-4803)=3.85, P=0.021; PHDD: F-(2,F-4804)=5.36, P=0.005) and also whether it occurred in the first or second half of treatment (PDA: F-(1,F-4803)=5.23, P=0.022; PHDD: F-(1,F-4804)=8.79, P=0.003). ConclusionsA patient's decision to stop taking medications during alcohol treatment appears to take place during a weeks-long process of disengagement from treatment. Patients who discontinue medications early in treatment or without medical consultation appear to drink more frequently and more heavily. C1 [Stout, Robert L.; Braciszewski, Jordan M.] Pacific Inst Res & Evaluat, Decis Sci Inst, Pawtucket, RI 02860 USA. [Subbaraman, Meenakshi Sabina] Univ Calif Berkeley, Sch Publ Hlth, Alcohol Res Grp, Berkeley, CA 94720 USA. [Kranzler, Henry R.] Univ Penn, Philadelphia, PA 19104 USA. [O'Malley, Stephanie S.] Yale Univ, New Haven, CT USA. [Falk, Daniel] NIAAA, Div Treatment & Recovery Res, Rockville, MD 20852 USA. RP Stout, RL (reprint author), Pacific Inst Res & Evaluat, Decis Sci Inst, 1005 Main St,Suite 8120, Pawtucket, RI 02860 USA. EM stout@pire.org FU American Society of Clinical Psychopharmacology; NIAAA; Pacific Institute for Research and Evaluation FX This research was initiated by the Alcohol Clinical Trials Initiative (ACTIVE) group, which works to improve methods for alcohol research [21]. It is sponsored by the American Society of Clinical Psychopharmacology and was supported partially by contract funding by NIAAA, and also by support from the Pacific Institute for Research and Evaluation. In addition to the authors, the following individuals are or were members of the ACTIVE work-group and provided intellectual input into this paper during attendance at workgroup meetings: Raymond Anton (Chair; Medical University of South Carolina); Earle Bain MD, Abbott Laboratories; Carla Canuso MD, Johnson & Johnson Pharmaceutical Research and Development, LLC; Marc de Somer MD, Alkermes; Ellen Dennehy, Eli Lilly; Jay Graham PharmD, GlaxoSmithKline; Thomas Kosten MD, Baylor College of Medicine MIC; Karl Mann MD, Central Institute of Mental Health, Mannheim, Germany; David McCann PhD, NIDA; Didier Meulien MD, Lundbeck; Roger Meyer MD, Best Practice Management; Charles O'Brien MD, PhD, University of Pennsylvania; Stephanie O'Malley PhD, Yale University School of Medicine; Joseph Palumbo MD, formerly of Johnson & Johnson Pharmaceutical Research and Development, LLC; Thomas Permutt PhD, FDA; Beatrice Rendenbach-Mueller PhD, Abbott Laboratories; Rebecca Robinson MS, Eli Lilly & Company; Bernard Silverman MD, Alkermes; Lars Torup PhD, Lundbeck; Susan VanMeter MD, GlaxoSmithKline; Celia Winchell MD, FDA; and Conrad Wong PhD, Eli Lilly. Sarah Timm has provided important administrative support to the ACTIVE group. NR 21 TC 3 Z9 3 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD DEC PY 2014 VL 109 IS 12 BP 2044 EP 2052 DI 10.1111/add.12700 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA AT2QY UT WOS:000344780300017 PM 25098969 ER PT J AU Gwadz, M Cleland, CM Belkin, M Ritchie, A Leonard, N Riedel, M Banfield, A Colon, P Elharrar, V Kagan, J Mildvan, D AF Gwadz, Marya Cleland, Charles M. Belkin, Mindy Ritchie, Amanda Leonard, Noelle Riedel, Marion Banfield, Angela Colon, Pablo Elharrar, Vanessa Kagan, Jonathan Mildvan, Donna CA ACT2 Collaborative Res Team TI ACT2 Peer-Driven Intervention Increases Enrollment into HIV/AIDS Medical Studies Among African Americans/Blacks and Hispanics: A Cluster Randomized Controlled Trial SO AIDS AND BEHAVIOR LA English DT Article DE Clinical trials; HIV/AIDS; African American; Black; Hispanic; Minority; Motivational Interviewing; Health care disparities ID AIDS CLINICAL-TRIALS; RACIAL/ETHNIC DISPARITIES; UNITED-STATES; HIV; MINORITIES; CARE; PARTICIPATION; GENDER; ACCESS; RECRUITMENT AB African American/Black and Hispanic persons living with HIV/AIDS ("AABH-PLHA") are under-represented in HIV/AIDS medical studies (HAMS). This paper evaluates the efficacy of a social/behavioral intervention to increase rates of screening for and enrollment into HAMS in these populations. Participants (N = 540) were enrolled into a cluster randomized controlled trial of an intervention designed to overcome multi-level barriers to HAMS. Primary endpoints were rates of screening for and enrollment into therapeutic/treatment-oriented and observational studies. Intervention arm participants were 30 times more likely to be screened than controls (49.3 % vs. 3.7 %; p < .001). Half (55.5 %) of those screened were eligible for HAMS, primarily observational studies. Nine out of ten found eligible enrolled (91.7 %), almost all into observational studies (95.2 %), compared to no enrollments among controls. Achieving appropriate representation of AABH-PLHA in HAMS necessitates modification of study inclusion criteria to increase the proportion found eligible for therapeutic HAMS, in addition to social/behavioral interventions. C1 [Gwadz, Marya; Cleland, Charles M.; Belkin, Mindy; Ritchie, Amanda; Leonard, Noelle; Banfield, Angela; Colon, Pablo] NYU, Ctr Drug Use & HIV Res, Coll Nursing, New York, NY 10003 USA. [Riedel, Marion] Columbia Univ, Sch Social Work, New York, NY USA. [Elharrar, Vanessa; Kagan, Jonathan] NIAID, NIH, Bethesda, MD 20892 USA. [Mildvan, Donna] Mt Sinai Beth Israel Med Ctr, Div Infect Dis, New York, NY USA. RP Gwadz, M (reprint author), NYU, Ctr Drug Use & HIV Res, Coll Nursing, 726 Broadway,10th Floor, New York, NY 10003 USA. EM mg2890@nyu.edu FU NIAID NIH HHS [R01 AI070005, R01AI070005]; NIDA NIH HHS [P30 DA011041, P30DA011041] NR 51 TC 3 Z9 3 U1 3 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 DEC PY 2014 VL 18 IS 12 BP 2409 EP 2422 DI 10.1007/s10461-014-0829-5 PG 14 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA AT1ZY UT WOS:000344731300016 PM 24961193 ER PT J AU English, D Lambert, SF Evans, MK Zonderman, AB AF English, Devin Lambert, Sharon F. Evans, Michele K. Zonderman, Alan B. TI Neighborhood Racial Composition, Racial Discrimination, and Depressive Symptoms in African Americans SO AMERICAN JOURNAL OF COMMUNITY PSYCHOLOGY LA English DT Article DE Racial discrimination; African American; Neighborhood racial composition; Sociodemographics; Racial health disparities ID RESIDENTIAL SEGREGATION; UNITED-STATES; PERCEIVED DISCRIMINATION; SOCIOECONOMIC-STATUS; MULTILEVEL ANALYSIS; MENTAL-HEALTH; BLACK; LIFE; ADOLESCENTS; DISPARITIES AB While evidence indicates that experienced racial discrimination is associated with increased depressive symptoms for African Americans, there is little research investigating predictors of experienced racial discrimination. This paper examines neighborhood racial composition and sociodemographic factors as antecedents to experienced racial discrimination and resultant levels of depressive symptoms among African American adults. The sample included 505 socioeconomically-diverse African American adults from Baltimore, MD. Study data were obtained via self-report and geocoding of participant addresses based on 2010 census data. Study hypotheses were tested using multiple pathways within a longitudinal Structural Equation Model. Experienced racial discrimination was positively associated with age and sex such that older individuals and males experienced increased levels of racial discrimination. In addition, the percentage of White individuals residing in a neighborhood was positively associated with levels of experienced racial discrimination for African American neighborhood residents. Experienced racial discrimination was positively associated with later depressive symptoms. Neighborhood-level contextual factors such as neighborhood racial composition and individual differences in sociodemographic characteristics appear to play an important role in the experience of racial discrimination and the etiology of depression in African American adults. C1 [English, Devin; Lambert, Sharon F.] George Washington Univ, Dept Psychol, Washington, DC 20052 USA. [Evans, Michele K.; Zonderman, Alan B.] NIA, Biomed Res Ctr, Baltimore, MD 21224 USA. RP English, D (reprint author), George Washington Univ, Dept Psychol, 2125 G St NW, Washington, DC 20052 USA. EM de5@gwmail.gwu.edu; slambert@gwu.edu; me42v@nih.gov; zonderman@nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 FU NIDA NIH HHS [F31 DA036288] NR 55 TC 4 Z9 4 U1 5 U2 27 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0091-0562 EI 1573-2770 J9 AM J COMMUN PSYCHOL JI Am. J. Community Psychol. PD DEC PY 2014 VL 54 IS 3-4 BP 219 EP 228 DI 10.1007/s10464-014-9666-y PG 10 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Social Work SC Public, Environmental & Occupational Health; Psychology; Social Work GA AS8ZT UT WOS:000344534100003 PM 24969707 ER PT J AU Li, TT Liao, XY Lochhead, P Morikawa, T Yamauchi, M Nishihara, R Inamura, K Kim, SA Mima, K Sukawa, Y Kuchiba, A Imamura, Y Baba, Y Shima, K Meyerhardt, JA Chan, AT Fuchs, CS Ogino, S Qian, ZR AF Li, Tingting Liao, Xiaoyun Lochhead, Paul Morikawa, Teppei Yamauchi, Mai Nishihara, Reiko Inamura, Kentaro Kim, Sun A. Mima, Kosuke Sukawa, Yasutaka Kuchiba, Aya Imamura, Yu Baba, Yoshifumi Shima, Kaori Meyerhardt, Jeffrey A. Chan, Andrew T. Fuchs, Charles S. Ogino, Shuji Qian, Zhi Rong TI SMO Expression in Colorectal Cancer: Associations with Clinical, Pathological, and Molecular Features SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; HEDGEHOG SIGNALING PATHWAY; COLON-CANCER; MICROSATELLITE INSTABILITY; BRAF MUTATION; LINE-1 HYPOMETHYLATION; PROMOTER METHYLATION; PIK3CA MUTATION; ACTIVATION; DIFFERENTIATION AB Smoothened, frizzled family receptor (SMO) is an important component of the hedgehog signaling pathway, which has been implicated in various human carcinomas. However, clinical, molecular, and prognostic associations of SMO expression in colorectal cancer remain unclear. Using a database of 735 colon and rectal cancers in the Nurse's Health Study and the Health Professionals Follow-up Study, we examined the relationship of tumor SMO expression (assessed by immunohistochemistry) to prognosis, and to clinical, pathological, and tumor molecular features, including mutations of KRAS, BRAF, and PIK3CA, microsatellite instability, CpG island methylator phenotype (CIMP), LINE-1 methylation, and expression of phosphorylated AKT and CTNNB1. SMO expression was detected in 370 tumors (50 %). In multivariate logistic regression analysis, SMO expression was independently inversely associated with phosphorylated AKT expression [odds ratio (OR) 0.48; 95 % confidence interval (CI) 0.34-0.67] and CTNNB1 nuclear localization (OR 0.48; 95 % CI 0.35-0.67). SMO expression was not significantly associated with colorectal cancer-specific or overall survival. However, in CIMP-high tumors, but not CIMP-low/0 tumors, SMO expression was significantly associated with better colorectal cancer-specific survival (log-rank P = 0.012; multivariate hazard ratio, 0.36; 95 % CI 0.13-0.95; P (interaction) = 0.035, for SMO and CIMP status). Our data reveal novel potential associations between the hedgehog, the WNT/CTNNB1, and the PI3K (phosphatidylinositol-4,5-bisphosphonate 3-kinase)/AKT pathways, supporting pivotal roles of SMO and hedgehog signaling in pathway networking. SMO expression in colorectal cancer may interact with tumor CIMP status to affect patient prognosis, although confirmation by future studies is needed. C1 [Li, Tingting; Liao, Xiaoyun; Lochhead, Paul; Yamauchi, Mai; Nishihara, Reiko; Inamura, Kentaro; Kim, Sun A.; Mima, Kosuke; Sukawa, Yasutaka; Kuchiba, Aya; Imamura, Yu; Meyerhardt, Jeffrey A.; Fuchs, Charles S.; Ogino, Shuji; Qian, Zhi Rong] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Li, Tingting; Liao, Xiaoyun; Lochhead, Paul; Yamauchi, Mai; Nishihara, Reiko; Inamura, Kentaro; Kim, Sun A.; Mima, Kosuke; Sukawa, Yasutaka; Kuchiba, Aya; Imamura, Yu; Meyerhardt, Jeffrey A.; Fuchs, Charles S.; Ogino, Shuji; Qian, Zhi Rong] Harvard Univ, Sch Med, Boston, MA USA. [Li, Tingting] Chinese Peoples Liberat Army Gen Hosp, Dept Geriatr Gastroenterol, Beijing, Peoples R China. [Morikawa, Teppei] Tokyo Univ Hosp, Dept Pathol, Tokyo 113, Japan. [Nishihara, Reiko; Kuchiba, Aya] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Inamura, Kentaro] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Baba, Yoshifumi] Kumamoto Univ, Dept Surg Gastroenterol, Kumamoto, Japan. [Shima, Kaori] Kagoshima Univ, Dept Oral Pathol, Kagoshima 890, Japan. [Chan, Andrew T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Li, TT (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM shuji_ogino@dfci.harvard.edu; zhirong_qian@dfci.harvard.edu FU USA National Institute of Health (NIH) [P01 CA87969, UM1 CA167552, P01 CA55075, R01 CA137178, P50 CA127003, R01 CA151993]; Bennett Family Fund for Targeted Therapies Research; Entertainment Industry Foundation through National Colorectal Cancer Research Alliance; Harvard University Frank Knox Memorial Fellowship; Chief Scientist Office, Scotland FX Supported in part by USA National Institute of Health (NIH) [P01 CA87969 (to S. E. Hankinson), UM1 CA167552 and P01 CA55075 (to W. C. Willett), R01 CA137178 (to A. T. C.), P50 CA127003 (to C. S. F.), and R01 CA151993 (to S.O.)]; the Bennett Family Fund for Targeted Therapies Research; and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. PL was supported by a Harvard University Frank Knox Memorial Fellowship and a fellowship from the Chief Scientist Office, Scotland. A. T. C is a Damon Runyon Clinical Investigator. We would like to thank the participants and staff of the Nurses' Health Study and the Health Professionals Follow-Up Study for their valuable contributions, as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR PA, RI, SC, TN, TX, VA, WA, and WY. In addition, this study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Certain data used in this publication were obtained from the DPH. The authors assume full responsibility for analyses and interpretation of these data. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. Funding agencies did not have any role in the design of the study; the collection, analysis, or interpretation of the data; the decision to submit the article for publication; or the writing of the article. NR 69 TC 8 Z9 8 U1 0 U2 11 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 DEC PY 2014 VL 21 IS 13 BP 4164 EP 4173 DI 10.1245/s10434-014-3888-y PG 10 WC Oncology; Surgery SC Oncology; Surgery GA AT0LA UT WOS:000344626400019 PM 25023548 ER PT J AU Van Zee, KJ Hansen, NM Barrio, AV Connor, CS Danforth, DN Euhus, DM Kulkarni, SA McCready, DR McLaughlin, S Wilke, LG AF Van Zee, Kimberly J. Hansen, Nora M. Barrio, Andrea V. Connor, Carol S. Danforth, David N. Euhus, David M. Kulkarni, Swati A. McCready, David R. McLaughlin, Sarah Wilke, Lee G. TI Commentary on the Canadian National Breast Screening Study SO ANNALS OF SURGICAL ONCOLOGY LA English DT Letter AB In the setting of the 25-year follow-up of the Canadian National Breast Screening Study, the Society of Surgical Oncology continues to endorse mammographic screening for women beginning at 40 years of age, while acknowledging that mammography has both risks and benefits. Further investigation is warranted to develop better screening methods and to determine optimal screening schedules for women based on their risk of future breast cancer and their imaging characteristics. C1 [Van Zee, Kimberly J.] Mem Sloan Kettering Canc Ctr, Dept Surg, Breast Serv, New York, NY 10021 USA. [Hansen, Nora M.] Northwestern Univ, Prentice Womens Hosp, Lynn Sage Comprehens Breast Ctr, Chicago, IL 60611 USA. [Barrio, Andrea V.] Bryn Mawr Hosp, Dept Surg, Bryn Mawr, PA USA. [Connor, Carol S.] Univ Kansas, Med Ctr, Dept Surg, Kansas City, KS 66103 USA. [Danforth, David N.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Euhus, David M.] Johns Hopkins Med, Div Surg Oncol, Baltimore, MD USA. [Kulkarni, Swati A.] Univ Chicago, Dept Surg, Chicago, IL 60637 USA. [McCready, David R.] Princess Margaret Canc Ctr, Dept Surg Oncol, Toronto, ON, Canada. [McLaughlin, Sarah] Mayo Clin Florida, Dept Surg, Jacksonville, FL USA. [Wilke, Lee G.] Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, Madison, WI USA. RP Van Zee, KJ (reprint author), Mem Sloan Kettering Canc Ctr, Dept Surg, Breast Serv, New York, NY 10021 USA. EM vanzeek@mskcc.org OI Van Zee, Kimberly/0000-0001-9550-4647 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 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD DEC PY 2014 VL 21 IS 13 BP 4397 EP 4398 DI 10.1245/s10434-014-3789-0 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA AT0LA UT WOS:000344626400050 PM 24859935 ER PT J AU Bao, YM Chetvernin, V Tatusova, T AF Bao, Yiming Chetvernin, Vyacheslav Tatusova, Tatiana TI Improvements to pairwise sequence comparison (PASC): a genome-based web tool for virus classification SO ARCHIVES OF VIROLOGY LA English DT Article ID FILOVIRUSES; SEARCH; GENUS AB The number of viral genome sequences in the public databases is increasing dramatically, and these sequences are playing an important role in virus classification. Pairwise sequence comparison is a sequence-based virus classification method. A program using this method calculates the pairwise identities of virus sequences within a virus family and displays their distribution, and visual analysis helps to determine demarcations at different taxonomic levels such as strain, species, genus and subfamily. Subsequent comparison of new sequences against existing ones allows viruses from which the new sequences were derived to be classified. Although this method cannot be used as the only criterion for virus classification in some cases, it is a quantitative method and has many advantages over conventional virus classification methods. It has been applied to several virus families, and there is an increasing interest in using this method for other virus families/groups. The Pairwise Sequence Comparison (PASC) classification tool was created at the National Center for Biotechnology Information. The tool's database stores pairwise identities for complete genomes/segments of 56 virus families/groups. Data in the system are updated every day to reflect changes in virus taxonomy and additions of new virus sequences to the public database. The web interface of the tool makes it easy to navigate and perform analyses. Multiple new viral genome sequences can be tested simultaneously with this system to suggest the taxonomic position of virus isolates in a specific family. PASC eliminates potential discrepancies in the results caused by different algorithms and/or different data used by researchers. C1 [Bao, Yiming; Chetvernin, Vyacheslav; Tatusova, Tatiana] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Bao, YM (reprint author), NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM bao@mail.nih.gov FU NIH, National Library of Medicine FX We thank Detlef Leipe and Olga Blinkova for comments on the manuscript. This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 34 TC 19 Z9 19 U1 0 U2 16 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0304-8608 EI 1432-8798 J9 ARCH VIROL JI Arch. Virol. PD DEC PY 2014 VL 159 IS 12 BP 3293 EP 3304 DI 10.1007/s00705-014-2197-x PG 12 WC Virology SC Virology GA AT2ZS UT WOS:000344804200012 PM 25119676 ER PT J AU Liu, JF Zhao, LY Xue, YX Shi, J Suo, L Luo, YX Chai, BS Yang, C Fang, Q Zhang, Y Bao, YP Pickens, CL Lu, L AF Liu, Jianfeng Zhao, Liyan Xue, Yanxue Shi, Jie Suo, Lin Luo, Yixiao Chai, Baisheng Yang, Chang Fang, Qin Zhang, Yan Bao, Yanping Pickens, Charles L. Lu, Lin TI An Unconditioned Stimulus Retrieval Extinction Procedure to Prevent the Return of Fear Memory SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Extinction; fear memory; hippocampus; reconsolidation; retrieval; unconditioned stimulus ID POSTTRAUMATIC-STRESS-DISORDER; CONDITIONED FEAR; CONTEXTUAL FEAR; EXPOSURE THERAPY; D-CYCLOSERINE; RECONSOLIDATION; AMYGDALA; CONSOLIDATION; RELAPSE; HUMANS AB Background: Conditioned fear memories can be updated by extinction during reconsolidation, and this effect is specific to the reactivated conditioned stimulus (CS). However, a traumatic event can be associated with several cues, and each cue can potentially trigger recollection of the event. We introduced a technique to target all diverse cues associated with an aversive event that causes fear. Methods: In human experiments, 161 subjects underwent modified fear conditioning, in which they were exposed to an unconditioned stimulus (US) or unreinforced CS to reactivate the memory and then underwent extinction, spontaneous recovery, and reinstatement. In animal experiments, 343 rats underwent contextual fear conditioning under a similar protocol as that used in the human experiments. We also explored the molecular alterations after US reactivation in rats. Results: Presentation of a lower intensity US before extinction disrupted the associations between the different CS and reactivated US in both humans and rats. This effect persisted for at least 6 months in humans and was selective to the reactivated US. This procedure was also effective for remote memories in both humans and rats. Compared with the CS, the US induced stronger endocytosis of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors 1 and 2 and stronger activation of protein kinase A, p70S6 kinase, and cyclic adenosine monophosphate response element binding protein in the dorsal hippocampus in rats. Conclusions: These findings demonstrate that a modified US retrieval extinction strategy may have a potential impact on therapeutic approaches to prevent the return of fear. C1 [Liu, Jianfeng; Zhao, Liyan; Yang, Chang; Lu, Lin] Peking Univ, Inst Mental Hlth, Beijing 100191, Peoples R China. [Liu, Jianfeng; Zhao, Liyan; Yang, Chang; Lu, Lin] Peking Univ, Minist Hlth, Key Lab Mental Hlth, Beijing 100191, Peoples R China. [Liu, Jianfeng; Zhao, Liyan; Xue, Yanxue; Shi, Jie; Luo, Yixiao; Chai, Baisheng; Zhang, Yan; Bao, Yanping; Lu, Lin] Peking Univ, Natl Inst Drug Dependence, Beijing 100191, Peoples R China. [Lu, Lin] Peking Univ, Peking Tsinghua Ctr Life Sci, Beijing 100191, Peoples R China. [Lu, Lin] Peking Univ, Int Data Grp, McGovern Inst Brain Res, Beijing 100191, Peoples R China. [Suo, Lin] China MeiTan Gen Hosp, Dept Pharm, Beijing, Peoples R China. [Chai, Baisheng; Yang, Chang; Fang, Qin] Guiyang Med Univ, Sch Pharm, Guiyang, Peoples R China. [Chai, Baisheng; Yang, Chang; Fang, Qin] Guiyang Med Univ, Affiliated Hosp, Guiyang, Peoples R China. [Pickens, Charles L.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. RP Lu, L (reprint author), Peking Univ, Inst Mental Hlth, 38 Xue Yuan Rd, Beijing 100191, Peoples R China. EM linlu@bjmu.edu.cn OI Liu, Jianfeng/0000-0002-3464-6462 FU National Basic Research Program of China [2011CB707805]; Natural Science Foundation of China [31230033, 31100809, 81221002, 81225009]; National Institutes of Health/National Institute on Drug Abuse FX This work was supported in part by the National Basic Research Program of China (Grant No. 2011CB707805) and Natural Science Foundation of China (Grant Nos. 31230033, 31100809, 81221002, and 81225009). The preparation of this article was supported in part by the National Institutes of Health/National Institute on Drug Abuse. We thank Dr. Yavin Shaham and Shiqiu Meng for their helpful comments on the manuscript. CLP is currently affiliated with the Department of Psychological Sciences, Kansas State University, Manhattan, Kansas. NR 41 TC 15 Z9 16 U1 4 U2 38 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 DEC 1 PY 2014 VL 76 IS 11 BP 895 EP 901 DI 10.1016/j.biopsych.2014.03.027 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AT2AO UT WOS:000344733200012 PM 24813334 ER PT J AU Fan, RZ Zhu, B Wang, YD AF Fan, Ruzong Zhu, Bin Wang, Yuedong TI Stochastic dynamic models and Chebyshev splines SO CANADIAN JOURNAL OF STATISTICS-REVUE CANADIENNE DE STATISTIQUE LA English DT Article DE Brownian motion; Ornstein-Uhlenbeck process; Reproducing kernel Hilbert space; smoothing splines; stochastic differential equations ID REGRESSION; PRIORS AB In this article, we establish a connection between a stochastic dynamic model (SDM) driven by a linear stochastic differential equation (SDE) and a Chebyshev spline, which enables researchers to borrow strength across fields both theoretically and numerically. We construct a differential operator for the penalty function and develop a reproducing kernel Hilbert space (RKHS) induced by the SDM and the Chebyshev spline. The general form of the linear SDE allows us to extend the well-known connection between an integrated Brownian motion and a polynomial spline to a connection between more complex diffusion processes and Chebyshev splines. One interesting special case is connection between an integrated Ornstein-Uhlenbeck process and an exponential spline. We use two real data sets to illustrate the integrated Ornstein-Uhlenbeck process model and exponential spline model and show their estimates are almost identical. The Canadian Journal of Statistics 42: 610-634; 2014 (c) 2014 Statistical Society of Canada Resume Les auteurs etablissent un lien entre un modele stochastique dynamique base sur une equation differentielle stochastique lineaire et une spline de Chebyshev, permettant aux chercheurs de transferer des connaissances dans ces champs respectifs, autant d'un point de vue theorique que numerique. Ils construisent un operateur differentiel pour la fonction de penalite et developpent un espace de Hilbert a noyau reproduisant decoulant du modele stochastique dynamique et de la spline de Chebyshev. La forme generale de l'equation differentielle stochastique lineaire permet de generaliser le lien bien connu entre un mouvement brownien integre et une spline polynomiale a un lien entre des processus de diffusion plus complexes et les splines de Chebyshev. Un cas particulier d'interet lie un processus d'Ornstein-Uhlenbeck integre et une spline exponentielle. Les auteurs utilisent deux jeux de donnees reelles pour illustrer le processus d'Ornstein-Uhlenbeck integre et un modele de spline exponentielle. Ils montrent que les estimes obtenus sont presque identiques. La revue canadienne de statistique xx: 1-25; 2014 (c) 2014 Societe statistique du Canada C1 [Fan, Ruzong] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Zhu, Bin] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Wang, Yuedong] Univ Calif Santa Barbara, Dept Stat & Appl Probabil, Santa Barbara, CA 93106 USA. RP Fan, RZ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. EM fanr@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Maryland, USA FX We thank the editors, an associate editor and two referees for constructive comments that substantially improved an earlier draft and revision. This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Maryland, USA (Ruzong Fan). NR 28 TC 0 Z9 0 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0319-5724 EI 1708-945X J9 CAN J STAT JI Can. J. Stat.-Rev. Can. Stat. PD DEC PY 2014 VL 42 IS 4 BP 610 EP 634 DI 10.1002/cjs.11233 PG 25 WC Statistics & Probability SC Mathematics GA AT2ZU UT WOS:000344804400007 PM 26045632 ER PT J AU Doty, TJ Japee, S Ingvar, M Ungerleider, LG AF Doty, Tracy J. Japee, Shruti Ingvar, Martin Ungerleider, Leslie G. TI Intersubject variability in fearful face processing: the link between behavior and neural activation SO COGNITIVE AFFECTIVE & BEHAVIORAL NEUROSCIENCE LA English DT Article DE Emotion; Fearful faces; Ventromedial prefrontal cortex; Subgenual cingulate cortex; Striatum; Affective value ID VENTROMEDIAL PREFRONTAL CORTEX; EMOTIONAL FACIAL EXPRESSIONS; EXPERIMENTALLY INDUCED ANXIETY; HUMAN AMYGDALA; FUNCTIONAL CONNECTIVITY; INDIVIDUAL-DIFFERENCES; PREDICTION ERRORS; VISUAL AWARENESS; ATTENTIONAL BIAS; SKIN-CONDUCTANCE AB Stimuli that signal threat show considerable variability in the extents to which they enhance behavior, even among healthy individuals. However, the neural underpinning of this behavioral variability is not well understood. By manipulating expectation of threat in an fMRI study of fearful versus neutral face categorization, we uncovered a network of areas underlying variability in threat processing in healthy adults. We explicitly altered expectations by presenting face images at three different expectation levels: 80 %, 50 %, and 20 %. Subjects were instructed to report as quickly and accurately as possible whether the face was fearful (signaled threat) or not. An uninformative cue preceded each face by 4 s. By taking the difference between reaction times (RTs) to fearful and neutral faces, we quantified an overall fear RT bias (i.e., faster to fearful than to neutral faces) for each subject. This bias correlated positively with late-trial fMRI activation (8 s after the face) during unexpected-fearful-face trials in bilateral ventromedial prefrontal cortex, the left subgenual cingulate cortex, and the right caudate nucleus, and correlated negatively with early-trial fMRI activation (4 s after the cue) during expected-neutral-face trials in bilateral dorsal striatum and the right ventral striatum. These results demonstrate that the variability in threat processing among healthy adults is reflected not only in behavior, but also in the magnitude of activation in medial prefrontal and striatal regions that appear to encode affective value. C1 [Doty, Tracy J.; Japee, Shruti; Ungerleider, Leslie G.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Doty, Tracy J.; Ingvar, Martin] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Doty, Tracy J.] US Army Res Lab, Translat Neurosci Branch, Human Res & Engn Directorate, Aberdeen Proving Ground, MD 21005 USA. RP Doty, TJ (reprint author), US Army Res Lab, Translat Neurosci Branch, Human Res & Engn Directorate, Aberdeen Proving Ground, MD 21005 USA. EM tracy.doty@alumni.duke.edu OI Doty, Tracy/0000-0001-9921-2457; Ingvar, Martin/0000-0002-9041-5714 FU Intramural NIH HHS [ZIA MH002035-33] NR 68 TC 6 Z9 6 U1 5 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-7026 EI 1531-135X J9 COGN AFFECT BEHAV NE JI Cogn. Affect. Behav. Neurosci. PD DEC PY 2014 VL 14 IS 4 BP 1438 EP 1453 DI 10.3758/s13415-014-0290-y PG 16 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA AT0TP UT WOS:000344648000020 PM 24841078 ER PT J AU Damiano, DL AF Damiano, Diane L. TI Meaningfulness of mean group results for determining the optimal motor rehabilitation program for an individual child with cerebral palsy SO DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY LA English DT Review ID INDUCED MOVEMENT THERAPY; PHYSICAL-THERAPY; RESEARCH DESIGNS; CLASSIFICATION; INTERVENTION; OUTCOMES; INFANTS; HEALTH; ADULTS; GAIT AB As research on the efficacy or effectiveness of interventions to improve motor functioning in cerebral palsy (CP) has accumulated and been incorporated into systematic reviews, the foundation for evidence-based practice in CP is growing. To determine whether an intervention is effective, clinical trials report mean group differences. However, even if a statistically significant mean group effect is found, this does not imply that this intervention was effective for each study participant or ensure positive outcomes for all with CP. A personalized approach to medical care is currently being advocated based primarily on increasingly recognized genetic variations in individual responses to medications and other therapies. A similar approach is also warranted, and perhaps more justifiable, in CP which includes a heterogeneous group of disorders. Even interventions deemed highly effective in CP demonstrate a range of individual responses along a continuum from a negative or negligible response to a strong positive effect, the bases for which remain incompletely understood. This narrative review recommends that the next critical step in advancing evidence-based practice is to implement research strategies to identify patient factors that predict treatment responses so we can not only answer the question what works', but also what works best, for whom'. C1 NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Damiano, DL (reprint author), NIH, Dept Rehabil Med, Ctr Clin, 10 Ctr Dr,Room 1-1469, Bethesda, MD 20892 USA. EM damianod@cc.nih.gov RI Damiano, Diane/B-3338-2010 OI Damiano, Diane/0000-0002-2770-5356 FU Intramural NIH HHS [Z99 CL999999] NR 36 TC 11 Z9 11 U1 1 U2 15 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 DEC PY 2014 VL 56 IS 12 BP 1141 EP 1146 DI 10.1111/dmcn.12505 PG 6 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA AT2SS UT WOS:000344786500008 PM 24919877 ER PT J AU Bao, W Tobias, D Olsen, S Zhang, CL AF Bao, Wei Tobias, Deirdre K. Olsen, Sjurdur F. Zhang, Cuilin TI Pre-pregnancy fried food consumption and the risk of gestational diabetes mellitus: a prospective cohort study SO DIABETOLOGIA LA English DT Article DE Diet; Fried food; Gestational diabetes mellitus ID TRANS-FATTY-ACIDS; END-PRODUCTS; LIFE-STYLE; DIETARY; QUESTIONNAIRE; DISEASE; NUTRITION; WOMEN; REPRODUCIBILITY; REGRESSION AB Fried foods are frequently consumed in Western countries. However, the health effects of frequent fried food consumption in humans are not well understood. We aimed to prospectively examine the association between pre-pregnancy fried food consumption and risk of incident gestational diabetes mellitus (GDM). We included 21,079 singleton pregnancies from 15,027 women in the Nurses' Health Study II cohort. Since 1991 and every 4 years thereafter, we collected diet information, including consumption of fried foods at home and away from home, using a validated food frequency questionnaire. We used generalised estimating equations with log-binomial models to estimate the RRs and 95% CIs. We documented 847 incident GDM pregnancies during 10 years of follow-up. After adjustment for age, parity, dietary and non-dietary factors, the RRs (95% CIs) of GDM among women who consumed total fried foods 1-3, 4-6 and a parts per thousand yen7 times/week, compared with those who consumed it less than once/week, were 1.13 (0.97, 1.32), 1.31 (1.08, 1.59) and 2.18 (1.53, 3.09), respectively (p for trend < 0.001). The association persisted after further adjustment for BMI (p for trend = 0.01). When analysed separately, we found a significant association of GDM with fried food consumption away from home, but not with fried food consumption at home. Frequent fried food consumption, particularly away from home, was significantly associated with a greater risk of incident GDM. Our study indicates potential benefits of limiting fried food consumption in the prevention of GDM in women of reproductive age. C1 [Bao, Wei; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Tobias, Deirdre K.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Tobias, Deirdre K.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Tobias, Deirdre K.] Harvard Univ, Sch Med, Boston, MA USA. [Olsen, Sjurdur F.] Statens Serum Inst, Ctr Fetal Programming, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. EM zhangcu@mail.nih.gov OI Bao, Wei/0000-0002-7301-5786 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN275201000020C]; National Institutes of Health [DK58845, CA50385, P30 DK46200, UM1 CA176726]; American Diabetes Association [7-12-MN-34] FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract No. HHSN275201000020C). The Nurses' Health Study II was funded by research grants DK58845, CA50385, P30 DK46200 and UM1 CA176726 from the National Institutes of Health. DKT was supported by a mentored fellowship from the American Diabetes Association (No. 7-12-MN-34). NR 35 TC 12 Z9 13 U1 0 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD DEC PY 2014 VL 57 IS 12 BP 2485 EP 2491 DI 10.1007/s00125-014-3382-x PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AT0MR UT WOS:000344630700010 PM 25303998 ER PT J AU Traynor, BJ Cleveland, DW AF Traynor, Bryan J. Cleveland, Don W. TI Special Issue on amyotrophic lateral sclerosis SO EXPERIMENTAL NEUROLOGY LA English DT Editorial Material ID ALS; CELLS C1 [Traynor, Bryan J.] NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Traynor, Bryan J.] Johns Hopkins Univ, Dept Neurol, Brain Sci Inst, Baltimore, MD 21218 USA. [Cleveland, Don W.] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA USA. [Cleveland, Don W.] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA USA. RP Traynor, BJ (reprint author), NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, NIH, 5500 Nathan Shock Dr, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA AG000933-02] NR 14 TC 0 Z9 0 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 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD DEC PY 2014 VL 262 SI SI BP 73 EP 74 DI 10.1016/j.expneurol.2014.08.020 PN B PG 2 WC Neurosciences SC Neurosciences & Neurology GA AS8PQ UT WOS:000344510800001 PM 25158310 ER PT J AU Wang, XT Pittman, GS Bandele, OJ Bischof, JJ Liu, G Brothers, JF Spira, A Bell, DA AF Wang, Xuting Pittman, Gary S. Bandele, Omari J. Bischof, Jason J. Liu, Gang Brothers, John F., II Spira, Avrum Bell, Douglas A. TI Linking polymorphic p53 response elements with gene expression in airway epithelial cells of smokers and cancer risk SO HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; LUNG-CANCER; IDENTIFICATION; EPIDEMIOLOGY; MUTATION; FIELD; LOCI AB Chronic cigarette smoking exposes airway epithelial cells to thousands of carcinogens, oxidants and DNA-damaging agents, creating a field of molecular injury in the airway and altering gene expression. Studies of cytologically normal bronchial epithelial cells from smokers have identified transcription-based biomarkers that may prove useful in early diagnosis of lung cancer, including a number of p53-regulated genes. The ability of p53 to regulate transcription is critical for tumor suppression, and this suggests that single-nucleotide polymorphisms (SNPs) in functional p53 binding sites (p53 response elements, or p53REs) that affect gene expression could influence susceptibility to cancer. To connect p53RE SNP genotype with gene expression and cancer risk, we identified a set of 204 SNPs in putative p53REs, and performed cis expression quantitative trait loci (eQTL) analysis, assessing associations between SNP genotypes and mRNA levels of adjacent genes in bronchial epithelial cells obtained from 44 cigarette smokers. To further test and validate these genotype-expression associations, we searched published eQTL studies from independent populations and determined that 53 % (39/74) of the bronchial epithelial eQTLs were observed in at least one of other studies. SNPs in p53REs were also evaluated for effects on p53-DNA binding using a quantitative in vitro protein-DNA binding assay. Last, based on linkage disequilibrium, we found 6 p53RE SNPs associated with gene expression were identified as cancer risk SNPs by either genome-wide association studies or candidate gene studies. We provide an approach for identifying and evaluating potentially functional SNPs that may modulate the airway gene expression response to smoking and may influence susceptibility to cancers. C1 [Wang, Xuting; Pittman, Gary S.; Bandele, Omari J.; Bischof, Jason J.; Bell, Douglas A.] NIEHS, Environm Genom Sect, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Liu, Gang; Brothers, John F., II; Spira, Avrum] Boston Univ, Dept Med, Sect Computat Biomed, Boston, MA 02118 USA. RP Bell, DA (reprint author), NIEHS, Environm Genom Sect, Mol Genet Lab, NIH, Mail Drop C3-03,111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM bell1@niehs.nih.gov OI Wang, Xuting/0000-0001-6781-8008 FU National Institute of Environmental Health Sciences, National Institutes of Health [ZO1-ES100475, Z01 ES046008]; National Institute of Health [U01ES016035, R01CA124640] FX This work was funded in part by the Intramural Research Program (projects: ZO1-ES100475 and Z01 ES046008) of the National Institute of Environmental Health Sciences, National Institutes of Health and grants to Avrum Spira from the National Institute of Health (U01ES016035, R01CA124640). We are grateful for comments from Drs. Daniel Menendez and Jack Taylor, NIEHS. NR 35 TC 2 Z9 2 U1 1 U2 11 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 DEC PY 2014 VL 133 IS 12 BP 1467 EP 1476 DI 10.1007/s00439-014-1483-8 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA AT5UK UT WOS:000345007600002 PM 25179167 ER PT J AU Guerrero, AD Dong, MB Zhao, YG Lau-Kilby, A Tarbell, KV AF Guerrero, Alan D. Dong, Matthew B. Zhao, Yongge Lau-Kilby, Annie Tarbell, Kristin V. TI Interleukin-2-mediated inhibition of dendritic cell development correlates with decreased CD135 expression and increased monocyte/macrophage precursors SO IMMUNOLOGY LA English DT Article DE dendritic cell; Flt3; interleukin-2 ID BONE-MARROW; IN-VIVO; ANTITUMOR IMMUNITY; GENE-EXPRESSION; GM-CSF; HOMEOSTASIS; TOLERANCE; LIGAND; MOUSE; DIFFERENTIATION AB We have previously shown that interleukin-2 (IL-2) inhibits dendritic cell (DC) development from mouse bone marrow (BM) precursors stimulated with the ligand for FMS-like tyrosine kinase 3 receptor (Flt3L), and have provided evidence that this inhibition occurs at the monocyte DC precursor stage of DC development. Here, we explored the mechanism of IL-2-mediated inhibition of DC development. First, we showed that these in vitro cultures accurately model DCs that develop in vivo by comparing gene and protein expression of the three main Flt3L-induced DC subsets from the BM, CD11b(+) and CD24(+) conventional DCs (cDCs) and plasmacytoid DCs (pDCs) with their respective ex vivo spleen DC subsets (CD11b(+), CD8(+) and pDCs). Next, gene expression changes were quantified in Flt3L DC subsets that developed in the presence of IL-2. These changes included increased expression of Bcl2l11, which encodes the apoptosis-inducing protein Bim, and decreased expression of Flt3 (CD135), the receptor that initiates DC development. Interleukin-2 also significantly reduced Flt3 protein expression on all three Flt3L DC subsets, and attenuated Flt3L-induced STAT3 phosphorylation in DCs. Based on these data, we hypothesized that decreased Flt3 signalling may divert BM precursors down monocyte and macrophage lineages. Indeed, addition of IL-2 led to increases in Flt3(-) cells, including cKit(+)Ly6C(+)CD11b(-) populations consistent with the recently identified committed monocyte/macrophage progenitor. Therefore, IL-2 can inhibit DC development via decreased signalling through Flt3 and increased monocyte/macrophage development. C1 [Guerrero, Alan D.; Dong, Matthew B.; Zhao, Yongge; Lau-Kilby, Annie; Tarbell, Kristin V.] NIDDK, Immune Tolerance Sect, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Tarbell, KV (reprint author), NIDDK, Immune Tolerance Sect, Diabet Endocrinol & Obes Branch, NIH,CRC,West Labs, Bldg 10,5-5940, Bethesda, MD 20892 USA. EM tarbellk@niddk.nih.gov OI Lau-Kilby, Annie/0000-0002-2666-1347; Tarbell, Kristin/0000-0003-3738-379X FU Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases FX We would like to acknowledge Alice Franks (Diabetes, Endocrinology, and Obesity Branch, NIDDK) for help with mouse husbandry, Heidi Sardon and Dr Phil McCoy from the NIDDK/NHLBI flow core for help with sorting, Dr Weiping Chen for bioinformatics support, and Mary Walter from the NIDDK clinical laboratory core for helping with running the Luminex Assay. We thank Dr Giorgio Trinchieri, Dr Amiran K. Dzutsev and Dr Romina S. Goldszmid (National Cancer Institute) for helpful discussions. This study used data assembled by the ImmGen consortium. This work was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases. ADG designed and performed experiments, analysed data and wrote the manuscript; MBD performed experiments, analysed data, and edited the manuscript. YZ performed experiments and analysed data; AL-K designed experiments and edited the manuscript; KVT designed experiments, analysed data and wrote the manuscript. NR 40 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 EI 1365-2567 J9 IMMUNOLOGY JI Immunology PD DEC PY 2014 VL 143 IS 4 BP 640 EP 650 DI 10.1111/imm.12345 PG 11 WC Immunology SC Immunology GA AT2RF UT WOS:000344781200015 PM 24954893 ER PT J AU Watts, DH Stek, A Best, BM Wang, JJ Capparelli, EV Cressey, TR Aweeka, F Lizak, P Kreitchmann, R Burchett, SK Shapiro, DE Hawkins, E Smith, E Mirochnick, M AF Watts, D. Heather Stek, Alice Best, Brookie M. Wang, Jiajia Capparelli, Edmund V. Cressey, Tim R. Aweeka, Francesca Lizak, Patty Kreitchmann, Regis Burchett, Sandra K. Shapiro, David E. Hawkins, Elizabeth Smith, Elizabeth Mirochnick, Mark CA IMPAACT 1026s Study Team TI Raltegravir Pharmacokinetics During Pregnancy SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; pregnancy; raltegravir; pharmacokinetics ID TREATMENT-NAIVE PATIENTS; HIV-1; THERAPY AB Objective: We evaluated the pharmacokinetics (PK) of raltegravir in HIV-infected women during pregnancy and postpartum. Methods: International Maternal Pediatric Adolescent AIDS Clinical Trials 1026s is an ongoing prospective study of antiretroviral PK during pregnancy (NCT00042289). Women receiving 400 mg raltegravir twice daily in combination antiretroviral therapy had intensive steady-state 12-hour PK profiles performed during pregnancy and at 6- to 12-week postpartum. Targets were trough concentration above 0.035 mu g/mL, the estimated 10th percentile in nonpregnant historical controls. Results: Median raltegravir area under the curve was 6.6 mu g.h/mL for second trimester (n = 16), 5.4 mu g.h/mL for third trimester (n = 41), and 11.6 mu g.h/mL postpartum (n = 38) (P = 0.03 postpartum vs second trimester, P = 0.001 pp vs third trimester). Trough concentrations were above the target in 69%, 80%, and 79% of second trimester, third trimester, and postpartum subjects, respectively, with wide variability (<0.010-0.917 mu g/mL), and no significant difference between third trimester and postpartum trough concentrations was detected. The median ratio of cord blood/maternal raltegravir concentrations was 1.5. HIV RNA levels were <400 copies per milliliter in 92% of women at delivery. Adverse events included elevated liver transaminases in 1 woman and vomiting in 1. All infants with known status are HIV uninfected. Conclusions: Median raltegravir area under the curve was reduced by approximately 50% during pregnancy; trough concentrations were frequently below target both during late pregnancy and postpartum. Raltegravir readily crossed the placenta. High rates of viral suppression at delivery and the lack of a clear relationship between raltegravir concentration and virologic effect in nonpregnant adults suggest that despite the decreased exposure during pregnancy, a higher dose is not necessary. C1 [Watts, D. Heather] US Dept State, Off Global AIDS Coordinator, Washington, DC 20520 USA. [Stek, Alice] Univ So Calif, Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. [Best, Brookie M.; Capparelli, Edmund V.] Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. [Best, Brookie M.; Capparelli, Edmund V.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, San Diego, CA 92103 USA. [Wang, Jiajia; Shapiro, David E.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA USA. [Cressey, Tim R.] Chiang Mai Univ, Program HIV Prevent & Treatment IRD URI 174, Dept Med Technol, Fac Associated Med Sci, Chiang Mai 50000, Thailand. [Aweeka, Francesca; Lizak, Patty] Univ Calif San Francisco, Dept Clin Pharm, Drug Res Unit, San Francisco, CA 94143 USA. [Kreitchmann, Regis] Irmandade Santa Casa Misericordia Porto Alegre, HIV AIDS Res Dept, Porto Alegre, RS, Brazil. [Burchett, Sandra K.] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA USA. [Hawkins, Elizabeth] Social & Sci Syst Inc, Silver Spring, MD USA. [Smith, Elizabeth] NIAID, Maternal Adolescent & Pediat Res Branch, Bethesda, MD 20892 USA. [Mirochnick, Mark] Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. RP Watts, DH (reprint author), Off Global AIDS Coordinator, 2100 Penn Ave,Suite 200, Washington, DC 20037 USA. EM wattsdh@state.gov FU National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [UM1AI068632, UM1AI068616, UM1AI106716]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH); National Center for Research Resources [UL1RR024134]; National Center for Advancing Translational Sciences, National Institutes of Health, through the Clinical and Translational Science Awards Program (CTSA) [UL1TR000003, UL1TR000101] 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) of the National Institutes of Health (NIH) under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC), and UM1AI106716 (IMPAACT LC), with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). The project described was also supported by the National Center for Research Resources, Grant UL1RR024134, and is now at the National Center for Advancing Translational Sciences, Grants UL1TR000003 and UL1TR000101 (previously UL1RR031975) from the National Center for Advancing Translational Sciences, National Institutes of Health, through the Clinical and Translational Science Awards Program (CTSA), a trademark of DHHS, part of the Roadmap Initiative, "Re-Engineering the Clinical Research Enterprise." NR 15 TC 12 Z9 12 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 1 PY 2014 VL 67 IS 4 BP 375 EP 381 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AT2NR UT WOS:000344771900007 PM 25162818 ER PT J AU Granader, Y Wallace, GL Hardy, KK Yerys, BE Lawson, RA Rosenthal, M Wills, MC Dixon, E Pandey, J Penna, R Schultz, RT Kenworthy, L AF Granader, Yael Wallace, Gregory L. Hardy, Kristina K. Yerys, Benjamin E. Lawson, Rachel A. Rosenthal, Michael Wills, Meagan C. Dixon, Eunice Pandey, Juhi Penna, Rebecca Schultz, Robert T. Kenworthy, Lauren TI Characterizing the Factor Structure of Parent Reported Executive Function in Autism Spectrum Disorders: The Impact of Cognitive Inflexibility SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Autism spectrum disorder; Cognitive flexibility; Executive functioning; Behavior Rating Inventory of Executive Function; Factor analysis ID CONFIRMATORY FACTOR-ANALYSIS; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; BEHAVIOR RATING INVENTORY; TRAUMATIC BRAIN-INJURY; DEVELOPMENTAL DISORDERS; DIAGNOSTIC INTERVIEW; REAL-WORLD; CHILDREN; SYMPTOMS; FLEXIBILITY AB Parents of children with autism spectrum disorders (ASD) consistently report executive functioning (EF) deficits. This study investigates the factor structure of the Behavior Rating Inventory of Executive Function (BRIEF) as reported by parents of children with ASD and typically developing children (TDC). BRIEFs for 411 children with ASD and 467 TDC were examined. Confirmatory factor analysis of a nine-factor model met thresholds for goodness-of-fit in TDC, but not in the ASD sample. We found globally elevated EF problems in the ASD sample, especially on the Shift scale. These findings confirm that children with ASD exhibit significant EF deficits. Further investigation is needed to understand the pervasive nature of cognitive inflexibility in children with ASD. C1 [Granader, Yael; Hardy, Kristina K.; Lawson, Rachel A.; Rosenthal, Michael; Wills, Meagan C.; Kenworthy, Lauren] Childrens Natl Med Ctr, Rockville, MD 20850 USA. [Wallace, Gregory L.; Dixon, Eunice] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Wallace, Gregory L.] George Washington Univ, Dept Speech & Hearing Sci, Washington, DC USA. [Yerys, Benjamin E.; Pandey, Juhi; Penna, Rebecca; Schultz, Robert T.] Childrens Hosp Philadelphia, Ctr Autism Res, Philadelphia, PA 19104 USA. [Yerys, Benjamin E.; Pandey, Juhi; Penna, Rebecca; Schultz, Robert T.] Univ Penn, Philadelphia, PA 19104 USA. [Lawson, Rachel A.] Loyola Univ Maryland, Baltimore, MD USA. RP Granader, Y (reprint author), Childrens Natl Med Ctr, 15245 Shady Grove Rd,Suite 350, Rockville, MD 20850 USA. EM ygranade@childrensnational.org; gregwallace@mail.nih.gov; kkhardy@childrensnational.org; YerysB@email.chop.edu; rlawson@loyola.edu; Michael.Rosenthal@childmind.org; meagancwills@gmail.com; euniceedixon@gmail.com; pandeyj@email.chop.edu; rebeccajpenna@gmail.com; schultzrt@email.chop.edu; Lkenwort@childrensnational.org OI Hardy, Kristina/0000-0002-5479-5043; Wallace, Gregory/0000-0003-0329-5054 FU NIMH NIH HHS [1RC1MH088791, RC1 MH088791] NR 52 TC 10 Z9 10 U1 6 U2 33 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 EI 1573-3432 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD DEC PY 2014 VL 44 IS 12 BP 3056 EP 3062 DI 10.1007/s10803-014-2169-8 PG 7 WC Psychology, Developmental SC Psychology GA AT3AM UT WOS:000344806500009 PM 24972681 ER PT J AU George, SM Alfano, CM Neuhouser, ML Smith, AW Baumgartner, RN Baumgartner, KB Bernstein, L Ballard-Barbash, R AF George, Stephanie M. Alfano, Catherine M. Neuhouser, Marian L. Smith, Ashley W. Baumgartner, Richard N. Baumgartner, Kathy B. Bernstein, Leslie Ballard-Barbash, Rachel TI Better postdiagnosis diet quality is associated with less cancer-related fatigue in breast cancer survivors SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Diet; Fatigue; Breast cancer survivor; Health behavior; Inflammation ID C-REACTIVE PROTEIN; PHYSICAL-ACTIVITY; OF-LIFE; HEALTH; INFLAMMATION; UPDATE; QUESTIONNAIRE; WOMEN; SERUM AB A comprehensive understanding of the role of modifiable health behaviors in effective management of cancer-related fatigue is needed. Among breast cancer survivors, we examined how postdiagnosis diet quality, independently and jointly with physical activity, is related to fatigue, and the potential mediating role of inflammation. Seven hundred seventy women diagnosed with stage 0-IIIA breast cancer in the Health, Eating, Activity, and Lifestyle study completed food frequency and physical activity questionnaires 30 months postdiagnosis. We scored diet quality using the Healthy Eating Index 2010 (HEI-2010). Serum concentrations of C-reactive protein (CRP) were measured in fasting 30-ml blood samples. Multidimensional fatigue was measured 41 months postdiagnosis using the 22-item revised Piper Fatigue Scale. In multivariate linear models, we determined whether fatigue was associated HEI-2010 quartiles (Q1-Q4), and a variable jointly reflecting HEI quartiles and physical activity levels. Survivors with better-quality diets (Q4 vs. Q1) had lower total fatigue (4.1 vs. 4.8, p-contrast = 0.003) and subscale scores (behavioral severity 3.4 vs. 4.2, p-contrast = 0.003; affective meaning 3.9 vs. 4.8, p-contrast = 0.007; sensory 4.4 vs. 5.2, p-contrast = 0.003; cognitive 4.6 vs. 5.0, p-contrast = 0.046). Least squares estimates of fatigue were similar in models including CRP. Compared to survivors with poor-quality diets and no physical activity, survivors with better-quality diets and meeting physical activity recommendations had significantly lower behavioral severity (3.2 vs. 4.7, p-contrast = 0.002) and sensory (3.8 vs. 4.8. p-contrast = 0.006) fatigue scores. In this large breast cancer survivor cohort, postdiagnosis diet quality was inversely and independently associated with fatigue. Future interventions designed to improve multiple energy balance behaviors can provide insight into their associations with fatigue. C1 [George, Stephanie M.; Smith, Ashley W.; Ballard-Barbash, Rachel] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Alfano, Catherine M.] NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Baumgartner, Richard N.; Baumgartner, Kathy B.] Univ Louisville, James Graham Brown Canc Ctr, Dept Epidemiol & Populat Hlth, Louisville, KY 40292 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Dept Populat Sci, Beckman Res Inst, Duarte, CA USA. RP George, SM (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,MSC 9762, Bethesda, MD 20892 USA. EM stephanie.george@nih.gov FU National Cancer Institute [N01-CN-75036-20, NO1-CN-05228, NO1-PC-67010]; Applied Research Program of the National Cancer Institute FX We would like to thank Dr. Charles L. Wiggins, Dr. Anne McTiernan, 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, and NO1-PC-67010 and, in part, by the Applied Research Program of the National Cancer Institute. NR 41 TC 8 Z9 8 U1 3 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 EI 1932-2267 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD DEC PY 2014 VL 8 IS 4 BP 680 EP 687 DI 10.1007/s11764-014-0381-3 PG 8 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA AT0IF UT WOS:000344619400017 PM 25001403 ER PT J AU Li, NZ Wang, WT Sati, P Pham, DL Butman, JA AF Li, Ningzhi Wang, Wen-Tung Sati, Pascal Pham, Dzung L. Butman, John A. TI Quantitative Assessment of Susceptibility-Weighted Imaging Processing Methods SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE susceptibility weighted imaging; homodyne filter; phase unwrapping; image contrast ID PHASE-UNWRAPPING ALGORITHM; MRI; VENOGRAPHY AB PurposeTo evaluate different susceptibility-weighted imaging (SWI) phase processing methods and parameter selection, thereby improving understanding of potential artifacts, as well as facilitating choice of methodology in clinical settings. Materials and MethodsTwo major phase processing methods, homodyne-filtering and phase unwrapping-high pass (HP) filtering, were investigated with various phase unwrapping approaches, filter sizes, and filter types. Magnitude and phase images were acquired from a healthy subject and brain injury patients on a 3T clinical Siemens MRI system. The results were evaluated based on image contrast-to-noise ratio and presence of processing artifacts. ResultsWhen using a relatively small filter size (32 pixels for the matrix size 512 x 512 pixels), all homodyne-filtering methods were subject to phase errors leading to 2% to 3% masked brain area in lower and middle axial slices. All phase unwrapping-filtering/smoothing approaches demonstrated fewer phase errors and artifacts compared to the homodyne-filtering approaches. For performing phase unwrapping, Fourier-based methods, although less accurate, were 2-4 orders of magnitude faster than the PRELUDE, Goldstein, and Quality-guide methods. ConclusionAlthough homodyne-filtering approaches are faster and more straightforward, phase unwrapping followed by HP filtering approaches perform more accurately in a wider variety of acquisition scenarios. J. Magn. Reson. Imaging 2014;40:1463-1473. (c) 2013 Wiley Periodicals, Inc. C1 [Li, Ningzhi; Pham, Dzung L.; Butman, John A.] Ctr Neurosci & Regenerat Med, Image Proc Core, Bethesda, MD 21046 USA. [Wang, Wen-Tung] Ctr Neurosci & Regenerat Med, Human Imaging Core, Bethesda, MD 21046 USA. [Sati, Pascal] NINDS, Translat Neuroradiol Unit, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Butman, John A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Li, NZ (reprint author), Ctr Neurosci & Regenerat Med, Image Proc Core, 10 Ctr Dr,B1N264B, Bethesda, MD 21046 USA. EM ningzhi.li@nih.gov RI Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 FU Department of Defense; National Institutes of Health in the Center for Neuroscience and Regenerative Medicine FX Contract grant sponsor: Department of Defense and The National Institutes of Health in the Center for Neuroscience and Regenerative Medicine. NR 20 TC 2 Z9 2 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD DEC PY 2014 VL 40 IS 6 BP 1463 EP 1473 DI 10.1002/jmri.24501 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AT2SQ UT WOS:000344786200024 PM 24923594 ER PT J AU Loya, SR Kawamoto, K Chatwin, C Huser, V AF Loya, Salvador Rodriguez Kawamoto, Kensaku Chatwin, Chris Huser, Vojtech TI Service Oriented Architecture for Clinical Decision Support: A Systematic Review and Future Directions SO JOURNAL OF MEDICAL SYSTEMS LA English DT Article DE Literature review; Service oriented architecture; Clinical decision support; Business process management; Service orientation ID INFORMATION-TECHNOLOGY; EXECUTION ENGINE; NATIONAL ACTION; CHALLENGES; GUIDELINES; EXPERIENCE; MANAGEMENT; STANDARD; QUALITY; ROADMAP AB The use of a service-oriented architecture (SOA) has been identified as a promising approach for improving health care by facilitating reliable clinical decision support (CDS). A review of the literature through October 2013 identified 44 articles on this topic. The review suggests that SOA related technologies such as Business Process Model and Notation (BPMN) and Service Component Architecture (SCA) have not been generally adopted to impact health IT systems' performance for better care solutions. Additionally, technologies such as Enterprise Service Bus (ESB) and architectural approaches like Service Choreography have not been generally exploited among researchers and developers. Based on the experience of other industries and our observation of the evolution of SOA, we found that the greater use of these approaches have the potential to significantly impact SOA implementations for CDS C1 [Loya, Salvador Rodriguez; Chatwin, Chris] Univ Sussex, Sch Engn & Informat, Brighton BN1 9QT, E Sussex, England. [Kawamoto, Kensaku] Univ Utah, Dept Biomed Informat, Salt Lake City, UT USA. [Huser, Vojtech] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Loya, SR (reprint author), Univ Sussex, Sch Engn & Informat, Shawcross Bldg, Brighton BN1 9QT, E Sussex, England. EM s.rodriguez-loya@sussex.ac.uk FU Intramural Research Program of the National Institutes of Health Clinical Center; National Library of Medicine; University Of Utah Department Of Biomedical Informatics FX VH is supported by the Intramural Research Program of the National Institutes of Health Clinical Center and the National Library of Medicine.; KK's effort for this review was supported by the University Of Utah Department Of Biomedical Informatics. KK has in the recent past or is currently serving as a consultant on CDS to the following organizations: the U.S. Office of the National Coordinator for Health IT, Partners HealthCare, RAND Corporation, ESAC, Inc., McKesson InterQual, ARUP Laboratories, Inflexxion, Inc., and Intelligent Automation, Inc. KK receives royalties for a Duke University-owned CDS technology for infectious disease management known as CustomID that he helped develop. KK was formerly a consultant for Religent, Inc. and a co-owner and consultant for Clinica Software, Inc., both of which provide commercial CDS services. KK no longer has a financial relationship with either Religent or Clinica Software. NR 82 TC 2 Z9 2 U1 6 U2 23 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0148-5598 EI 1573-689X J9 J MED SYST JI J. Med. Syst. PD DEC PY 2014 VL 38 IS 12 AR 140 DI 10.1007/s10916-014-0140-z PG 22 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA AS9IH UT WOS:000344556000002 PM 25325996 ER PT J AU Livingston, DP Tuong, TD Kissling, GE Cullen, JM AF Livingston, David P., III Tuong, Tan D. Kissling, Grace E. Cullen, John M. TI Visualizing surface area and volume of lumens in three dimensions using images from histological sections SO JOURNAL OF MICROSCOPY LA English DT Article DE 3-D reconstruction; histology; liver; negative space; portal tract AB Visualizing the interior (lumen) of a tubular structure within tissue can provide a unique perspective on anatomical organization of the tissue. Portal tracts of the liver contain several vessels and ducts in various patterns of intertwining branches and are an example of such spaces. An inexpensive method, using light microscopy and a sample of conventionally stained canine livers, was used to colorize and allow visualization of the lumens of vessels within the portal tract in three dimensions. When the colour of the background was digitally cleared and the lumen filled with a solid colour, it was possible to measure areas and volumes of the portal vein, arteries, bile ducts and lymphatics. Significant differences between vessels and ducts across lobes and gender in control samples are discussed. Differences were also found between control and mixed breed dogs and between controls and a dog that died of accidental traumatic haemorrhage. These differences are discussed in relation to visualizing lumens using images generated from a light microscope. Vessels in plants such as xylem and continuously formed spaces resulting from ice formation are other examples where this technique could be applied. C1 [Livingston, David P., III; Tuong, Tan D.] ARS, USDA, Raleigh, NC USA. [Livingston, David P., III; Tuong, Tan D.] N Carolina State Univ, Dept Crop Sci, Raleigh, NC 27695 USA. [Kissling, Grace E.] NIEHS, Res Triangle Pk, NC 27709 USA. [Cullen, John M.] N Carolina State Univ, Coll Vet Med, Raleigh, NC USA. RP Livingston, DP (reprint author), USDA, 840 Method Rd,Unit 3, Raleigh, NC 27695 USA. EM dpl@ncsu.edu FU Intramural NIH HHS [ZIA ES103106-03] NR 9 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-2720 EI 1365-2818 J9 J MICROSC-OXFORD JI J. Microsc.. PD DEC PY 2014 VL 256 IS 3 BP 190 EP 196 DI 10.1111/jmi.12171 PG 7 WC Microscopy SC Microscopy GA AT0TR UT WOS:000344648200004 PM 25204459 ER PT J AU Johnson, B Neuberger, T Gay, M Hallett, M Slobounov, S AF Johnson, Brian Neuberger, Thomas Gay, Michael Hallett, Mark Slobounov, Semyon TI Effects of Subconcussive Head Trauma on the Default Mode Network of the Brain SO JOURNAL OF NEUROTRAUMA LA English DT Article DE default mode network; concussion; subconcussive head trauma; resting-state ID COLLEGIATE FOOTBALL PLAYERS; FUNCTIONAL CONNECTIVITY; RECURRENT CONCUSSION; ORBITOFRONTAL CORTEX; INJURY; IMPACT; MILD; ENCEPHALOPATHY; FMRI; NEUROINFLAMMATION AB Although they are less severe than a full blown concussive episodes, subconcussive impacts happen much more frequently and current research has suggested this form of head trauma may have an accumulative effect and lead to neurological impairment later in life. To investigate the acute effects that subconcussive head trauma may have on the default mode network of the brain resting-state, functional magnetic resonance was performed. Twenty-four current collegiate rugby players were recruited and all subjects underwent initial scanning 24 h prior to a scheduled full contact game to provide a baseline. Follow-up scanning of the rugby players occurred within 24 h following that game to assess acute effects from subconcussive head trauma. Differences between pre-game and post-game scans showed both increased connectivity from the left supramarginal gyrus to bilateral orbitofrontal cortex and decreased connectivity from the retrosplenial cortex and dorsal posterior cingulate cortex. To assess whether or not a history of previous concussion may lead to a differential response following subconcussive impacts, subjects were further divided into two subgroups based upon history of previous concussion. Individuals with a prior history of concussion exhibited only decreased functional connectivity following exposure to subconcussive head trauma, while those with no history showed increased connectivity. Even acute exposure to subconcussive head trauma demonstrates the ability to alter functional connectivity and there is possible evidence of a differential response in the brain for those with and without a history of concussion. C1 [Johnson, Brian; Gay, Michael; Slobounov, Semyon] Penn State Univ, Dept Kinesiol, University Pk, PA 16802 USA. [Neuberger, Thomas] Penn State Univ, Dept Bioengn, University Pk, PA 16802 USA. [Neuberger, Thomas] Penn State Univ, Huck Inst Life Sci, University Pk, PA 16802 USA. [Hallett, Mark; Slobounov, Semyon] NINDS, NIH, Bethesda, MD 20892 USA. [Slobounov, Semyon] Penn State Milton S Hershey Med Ctr, Dept Neurosurg, Hershey, PA USA. RP Johnson, B (reprint author), Penn State Univ, Dept Kinesiol, Ctr Sport Concuss Res, 19 Recreat Bldg, University Pk, PA 16802 USA. EM bdj5039@psu.edu FU American Society of Radiological Technologists Education and Research Foundation FX This research was partly supported by The American Society of Radiological Technologists Education and Research Foundation. NR 45 TC 11 Z9 11 U1 1 U2 11 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 DEC 1 PY 2014 VL 31 IS 23 BP 1907 EP 1913 DI 10.1089/neu.2014.3415 PG 7 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AT6US UT WOS:000345075500002 PM 25010992 ER PT J AU Shakir, NA George, AK Siddiqui, MM Rothwax, JT Rais-Bahrami, S Stamatakis, L Su, D Okoro, C Raskolnikov, D Walton-Diaz, A Simon, R Turkbey, B Choyke, PL Merino, MJ Wood, BJ Pinto, PA AF Shakir, Nabeel A. George, Arvin K. Siddiqui, M. Minhaj Rothwax, Jason T. Rais-Bahrami, Soroush Stamatakis, Lambros Su, Daniel Okoro, Chinonyerem Raskolnikov, Dima Walton-Diaz, Annerleim Simon, Richard Turkbey, Baris Choyke, Peter L. Merino, Maria J. Wood, Bradford J. Pinto, Peter A. TI Identification of Threshold Prostate Specific Antigen Levels to Optimize the Detection of Clinically Significant Prostate Cancer by Magnetic Resonance Imaging/Ultrasound Fusion Guided Biopsy SO JOURNAL OF UROLOGY LA English DT Article DE prostate; prostatic neoplasms; diagnostic imaging; prostate-specific antigen; biopsy ID TRANSRECTAL ULTRASOUND BIOPSY; PRIOR NEGATIVE BIOPSY; ACTIVE SURVEILLANCE; MEN; RISK; MR AB Purpose: Prostate specific antigen sensitivity increases with lower threshold values but with a corresponding decrease in specificity. Magnetic resonance imaging/ultrasound targeted biopsy detects prostate cancer more efficiently and of higher grade than standard 12-core transrectal ultrasound biopsy but the optimal population for its use is not well defined. We evaluated the performance of magnetic resonance imaging/ultrasound targeted biopsy vs 12-core biopsy across a prostate specific antigen continuum. Materials and Methods: We reviewed the records of all patients enrolled in a prospective trial who underwent 12-core transrectal ultrasound and magnetic resonance imaging/ultrasound targeted biopsies from August 2007 through February 2014. Patients were stratified by each of 4 prostate specific antigen cutoffs. The greatest Gleason score using either biopsy method was compared in and across groups as well as across the population prostate specific antigen range. Clinically significant prostate cancer was defined as Gleason 7 (4 + 3) or greater. Univariate and multivariate analyses were performed. Results: A total of 1,003 targeted and 12-core transrectal ultrasound biopsies were performed, of which 564 diagnosed prostate cancer for a 56.2% detection rate. Targeted biopsy led to significantly more upgrading to clinically significant disease compared to 12-core biopsy. This trend increased more with increasing prostate specific antigen, specifically in patients with prostate specific antigen 4 to 10 and greater than 10 ng/ml. Prostate specific antigen 5.2 ng/ml or greater captured 90% of upgrading by targeted biopsy, corresponding to 64% of patients who underwent multiparametric magnetic resonance imaging and subsequent fusion biopsy. Conversely a greater proportion of clinically insignificant disease was detected by 12-core vs targeted biopsy overall. These differences persisted when controlling for potential confounders on multivariate analysis. Conclusions: Prostate cancer upgrading with targeted biopsy increases with an increasing prostate specific antigen cutoff. Above a prostate specific antigen threshold of 5.2 ng/ml most upgrading to clinically significant disease was achieved by targeted biopsy. In our population this corresponded to potentially sparing biopsy in 36% of patients who underwent multiparametric magnetic resonance imaging. Below this value 12-core biopsy detected more clinically insignificant cancer. Thus, the diagnostic usefulness of targeted biopsy is optimized in patients with prostate specific antigen 5.2 ng/ml or greater. C1 [Shakir, Nabeel A.; George, Arvin K.; Siddiqui, M. Minhaj; Rothwax, Jason T.; Rais-Bahrami, Soroush; Stamatakis, Lambros; Su, Daniel; Okoro, Chinonyerem; Raskolnikov, Dima; Walton-Diaz, Annerleim; Pinto, Peter A.] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Simon, Richard] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Wood, Bradford J.; Pinto, Peter A.] NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Wood, Bradford J.; Pinto, Peter A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,MSC 1210,Bldg 10,CRC Room 2W-5940, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov OI Siddiqui, Mohummad/0000-0002-4484-6820; Rais-Bahrami, Soroush/0000-0001-9466-9925 FU National Institutes of Health Intramural Research Program, National Cancer Institute, Center for Cancer Research; National Institutes of Health Medical Research Scholars Program (Pfizer); National Institutes of Health Medical Research Scholars Program (The Doris Duke Charitable Foundation); National Institutes of Health Medical Research Scholars Program (The Alexandria Real Estate Equities); National Institutes of Health Medical Research Scholars Program (Howard Hughes Medical Institute) FX Supported by the National Institutes of Health Intramural Research Program, National Cancer Institute, Center for Cancer Research and the National Institutes of Health Medical Research Scholars Program (Pfizer, The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities, Mr. and Mrs. Joel S. Marcus, the Howard Hughes Medical Institute and other private donors). NR 24 TC 25 Z9 25 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD DEC PY 2014 VL 192 IS 6 BP 1642 EP 1648 DI 10.1016/j.juro.2014.08.002 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AT9AF UT WOS:000345219300017 PM 25117476 ER PT J AU Moore, IN Lamirande, EW Paskel, M Donahue, D Qin, J Subbarao, K AF Moore, Ian N. Lamirande, Elaine W. Paskel, Myeisha Donahue, Danielle Qin, Jing Subbarao, Kanta TI Severity of Clinical Disease and Pathology in Ferrets Experimentally Infected with Influenza Viruses Is Influenced by Inoculum Volume SO JOURNAL OF VIROLOGY LA English DT Article ID AIRBORNE TRANSMISSION; PROTECTS FERRETS; A/H5N1 VIRUS; A VIRUS; IN-VIVO; H1N1; PATHOGENESIS; MICE; H5N1; IMMUNIZATION AB Ferrets are a valuable model for influenza virus pathogenesis, virus transmission, and antiviral therapy studies. However, the contributions of the volume of inoculum administered and the ferret's respiratory tract anatomy to disease outcome have not been explored. We noted variations in clinical disease outcomes and the volume of inoculum administered and investigated these differences by administering two influenza viruses (A/California/07/2009 [H1N1 pandemic] and A/Minnesota/11/2010 [H3N2 variant]) to ferrets intranasally at a dose of 10(6) 50% tissue culture infective doses in a range of inoculum volumes (0.2, 0.5, or 1.0 ml) and followed viral replication, clinical disease, and pathology over 6 days. Clinical illness and respiratory tract pathology were the most severe and most consistent when the viruses were administered in a volume of 1.0 ml. Using a modified micro-computed tomography imaging method and examining gross specimens, we found that the right main-stem bronchus was consistently larger in diameter than the left main-stem bronchus, though the latter was longer and straighter. These anatomic features likely influence the distribution of the inoculum in the lower respiratory tract. A 1.0-ml volume of inoculum is optimal for delivery of virus to the lower respiratory tract of ferrets, particularly when evaluation of clinical disease is desired. Furthermore, we highlight important anatomical features of the ferret lung that influence the kinetics of viral replication, clinical disease severity, and lung pathology. IMPORTANCE Ferrets are a valuable model for influenza virus pathogenesis, virus transmission, and antiviral therapy studies. Clinical disease in ferrets is an important parameter in evaluating the virulen ce of novel influenza viruses, and findings are extrapolated to virulence in humans. Therefore, it is highly desirable that the data from different laboratories be accurate and reproducible. We have found that, even when the same virus was administered at similar doses, different investigators reported a range of clinical disease outcomes, from asymptomatic infection to severe weight loss, ocular and nasal discharge, sneezing, and lethargy. We found that a wide range of inoculum volumes was used to experimentally infect ferrets, and we sought to determine whether the variations in disease outcome were the result of the volume of inoculum administered. These data highlight some less explored features of the model, methods of experimental infection, and clinical disease outcomes in a research setting. C1 [Moore, Ian N.; Lamirande, Elaine W.; Paskel, Myeisha; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Donahue, Danielle] NIAID, Mouse Imaging Facil, NIH, Bethesda, MD 20892 USA. [Qin, Jing] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Subbarao, K (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID) FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID). NR 37 TC 10 Z9 10 U1 0 U2 5 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 DEC PY 2014 VL 88 IS 23 BP 13879 EP 13891 DI 10.1128/JVI.02341-14 PG 13 WC Virology SC Virology GA AT3CI UT WOS:000344812800030 PM 25187553 ER PT J AU Bouvin-Pley, M Morgand, M Meyer, L Goujard, C Moreau, A Mouquet, H Nussenzweig, M Pace, C Ho, D Bjorkman, PJ Baty, D Chames, P Pancera, M Kwong, PD Poignard, P Barin, F Braibant, M AF Bouvin-Pley, M. Morgand, M. Meyer, L. Goujard, C. Moreau, A. Mouquet, H. Nussenzweig, M. Pace, C. Ho, D. Bjorkman, P. J. Baty, D. Chames, P. Pancera, M. Kwong, P. D. Poignard, P. Barin, F. Braibant, M. TI Drift of the HIV-1 Envelope Glycoprotein gp120 toward Increased Neutralization Resistance over the Course of the Epidemic: a Comprehensive Study Using the Most Potent and Broadly Neutralizing Monoclonal Antibodies SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; N-GLYCAN RECOGNITION; IN-VIVO; DEPENDENT EPITOPE; STRUCTURAL BASIS; RATIONAL DESIGN; HUMANIZED MICE; CD4 BINDING; DOMAIN; SELECTION AB Extending our previous analyses to the most recently described monoclonal broadly neutralizing antibodies (bNAbs), we confirmed a drift of HIV-1 clade B variants over 2 decades toward higher resistance to bNAbs targeting almost all the identified gp120-neutralizing epitopes. In contrast, the sensitivity to bNAbs targeting the gp41 membrane-proximal external region remained stable, suggesting a selective pressure on gp120 preferentially. Despite this evolution, selected combinations of bNAbs remain capable of neutralizing efficiently most of the circulating variants. C1 [Bouvin-Pley, M.; Morgand, M.; Moreau, A.; Barin, F.; Braibant, M.] Univ Tours, INSERM, U966, Tours, France. [Meyer, L.; Goujard, C.] Univ Paris 11, CESP, INSERM, U1018, Paris, France. [Meyer, L.; Goujard, C.] Hop Bicetre, AP HP, Le Kremlin Bicetre, France. [Mouquet, H.] Inst Pasteur, Dept Immunol, Lab Humoral Response Pathogens, F-75724 Paris, France. [Nussenzweig, M.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA. [Pace, C.; Ho, D.] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA. [Bjorkman, P. J.] CALTECH, Pasadena, CA 91125 USA. [Baty, D.; Chames, P.] CNRS, INSERM, CRCM, Inst Paoli Calmettes,UMR7258,U1068, Marseille, France. [Pancera, M.; Kwong, P. D.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Poignard, P.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Poignard, P.] Neutralizing Antibody Ctr, Int AIDS Vaccine Initiat, La Jolla, CA USA. [Barin, F.] CHU Bretonneau, Lab Bacteriol Virol, F-37044 Tours, France. [Barin, F.] CHU Bretonneau, Ctr Natl Reference VIH, F-37044 Tours, France. RP Braibant, M (reprint author), Univ Tours, INSERM, U966, Tours, France. EM braibant@med.univ-tours.fr RI poignard, pascal/N-6678-2013; Chames, Patrick/R-1800-2016; OI Chames, Patrick/0000-0002-6104-6286; Baty, Daniel/0000-0001-8443-4444 FU Agence Nationale de Recherches sur le SIDA et les hepatites (ANRS, Paris, France); Vaccine Research Center, NIAID, NIH; Region Centre and Sidaction (France); ANRS FX This work was supported by the Agence Nationale de Recherches sur le SIDA et les hepatites (ANRS, Paris, France) and in part by the intramural program of the Vaccine Research Center, NIAID, NIH. Melanie Bouvin-Pley was supported by doctoral fellowships from the Region Centre and Sidaction (France). Marion Morgand was supported by a doctoral fellowship from the ANRS. NR 48 TC 13 Z9 13 U1 0 U2 12 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 DEC PY 2014 VL 88 IS 23 BP 13910 EP 13917 DI 10.1128/JVI.02083-14 PG 8 WC Virology SC Virology GA AT3CI UT WOS:000344812800033 PM 25231299 ER PT J AU Tu, TW Budde, MD Xie, MQ Chen, YJ Wang, Q Quirk, JD Song, SK AF Tu, Tsang-Wei Budde, Matthew D. Xie, Mingqiang Chen, Ying-Jr Wang, Qing Quirk, James D. Song, Sheng-Kwei TI Phase-aligned multiple spin-echo averaging: a simple way to improve signal-to-noise ratio of in vivo mouse spinal cord diffusion tensor image SO MAGNETIC RESONANCE IMAGING LA English DT Article DE Bayesian phasing analysis; Multiple spin-echo; DTI; Spinal cord ID CARR-PURCELL SEQUENCES; WHITE-MATTER PATHOLOGY; OPTIC-NERVE; MR-IMAGES; MAGNITUDE IMAGES; RETINAL ISCHEMIA; AXONAL INJURY; DETECTS; TIME; COEFFICIENT AB Purpose: To improve signal-noise-ratio of in vivo mouse spinal cord diffusion tensor imaging using-phase aligned multiple spin-echo technique. Material and methods: In vivo mouse spinal cord diffusion tensor imaging maps generated by multiple spin-echo and conventional spin-echo diffusion weighting were examined to demonstrate the efficacy of multiple spin-echo diffusion sequence to improve image quality and throughput. Effects of signal averaging using complex, magnitude and phased images from multiple spin-echo diffusion weighting were also assessed. Bayesian probability theory was used to generate phased images by moving the coherent signals to the real channel to eliminate the effect of phase variation between echoes while preserving the Gaussian noise distribution. Signal averaging of phased multiple spin-echo images potentially solves both the phase incoherence problem and the bias of the elevated Rician noise distribution in magnitude image. The proposed signal averaging with Bayesian phase-aligned multiple spin-echo images approach was compared to the conventional spin-echo data acquired with doubling the scan time. The diffusion tensor imaging parameters were compared in the mouse contusion spinal cord injury. Significance level (p-value) and effect size (Cohen's d) were reported between the control and contused spinal cord to inspect the sensitivity of each approach in detecting white matter pathology. Results: Compared to the spin-echo image, the signal-noise-ratio increased to 1.84-fold using the phased image averaging and to 1.30-fold using magnitude image averaging in the spinal cord white matter. Multiple spin-echo phased image averaging showed improved image quality of the mouse spinal cord among the tested methods. Diffusion tensor imaging metrics obtained from multiple spin-echo phased images using three echoes and two averages closely agreed with those derived by spin-echo magnitude data with four averages (two times more in acquisition time). The phased image averaging correctly reflected pathological features in contusion spinal cord injury. Conclusion: Our in vivo imaging results indicate that averaging the phased multiple spin-echo images yields an 84% signal-noise-ratio increase over the spin-echo images and a 41% gain over the magnitude averaged multiple spin-echo images with equal acquisition time. Current results from the animal model of spinal cord injury suggest that the phased multiple spin-echo images could be used to improve signal-noise-ratio. (C) 2014 Elsevier Inc. All rights reserved. C1 [Tu, Tsang-Wei] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Budde, Matthew D.] Med Coll Wisconsin, Dept Neurosurg, Milwaukee, WI 53226 USA. [Xie, Mingqiang; Quirk, James D.] Washington Univ, Dept Pathol & Immunol, St Louis, MO USA. [Chen, Ying-Jr] Washington Univ, Dept Chem, St Louis, MO 63130 USA. [Wang, Qing; Song, Sheng-Kwei] Washington Univ, Dept Radiol, St Louis, MO 63130 USA. RP Song, SK (reprint author), Washington Univ, Dept Radiol, St Louis, MO 63130 USA. EM ssong@wustl.edu FU NINDS NIH HHS [P01 NS059560, P01- NS 059560, R01 - NS047592, R01 NS047592] NR 59 TC 2 Z9 2 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X EI 1873-5894 J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD DEC PY 2014 VL 32 IS 10 BP 1335 EP 1343 DI 10.1016/j.mri.2014.07.004 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AT1WM UT WOS:000344721800025 PM 25087856 ER PT J AU Heitzeg, MM Villafuerte, S Weiland, BJ Enoch, MA Burmeister, M Zubieta, JK Zucker, RA AF Heitzeg, Mary M. Villafuerte, Sandra Weiland, Barbara J. Enoch, Mary-Anne Burmeister, Margit Zubieta, Jon-Kar Zucker, Robert A. TI Effect of GABRA2 Genotype on Development of Incentive-Motivation Circuitry in a Sample Enriched for Alcoholism Risk SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID REWARD ANTICIPATION; GABA(A) RECEPTORS; NUCLEUS-ACCUMBENS; ADOLESCENT BRAIN; ALPHA-2 SUBUNIT; DEPENDENCE; BEHAVIOR; NEUROBIOLOGY; ACTIVATION; CHILDREN AB Heightened reactivity of the incentive-motivation system has been proposed to underlie adolescent-typical risky behaviors, including problem alcohol involvement. However, even in adolescence considerable individual variation in these behaviors exists, which may have genetic underpinnings and be related to variations in risk for later alcohol use disorder (AUD). Variants in GABRA2 have been associated with adult alcohol dependence as well as phenotypic precursors, including impulsiveness and extemalizing behaviors. We investigated the impact of GABRA2 on the developmental trajectory of nucleus accumbens (NAcc) activation during anticipation of monetary reward from childhood to young adulthood. Functional MRI during a monetary incentive delay task was collected in 175 participants, with the majority (n = 151) undergoing repeated scanning at 1 - to 2-year intervals. One group entered the study at age 8-13 years (n = 76) and another entered at age 18-23 years (n = 99). Most participants were children of alcoholics (79%) and thus at heightened risk for AUD. A total of 473 sessions were completed, covering ages 8-27 years. NAcc activation was heightened during adolescence compared with childhood and young adulthood. GABRA2 genotype (SNP rs279858) was associated with individual differences in NAcc activation specifically during adolescence, with the minor allele (G) associated with greater activation. Furthermore, NAcc activation mediated an effect of genotype on alcohol problems (n = 104). This work demonstrates an impact of GABRA2 genotype on incentive-motivation neurocircuitry in adolescence, with implications for vulnerability to alcoholism. These findings represent an important step toward understanding the genetic and neural basis of individual differences in how risk for addiction unfolds across development. C1 [Heitzeg, Mary M.; Villafuerte, Sandra; Weiland, Barbara J.; Burmeister, Margit; Zubieta, Jon-Kar; Zucker, Robert A.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Heitzeg, Mary M.; Weiland, Barbara J.; Zucker, Robert A.] Univ Michigan, Addict Res Ctr, Ann Arbor, MI 48109 USA. [Villafuerte, Sandra; Burmeister, Margit; Zubieta, Jon-Kar] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. [Weiland, Barbara J.] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. [Enoch, Mary-Anne] NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. [Burmeister, Margit] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. RP Heitzeg, MM (reprint author), Univ Michigan, Dept Psychiat, 4250 Plymouth Rd, Ann Arbor, MI 48109 USA. EM mheitzeg@umich.edu FU Phil F. Jenkins Research Fund; Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH; [R01 DA027261]; [R01 AA12217]; [R37 AA07065]; [K01 DA020088] FX This work was supported by R01 DA027261 to MMH, JKZ, and RAZ, R01 AA12217 to RAZ and MMH, R37 AA07065 to RAZ, and K01 DA020088 to MMH, and by the Phil F. Jenkins Research Fund (JKZ). This research was also supported in part by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH (MAE). NR 50 TC 14 Z9 14 U1 6 U2 24 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 DEC PY 2014 VL 39 IS 13 BP 3077 EP 3086 DI 10.1038/npp.2014.161 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AT3KT UT WOS:000344834600016 PM 24975023 ER PT J AU Heilig, MA AF Heilig, Markus A. TI Daniel W. Hommer In Memoriam SO NEUROPSYCHOPHARMACOLOGY LA English DT Biographical-Item C1 NIAAA, NIH, Bethesda, MD 20852 USA. RP Heilig, MA (reprint author), NIAAA, NIH, Bethesda, MD 20852 USA. EM markus.heilig@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 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 DEC PY 2014 VL 39 IS 13 BP 3128 EP 3128 DI 10.1038/npp.2014.249 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AT3KT UT WOS:000344834600023 PM 25381706 ER PT J AU Skolnick, P AF Skolnick, Phil TI Harry L June In Memoriam SO NEUROPSYCHOPHARMACOLOGY LA English DT Biographical-Item C1 Natl Inst Drug Abuse, Div Pharmacotherapies & Med Consequences Drug Abu, Bethesda, MD 20892 USA. RP Skolnick, P (reprint author), Natl Inst Drug Abuse, Div Pharmacotherapies & Med Consequences Drug Abu, Bethesda, MD 20892 USA. EM phil.skolnick@nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 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 DEC PY 2014 VL 39 IS 13 BP 3135 EP 3135 DI 10.1038/npp.2014.254 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AT3KT UT WOS:000344834600028 PM 25381711 ER PT J AU Musci, RJ Bradshaw, CP Maher, B Uhl, GR Kellam, SG Ialongo, NS AF Musci, Rashelle J. Bradshaw, Catherine P. Maher, Brion Uhl, George R. Kellam, Sheppard G. Ialongo, Nicholas S. TI Reducing Aggression and Impulsivity Through School-Based Prevention Programs: A Gene by Intervention Interaction SO PREVENTION SCIENCE LA English DT Article DE Aggression; Impulsivity; Genes; Brain-derived neurotrophic factor; Intervention; Schools ID STATE-OCCASION MODEL; DISRUPTIVE BEHAVIOR; SOCIOECONOMIC-STATUS; DISORDER; ASSOCIATION; OUTCOMES; BDNF; ENVIRONMENT; 1ST-GRADE; CLASSROOM AB A variety of school-based, universal preventive interventions have been developed to address behavioral and mental health problems. Unfortunately, few have been evaluated within the context of randomized controlled trials with long-term follow-up. Even fewer still have examined the potential genetic factors that may drive differential impact of the intervention. In the present analysis, we examine the extent to which the longitudinal effects of two elementary school-based interventions were moderated by the brain-derived neurotrophic factor (BDNF) gene, which has been linked with aggression and impulsive behaviors. The sample included 678 urban, primarily African American children who were randomly assigned along with their teachers to one of three first grade classroom conditions: classroom-centered (CC) intervention, Family School Partnership (FSP), or a control condition. The teacher ratings of the youth's aggressive and impulsive behavior were obtained at baseline and in grades 6-12. Single-nucleotide polymorphisms (SNPs) from the BDNF gene were extracted from the genome-wide data. Longitudinal latent trait-state-error models indicated a significant interaction between a particular profile of the BDNF SNP cluster (46 % of sample) and CC intervention on impulsivity (beta = -.27, p < .05). A similar interaction was observed for the BDNF SNP cluster and the CC intervention on aggression (beta = -.14, p < .05). The results suggest that the impacts of preventive interventions in early elementary school on late adolescent outcomes of impulsivity and aggression can be potentially modified by genetic factors, such as BDNF. However, replication of these results is necessary before firm conclusions can be drawn. C1 [Musci, Rashelle J.; Bradshaw, Catherine P.; Maher, Brion; Kellam, Sheppard G.; Ialongo, Nicholas S.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD 21205 USA. [Uhl, George R.] NIDA, Mol Neurobiol Div, Intramural Res Program, Baltimore, MD USA. RP Musci, RJ (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Rm 806,624 N Broadway,Hampton House 850t, Baltimore, MD 21205 USA. EM rmusci@jhsph.edu FU Intramural NIH HHS; NIDA NIH HHS [R37 DA11796, R01 DA011796, R37 DA011796]; NIMH NIH HHS [MH57005, R01 MH057005, T32 MH018834, T32 MH18834]; PHS HHS [T71MC08054] NR 45 TC 9 Z9 9 U1 3 U2 17 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 EI 1573-6695 J9 PREV SCI JI Prev. Sci. PD DEC PY 2014 VL 15 IS 6 BP 831 EP 840 DI 10.1007/s11121-013-0441-3 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AT3AN UT WOS:000344806700009 PM 24178584 ER PT J AU Musci, RJ Bradshaw, CP Maher, B Uhl, GR Kellam, SG Ialongo, NS AF Musci, Rashelle J. Bradshaw, Catherine P. Maher, Brion Uhl, George R. Kellam, Sheppard G. Ialongo, Nicholas S. TI Reducing Aggression and Impulsivity Through School-Based Prevention Programs: A Gene by Intervention Interaction (vol 15, pg 831, 2014) SO PREVENTION SCIENCE LA English DT Correction C1 [Musci, Rashelle J.; Bradshaw, Catherine P.; Maher, Brion; Kellam, Sheppard G.; Ialongo, Nicholas S.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD 21205 USA. [Uhl, George R.] NIDA, Mol Neurobiol Div, Intramural Res Program, Baltimore, MD USA. RP Musci, RJ (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Rm 806,624 N Broadway,Hampton House 850t, Baltimore, MD 21205 USA. EM rmusci@jhsph.edu NR 1 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 EI 1573-6695 J9 PREV SCI JI Prev. Sci. PD DEC PY 2014 VL 15 IS 6 BP 841 EP 841 DI 10.1007/s11121-014-0504-0 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AT3AN UT WOS:000344806700010 PM 25149870 ER PT J AU Augier, E Flanigan, M Dulman, RS Pincus, A Schank, JR Rice, KC Kejun, C Heilig, M Tapocik, JD AF Augier, E. Flanigan, M. Dulman, R. S. Pincus, A. Schank, J. R. Rice, K. C. Kejun, C. Heilig, M. Tapocik, J. D. TI Wistar rats acquire and maintain self-administration of 20 % ethanol without water deprivation, saccharin/sucrose fading, or extended access training SO PSYCHOPHARMACOLOGY LA English DT Article DE EtOH; Self-administration; Addiction ID NUCLEUS-ACCUMBENS; ANIMAL-MODELS; NALTREXONE; ADDICTION; SEEKING; SUGAR; EXPRESSION; EFFICACY; BEHAVIOR; CHOICE AB Rationale Operant self-administration (SA) is an important model of motivation to consume ethanol (EtOH), but low rates of voluntary consumption in rats are thought to necessitate water deprivation and saccharin/sucrose fading for acquisition of responding. Objectives Here, we sought to devise an effective model of SA that does not use water deprivation or saccharin/sucrose fading. Methods First, we tested if Wistar rats would acquire and maintain SA behavior of 20 % EtOH under two conditions, water deprivation (WD) and non-water deprivation (NWD). Second, we tested the efficacy of our SA procedure by confirming a prior study which found that the NK1 antagonist L822429 specifically blocked stress-induced reinstatement of EtOH seeking but not SA. Finally, we assessed the effect of naltrexone, an FDA-approved medication for alcohol dependence that has been shown to suppress EtOH SA in rodents. Results Lever presses (LPs) and rewards were consistent with previous reports that utilized WD and saccharin/sucrose fading. Similar to previous findings, we found that L822429 blocked stress-induced reinstatement but not baseline SA of 20 % EtOH. Moreover, naltrexone dose-dependently decreased alcohol intake and motivation to consume alcohol for rats that are self-administering 20 % EtOH. Conclusions Our findings provide a method for voluntary oral EtOH SA in rats that is convenient for experimenters and eliminates the potential confound of sweeteners in EtOH-operant SA studies. Unlike models that use intermittent access to 20 % EtOH, this method does not induce escalation, and based on pharmacological experiments, it appears to be driven by the positive reinforcing effects of EtOH. C1 [Augier, E.; Flanigan, M.; Dulman, R. S.; Pincus, A.; Schank, J. R.; Heilig, M.; Tapocik, J. D.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Rice, K. C.; Kejun, C.] NIDA, Chem Biol Res Branch, NIH, Bethesda, MD 20892 USA. RP Augier, E (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. EM eric.augier@nih.gov OI Flanigan, Meghan/0000-0002-3185-7459 FU National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX 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. NR 24 TC 5 Z9 5 U1 3 U2 13 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 DEC PY 2014 VL 231 IS 23 BP 4561 EP 4568 DI 10.1007/s00213-014-3605-3 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AT3XY UT WOS:000344869900013 PM 24858375 ER PT J AU Cuthbert, BN AF Cuthbert, Bruce N. TI Translating intermediate phenotypes to psychopathology: The NIMH Research Domain Criteria SO PSYCHOPHYSIOLOGY LA English DT Article DE Research Domain Criteria; RDoC; Intermediate phenotypes; Endophenotypes; Psychopathology ID DISORDERS; CHALLENGES AB The Research Domain Criteria project (RDoC) was initiated by the National Institute of Mental Health in early 2009 to develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures. RDoC provides a framework for psychopathology research intended to explicate specific aspects of functional impairment by studying relevant brain-behavior relationships, in contrast to the current heterogeneous categories of mental disorders defined by various groupings of symptoms. Endophenotypes fit naturally into the RDoC context since they are typically conceived to be closer to fundamental neural and psychological mechanisms than more abstracted disorder categories. Consequently, the genomic aspects of endophenotypes take on particular significance for understanding genetic risk architectures in such an approach to psychopathology. C1 NIMH, Bethesda, MD 20892 USA. RP Cuthbert, BN (reprint author), NIMH, 6001 Execut Blvd,Room 7121,MSC 9632, Bethesda, MD 20892 USA. EM bcuthber@mail.nih.gov NR 10 TC 21 Z9 21 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD DEC PY 2014 VL 51 IS 12 SI SI BP 1205 EP 1206 DI 10.1111/psyp.12342 PG 2 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA AT2SL UT WOS:000344785500003 PM 25387702 ER PT J AU Goldman, D AF Goldman, David TI The missing heritability of behavior: The search continues SO PSYCHOPHYSIOLOGY LA English DT Article DE Genome-wide association; Heritability; Endophenotype; Intermediate phenotype; Founder population; Rare allele; Polygenicity; Minnesota Center for Twin and Family Research ID ASSOCIATION; GENES AB Genetic variation altering behavior is elusive. This commentary discusses implications for the search for missing heritability posed by a unified series of studies from the Minnesota Center for Twin and Family Research. Endophenotypes are measured in a longitudinal cohort including twins, analyzed for heritability and genetically mapped via genome-wide association and genome sequencing. The genes identified account for a fraction of the heritability, but the manner in which the studies were conducted points to explanations other than methodology. The MCTFR data are an unprecedented addition to the research information commons. Other gene discoveries will follow when they are analyzed in new ways and in combination with other studies. Even larger samples may be needed. Alternatively or in addition, locus identification, especially rare alleles, may require the study of families and population isolates with founder characteristics. C1 [Goldman, David] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. RP Goldman, D (reprint author), NIAAA, Neurogenet Lab, 5625 Fishers Lane,Suite 3S32,MSC 9412, Rockville, MD 20852 USA. EM davidgoldman@mail.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural NIH HHS [Z01 AA000280-18] NR 6 TC 4 Z9 4 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD DEC PY 2014 VL 51 IS 12 SI SI BP 1327 EP 1328 DI 10.1111/psyp.12362 PG 2 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA AT2SL UT WOS:000344785500015 PM 25387714 ER PT J AU Powell-Wiley, TM Miller, PE Agyemang, P Agurs-Collins, T Reedy, J AF Powell-Wiley, Tiffany M. Miller, Paige E. Agyemang, Priscilla Agurs-Collins, Tanya Reedy, Jill TI Perceived and objective diet quality in US adults: a cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) SO PUBLIC HEALTH NUTRITION LA English DT Article DE Diet quality perception; Psychosocial factors; National Health and Nutrition; Examination Survey; Dietary Approaches to Stop; Hypertension ID BODY-MASS INDEX; VEGETABLE CONSUMPTION; SODIUM REDUCTION; BLOOD-PRESSURE; HEART-DISEASE; HYPERTENSION; OBESITY; ASSOCIATION; ADHERENCE; TRIAL AB Objective: The Dietary Approaches to Stop Hypertension (DASH) dietary pattern has been shown to reduce cardiometabolic risk. Little is understood about the relationship between objective diet quality and perceived diet quality (PDQ), a potential psychosocial barrier to appropriate dietary intake. We compared PDQ and diet quality measured by a nutrient-based DASH index score in the USA. Design: Cross-sectional study. Participants in the 2005-2006 National Health and Nutrition Examination Survey (NHANES) rated diet quality on a 5-point Likert scale and PDQ scores were generated (low, medium, high). A single 24 h dietary recall was used to estimate DASH index scores (range 0-9 points) by assigning 0, 0.5 or 1 point (optimal) for nine target nutrients: total fat, saturated fat, protein, cholesterol, fibre, Ca, Mg, K and Na. Setting: Nationally representative sample of the US population. Subjects: Adults aged >= 19 years in 2005-2006 NHANES (n 4419). Results: Participants with high PDQ (33 %) had higher DASH index scores (mean 3.0 (SD 0.07)) than those with low PDQ (mean 2.5 (SD 0.06), P, 0.001), but average scores did not align with targets for intermediate or optimal DASH accordance. Adults with high PDQ reported higher total fat, saturated fat and Na intakes compared with optimal DASH nutrient goals. Differences between those with high v. low PDQ were similar for Whites and Blacks, but there was no difference between PDQ groups for Mexican Americans. Conclusions: Among Whites and Blacks, but not Mexican Americans, high PDQ may be associated with higher diet quality, but not necessarily a diet meeting DASH nutrient goals. This disconnect between PDQ and actual diet quality may serve as a target in obesity prevention. C1 [Powell-Wiley, Tiffany M.; Agyemang, Priscilla] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Powell-Wiley, Tiffany M.; Miller, Paige E.; Reedy, Jill] NCI, Appl Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Miller, Paige E.; Reedy, Jill] NCI, Risk Factor Monitoring & Methods Branch, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Agurs-Collins, Tanya] NCI, Hlth Behav Res Branch, Behav Res Program, Div Canc Control & Populat Sci,NIH, Bethesda, MD 20892 USA. RP Powell-Wiley, TM (reprint author), NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10 Room 5E3340, Bethesda, MD 20892 USA. EM tiffany.powell@nih.gov FU Division of Intramural Research of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) FX Funding for T. M. P.-W. and P. A. was provided by the Division of Intramural Research of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH). The Division of Intramural Research at NHLBI, NIH had no role in the design, analysis or writing of this article. NR 42 TC 4 Z9 4 U1 2 U2 16 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1368-9800 EI 1475-2727 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD DEC PY 2014 VL 17 IS 12 BP 2641 EP 2649 DI 10.1017/S1368980014000196 PG 9 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA AS9EH UT WOS:000344545400004 PM 24636343 ER PT J AU Oh, A Erinosho, T Dunton, G Perna, FM Berrigan, D AF Oh, April Erinosho, Temitope Dunton, Genevieve Perna, Frank M. Berrigan, David TI Cross-sectional examination of physical and social contexts of episodes of eating and drinking in a national sample of US adults SO PUBLIC HEALTH NUTRITION LA English DT Article DE Eating episodes; Social context; Physical context; Eating behaviours ID INCREASED MEAL INTAKE; TIME USE SURVEY; FOOD; POPULATION; BEHAVIOR; WOMEN; PREVENTION; SETTINGS; VALIDITY; OBESITY AB Objective: The current study characterizes associations between physical and social contexts of self-reported primary episodes of eating/drinking and socio-demographic and obesity-related variables in US adults. Design: Multinomial logistic regression was used to analyse a nationally representative sample of adults from the 2006-2008 American Time Use Survey. Models identifying physical (where) and social (whom) contexts of primary eating/drinking episodes at the population level, controlling for demographic characteristics, weight status and time of eating, were conducted. Setting: USA. Subjects: A nationally representative sample of US adults (n 21 315). Results: Eating/drinking with immediate family was positively associated with age (OR = 1.15 (95% CI 1.04, 1.27) to 1.23 (95% CI 1.09, 1.39)), education level (OR = 1.16 (95% CI 1.03, 1.30) to 1.36 (95% CI 1.21, 1.54)), obesity (OR = 1.13 (95% CI 1.04, 1.22)), children in the household (OR = 3.39 (95% CI 3.14, 3.66)) and time of day (OR = 1.70 (95% CI 1.39, 2.07) to 5.73 (95% CI 4.70, 6.99)). Eating in the workplace was negatively associated with female gender (OR = 0.65 (95% CI 0.60, 0.70)) and children in the household (OR = 0.90 (95% CI 0.83, 0.98)), while positively associated with non-white status (OR5 = 1.14 (95% CI 1.01, 1.29) to 1.47 (95% CI 1.32, 1.65)) and time of day (OR = 0.25 (95% CI 0.28, 0.30) to 5.65 (95% CI 4.66, 6.85)). Women (OR50.80 (95% CI 0.74, 0.86)), those aged >34 years (OR = 0.48 (95% CI 0.43, 0.54) to 0.83 (95% CI 0.74, 0.93)) and respondents with children (OR = 0.69 (95% CI 0.63, 0.75)) were less likely to eat in a restaurant/bar/retail than at home. Overweight and obese respondents had a greater odds of reporting an episode of eating in social situations v. alone (e.g. immediate family and extended family; OR = 1.13 (95% CI 1.04, 1.22)) and episodes occurring in restaurant/bar/retail locations (OR = 1.12 (95% CI 1.03, 1.23) to 1.14 (95% CI 1.05, 1.24)). Conclusions: Findings underscore the multidimensional nature of describing eating/drinking episodes. Social and physical contexts for eating/drinking and their demographic correlates suggest opportunities for tailoring interventions related to diet and may inform intervention targeting and scope. C1 [Oh, April] SAIC Frederick Inc, Div Canc Control & Populat Sci,NCI Frederick, Clin Monitoring Res Program Directorate CMRP, Support Natl Canc Inst,Hlth Behav Res Branch, Rockville, MD 21702 USA. [Erinosho, Temitope] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Dunton, Genevieve] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Perna, Frank M.; Berrigan, David] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. RP Oh, A (reprint author), SAIC Frederick Inc, Div Canc Control & Populat Sci,NCI Frederick, Clin Monitoring Res Program Directorate CMRP, Support Natl Canc Inst,Hlth Behav Res Branch, 6130 Execut Blvd,Room 4039,MSC 7335, Rockville, MD 21702 USA. EM ohay@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX Sources of funding: 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. 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. The National Cancer Institute had no role in the design, analysis or writing of this article. NR 33 TC 2 Z9 2 U1 3 U2 15 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1368-9800 EI 1475-2727 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD DEC PY 2014 VL 17 IS 12 BP 2721 EP 2729 DI 10.1017/S1368980013003315 PG 9 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA AS9EH UT WOS:000344545400013 PM 24477030 ER PT J AU Brandt, DE Ho, PS Chan, L Rasch, EK AF Brandt, Diane E. Ho, Pei-Shu Chan, Leighton Rasch, Elizabeth K. TI Conceptualizing disability in US national surveys: application of the World Health Organization's (WHO) International Classification of Functioning, Disability, and Health (ICF) framework SO QUALITY OF LIFE RESEARCH LA English DT Article DE Disability; Survey; ICF; Data; Coding; Impairment ID PARTICIPATION; INSTRUMENTS AB Disability data inform resource allocation and utilization, characterize functioning and changes over time, and provide a mechanism to monitor progress toward promoting and protecting the rights of individuals with disability. Data collection efforts, however, define and measure disability in varied ways. Our objective was to see how the content of disability measures differed in five US national surveys and over time. Using the WHO ICF as a conceptual framework for measuring disability, we assessed the National Health Interview Survey (NHIS), Current Population Survey (CPS), Survey of Income and Program Participation (SIPP), National Survey of SSI Children and Families (NSCF), and American Community Survey (ACS) for their content coverage of disability relative to each of the four ICF components (i.e., body functions, body structures, activities and participation, and environment). We used second-level ICF three-digit codes to classify question content into categories within each ICF component and computed the proportion of categories within each ICF component that was represented in the questions selected from these five surveys. The disability measures varied across surveys and years. The NHIS captured a greater proportion of the ICF body functions and body structures components than did other surveys. The SIPP captured the most content of the ICF activities and participation component, and the NSCF contained the most content of the ICF environmental factors component. This research successfully illustrated demonstrated the utility of the ICF in examining the content of disability measures in five national surveys and over time. C1 [Brandt, Diane E.; Ho, Pei-Shu; Chan, Leighton; Rasch, Elizabeth K.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Brandt, DE (reprint author), NIH, Dept Rehabil Med, Ctr Clin, 6100 Execut Blvd Rm 3C01 MSC 7515, Bethesda, MD 20892 USA. EM brandtdi@cc.nih.gov FU National Institutes of Health, Clinical Research Center; US Social Security Administration FX The authors would like to express gratitude to Barbara Altman, PhD for her guidance in this project and to Zabelle Zakarian, ScD, for her ICF coding suggestions. This research was supported by the Intramural Research Program of the National Institutes of Health, Clinical Research Center and through an Inter-Agency Agreement with the US Social Security Administration. This manuscript does not contain clinical studies or patient data. NR 31 TC 1 Z9 1 U1 3 U2 11 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 DEC PY 2014 VL 23 IS 10 BP 2663 EP 2671 DI 10.1007/s11136-014-0740-6 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AT2RQ UT WOS:000344783000002 PM 24948041 ER PT J AU Pluta, RM Bacher, J Skopets, B Hoffmann, V AF Pluta, Ryszard M. Bacher, John Skopets, Boris Hoffmann, Victoria TI A Non-Human Primate Model of Aneurismal Subarachnoid Hemorrhage (SAH) SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Intracranial aneurysm; Subarachnoid hemorrhage; SAH; Vasospasm; Animal model; Non-human primate ID DELAYED CEREBRAL VASOSPASM; DOUBLE-BLIND; RECEPTOR ANTAGONIST; ANEURYSM-TRIAL; BLOOD-FLOW; PHASE IIA; CLAZOSENTAN; ISCHEMIA; MECHANISMS; ENDOTHELIN AB Aneurismal subarachnoid hemorrhage (SAH) is relatively rare form of hemorrhagic stroke, which produces significant social and medical challenges. As it affects people in their high productivity age and leaves 50 % of them dead and almost 70 % of survivors disabled, many of them severely, the reasons of such a dismal outcome have been intensively researched all over the world. Nevertheless, despite more than a half a century of clinical and scientific effort and dramatic improvement of surgical repair of aneurysms, the causes of poor outcome remain enigmatic. Introduction of numerous in vitro and in vivo models to study the unleashed by SAH mechanisms that injured the brain significantly advanced our understanding of biology of cerebral vessels, brain responses to intracranial pressure changes, and the presence of blood clot in subarachnoid space. One of the most important animal models that significantly contributed to those advances has been a non-human primate model introduced at the Bryce Weir laboratory in the University of Alberta, Canada, in 1984. Since then, this model, with some modifications, has been successfully used in several animal laboratories in the USA, Canada, and Japan. We present the model characteristics and describe in details medical, surgical, imagining techniques that we have used at the Surgical Neurology Branch of the National Institute of Neurological Disorders and Stroke from 1989. C1 [Pluta, Ryszard M.] NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. [Bacher, John; Skopets, Boris; Hoffmann, Victoria] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. RP Pluta, RM (reprint author), NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. EM rysiek.pluta@excite.com FU Intramural Research Program of the NIH, NINDS FX This research was supported in part by the Intramural Research Program of the NIH, NINDS. NR 42 TC 8 Z9 8 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 EI 1868-601X J9 TRANSL STROKE RES JI Transl. Stroke Res. PD DEC PY 2014 VL 5 IS 6 BP 681 EP 691 DI 10.1007/s12975-014-0371-9 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AS8ZC UT WOS:000344532400007 PM 25216692 ER PT J AU Hattori, T Orimo, S Hallett, M Wu, T Inaba, A Azuma, R Mizusawa, H AF Hattori, T. Orimo, S. Hallett, M. Wu, T. Inaba, A. Azuma, R. Mizusawa, H. TI Relationship and factor structure in multisystem neurodegeneration in Parkinson's disease SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Article DE Parkinson's disease; cardiac sympathetic degeneration; olfactory impairment; cognitive impairment; relationship; factor analysis ID COGNITIVE IMPAIRMENT; OLFACTORY DYSFUNCTION; DEMENTIA; DEGENERATION; PATHOLOGY; SEVERITY; STAGE; RISK AB ObjectivesParkinson's disease (PD) is a multisystem neurodegenerative disease. We aimed to identify the relationship and factor structure among its different features. Materials & methodsMotor, olfactory and cognitive function, and cardiac sympathetic denervation were evaluated in 125 patients with PD using the Unified Parkinson's Disease Rating Scale (UPDRS) part III score, odor stick identification test for the Japanese (OSIT-J), Mini-Mental State Examination (MMSE), and [I-123] meta-iodobenzylguanidine (MIBG) cardiac scintigraphy (heart-to-mediastinum (H/M) ratio). Pearson's correlation and multiple regression analysis were used to evaluate the association among the four measures with age, gender, and disease duration as the covariates. Exploratory factor analysis was used to identify the underlying factor structure among the measures and covariates. ResultsPearson's correlation and multiple regression analysis showed correlations between OSIT-J score and MIBG H/M ratio, OSIT-J and MMSE scores, UPDRS part III score and MIBG H/M ratio, UPDRS part III score and disease duration, and MMSE score and age. Factor analysis identified three factors: (i) age and MMSE score; (ii) MIBG H/M ratio and OSIT-J score; and (iii) UPDRS part III score and disease duration. ConclusionsOur results suggest that aging, PD-related pathogenesis, and disease duration underlie the multisystem neurodegeneration present in PD. Moreover, age and disease duration are the major risk factors for cognitive impairment and motor symptoms, respectively. Olfactory impairment and cardiac sympathetic denervation are strongly associated in PD. C1 [Hattori, T.; Mizusawa, H.] Tokyo Med & Dent Univ, Grad Sch, Dept Neurol & Neurol Sci, Tokyo 1138519, Japan. [Hattori, T.; Orimo, S.; Inaba, A.; Azuma, R.] Kanto Cent Hosp, Dept Neurol, Tokyo, Japan. [Hattori, T.; Hallett, M.] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Wu, T.] NINDS, Clin Neurosci Branch, NIH, Bethesda, MD 20892 USA. RP Hattori, T (reprint author), Tokyo Med & Dent Univ, Grad Sch, Dept Neurol & Neurol Sci, Bunkyo Ku, 1-5-45 Yushima, Tokyo 1138519, Japan. EM takaaki-hattori@umin.ac.jp FU NINDS FX This study had no funding. Dr. Hallett, and currently Dr. Hattori, are supported by the NINDS Intramural Program. NR 35 TC 3 Z9 3 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-6314 EI 1600-0404 J9 ACTA NEUROL SCAND JI Acta Neurol. Scand. PD DEC PY 2014 VL 130 IS 6 BP 347 EP 353 DI 10.1111/ane.12273 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA AS4JZ UT WOS:000344242800001 PM 25209841 ER PT J AU Raran-Kurussi, S Waugh, DS AF Raran-Kurussi, Sreejith Waugh, David S. TI Unrelated Solubility-Enhancing Fusion Partners MBP and NusA Utilize a Similar Mode of Action SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Article DE chaperone; fusion partners; inclusion bodies; MBP; NusA; solubility-enhancers ID MALTOSE-BINDING PROTEIN; HPV E6 ONCOPROTEIN; ESCHERICHIA-COLI; EXPRESSION AB The tendency of recombinant proteins to accumulate in the form of insoluble aggregates in Escherichia coli is a major hindrance to their overproduction. One of the more effective approaches to circumvent this problem is to use translation fusion partners {solubility-enhancers (SEs)}. E. coli maltose-binding protein (MBP) and N-utilization substance A (NusA) are arguably the most effective solubilizing agents that have been discovered so far. Here, we show that although these two proteins are structurally, functionally, and physicochemically distinct, they influence the solubility and folding of their fusion partners in a very similar manner. These SEs act as "holdases" that prevent the aggregation of their fusion partners. Subsequent folding of the passenger proteins, when it occurs, is either spontaneous or chaperone-mediated. (C) 2014 Wiley Periodicals, Inc. C1 [Raran-Kurussi, Sreejith; Waugh, David S.] NCI, Prot Engn Sect, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21701 USA. RP Waugh, DS (reprint author), NCI, Prot Engn Sect, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21701 USA. EM waughd@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX Contract grant sponsor: Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research NR 21 TC 2 Z9 2 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3592 EI 1097-0290 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD DEC PY 2014 VL 111 IS 12 BP 2407 EP 2411 DI 10.1002/bit.25317 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA AS6QX UT WOS:000344388600005 PM 24942647 ER PT J AU Giannelou, A Zhou, Q Kastner, DL AF Giannelou, Angeliki Zhou, Qing Kastner, Daniel L. TI When less is more: primary immunodeficiency with an autoinflammatory kick SO CURRENT OPINION IN ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Review DE autoinflammation and PLC2-associated antibody deficiency and immune dysregulation; deficiency of adenosine deaminase 2; PLC2-associated antibody deficiency and immune dysregulation; vasculitis; vasculopathy ID FAMILIAL MEDITERRANEAN FEVER; ADENOSINE-DEAMINASE 2; GENERALIZED PUSTULAR PSORIASIS; ENCODING MEVALONATE KINASE; PHOSPHOLIPASE C-GAMMA-2; PROTEASOME SUBUNIT; BLAU-SYNDROME; PAPA SYNDROME; MUTATIONS; DISEASE AB Purpose of reviewNext-generation sequencing is revolutionizing the molecular taxonomy of human disease. Recent studies of patients with unexplained autoinflammatory disorders reveal germline genetic mutations that target important regulators of innate immunity.Recent findingsWhole-exome analyses of previously undiagnosed patients have catalyzed the recognition of two new disease genes. First, a phenotypic spectrum, including livedo racemosa, fever with early-onset stroke, polyarteritis nodosa, and Sneddon syndrome, is caused by loss-of-function mutations in cat eye syndrome chromosome region, candidate 1 (CECR1), encoding adenosine deaminase 2. Adenosine deaminase 2 is a secreted protein expressed primarily in myeloid cells, and a regulator of macrophage differentiation and endothelial development. Disease-associated mutations impair anti-inflammatory M2 macrophage differentiation. Second, patients presenting with cold-induced urticaria, granulomatous rash, autoantibodies, and common variable immunodeficiency, or with blistering skin lesions, bronchiolitis, enterocolitis, ocular inflammation, and mild immunodeficiency harbor distinct mutations in phospholipase C-2, encoding a signaling molecule expressed in natural killer cells, mast cells, and B lymphocytes. These mutations inhibit the function of a phospholipase C-2 autoinhibitory domain, causing increased or constitutive signaling.SummaryThese findings underscore the power of next-generation sequencing, demonstrating how the primary deficiency of key molecular regulators or even regulatory motifs may lead to autoinflammation, and suggesting a possible role for cat eye syndrome chromosome region, candidate 1 and phospholipase C-2 in common diseases. C1 [Giannelou, Angeliki; Zhou, Qing; Kastner, Daniel L.] NHGRI, Inflammatory Dis Sect, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Giannelou, A (reprint author), NHGRI, Inflammatory Dis Sect, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM angeliki.giannelou@nih.gov RI Yu, Xiaomin/I-6407-2016 FU National Human Genome Research Institute FX This work was supported by the Intramural Research Program of the National Human Genome Research Institute. The authors thank Dr Ivona Aksentijevich for critical reading of the manuscript, and for helping in preparing figures, and Patrycja Hoffmann for verifying clinical data. NR 53 TC 9 Z9 9 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1528-4050 EI 1473-6322 J9 CURR OPIN ALLERGY CL JI Curr. Opin. Allergy Clin. Immunol. PD DEC PY 2014 VL 14 IS 6 BP 491 EP 500 DI 10.1097/ACI.0000000000000117 PG 10 WC Allergy; Immunology SC Allergy; Immunology GA AS9DS UT WOS:000344544000001 PM 25337682 ER PT J AU Wang, QS Chu, CH Oyarzabal, E Jiang, LL Chen, SH Wilson, B Qian, L Hong, JS AF Wang, Qingshan Chu, Chun-Hsien Oyarzabal, Esteban Jiang, Lulu Chen, Shih-Heng Wilson, Belinda Qian, Li Hong, Jau-Shyong TI Subpicomolar Diphenyleneiodonium Inhibits Microglial NADPH Oxidase with High Specificity and Shows Great Potential as a Therapeutic Agent for Neurodegenerative Diseases SO GLIA LA English DT Article DE microglia; NADPH oxidase; neuroinflammation; oxidative stress; Parkinson's disease ID PARKINSONS-DISEASE; OXIDATIVE STRESS; DOPAMINERGIC NEURODEGENERATION; FEMTOMOLAR CONCENTRATIONS; MEDIATED NEUROTOXICITY; NOX ENZYMES; NEUROINFLAMMATION; INFLAMMATION; ACTIVATION; NEUROPROTECTION AB Activation of microglial NADPH oxidase (NOX2) plays a critical role in mediating neuroinflammation, which is closely linked with the pathogenesis of a variety of neurodegenerative diseases, including Parkinson's disease (PD). The inhibition of NOX2-generated superoxide has become an effective strategy for developing disease-modifying therapies for PD. However, the lack of specific and potent NOX2 inhibitors has hampered the progress of this approach. Diphenyleneiodonium (DPI) is a widely used, long-acting NOX2 inhibitor. However, due to its non-specificity for NOX2 and high cytotoxicity at standard doses (mu M), DPI has been precluded from human studies. In this study, using ultra-low doses of DPI, we aimed to: (1) investigate whether these problems could be circumvented and (2) determine whether ultra-low doses of DPI were able to preserve its utility as a potent NOX2 inhibitor. We found that DPI at subpicomolar concentrations (10(-14) and 10(-13) M) displays no toxicity in primary midbrain neuron-glia cultures. More importantly, we observed that subpicomolar DPI inhibited phorbol myristate acetate (PMA)-induced activation of NOX2. The same concentrations of DPI did not inhibit the activities of a series of flavoprotein-containing enzymes. Furthermore, potent neuroprotective efficacy was demonstrated in a post-treatment study. When subpicomolar DPI was added to neuron-glia cultures pretreated with lipopolysaccharide, 1-methyl-4-phenylpyridinium or rotenone, it potently protected the dopaminergic neurons. In summary, DPI's unique combination of high specificity toward NOX2, low cytotoxicity and potent neuroprotective efficacy in post-treatment regimens suggests that subpicomolar DPI may be an ideal candidate for further animal studies and potential clinical trials. GLIA 2014;62:2034-2043 Main Points DPI at ultra-low doses displays no cytotoxicity. DPI at ultra-low doses exhibits high specificity towards NOX2. DPI at ultra-low doses has therapeutic potential. C1 [Wang, Qingshan; Chu, Chun-Hsien; Oyarzabal, Esteban; Jiang, Lulu; Chen, Shih-Heng; Wilson, Belinda; Qian, Li; Hong, Jau-Shyong] NIEHS, Neuropharmacol Sect, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. RP Hong, JS (reprint author), NIEHS, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM hong3@niehs.nih.gov OI Chen, Shih-Heng/0000-0002-5853-6903 FU NIH, National Institute of Environmental Health Sciences (Intramural Research Program) FX Grant sponsor: NIH, National Institute of Environmental Health Sciences (Intramural Research Program). NR 39 TC 10 Z9 10 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 EI 1098-1136 J9 GLIA JI Glia PD DEC PY 2014 VL 62 IS 12 BP 2034 EP 2043 DI 10.1002/glia.22724 PG 10 WC Neurosciences SC Neurosciences & Neurology GA AS4HX UT WOS:000344236000010 PM 25043383 ER PT J AU Awada, R Saulnier-Blache, JS Gres, S Bourdon, E Rondeau, P Parimisetty, A Orihuela, R Harry, GJ d'Hellencourt, CL AF Awada, Rana Saulnier-Blache, Jean Sebastien Gres, Sandra Bourdon, Emmanuel Rondeau, Philippe Parimisetty, Avinash Orihuela, Ruben Harry, G. Jean d'Hellencourt, Christian Lefebvre TI Autotaxin Downregulates LPS-Induced Microglia Activation and Pro-Inflammatory Cytokines Production SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE AUTOTAXIN; MICROGLIA; INFLAMMATION; LYSOPHOSPHATIDIC ACID ID CENTRAL-NERVOUS-SYSTEM; TUMOR-NECROSIS-FACTOR; LYSOPHOSPHATIDIC ACID PRODUCTION; LYSOPHOSPHOLIPASE-D; MULTIPLE-SCLEROSIS; INTERFERON-GAMMA; FACTOR-ALPHA; THP-1 CELLS; EXPRESSION; RECEPTORS AB Inflammation is essential in defense against infection or injury. It is tightly regulated, as over-response can be detrimental, especially in immune-privileged organs such as the central nervous system (CNS). Microglia constitutes the major source of inflammatory factors, but are also involved in the regulation of the inflammation and in the reparation. Autotaxin (ATX), a phospholipase D, converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA) and is upregulated in several CNS injuries. LPA, a pleiotropic immunomodulatory factor, can induce multiple cellular processes including morphological changes, proliferation, death, and survival. We investigated ATX effects on microglia inflammatory response to lipopolysaccharide (LPS), mimicking gram-negative infection. Murine BV-2 microglia and stable transfected, overexpressing ATX-BV-2 (A+) microglia were treated with LPS. Tumor necrosis factor (TNF), interleukin (IL)-6, and IL-10 mRNA and proteins levels were examined by qRT-PCR and ELISA, respectively. Secreted LPA was quantified by a radioenzymatic assay and microglial activation markers (CD11b, CD14, B7.1, and B7.2) were determined by flow cytometry. ATX expression and LPA production were significantly enhanced in LPS treated BV-2 cells. LPS induction of mRNA and protein level for TNF and IL-6 were inhibited in A+ cells, while IL-10 was increased. CD11b, CD14, and B7.1, and B7.2 expressions were reduced in A+ cells. Our results strongly suggest deactivation of microglia and an IL-10 inhibitory of ATX with LPS induced microglia activation. J. Cell. Biochem. 115: 2123-2132, 2014. (c) 2014 Wiley Periodicals, Inc. C1 [Awada, Rana; Bourdon, Emmanuel; Rondeau, Philippe; Parimisetty, Avinash; d'Hellencourt, Christian Lefebvre] Univ La Reunion, GEICO, EA 4516, St Clotilde, Reunion. [Saulnier-Blache, Jean Sebastien; Gres, Sandra] Inst Malad Metab & Cardiovasc I2MC, INSERM, U1048, Toulouse 4, France. [Orihuela, Ruben; Harry, G. Jean] NIEHS, Neurotoxicol Grp, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP d'Hellencourt, CL (reprint author), Univ Reunion, GEICO, EA 4516, 15,Ave Rene Cassin,CS 92003, F-97715 St Denis De La Reunion 09, France. EM Christian.Lefebvre-d-Hellencourt@univ-reunion.fr OI ORIHUELA, RUBEN/0000-0001-6718-6194; Parimisetty, Avinash/0000-0003-0174-4442 FU Conseil Regional de La Reunion, Europe (CPER/FEDER); Ministere de L'enseignement Superieur et de la Recherche; Fondation de la Recherche Medicale (France) [LRM20100618582] FX Grant sponsor: Conseil Regional de La Reunion, Europe (CPER/FEDER); Grant sponsor: Ministere de L'enseignement Superieur et de la Recherche; Grant sponsor: Fondation de la Recherche Medicale (France); Grant number: LRM20100618582. NR 47 TC 10 Z9 10 U1 0 U2 25 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 DEC PY 2014 VL 115 IS 12 BP 2123 EP 2132 DI 10.1002/jcb.24889 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AS0ZB UT WOS:000344004200009 PM 25053164 ER PT J AU Carvalho, AF Rocha, DQC McIntyre, RS Mesquita, LM Koehler, CA Hyphantis, TN Sales, PMG Machado-Vieira, R Berk, M AF Carvalho, Andre F. Rocha, Davi Q. C. McIntyre, Roger S. Mesquita, Lucas M. Koehler, Cristiano A. Hyphantis, Thomas N. Sales, Paulo M. G. Machado-Vieira, Rodrigo Berk, Michael TI Adipokines as emerging depression biomarkers: A systematic review and meta-analysis SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Major depressive disorder; Meta-analysis; Adiponectin; Leptin; Resistin; Biomarkers ID LEPTIN-DEFICIENT PATIENTS; BODY-MASS INDEX; MAJOR DEPRESSION; ANTIDEPRESSANT TREATMENT; MOOD DISORDERS; CIRCULATING GHRELIN; INSULIN SENSITIVITY; METABOLIC SYNDROME; ADIPONECTIN RATIO; HUMAN OBESITY AB Adiponectin, leptin and resistin may play a role in the pathophysiology of major depressive disorder (MDD). However, differences in peripheral levels of these hormones are inconsistent across diagnostic and intervention studies. Therefore, we performed meta-analyses of diagnostic studies (i.e., MDD subjects versus healthy controls) and intervention investigations (i.e., pre-vs. post-antidepressant treatment) in MDD. Adiponectin (N = 1278; Hedge's g = -0.35; P = 0.16) and leptin (N = 893; Hedge's g = -0.018; P = 0.93) did not differ across diagnostic studies. Meta-regression analyses revealed that gender and depression severity explained the heterogeneity observed in adiponectin diagnostic studies, while BMI and the difference in BMI between MDD individuals and controls explained the heterogeneity of leptin diagnostic studies. Subgroup analyses revealed that adiponectin peripheral levels were significantly lower in MOD participants compared to controls when assayed with RIA, but not ELISA. Leptin levels were significantly higher in individuals with mild/moderate depression versus controls. Resistin serum levels were lower in MOD individuals compared to healthy controls (N = 298; Hedge's g = -0.25; P = 0.03). Leptin serum levels did not change after antidepressant treatment. However, heterogeneity was significant and sample size was low (N = 108); consequently meta-regression analysis could not be performed. Intervention meta-analyses could not be performed for adiponectin and resistin (i.e., few studies met inclusion criteria). In conclusion, this systematic review and meta-analysis underscored that relevant moderators/confounders (e.g., BMI, depression severity and type of assay) should be controlled for when considering the role of leptin and adiponectin as putative MDD diagnostic biomarkers. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Carvalho, Andre F.; Rocha, Davi Q. C.; Mesquita, Lucas M.; Sales, Paulo M. G.] Univ Fed Ceara, Fac Med, Translat Psychiat Res Grp, BR-60430040 Fortaleza, Ceara, Brazil. [McIntyre, Roger S.] Univ Toronto, Dept Pharmacol, Toronto, ON, Canada. [McIntyre, Roger S.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [McIntyre, Roger S.] Univ Toronto, Mood Disorders Psychopharmacol Unit, Toronto, ON, Canada. [Koehler, Cristiano A.] Fed Univ Rio Grande do Norte UFRN, Memory Res Lab, Brain Inst ICe, Natal, RN, Brazil. [Hyphantis, Thomas N.] Univ Ioaninna, Sch Med, Dept Psychiat, Ioaninna, Greece. [Machado-Vieira, Rodrigo] NIMH, Bethesda, MD 20892 USA. [Machado-Vieira, Rodrigo] Univ Sao Paulo, Neurosci Lab, LIM 27, Dept & Inst Psychiat, BR-05508 Sao Paulo, Brazil. [Machado-Vieira, Rodrigo] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, Sao Paulo, Brazil. [Berk, Michael] Deakin Univ, Sch Med, IMPACT Strateg Res Ctr, Geelong, Vic 3217, Australia. [Berk, Michael] Florey Inst Neurosci & Mental Hlth, Geelong, Vic, Australia. [Berk, Michael] Univ Melbourne, Orygen Youth Hlth Res Ctr, Parkville, Vic 3052, Australia. RP Carvalho, AF (reprint author), Univ Fed Ceara, Fac Med, Rua Prof Costa Mendes 1608,4 Andar, BR-60430040 Fortaleza, Ceara, Brazil. EM andrefc7@terra.com.br RI MACHADO-VIEIRA, RODRIGO/D-8293-2012; OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; Berk, Michael/0000-0002-5554-6946 FU Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (Brazil; Level 2); NHMRC Senior Principal Research Fellowship [1059660] FX AFC was supported by a research scholarship from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (Brazil; Level 2). MB is supported by a NHMRC Senior Principal Research Fellowship 1059660. NR 75 TC 16 Z9 17 U1 3 U2 22 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 DEC PY 2014 VL 59 BP 28 EP 37 DI 10.1016/j.jpsychires.2014.08.002 PG 10 WC Psychiatry SC Psychiatry GA AS3WJ UT WOS:000344205700005 PM 25183029 ER PT J AU Bremer, AA AF Bremer, Andrew A. TI Resveratrol Use in Metabolic Syndrome SO METABOLIC SYNDROME AND RELATED DISORDERS LA English DT Editorial Material ID SMALL-MOLECULE ACTIVATORS; ENERGY-METABOLISM; LIFE-SPAN; SIRT1; DISEASE; SUPPLEMENTATION; PGC-1-ALPHA; PROTECTS; SIRTUINS; MICE C1 NIDDK, Bethesda, MD 20892 USA. RP Bremer, AA (reprint author), NIDDK, Bldg 2DEM,Room 6107,6707 Democracy Blvd, Bethesda, MD 20892 USA. EM andrew.bremer@nih.gov NR 20 TC 0 Z9 0 U1 2 U2 11 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 DEC 1 PY 2014 VL 12 IS 10 BP 493 EP 495 DI 10.1089/met.2014.1505 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AT3XR UT WOS:000344868700001 PM 25229675 ER PT J AU Gooskens, S Gadd, S Meerzaman, D Khan, J de Krijger, R van den Heuvel-Eibrink, M Auvil, JG Gerhard, D Gerhard, D Smith, M Perlman, E AF Gooskens, S. Gadd, S. Meerzaman, D. Khan, J. de Krijger, R. van den Heuvel-Eibrink, M. Auvil, J. Guidry Gerhard, D. Gerhard, D. Smith, M. Perlman, E. TI COMPREHENSIVE MOLECULAR CHARACTERIZATION OF CLEAR CELL SARCOMA OF THE KIDNEY (CCSK): A CHILDREN'S ONCOLOGY GROUP TARGET PROJECT SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Gooskens, S.; van den Heuvel-Eibrink, M.] Erasmus MC Sophia Childrens Hosp, Dept Pediat Hematol & Oncol, Rotterdam, Netherlands. [Gadd, S.; Perlman, E.] Northwestern Univ, Dept Pathol, Feinberg Sch Med, Chicago, IL 60611 USA. [Gadd, S.; Perlman, E.] Robert H Lurie Canc Ctr, Chicago, IL USA. [Meerzaman, D.] NCI, Ctr Biomed Informat & Informat Technol, NIH, Bethesda, MD 20892 USA. [Khan, J.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [de Krijger, R.] Josephine Nefkens Inst Erasmus MC, Dept Pathol, Rotterdam, Netherlands. [Auvil, J. Guidry; Gerhard, D.; Gerhard, D.] NCI, Off Canc Genom, Bethesda, MD 20892 USA. [Smith, M.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC PY 2014 VL 61 SU 2 MA O-091 BP S129 EP S130 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100092 ER PT J AU Ooms, AHAG Gadd, S Gerhard, DS Smith, MA Guidry-Auvil, JM Dome, JS van den Heuvel-Eibrink, MM de Krijger, RR Perlman, EJ AF Ooms, A. H. A. G. Gadd, S. Gerhard, D. S. Smith, M. A. Guidry-Auvil, J. M. Dome, J. S. van den Heuvel-Eibrink, M. M. de Krijger, R. R. Perlman, E. J. TI ARE THERE ANAPLASTIC WILMS TUMORS THAT RETAIN AN INTACT P53 PATHWAY? SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Ooms, A. H. A. G.; Gadd, S.; Perlman, E. J.] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL USA. [Gerhard, D. S.; Guidry-Auvil, J. M.] NCI, Off Canc Genom, Bethesda, MD 20892 USA. [Smith, M. A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Dome, J. S.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [van den Heuvel-Eibrink, M. M.] Sophia Childrens Univ Hosp, Erasmus MC, Rotterdam, Netherlands. [de Krijger, R. R.] Erasmus MC, Rotterdam, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC PY 2014 VL 61 SU 2 MA O-245 BP S167 EP S167 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100243 ER PT J AU Cropp, CD Robbins, CM Sheng, X Hennis, AJM Carpten, JD Waterman, L Worrell, R Schwantes-An, TH Trent, JM Haiman, CA Leske, MC Wu, SY Bailey-Wilson, JE Nemesure, B AF Cropp, Cheryl D. Robbins, Christiane M. Sheng, Xin Hennis, Anselm J. M. Carpten, John D. Waterman, Lyndon Worrell, Ronald Schwantes-An, Tae-Hwi Trent, Jeffrey M. Haiman, Christopher A. Leske, M. Cristina Wu, Suh-Yuh Bailey-Wilson, Joan E. Nemesure, Barbara TI 8q24 Risk Alleles and Prostate Cancer in African-Barbadian Men SO PROSTATE LA English DT Article DE association; genetic; prostate cancer; 8q24; Caribbean and risk factors ID GENOME-WIDE ASSOCIATION; SAMPLE-SIZE REQUIREMENTS; GENETIC-VARIANTS; EUROPEAN-AMERICANS; BREAST-CANCER; LOCUS; METAANALYSIS; POPULATION; REPLICATION; DESCENT AB BACKGROUNDAfrican American men (AA) exhibit a disproportionate share of prostate cancer (PRCA) incidence, morbidity, and mortality. Several genetic association studies have implicated select 8q24 loci in PRCA risk in AA. The objective of this investigation is to evaluate the association between previously reported 8q24 risk alleles and PRCA in African-Barbadian (AB) men known to have high rates of PRCA. METHODSTen previously reported candidate tag SNPs were genotyped and/or imputed in the 8q24 region in 532 AB men with PRCA and 513 AB controls from the Prostate Cancer in a Black Population (PCBP) study. RESULTSRs2124036 was significant in AB men, (OR=2.7, 95% CI (1.3-5.3), P=0.005, Empirical (max (T), corrected for multiple testing) P=0.03) for the homozygous C/C genotype. Only a single SNP from this region remained statistically significant in our analysis of our AB population. These results may indicate the presence of a founder effect or due to the chosen SNPs not tagging an ancestral haplotype bearing the 8q24 risk allele(s) in this population or could reflect inadequate power to detect an association. We conducted a meta-analysis including our AB population along with two additional African Caribbean populations from Tobago and Jamaica for SNPs rs16901979 and rs1447295. Meta-analysis results were most significant for rs16901979 A allele (Z score 2.73; P=0.006) with a summary OR=1.31 (95% CI: 1.09-1.58). CONCLUSIONSAdditional studies are needed to provide deeper genotype coverage to further interrogate the 8q24 region to understand its contribution to PRCA in this population. Prostate 74: 1579-1588, 2014. (c) 2014 Wiley Periodicals, Inc. C1 [Cropp, Cheryl D.; Schwantes-An, Tae-Hwi; Bailey-Wilson, Joan E.] NHGRI, Computat & Stat Gen Branch, NIH, Baltimore, MD 21224 USA. [Robbins, Christiane M.; Carpten, John D.; Trent, Jeffrey M.] Translat Gen Res Inst TGen, Integrated Canc Genom Div, Phoenix, AZ USA. [Sheng, Xin; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hennis, Anselm J. M.; Waterman, Lyndon; Worrell, Ronald] Univ W Indies, Chron Dis Res Ctr, Bridgetown, Barbados. [Hennis, Anselm J. M.; Waterman, Lyndon; Worrell, Ronald] Univ W Indies, Fac Med Sci, Bridgetown, Barbados. [Leske, M. Cristina; Wu, Suh-Yuh; Nemesure, Barbara] SUNY Stony Brook, Med Ctr, Dept Prevent Med, Stony Brook, NY 11794 USA. RP Bailey-Wilson, JE (reprint author), NHGRI, NIH, 333 Cassell Dr,Suite 1200, Baltimore, MD 21224 USA. EM jebw@mail.nih.gov OI Bailey-Wilson, Joan/0000-0002-9153-2920 FU Intramural Research Program of the National Human Genome Research Institute, NIH (JEBW); Intramural Research Program of the National Human Genome Research Institute, NIH (CDC); Intramural Research Program of the National Human Genome Research Institute, NIH (TSA); NIH [N01HG25487]; National Cancer Institute, NIH [R01CA114379] FX We would like to acknowledge the Barbados National Cancer Study Group. CDC is the recipient of an NHGRI Health Disparities Research Fellowship. This project was supported by the Intramural Research Program of the National Human Genome Research Institute, NIH (JEBW, CDC, TSA and contract N01HG25487) and by the National Cancer Institute, NIH (grant R01CA114379). NR 53 TC 6 Z9 6 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 EI 1097-0045 J9 PROSTATE JI Prostate PD DEC PY 2014 VL 74 IS 16 BP 1579 EP 1588 DI 10.1002/pros.22871 PG 10 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA AS1OZ UT WOS:000344051300001 PM 25252079 ER PT J AU Bouchelion, A Zhang, ZJ Li, YC Qian, HH Mukherjee, AB AF Bouchelion, Ashleigh Zhang, Zhongjian Li, Yichao Qian, Haohua Mukherjee, Anil B. TI Mice homozygous for c.451C > T mutation in Cln1 gene recapitulate INCL phenotype SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article AB Objective: Nonsense mutations account for 5-70% of all genetic disorders. In the United States, nonsense mutations in the CLN1/PPT1 gene underlie >40% of the patients with infantile neuronal ceroid lipofuscinosis (INCL), a devastating neurodegenerative lysosomal storage disease. We sought to generate a reliable mouse model of INCL carrying the most common Ppt1 nonsense mutation (c.451C>T) found in the United States patient population to provide a platform for evaluating nonsense suppressors in vivo. Methods: We knocked-in c.451C>T nonsense mutation in the Ppt1 gene in C57 embryonic stem (ES) cells using a targeting vector in which LoxP flanked the Neo cassette, which was removed from targeted ES cells by electroporating Cre. Two independently targeted ES clones were injected into blastocysts to generate syngenic C57 knock-in mice, obviating the necessity for extensive backcrossing. Results: Generation of Ppt1-KI mice was confirmed by DNA sequencing, which showed the presence of c.451C>T mutation in the Ppt1 gene. These mice are viable and fertile, although they developed spasticity (a "clasping" phenotype) at a median age of 6 months. Autofluorescent storage materials accumulated throughout the brain regions and in visceral organs. Electron microscopic analysis of the brain and the spleen showed granular osmiophilic deposits. Increased neuronal apoptosis was particularly evident in cerebral cortex and abnormal histopathological and electroretinographic (ERG) analyses attested striking retinal degeneration. Progressive deterioration of motor coordination and behavioral parameters continued until eventual death. Interpretation: Our findings show that Ppt1-KI mice reliably recapitulate INCL phenotype providing a platform for testing the efficacy of existing and novel nonsense suppressors in vivo. C1 [Bouchelion, Ashleigh; Zhang, Zhongjian; Mukherjee, Anil B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Sect Dev Genet, Bethesda, MD USA. [Li, Yichao; Qian, Haohua] NEI, Visual Funct Core HNW2 L, NIH, Bethesda, MD 20892 USA. RP Mukherjee, AB (reprint author), NICHD, NIH, Bldg 10,Rm 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM mukherja@exchange.nih.gov NR 39 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD DEC PY 2014 VL 1 IS 12 BP 1006 EP 1023 DI 10.1002/acn3.144 PG 18 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V45KP UT WOS:000209815800005 PM 25574475 ER PT J AU Roda, RH Schindler, AB Blackstone, C Mammen, AL Corse, AM Lloyd, TE AF Roda, Ricardo H. Schindler, Alice B. Blackstone, Craig Mammen, Andrew L. Corse, Andrea M. Lloyd, Thomas E. TI Laing distal myopathy pathologically resembling inclusion body myositis SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article AB Mutations in MYH7 cause autosomal dominant Laing distal myopathy. We present a family with a previously reported deletion (c.5186_5188delAGA, p.K1729del). Muscle pathology in one family member was characterized by an inflammatory myopathy with rimmed vacuoles, increased MHC Class I expression, and perivascular and endomysial muscle inflammation comprising CD3(+), CD4(+), CD8(+), and CD68(+) inflammatory cells. Interestingly, this biopsy specimen contained TDP-43, p62, and SMI-31-positive protein aggregates typical of inclusion body myositis. These findings should alert physicians to the possibility that patients with MYH7 mutations may have muscle biopsies showing pathologic findings similar to inclusion body myositis. C1 [Roda, Ricardo H.] NYU, Dept Neurol, Langone Med Ctr, Neuromuscular Disorders Div, New York, NY 10016 USA. [Roda, Ricardo H.] NYU, Langone Med Ctr, Dept Neurol, Neurogenet Div, New York, NY 10016 USA. [Roda, Ricardo H.; Blackstone, Craig] NINDS, Cell Biol Sect, Neurogenet Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Schindler, Alice B.] NINDS, Natl Hereditary Neurol Dis Sect, Neurogenet Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Mammen, Andrew L.; Corse, Andrea M.; Lloyd, Thomas E.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Mammen, Andrew L.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Mammen, Andrew L.] NIAMSD, Muscle Dis Unit, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Lloyd, Thomas E.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Roda, RH (reprint author), NYU, Dept Neurol, Ctr Ambulatory Care, 240 East 38th, New York, NY 10016 USA. EM ricardo.roda@nyumc.org FU NINDS NIH HHS [R01 NS082563] NR 16 TC 1 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD DEC PY 2014 VL 1 IS 12 BP 1053 EP 1058 DI 10.1002/acn3.140 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V45KP UT WOS:000209815800010 PM 25574480 ER PT J AU Stopfer, M AF Stopfer, Mark TI Central processing in the mushroom bodies SO CURRENT OPINION IN INSECT SCIENCE LA English DT Article AB The mushroom bodies in the insect brain serve as a central information processing area. Here, focusing mainly on olfaction, I discuss functionally related roles the mushroom bodies play in signal gain control, response sparsening, the separation of similar signals (decorrelation), and learning and memory. In sum, the mushroom bodies assemble and format a context-appropriate representation of the insect's world. C1 [Stopfer, Mark] NIH, NICHD, Bldg 35,35 Lincoln Dr,Rm 3E 623,Msc 3715, Bethesda, MD 20892 USA. RP Stopfer, M (reprint author), NIH, NICHD, Bldg 35,35 Lincoln Dr,Rm 3E 623,Msc 3715, Bethesda, MD 20892 USA. EM stopferm@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 41 TC 3 Z9 3 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2214-5745 EI 2214-5753 J9 CURR OPIN INSECT SCI JI Curr. Opin. Insect Sci. PD DEC PY 2014 VL 6 BP 99 EP 103 DI 10.1016/j.cois.2014.10.009 PG 5 WC Biology; Ecology; Entomology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Entomology GA V41XN UT WOS:000209579000017 PM 25621203 ER PT J AU McMahon, FJ AF McMahon, Francis J. TI Prediction of treatment outcomes in psychiatry-where do we stand? SO DIALOGUES IN CLINICAL NEUROSCIENCE LA English DT Article DE pharmacogenetics; biomarker; adverse event; personalized medicine AB Psychiatric treatment relies on a solid armamentarium of pharmacologic and nonpharmacologic treatment modalities that perform reasonably well for many patients but leave others in a state of chronic disability or troubled by problematic side effects. Treatment planning in psychiatry remains an art that depends on considerable trial and error. Thus, there is an urgent need for better tools that will provide a means for matching individual patients with the most effective treatments while minimizing the risk of adverse events. This review will consider the current state of the science in predicting treatment outcomes in psychiatry. Genetic and other biomarkers will be considered alongside clinical, diagnostic, and family history data. Problems inherent in prediction medicine will also be discussed, along with recent developments that support the hope that psychiatry can do a better job in quickly identifying the best treatments for each patient. (C) 2014, AICH - Servier Research Group C1 [McMahon, Francis J.] Int Soc Psychiat Genet, Brentwood, TN USA. [McMahon, Francis J.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [McMahon, Francis J.] NIMH, Intramural Res Program, Human Genet Branch, Bethesda, MD 20892 USA. RP McMahon, FJ (reprint author), 35 Convent Dr,Room 1A203, Bethesda, MD 20892 USA. EM mcmahonf@mail.nih.gov OI McMahon, Francis/0000-0002-9469-305X NR 93 TC 4 Z9 5 U1 0 U2 0 PU INST CONFERENCE HIPPOCRATE PI SURESNESS-CEDEX PA 50 RUE CARNOT, SURESNESS-CEDEX, 92284, FRANCE SN 1294-8322 EI 1958-5969 J9 DIALOGUES CLIN NEURO JI Dialogues Clin. Neurosci. PD DEC PY 2014 VL 16 IS 4 BP 455 EP 464 PG 10 WC Neurosciences SC Neurosciences & Neurology GA V45QS UT WOS:000209831700002 PM 25733951 ER PT J AU Fauci, AS AF Fauci, Anthony S. TI C. EVERETT KOOP 14 OCTOBER 1916 . 25 FEBRUARY SO PROCEEDINGS OF THE AMERICAN PHILOSOPHICAL SOCIETY LA English DT Biographical-Item C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, NIH, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 1 PU AMER PHILOSOPHICAL SOC PI PHILADELPHIA PA 104 SOUTH FIFTH ST, PHILADELPHIA, PA 19106-3387 USA SN 0003-049X EI 2326-9243 J9 P AM PHILOS SOC JI Proc. Amer. Philos. Soc. PD DEC PY 2014 VL 158 IS 4 BP 455 EP 460 PG 6 WC Humanities, Multidisciplinary SC Arts & Humanities - Other Topics GA CV4SW UT WOS:000364257800014 PM 26665591 ER PT J AU Gilbert, JA Ball, M Blainey, P Blaser, MJ Bohannan, BJ Bateman, A Bunge, J Dominguez-Bello, MG Epstein, S Fierer, N Gevers, D Grikscheit, T Hamdan, LJ Harvey, J Huttenhower, C Kirkup, B Kong, HH Lauber, C Lemon, KP Lynch, SV Martin, L Mello, C Palma, J Parker, R Petrosino, J Segre, JA Vosshall, L Yi, R Knight, R AF Gilbert, Jack A. Ball, Madeleine Blainey, Paul Blaser, Martin J. Bohannan, Brendan Jm Bateman, Ashley Bunge, John Dominguez-Bello, Maria Gloria Epstein, Slava Fierer, Noah Gevers, Dirk Grikscheit, Tracy Hamdan, Leila J. Harvey, James Huttenhower, Curtis Kirkup, Benjamin Kong, Heidi H. Lauber, Christian Lemon, Katherine P. Lynch, Susan V. Martin, Lance Mello, Charlene Palma, Joseph Parker, Roy Petrosino, Joseph Segre, Julia A. Vosshall, Leslie Yi, Rui Knight, Rob TI Meeting report for the 1st skin microbiota workshop, boulder, CO October 15-16 2012 SO STANDARDS IN GENOMIC SCIENCES LA English DT Article DE Skin microbiome; Army; Bioinformatics AB This report details the outcome of the 1st Skin Microbiota Workshop, Boulder, CO, held on October 15th-16th 2012. The workshop was arranged to bring Department of Defense personnel together with experts in microbial ecology, human skin physiology and anatomy, and computational techniques for interrogating the microbiome to define research frontiers at the intersection of these important areas. The workshop outlined a series of questions and created several working groups to address those questions, specifically to promote interdisciplinary activity and potential future collaboration. The US Army provided generous grant support and the meeting was organized and hosted by the University of Colorado at Boulder. A primary forward vision of the meeting was the importance of understanding skin microbial communities to improve the health and stealth of US Army warfighters. C1 [Gilbert, Jack A.] Argonne Natl Lab, 9700 S Cass Ave, Argonne, IL 60439 USA. [Gilbert, Jack A.] Univ Chicago, Dept Ecol & Evolut, Chicago, IL 60637 USA. [Ball, Madeleine] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. Broad Inst & MIT Dept Biol Engn, Cambridge, MA USA. [Blaser, Martin J.] NYU Langone Med Ctr, Dept Med, New York, NY USA. New York Harbor VA Med Ctr, New York, NY USA. [Bohannan, Brendan Jm; Bateman, Ashley] Univ Oregon, Inst Ecol & Evolut, Eugene, OR 97403 USA. [Bunge, John] Cornell Univ, Dept Stat Sci, Ithaca, NY USA. [Dominguez-Bello, Maria Gloria] NYU, Dept Med, New York, NY 10016 USA. [Dominguez-Bello, Maria Gloria] Univ Puerto Rico, Dept Biol, Mayaguez, PR USA. [Epstein, Slava] Northeastern Univ, Dept Biol, Boston, MA 02115 USA. [Fierer, Noah] Univ Colorado, Dept Ecol & Evolutionary Biol, Boulder, CO 80309 USA. [Fierer, Noah; Lauber, Christian] Univ Colorado, CIRES, Boulder, CO 80309 USA. [Gevers, Dirk] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Grikscheit, Tracy] Childrens Hosp Los Angeles, Saban Res Inst, USC, Div Pediat Surg,Keck Sch Med, Los Angeles, CA 90027 USA. [Hamdan, Leila J.] George Mason Univ, Manassas, VA 20110 USA. [Harvey, James] US Army Res Off, Res Triangle Pk, NC USA. [Huttenhower, Curtis] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Kirkup, Benjamin] Walter Reed Army Inst Res, Dept Wound Infect, Silver Spring, MD USA. [Kirkup, Benjamin] Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. [Kong, Heidi H.] NCI, NIH, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Lemon, Katherine P.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Lemon, Katherine P.] Boston Childrens Hosp, Div Infect Dis, Boston, MA USA. [Lynch, Susan V.] Univ Calif San Francisco, Dept Med, Div Gastroenterol, San Francisco, CA USA. [Martin, Lance] Stanford Univ, Sch Med, Dept Bioengn, Program Epithelial Biol, Stanford, CA 94305 USA. [Martin, Lance] Stanford Univ, Stanford, CA 94305 USA. [Mello, Charlene; Palma, Joseph] US Natick Soldier Ctr, Natick, MA USA. [Parker, Roy; Knight, Rob] Howard Hughes Med Inst, Boulder, CO USA. [Parker, Roy; Knight, Rob] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. [Parker, Roy; Knight, Rob] Univ Colorado, BioFrontiers Inst, Boulder, CO 80309 USA. [Petrosino, Joseph] Baylor Coll Med, Dept Mol Virol & Microbiol, Alkek Ctr Metagen & Microbiome Res, Houston, TX 77030 USA. [Segre, Julia A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Vosshall, Leslie] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA. [Yi, Rui] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA. RP Gilbert, JA (reprint author), Argonne Natl Lab, 9700 S Cass Ave, Argonne, IL 60439 USA. EM gilbertjack@gmail.com OI Blainey, Paul/0000-0002-4889-8783; Kirkup, Benjamin/0000-0002-8722-6218; Kong, Heidi/0000-0003-4424-064X FU U.S. Army Research Laboratory; U.S. Army Research Office [W911NF-12-1-0513] FX This workshop was supported in part by the U.S. Army Research Laboratory and the U.S. Army Research Office under grant number W911NF-12-1-0513. We thank Wally Buchholtz, who is the program manager for this program, and Jerry Kennedy and Ulla Westermann for superb assistance on the logistics. NR 26 TC 0 Z9 1 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1944-3277 J9 STAND GENOMIC SCI JI Stand. Genomic Sci. PD DEC PY 2014 VL 9 IS 1 AR 13 DI 10.1186/1944-3277-9-13 PG 7 WC Genetics & Heredity; Microbiology SC Genetics & Heredity; Microbiology GA V45LA UT WOS:000209816900013 ER PT J AU Hu, H Huang, P Weiss, OJ Yan, XF Yue, XY Zhang, MG Tang, YX Nie, LM Ma, Y Niu, G Wu, KC Chen, XY AF Hu, Hao Huang, Peng Weiss, Orit Jacobson Yan, Xuefeng Yue, Xuyi Zhang, Molly Gu Tang, Yuxia Nie, Liming Ma, Ying Niu, Gang Wu, Kaichun Chen, Xiaoyuan TI PET and NIR optical imaging using self-illuminating Cu-64-doped chelator-free gold nanoclusters SO BIOMATERIALS LA English DT Article DE Gold nanocluster; Cu-64 doping; Cerenkov effect; Positron emission tomography; Optical imaging ID QUANTUM DOTS; PHOTODYNAMIC THERAPY; CANCER; NANOPARTICLES; LIGHT; TOOL AB Self-illuminating fluorescence imaging without autofluorescence background interference has recently aroused more research interests in molecular imaging. Currently, only a few self-illuminating probes were developed, based mainly on toxic quantum dots such as CdSe, CdTe. Herein, we report a novel design of nontoxic self-illuminating gold nanocluster (Cu-64-doped AuNCs) for dual-modality positron emission tomography (PET) and near-infrared (NIR) fluorescence imaging based on Cerenkov resonance energy transfer (CRET). PET radionuclide Cu-64 was introduced by a chelator-free doping method, which played dual roles as the energy donor and the PET imaging source. Meanwhile, AuNCs acted as the energy acceptor for NIR fluorescence imaging. Cu-64-doped AuNCs exhibited efficient CRET-NIR and PET imaging both in vitro and in vivo. In a U87MG glioblastoma xenograft model, Cu-64-doped AuNCs showed high tumor uptake (14.9 %ID/g at 18 h) and produced satisfactory tumor self-illuminating NIR images in the absence of external excitation. This self-illuminating nanocluster with non-toxicity and good biocompatibility can be employed as a novel imaging contrast agent for biomedical applications, especially for molecular imaging. Published by Elsevier Ltd. C1 [Hu, Hao; Wu, Kaichun] Fourth Mil Med Univ, State Key Lab Canc Biol, Xian 710032, Peoples R China. [Hu, Hao; Wu, Kaichun] Fourth Mil Med Univ, Xijing Hosp Digest Dis, Xian 710032, Peoples R China. [Hu, Hao; Huang, Peng; Weiss, Orit Jacobson; Yan, Xuefeng; Yue, Xuyi; Zhang, Molly Gu; Tang, Yuxia; Nie, Liming; Ma, Ying; Niu, Gang; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Nie, Liming] Xiamen Univ, Sch Publ Hlth, State Key Lab Mol Vaccinol & Mol Diagnost, Ctr Mol Imaging & Translat Med, Xiamen, Peoples R China. RP Chen, XY (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, 35A Convent Dr GD937, Bethesda, MD 20892 USA. EM kaicwu@fmmu.edu.cn; shawn.chen@nih.gov RI Huang, Peng/H-9985-2013; Nie, Liming/F-7718-2016; Huang, Peng/R-2480-2016 OI Huang, Peng/0000-0003-3651-7813 FU National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); National Key Basic Research Program (973 Project) [2010CB933901, 2013CB733802, 2014CB744503]; National Natural Science Foundation of China [81272987, 81090270, 81090273, 81401465, 81370585] FX This work was supported, in part, by the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), the National Key Basic Research Program (973 Project) (2010CB933901, 2013CB733802, 2014CB744503) and the National Natural Science Foundation of China (No. 81272987, No.81090270, No.81090273, No. 81401465, and No.81370585). We also thank Dr. Jie Lu, Dale Kiesewetter, and Andrea Balbo for their technical support. NR 26 TC 24 Z9 24 U1 8 U2 132 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 DEC PY 2014 VL 35 IS 37 BP 9868 EP 9876 DI 10.1016/j.biomaterials.2014.08.038 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA AR5QX UT WOS:000343639700012 PM 25224367 ER PT J AU Felsenfeld, G AF Felsenfeld, Gary TI THE EVOLUTION OF EPIGENETICS SO PERSPECTIVES IN BIOLOGY AND MEDICINE LA English DT Article ID DNA METHYLATION; CHROMATIN-STRUCTURE; HISTONE; INHERITANCE; MECHANISMS; DROSOPHILA; YEAST; PARAMUTATION; ACTIVATION; REPRESSOR AB Early studies of the developing embryo raised the question of how a fertilized egg could give rise to a complex multicellular organism containing many different kinds of cells. The term epigenetics originally referred to the study of these processes. With the advent of detailed knowledge of mechanisms of gene expression, this definition was superseded by another: epigenetics concerned the transmission of phenotype through mitosis or the germ line by mechanisms that did not involve changes in the DNA sequence. Much effort has been spent in attempting to identify and characterize these events. Work initially focused on DNA methylation as an epigenetic mark, but more recently there has been an emphasis on histone modifications as possible carriers of epigenetic information. However, there is confusion between situations in which the modifications may be propagated through cell division, thus helping to maintain a pattern of gene expression, and situations in which the modifications are simply part of the transcriptional apparatus. Arguments about the role of the histones have led to a reexamination of the definition of epigenetics and the primary events in development leading to cell type specific gene expression patterns. C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM gary.felsenfeld@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH. NR 51 TC 4 Z9 4 U1 1 U2 37 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0031-5982 EI 1529-8795 J9 PERSPECT BIOL MED JI Perspect. Biol. Med. PD WIN PY 2014 VL 57 IS 1 SI SI BP 132 EP 148 PG 17 WC History & Philosophy Of Science; Medicine, Research & Experimental SC History & Philosophy of Science; Research & Experimental Medicine GA AR1OZ UT WOS:000343355800010 PM 25345707 ER PT J AU Lohith, TG Xu, R Tsujikawa, T Morse, CL Anderson, KB Gladding, RL Zoghbi, SS Fujita, M Innis, RB Pike, VW AF Lohith, Talakad G. Xu, Rong Tsujikawa, Tetsuya Morse, Cheryl L. Anderson, Kacey B. Gladding, Robert L. Zoghbi, Sami S. Fujita, Masahiro Innis, Robert B. Pike, Victor W. TI Evaluation in Monkey of Two Candidate PET Radioligands, [C-11]RX-1 and [F-18]RX-2, for Imaging Brain 5-HT4 Receptors SO SYNAPSE LA English DT Article DE PET; imaging; 5-HT4; radioligand; carbon-11; fluorine-18; brain ID POSITRON-EMISSION-TOMOGRAPHY; POSTMORTEM HUMAN BRAIN; SEROTONIN 4 RECEPTORS; IN-VIVO; ALZHEIMERS-DISEASE; FREE-FRACTION; RADIOTRACERS; AFFINITY; BINDING; BETA AB The serotonin subtype-4 (5-HT4) receptor, which is known to be involved physiologically in learning and memory, and pathologically in Alzheimer's disease, anxiety, and other neuropsychiatric disordershas few radioligands readily available for imaging in vivo. We have previously reported two novel 5-HT4 receptor radioligands, namely [methoxy-C-11](1-butylpiperidin-4-yl)methyl 4-amino-3-methoxybenzoate; [C-11]RX-1), and the [F-18]3-fluoromethoxy analog ([F-18]RX-2), and in this study we evaluated them by PET in rhesus monkey. Brain scans were performed at baseline, receptor preblock or displacement conditions using SB 207710, a 5-HT4 receptor antagonist, on the same day for [C-11]RX-1 and on different days for [F-18]RX-2. Specific-to-nondisplaceable ratio (BPND) was measured with the simplified reference tissue model from all baseline scans. To determine specific binding, total distribution volume (V-T) was also measured in some monkeys by radiometabolite-corrected arterial input function after ex vivo inhibition of esterases from baseline and blocked scans. Both radioligands showed moderate to high peak brain uptake of radioactivity (2-6 SUV). Regional BPND values were in the rank order of known 5-HT4 receptor distribution with a trend for higher BPND values from [F-18]RX-2. One-tissue compartmental model provided good fits with well identified V-T values for both radioligands. In the highest 5-HT4 receptor density region, striatum, 50-60% of total binding was specific. The V-T in receptor-poor cerebellum reached stable values by about 60 min for both radioligands indicating little influence of radiometabolites on brain signal. In conclusion, both [C-11]RX-1 and [F-18]RX-2 showed positive attributes for PET imaging of brain 5-HT4 receptors, validating the radioligand design strategy. Synapse 68:613-623, 2014. (c) 2014 Wiley Periodicals, Inc. C1 [Lohith, Talakad G.; Xu, Rong; Tsujikawa, Tetsuya; Morse, Cheryl L.; Anderson, Kacey B.; Gladding, Robert L.; Zoghbi, Sami S.; Fujita, Masahiro; Innis, Robert B.; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Pike, VW (reprint author), NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. EM pikev@mail.nih.gov FU National Institutes of Health (NIMH) FX Contract grant sponsor: Intramural Research Program of the National Institutes of Health (NIMH). NR 48 TC 3 Z9 3 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-4476 EI 1098-2396 J9 SYNAPSE JI Synapse PD DEC PY 2014 VL 68 IS 12 BP 613 EP 623 DI 10.1002/syn.21773 PG 11 WC Neurosciences SC Neurosciences & Neurology GA AR7JZ UT WOS:000343756900006 ER PT J AU Tucker, CA Bevans, KB Teneralli, RE Smith, AW Bowles, HR Forrest, CB AF Tucker, Carole A. Bevans, Katherine B. Teneralli, Rachel E. Smith, Ashley Wilder Bowles, Heather R. Forrest, Christopher B. TI Self-reported Pediatric Measures of Physical Activity, Sedentary Behavior, and Strength Impact for PROMIS: Conceptual Framework SO PEDIATRIC PHYSICAL THERAPY LA English DT Article DE adolescent; child; female; health status; humans; information systems; male; outcome assessment (health care)/methods; parents; pediatrics/methods; physical activities; quality of life; sedentary lifestyle; strengthening ID CHILDRENS PARTICIPATION; HEALTH; PERSPECTIVES; PERFORMANCE; OUTCOMES; ADULTS AB Purpose: Children's physical activity (PA) levels are commonly assessed in pediatric clinical research, but rigorous self-report assessment tools for children are scarce, and computer adaptive test implementations are rare. Our objective was to improve pediatric self-report measures of activity using semistructured interviews with experts and children for conceptualization of a child-informed framework. Methods: Semistructured interviews were conducted to conceptualize PA, sedentary behaviors, and strengthening activities. We performed systematic literature reviews to identify item-level concepts used to assess these 3 domains. Results: We developed conceptual frameworks for each domain using words and phrases identified by children as relevant. Conclusions: Semistructured interview methods provide valuable information of children's perspectives and the ways children recall previous activities. Conceptualized domains of PA are based on the literature and expert views, which also reflect children's experiences and understanding, providing a basis for pediatric self-report instruments. C1 [Tucker, Carole A.] Temple Univ, Coll Hlth Profess & Social Work, Dept Phys Therapy, Philadelphia, PA 19140 USA. [Teneralli, Rachel E.; Bowles, Heather R.; Forrest, Christopher B.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA USA. [Bevans, Katherine B.; Forrest, Christopher B.] Univ Penn Sch Med, Dept Pediat, Philadelphia, PA USA. [Smith, Ashley Wilder; Bowles, Heather R.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Tucker, CA (reprint author), Temple Univ, Coll Hlth Profess & Social Work, 3307 N Broad St, Philadelphia, PA 19140 USA. EM carole.tucker@temple.edu FU NIH/NIAMS [U01 AR057956]; National Institutes of Health (NIH) Common Fund Initiative [U54AR057951, U01AR052177, U54AR057943, U54AR057926, U01AR057948, U01AR057954, U01AR052171, U01AR052181, U01AR057956, U01AR052158, U01AR057929, U01AR057936, U01AR052155, U01AR057971, U01AR057940, U01AR057967, U01AR052186] FX Grant Support: This work was funded by NIH/NIAMS as U01 AR057956 (PI-Forrest, CB): Pediatric PROMIS: Advancing the Measurement and Conceptualization of Child Health. PROMIS was funded with cooperative agreements from the National Institutes of Health (NIH) Common Fund Initiative (Northwestern University, PI: David Cella, PhD, U54AR057951, U01AR052177; Northwestern University, PI: Richard C. Gershon, PhD, U54AR057943; American Institutes for Research, PI: Susan (San) D. Keller, PhD, U54AR057926; State University of New York, Stony Brook, PIs: Joan E. Broderick, PhD and Arthur A. Stone, PhD, U01AR057948, U01AR052170; University of Washington, Seattle, PIs: Heidi M. Crane, MD, MPH, Paul K. Crane, MD, MPH, and Donald L. Patrick, PhD, U01AR057954; University of Washington, Seattle, PI: Dagmar Amtmann, PhD, U01AR052171; University of North Carolina, Chapel Hill, PI: Harry A. Guess, MD, PhD (deceased), Darren A. DeWalt, MD, MPH, U01AR052181; Children's Hospital of Philadelphia, PI: Christopher B. Forrest, MD, PhD, U01AR057956; Stanford University, PI: James F. Fries, MD, U01AR052158; Boston University, PIs: Alan Jette, PT, PhD, Stephen M. Haley, PhD (deceased), and David Scott Tulsky, PhD (University of Michigan, Ann Arbor), U01AR057929; University of California, Los Angeles, PIs: Dinesh Khanna, MD (University of Michigan, Ann Arbor) and Brennan Spiegel, MD, MSHS, U01AR057936; University of Pittsburgh, PI: Paul A. Pilkonis, PhD, U01AR052155; Georgetown University, PIs: Carol. M. Moinpour, PhD (Fred Hutchinson Cancer Research Center, Seattle) and Arnold L. Potosky, PhD, U01AR057971; Children's Hospital Medical Center, Cincinnati, PI: Esi M. Morgan DeWitt, MD, MSCE, U01AR057940; University of Maryland, Baltimore, PI: Lisa M. Shulman, MD, U01AR057967; and Duke University, PI: Kevin P. Weinfurt, PhD, U01AR052186). NIH Science Officers on this project have included Deborah Ader, PhD, Vanessa Ameen, MD (deceased), Susan Czajkowski, PhD, Basil Eldadah, MD, PhD, Lawrence Fine, MD, DrPH, Lawrence Fox, MD, PhD, Lynne Haverkos, MD, MPH, Thomas Hilton, PhD, Laura Lee Johnson, PhD, Michael Kozak, PhD, Peter Lyster, PhD, Donald Mattison, MD, Claudia Moy, PhD, Louis Quatrano, PhD, Bryce Reeve, PhD, William Riley, PhD, Peter Scheidt, MD, Ashley Wilder Smith, PhD, MPH, Susana Serrate-Sztein, MD, William Phillip Tonkins, DrPH, Ellen Werner, PhD, Tisha Wiley, PhD, and James Witter, MD, PhD. The contents of this article uses data developed under PROMIS. These contents do not necessarily represent an endorsement by the US Federal Government or PROMIS. See www.nihpromis.org for additional information on the PROMIS initiative. NR 29 TC 2 Z9 2 U1 1 U2 25 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0898-5669 EI 1538-005X J9 PEDIATR PHYS THER JI Pediatr. Phys. Ther. PD WIN PY 2014 VL 26 IS 4 BP 376 EP 384 DI 10.1097/PEP.0000000000000073 PG 9 WC Pediatrics; Rehabilitation SC Pediatrics; Rehabilitation GA AQ6AA UT WOS:000342888500002 PM 25251789 ER PT J AU Tucker, CA Bevans, KB Teneralli, RE Smith, AW Bowles, HR Forrest, CB AF Tucker, Carole A. Bevans, Katherine B. Teneralli, Rachel E. Smith, Ashley Wilder Bowles, Heather R. Forrest, Christopher B. TI Self-reported Pediatric Measures of Physical Activity, Sedentary Behavior, and Strength Impact for PROMIS: Item Development SO PEDIATRIC PHYSICAL THERAPY LA English DT Article DE adolescent; child; female; health status; humans; information systems; male; outcome assessment (health care)/methods; parents; pediatrics/methods; physical activities; quality of life; sedentary lifestyle; strengthening ID COMPUTERIZED ADAPTIVE ASSESSMENT; OUTCOMES MEASUREMENT; BANKING AB Background: Children's activity level is commonly assessed in clinical research, but rigorous assessment tools for children are scarce. Our objectives were to improve pediatric activity self-report measures using qualitative methods to develop item pools that measure these concepts. Methods: On the basis of the items generated from our conceptual framework development, we applied cognitive interviews and comprehensibility reviews to ensure children readily understood the items. Results: Our methods resulted in 129 unique items physical activities (80 items), sedentary behaviors (23 items), and strengthening activities (26 items) that were comprehensible to children between the ages of 8 and 18 years. Comprehensibility review resulted in the deletion of 4 items. Conclusions: The resultant item pools reflect children's experiences and understanding of the concepts of physical activities, sedentary behaviors, and strengthening activities. The item pools will undergo calibration using item response theory to support computer-adaptive test administration of self-and proxy-reported outcomes. C1 [Tucker, Carole A.] Temple Univ, Coll Hlth Profess & Social Work, Dept Phys Therapy, Philadelphia, PA 19140 USA. [Teneralli, Rachel E.; Forrest, Christopher B.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Bevans, Katherine B.; Forrest, Christopher B.] Univ Pennsylvania Sch Med, Dept Pediat, Philadelphia, PA USA. [Smith, Ashley Wilder; Bowles, Heather R.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Tucker, CA (reprint author), Temple Univ, Coll Hlth Profess & Social Work, 3307 North Broad St, Philadelphia, PA 19140 USA. EM carole.tucker@temple.edu FU NIH/NIAMS [U01 AR057956]; National Institutes of Health (NIH) Common Fund Initiative (Northwestern University) [U54AR057951, U01AR052177, U54AR057943]; National Institutes of Health (NIH) Common Fund Initiative (American Institutes for Research) [U54AR057926]; National Institutes of Health (NIH) Common Fund Initiative (State University of New York, Stony Brook) [U01AR057948, U01AR052170]; National Institutes of Health (NIH) Common Fund Initiative (University of Washington, Seattle) [U01AR057954, U01AR052171]; National Institutes of Health (NIH) Common Fund Initiative (University of North Carolina, Chapel Hill) [U01AR052181]; National Institutes of Health (NIH) Common Fund Initiative (Children's Hospital of Philadelphia) [U01AR057956]; National Institutes of Health (NIH) Common Fund Initiative (Stanford University) [U01AR052158]; National Institutes of Health (NIH) Common Fund Initiative (Boston University) [U01AR057929]; National Institutes of Health (NIH) Common Fund Initiative (University of California, Los Angeles) [U01AR057936]; National Institutes of Health (NIH) Common Fund Initiative (University of Pittsburgh) [U01AR052155]; National Institutes of Health (NIH) Common Fund Initiative (Georgetown University) [U01AR057971]; National Institutes of Health (NIH) Common Fund Initiative (Children's Hospital Medical Center, Cincinnati) [U01AR057940]; National Institutes of Health (NIH) Common Fund Initiative (University of Maryland, Baltimore) [U01AR057967]; National Institutes of Health (NIH) Common Fund Initiative (Duke University) [U01AR052186] FX Grant support: This work was funded by NIH/NIAMS as U01 AR057956 (PI: Forrest, CB): Pediatric PROMIS: Advancing the Measurement and Conceptualization of Child Health. PROMIS was funded with cooperative agreements from the National Institutes of Health (NIH) Common Fund Initiative (Northwestern University, PI: David Cella, PhD, U54AR057951, U01AR052177; Northwestern University, PI: Richard C. Gershon, PhD, U54AR057943; American Institutes for Research, PI: Susan (San) D. Keller, PhD, U54AR057926; State University of New York, Stony Brook, PIs: Joan E. Broderick, PhD, and Arthur A. Stone, PhD, U01AR057948, U01AR052170; University of Washington, Seattle, PIs: Heidi M. Crane, MD, MPH, Paul K. Crane, MD, MPH, and Donald L. Patrick, PhD, U01AR057954; University of Washington, Seattle, PI: Dagmar Amtmann, PhD, U01AR052171; University of North Carolina, Chapel Hill, PI: Harry A. Guess, MD, PhD (deceased), Darren A. DeWalt, MD, MPH, U01AR052181; Children's Hospital of Philadelphia, PI: Christopher B. Forrest, MD, PhD, U01AR057956; Stanford University, PI: James F. Fries, MD, U01AR052158; Boston University, PIs: Alan Jette, PT, PhD, Stephen M. Haley, PhD (deceased), and David Scott Tulsky, PhD (University of Michigan, Ann Arbor), U01AR057929; University of California, Los Angeles, PIs: Dinesh Khanna, MD (University of Michigan, Ann Arbor) and Brennan Spiegel, MD, MSHS, U01AR057936; University of Pittsburgh, PI: Paul A. Pilkonis, PhD, U01AR052155; Georgetown University, PI's: Carol. M. Moinpour, PhD (Fred Hutchinson Cancer Research Center, Seattle) and Arnold L. Potosky, PhD, U01AR057971; Children's Hospital Medical Center, Cincinnati, PI: Esi M. Morgan DeWitt, MD, MSCE, U01AR057940; University of Maryland, Baltimore, PI: Lisa M. Shulman, MD, U01AR057967; and Duke University, PI: Kevin P. Weinfurt, PhD, U01AR052186. NIH Science Officers on this project have included Deborah Ader, PhD, Vanessa Ameen, MD (deceased), Susan Czajkowski, PhD, Basil Eldadah, MD, PhD, Lawrence Fine, MD, DrPH, Lawrence Fox, MD, PhD, Lynne Haverkos, MD, MPH, Thomas Hilton, PhD, Laura Lee Johnson, PhD, Michael Kozak, PhD, Peter Lyster, PhD, Donald Mattison, MD, Claudia May, PhD, Louis Quatrano, PhD, Bryce Reeve, PhD, William Riley, PhD, Peter Scheidt, MD, Ashley Wilder Smith, PhD, MPH, Susana Serrate-Sztein, MD, William Phillip Tonkins, DrPH, Ellen Werner, PhD, Tisha Wiley, PhD, and James Witter, MD, PhD. NR 11 TC 2 Z9 2 U1 1 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0898-5669 EI 1538-005X J9 PEDIATR PHYS THER JI Pediatr. Phys. Ther. PD WIN PY 2014 VL 26 IS 4 BP 385 EP 392 DI 10.1097/PEP.0000000000000074 PG 8 WC Pediatrics; Rehabilitation SC Pediatrics; Rehabilitation GA AQ6AA UT WOS:000342888500003 PM 25251790 ER PT J AU Carruthers, K Zampieri, C Damiano, D AF Carruthers, Kadir Zampieri, Cris Damiano, Diane TI Relating motor and cognitive interventions in animals and humans SO TRANSLATIONAL NEUROSCIENCE LA English DT Article DE Neurological disorders; Exercise; Cognitive training; Movement; Cognition; Intervention; Animals; Humans ID TRAUMATIC BRAIN-INJURY; MEDIATED FUNCTIONAL IMPROVEMENT; RANDOMIZED CONTROLLED-TRIAL; ADULT DENTATE GYRUS; PHYSICAL-ACTIVITY; NEUROTROPHIC FACTOR; VOLUNTARY EXERCISE; OLDER-ADULTS; RAT HIPPOCAMPUS; SYNAPTIC-PLASTICITY AB Cognition and motor performance are essential components of human functioning. Recent research has provided evidence that these two domains are more interrelated than previously thought. This is a potentially important area of research with many questions that warrant further exploration and have practical implications to the field of neurological rehabilitation. In this review of literature we included animals and humans in healthy conditions as well as pathological conditions affecting the central nervous system. Our primary goal was to comprehensively review the relevant basic science and clinical literature on the effects of motor interventions on cognitive function and vice versa. We found more evidence supporting positive effects of exercise on cognition than effects of cognitive training on motor function. In addition, we examined the extent to which findings from animal literature have been or can be translated to humans. We found that, with the exception of one study in monkeys, most animal studies which investigate rodents are somewhat challenging to translate to human studies, independent of the intervention employed. It is difficult to find a human parallel to exercise in rodents, because both the voluntary and forced exercise paradigms used in rodents happen in a different context than humans. In addition it is difficult to find an animal parallel to cognitive training in humans, because the environmental enrichment intervention cannot be considered "purely" cognitive stimulation as it also involves sensory, motor and social components. We conclude the review by suggesting avenues for future research and intervention strategies. C1 [Carruthers, Kadir; Zampieri, Cris; Damiano, Diane] NIH, Ctr Clin, Dept Rehabil Med, Funct & Appl Biomech Sect, Bethesda, MD 20892 USA. RP Carruthers, K (reprint author), NIH, Ctr Clin, Dept Rehabil Med, Funct & Appl Biomech Sect, Bethesda, MD 20892 USA. EM zampierigallac@cc.nih.gov RI Damiano, Diane/B-3338-2010 OI Damiano, Diane/0000-0002-2770-5356 FU Intramural Research Program of the National Institutes of Health, Clinical Center, Rehabilitation Medicine Department [10-CC-0150]; Center for Neuroscience and Regenerative Medicine (CNRM); NIH; Pfizer Inc FX This research was supported by the Intramural Research Program of the National Institutes of Health, Clinical Center, Rehabilitation Medicine Department (Protocol #10-CC-0150), and by the Center for Neuroscience and Regenerative Medicine (CNRM). This research was also made possible through the NIH Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer Inc (via a grant to the Foundation for NIH from Pfizer Inc). Dr. Carruthers was a trainee in the program when this research was conducted. Dr. Zampieri and Dr. Damiano are employed by the NIH. NR 100 TC 0 Z9 0 U1 0 U2 49 PU DE GRUYTER OPEN LTD PI WARSAW PA SOLIPSKA 14A-1, 02-482 WARSAW, POLAND SN 2081-3856 EI 2081-6936 J9 TRANSL NEUROSCI JI Transl. Neurosci. PD DEC PY 2014 VL 5 IS 4 BP 227 EP 238 DI 10.2478/s13380-014-0233-7 PG 12 WC Neurosciences SC Neurosciences & Neurology GA AP6VD UT WOS:000342215200001 ER PT J AU Kenney, MK Wang, J Iannotti, R AF Kenney, Mary Kay Wang, Jing Iannotti, Ron TI Residency and Racial/Ethnic Differences in Weight Status and Lifestyle Behaviors Among US Youth SO JOURNAL OF RURAL HEALTH LA English DT Article DE physical activity; adolescent obesity; sedentary behavior; racial/ethnic disparity; obesogenic eating ID BODY-MASS INDEX; CHILDHOOD OBESITY PREVENTION; PHYSICAL-ACTIVITY; ADOLESCENT OBESITY; OVERWEIGHT STATUS; HEALTH BEHAVIORS; RURAL CHILDREN; UNITED-STATES; URBAN; SEGREGATION AB Purpose Elevated risk for obesity is found in rural environments and in some minority populations. It is unclear whether living in rural or nonmetropolitan areas and being a minority compound the risk of obesity beyond that of either factor acting alone. Our purpose was to examine adolescent obesity in light of the potential concomitant influences of race/ethnicity, residency, and obesity-related lifestyle behaviors. Methods We assessed obesity prevalence, physical activity, consumption of fatty snack foods, and screen time in 8,363 US adolescents based on variation in race/ethnicity and residency. Descriptive, bivariate, and multivariate statistics were used to: (1) calculate race- and residency-based rates of obesity and obesity-related lifestyle behaviors and (2) generate race- and residency-based obesity odds ratios as a function of those same behaviors. Findings The results indicated that nonmetropolitan black youth had the highest risk of obesity (26%), rate of consuming fatty snack foods on more than 2 days/week (86%), and rate of spending more than 2 hours/day in screen time (91%) compared to white metropolitan youth. Compared to their metropolitan counterparts, black nonmetropolitan youth had greater odds of being obese if they exercised less than daily (1.71 times), ate fatty snack foods on more than 2 days/week (1.65 times), or spent more than 2 hours/day in screen time (1.64 times). Conclusions Race/ethnicity and residency may have a compounding effect on the risk of obesity. Prevention and intervention must be viewed in a socioecological framework that recognizes the importance of culture and community on obesity-related behaviors. C1 [Kenney, Mary Kay] US Dept Hlth & Human Serv, Hlth Resources & Serv Adm, Maternal & Child Hlth Bur, Rockville, MD 20857 USA. [Wang, Jing; Iannotti, Ron] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, US Dept Hlth & Human Serv, Rockville, MD 20857 USA. RP Kenney, MK (reprint author), US Dept Hlth & Human Serv, Hlth Resources & Serv Adm, Maternal & Child Hlth Bur, 5600 Fishers Lane,Rm 18-41, Rockville, MD 20857 USA. EM mkenney@hrsa.gov RI Dey, Kamalesh/E-6568-2017 FU Intramural NIH HHS [Z99 HD999999] NR 60 TC 4 Z9 4 U1 2 U2 274 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0890-765X EI 1748-0361 J9 J RURAL HEALTH JI J. Rural Health PD WIN PY 2014 VL 30 IS 1 BP 89 EP 100 DI 10.1111/jrh.12034 PG 12 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AF0MN UT WOS:000334408800010 PM 24383488 ER PT J AU Larson, JK Carvan, MJ Teeguarden, JG Watanabe, G Taya, K Krystofiak, E Hutz, RJ AF Larson, Jeremy K. Carvan, Michael J., III Teeguarden, Justin G. Watanabe, Gen Taya, Kazuyoshi Krystofiak, Evan Hutz, Reinhold J. TI Low-dose gold nanoparticles exert subtle endocrine-modulating effects on the ovarian steroidogenic pathway ex vivo independent of oxidative stress SO NANOTOXICOLOGY LA English DT Article DE nanotoxicology; genomics ID IN-VITRO; DISRUPTING CHEMICALS; GRANULOSA-CELLS; TOXICITY; INHIBIN; MODEL; GENERATION; APOPTOSIS; EXPOSURE; MICE AB Gold nanoparticles (GNPs) have gained considerable attention for application in science and industry. However, the untoward effects of such particles on female fertility remain unclear. The objectives of this study were to (1) examine the effects of 10-nm GNPs on progesterone and estradiol-17 beta accumulation by rat ovaries ex vivo and (2) to identify the locus/loci whereby GNPs modulate steroidogenesis via multiple-reference gene quantitative real-time RT-PCR. Regression analyses indicated a positive relationship between both Star (p < 0.05, r(2) = 0.278) and Cyp11a1 (p < 0.001, r(2) = 0.366) expression and P4 accumulation upon exposure to 1.43 x 10(6) GNPs/mL. Additional analyses showed that E2 accumulation was positively associated with Hsd3b1 (p < 0.05, r(2) = 0.181) and Cyp17a1 (p < 0.01, r(2) = 0.301) expression upon exposure to 1.43 x 1(3) and 1.43 x 10(9) GNPs/mL, respectively. These results suggest a subtle treatment-dependent impact of low-dose GNPs on the relationship between progesterone or estradiol-17 beta and specific steroidogenic target genes, independent of oxidative stress or inhibin. C1 [Larson, Jeremy K.; Carvan, Michael J., III; Krystofiak, Evan; Hutz, Reinhold J.] Univ Wisconsin, Milwaukee, WI 53211 USA. [Larson, Jeremy K.; Carvan, Michael J., III; Hutz, Reinhold J.] NIEHS Childrens Environm Hlth Sci Core Ctr, Childrens Res Inst, Milwaukee, WI 53211 USA. [Carvan, Michael J., III] Univ Wisconsin, Sch Freshwater Sci, Milwaukee, WI 53211 USA. [Teeguarden, Justin G.] Pacific NW Natl Lab, Richland, WA 99352 USA. [Watanabe, Gen; Taya, Kazuyoshi] Tokyo Univ Agr & Technol, Vet Physiol Lab, Tokyo, Japan. RP Hutz, RJ (reprint author), Univ Wisconsin, 1921 E Hartford Ave, Milwaukee, WI 53211 USA. EM rjhutz@uwm.edu RI Geracitano, Laura/E-6926-2013; Watanabe, Gen/G-1134-2013; OI Watanabe, Gen/0000-0001-7611-4678; Teeguarden, Justin/0000-0003-3817-4391; Carvan, Michael/0000-0002-9190-9417 FU Children's Environmental Health Sciences Core Center at the University of Wisconsin-Milwaukee and Children's Research Institute [NIEHS P30 ES004184 PRJ32IR] FX We thank R. Klaper for allowing our use of the Malvern Zetasizer Nano Z, Q. Liu for his assistance with molecular techniques, and D. Arndt for acquisition of the SEM micrographs. We express sincere gratitude to J. Ghorai and P. Dunn for their advice on statistical analyses. We thank H. Owen for his advice on imaging strategies. We thank M. Gajdardziska-Josifovska, M. Schofield and D. Robertson for their collaborative acquisition of high-resolution TEM micrographs. We also thank M. Engelhard of the Environmental Molecular Sciences Laboratory (EMSL) at Pacific Northwest National Laboratory, for characterizing our GNPs via X-ray photoelectron spectroscopy. This research was supported by the Children's Environmental Health Sciences Core Center at the University of Wisconsin-Milwaukee and Children's Research Institute (NIEHS P30 ES004184 PRJ32IR). NR 44 TC 2 Z9 2 U1 2 U2 359 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1743-5390 EI 1743-5404 J9 NANOTOXICOLOGY JI Nanotoxicology PD DEC PY 2014 VL 8 IS 8 BP 856 EP 866 DI 10.3109/17435390.2013.837208 PG 11 WC Nanoscience & Nanotechnology; Toxicology SC Science & Technology - Other Topics; Toxicology GA 267XF UT WOS:000328131000005 PM 23992423 ER PT J AU Feng, XD Chen, QM Gutkind, JS AF Feng, Xiaodong Chen, Qianming Gutkind, J. Silvio TI Oncotargeting G proteins: The Hippo in the room SO ONCOTARGET LA English DT Editorial Material DE YAP; GNAQ; GNA11; Melanoma, Cancer, Signal transduction; Rho GTPases ID UVEAL MELANOMA; YAP; CIRCUITRY C1 [Feng, Xiaodong; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Feng, Xiaodong; Chen, Qianming] Sichuan Univ, West China Hosp Stomatol, State Key Lab Oral Dis, Chengdu 610064, Sichuan, Peoples R China. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM sg39v@nih.gov FU Intramural NIH HHS; NIDCR NIH HHS [Z01 DE000551] NR 8 TC 5 Z9 5 U1 0 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 30 PY 2014 VL 5 IS 22 BP 10997 EP 10999 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ2AQ UT WOS:000348037400008 PM 25526026 ER PT J AU David, KA Unger, FT Uhlig, P Juhl, H Moore, HM Compton, C Nashan, B Dorner, A de Weerth, A Zornig, C AF David, Kerstin A. Unger, Florian T. Uhlig, Philipp Juhl, Hartmut Moore, Helen M. Compton, Carolyn Nashan, Bjorn Dorner, Arnulf de Weerth, Andreas Zornig, Carsten TI Surgical procedures and postsurgical tissue processing significantly affect expression of genes and EGFR-pathway proteins in colorectal cancer tissue SO ONCOTARGET LA English DT Article DE Biospecimen; predictive biomarker; drug development; tissue quality; EGFR pathway; phosphoproteins ID ISCHEMIA AB An understanding of tissue data variability in relation to processing techniques during and postsurgery would be desirable when testing surgical specimens for clinical diagnostics, drug development, or identification of predictive biomarkers. Specimens of normal and colorectal cancer (CRC) tissues removed during colon and liver resection surgery were obtained at the beginning of surgery and postsurgically, tissue was fixed at 10, 20, and 45 minutes. Specimens were analyzed from 50 patients with primary CRC and 43 with intrahepatic metastasis of CRC using a whole genome gene expression array. Additionally, we focused on the epidermal growth factor receptor pathway and quantified proteins and their phosphorylation status in relation to tissue processing timepoints. Gene and protein expression data obtained from colorectal and liver specimens were influenced by tissue handling during surgery and by postsurgical processing time. To obtain reliable expression data, tissue processing for research and diagnostic purposes needs to be highly standardized. C1 [David, Kerstin A.; Unger, Florian T.; Uhlig, Philipp; Juhl, Hartmut] Indivumed GmbH, Hamburg, Germany. [Moore, Helen M.] NCI, Biorepositories & Biospecimen Res Branch, NIH, Bethesda, MD 20892 USA. [Compton, Carolyn] Arizona State Univ, Phoenix, AZ USA. [Nashan, Bjorn] Univ Hosp Hamburg Eppendorf, Clin Hepatobiliary Surg & Transplantat Surg, Hamburg, Germany. [Dorner, Arnulf; de Weerth, Andreas] Agaples Diakonieklinikum Hamburg, Clin Gen & Visceral Surg, Hamburg, Germany. [Dorner, Arnulf; de Weerth, Andreas] Agaples Diakonieklinikum Hamburg, Gastroenterol Clin, Hamburg, Germany. [Zornig, Carsten] Israelit Krankenhaus Hamburg, Surg Clin, Hamburg, Germany. RP Juhl, H (reprint author), Indivumed GmbH, Hamburg, Germany. EM juhl@indivumed.com FU Indivumed FX Medical editing services were provided by Rhian Harper-Owen on behalf of Complete Medical Communications, funded by Indivumed. NR 17 TC 8 Z9 8 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 30 PY 2014 VL 5 IS 22 BP 11017 EP 11028 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ2AQ UT WOS:000348037400012 PM 25526028 ER PT J AU Dzinic, SH Chen, K Thakur, A Kaplun, A Bonfil, RD Li, XH Liu, JS Bernardo, MM Saliganan, A Back, JB Yano, H Schalk, DL Tomaszewski, EN Beydoun, AS Dyson, G Mujagic, A Krass, D Dean, I Mi, QS Heath, E Sakr, W Lum, LG Sheng, SJ AF Dzinic, Sijana H. Chen, Kang Thakur, Archana Kaplun, Alexander Bonfil, R. Daniel Li, Xiaohua Liu, Jason Bernardo, M. Margarida Saliganan, Allen Back, Jessica B. Yano, Hiroshi Schalk, Dana L. Tomaszewski, Elyse N. Beydoun, Ahmed S. Dyson, Gregory Mujagic, Adelina Krass, David Dean, Ivory Mi, Qing-Sheng Heath, Elisabeth Sakr, Wael Lum, Lawrence G. Sheng, Shijie TI No Maspin expression in prostate tumor elicits host anti-tumor immunity SO ONCOTARGET LA English DT Article DE prostate tumor xenograft; tumorigenicity; flow cytometry; CD11b(+)Ly6G(high) neutrophils; neutrophil maturation and chemotaxis; B-cell antibody response; Cr-51-release assay; antibody-dependent cellular cytotoxicity; lymphangiogenesis; intratumoral fibrosis; angiogenesis; leukocyte-filled lytic and necrotic centers ID CELL LUNG-CANCER; SUPPRESSOR PROTEIN MASPIN; PLASMINOGEN-ACTIVATOR; INDUCED APOPTOSIS; IMPROVED SURVIVAL; PROGNOSTIC-FACTOR; EPITHELIAL-CELLS; BREAST-CANCER; VEGF-A; NUCLEAR AB The goal of the current study is to examine the biological effects of epithelial-specific tumor suppressor maspin on tumor host immune response. Accumulated evidence demonstrates an anti-tumor effect of maspin on tumor growth, invasion and metastasis. The molecular mechanism underlying these biological functions of maspin is thought to be through histone deacetylase inhibition, key to the maintenance of differentiated epithelial phenotype. Since tumor-driven stromal reactivities co-evolve in tumor progression and metastasis, it is not surprising that maspin expression in tumor cells inhibits extracellular matrix degradation, increases fibrosis and blocks hypoxia-induced angiogenesis. Using the athymic nude mouse model capable of supporting the growth and progression of xenogeneic human prostate cancer cells, we further demonstrate that maspin expression in tumor cells elicits neutrophil- and B cells-dependent host tumor immunogenicity. Specifically, mice bearing maspin-expressing tumors exhibited increased systemic and intratumoral neutrophil maturation, activation and antibody-dependent cytotoxicity, and decreased peritumoral lymphangiogenesis. These results reveal a novel biological function of maspin in directing host immunity towards tumor elimination that helps explain the significant reduction of xenograft tumor incidence in vivo and the clinical correlation of maspin with better prognosis of several types of cancer. Taken together, our data raised the possibility for novel maspin-based cancer immunotherapies. C1 [Dzinic, Sijana H.; Kaplun, Alexander; Bonfil, R. Daniel; Li, Xiaohua; Liu, Jason; Bernardo, M. Margarida; Beydoun, Ahmed S.; Mujagic, Adelina; Krass, David; Dean, Ivory; Sakr, Wael; Sheng, Shijie] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. [Dzinic, Sijana H.; Chen, Kang; Thakur, Archana; Kaplun, Alexander; Bonfil, R. Daniel; Li, Xiaohua; Liu, Jason; Bernardo, M. Margarida; Saliganan, Allen; Back, Jessica B.; Yano, Hiroshi; Schalk, Dana L.; Tomaszewski, Elyse N.; Beydoun, Ahmed S.; Dyson, Gregory; Mujagic, Adelina; Krass, David; Dean, Ivory; Mi, Qing-Sheng; Sakr, Wael; Lum, Lawrence G.; Sheng, Shijie] Barbara Ann Karmanos Canc Inst, Tumor Biol & Microenvironm Program, Detroit, MI USA. [Chen, Kang] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Chen, Kang; Mi, Qing-Sheng; Lum, Lawrence G.] Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48201 USA. [Chen, Kang; Thakur, Archana; Back, Jessica B.; Yano, Hiroshi; Schalk, Dana L.; Tomaszewski, Elyse N.; Dyson, Gregory; Lum, Lawrence G.; Sheng, Shijie] Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI USA. [Chen, Kang] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Perinatol Res Branch, NIH, Detroit, MI USA. [Chen, Kang] NIAID, Mucosal Immunol Studies Team, NIH, Bethesda, MD 20892 USA. [Bonfil, R. Daniel; Saliganan, Allen; Heath, Elisabeth] Wayne State Univ, Sch Med, Dept Urol, Detroit, MI USA. [Mi, Qing-Sheng] Henry Ford Hlth Syst, Detroit, MI USA. [Lum, Lawrence G.] Wayne State Univ, Sch Med, Dept Med, Detroit, MI 48201 USA. [Heath, Elisabeth] Barbara Ann Karmanos Canc Inst, Mol Therapeut Program, Detroit, MI USA. RP Sheng, SJ (reprint author), Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. EM ssheng@med.wayne.edu FU NIH [CA127735, CA084176, P30CA022453]; Fund for Cancer Research; Ruth Sager Memorial Fund; Perinatology Research Branch of the National Institutes of Child Health and Development, Wayne State University FX This work was supported by NIH grants (CA127735 and CA084176 to Sheng, S.), Fund for Cancer Research (to Sheng, S. and Heath, H.), and the Ruth Sager Memorial Fund (to Sheng, S). The Microscopy, Imaging and Cytometry Resources Core is supported, in part, by NIH Center grant P30CA022453 to The Karmanos Cancer Institute, Wayne State University and the Perinatology Research Branch of the National Institutes of Child Health and Development, Wayne State University. NR 57 TC 7 Z9 8 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 NOV 30 PY 2014 VL 5 IS 22 BP 11225 EP 11236 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ2AQ UT WOS:000348037400028 PM 25373490 ER PT J AU Proschan, M Glimm, E Posch, M AF Proschan, Michael Glimm, Ekkehard Posch, Martin TI Connections between permutation and t-tests: relevance to adaptive methods SO STATISTICS IN MEDICINE LA English DT Article DE adaptive methods in clinical trials; blinded sample size recalculation; p-value combination functions; permutation tests; asymptotic distribution; complete sufficient statistic ID SAMPLE-SIZE REESTIMATION; I ERROR RATE; TRIALS AB A permutation test assigns a p-value by conditioning on the data and treating the different possible treatment assignments as random. The fact that the conditional type I error rate given the data is controlled at level ensures validity of the test even if certain adaptations are made. We show the connection between permutation and t-tests, and use this connection to explain why certain adaptations are valid in a t-test setting as well. We illustrate this with an example of blinded sample size recalculation. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Proschan, Michael] NIAID, Bethesda, MD 20892 USA. [Glimm, Ekkehard] Novartis Pharmaceut, Basel, Switzerland. [Posch, Martin] Med Univ Vienna, Ctr Med Stat Informat & Intelligent Syst, Vienna, Austria. RP Proschan, M (reprint author), NIAID, Biostat Res Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ProschaM@niaid.nih.gov RI Posch, Martin/C-7907-2009 OI Posch, Martin/0000-0001-8499-8573 FU Austrian Science Fund (FWF) [P23167] FX We would like to thank the referees for very helpful comments that improved the clarity and quality of the manuscript. Martin Posch was supported by the Austrian Science Fund (FWF):P23167. NR 24 TC 3 Z9 3 U1 0 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 NOV 30 PY 2014 VL 33 IS 27 BP 4734 EP 4742 DI 10.1002/sim.6288 PG 9 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 AT0KW UT WOS:000344626000005 PM 25156155 ER PT J AU Lin, DD Cao, HB Calhoun, VD Wang, YP AF Lin, Dongdong Cao, Hongbao Calhoun, Vince D. Wang, Yu-Ping TI Sparse models for correlative and integrative analysis of imaging and genetic data SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Imaging genetics; Sparse modeling; Correspondence analysis; Integration; Classification ID CANONICAL CORRELATION-ANALYSIS; PARTIAL LEAST-SQUARES; GENOME-WIDE ASSOCIATION; AUDITORY ODDBALL TASK; ALZHEIMERS-DISEASE; SNP DATA; VARIABLE SELECTION; FUNCTIONAL MRI; GROUP LASSO; SCHIZOPHRENIA AB The development of advanced medical imaging technologies and high-throughput genomic measurements has enhanced our ability to understand their interplay as well as their relationship with human behavior by integrating these two types of datasets. However, the high dimensionality and heterogeneity of these datasets presents a challenge to conventional statistical methods; there is a high demand for the development of both correlative and integrative analysis approaches. Here, we review our recent work on developing sparse representation based approaches to address this challenge. We show how sparse models are applied to the correlation and integration of imaging and genetic data for biomarker identification. We present examples on how these approaches are used for the detection of risk genes and classification of complex diseases such as schizophrenia. Finally, we discuss future directions on the integration of multiple imaging and genomic datasets including their interactions such,as epistasis. (C) 2014 Elsevier B.V. All rights reserved. C1 [Lin, Dongdong; Wang, Yu-Ping] Tulane Univ, Dept Biomed Engn, New Orleans, LA 70118 USA. [Lin, Dongdong; Wang, Yu-Ping] Tulane Univ, Ctr Genom & Bioinformat, New Orleans, LA 70112 USA. [Cao, Hongbao] NIMH, Unit Stat Genom, Intramural Res Program, NIH, Bethesda, MD 20852 USA. [Calhoun, Vince D.] Mind Res Network, Albuquerque, NM 87106 USA. [Calhoun, Vince D.] LBERI, Albuquerque, NM 87106 USA. [Calhoun, Vince D.] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA. RP Wang, YP (reprint author), Tulane Univ, Dept Biomed Engn, New Orleans, LA 70118 USA. EM dlin5@tulane.edu; hongbao.cao@nih.gov; vcalhoun@unm.edu; wyp@tulane.edu RI Lin, Dongdong/A-8337-2017 FU NIH grants [NIBIB 2R01EB000840, COBRE 5P20RR021938/P20GM103472, R01GM109068, R01MH104680] FX This work is partially supported by NIH grants (NIBIB 2R01EB000840, COBRE 5P20RR021938/P20GM103472, R01GM109068, and R01MH104680). NR 86 TC 6 Z9 6 U1 0 U2 13 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 NOV 30 PY 2014 VL 237 BP 69 EP 78 DI 10.1016/j.jneumeth.2014.09.001 PG 10 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AS3XZ UT WOS:000344209700009 PM 25218561 ER PT J AU Tudorascu, DL Rosano, C Venkatraman, VK MacCloud, RL Harris, T Yaffe, K Newman, AB Aizenstein, HJ AF Tudorascu, Dana L. Rosano, Caterina Venkatraman, Vijay K. MacCloud, Rebecca L. Harris, Tamara Yaffe, Kristine Newman, Anne B. Aizenstein, Howard J. TI Multimodal MRI markers support a model of small vessel ischemia for depressive symptoms in very old adults SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE MRI markers; Depression; Geriatric ID LATE-LIFE DEPRESSION; WHITE-MATTER HYPERINTENSITIES; RISK-FACTORS; MAJOR DEPRESSION; ABNORMALITIES; SEGMENTATION; ANISOTROPY; DISORDERS; THRESHOLD; SEVERITY AB In older adults, depressive symptoms are associated with lower quality of life, high morbidity and mortality. This study aims to identify brain magnetic resonance imaging (MRI) features associated with late-life depressive symptoms in the population. Older community-dwelling adults (n=314) from the Health ABC study underwent brain MRL Logistic regression was used to characterize the relationships between depressive symptoms (Center for Epidemiologic Studies of Depression scale, CES-D) and the following whole-brain variables: white matter hyperintensity (WMH) burden, fractional anisotropy (FA), and gray matter volume (GMV). Analyses examining possible regional differences between the CES-D groups controlled for Modified Mini-Mental State Examination score and diabetes status. The relative importance of localization of the markers was examined by comparing the distribution of significant peaks across the brain. Each whole-brain variable showed loss of integrity associated with high CES-D. For GMV, the odds ratio (OR)=0.84 (95% confidence interval (Cl) 0.74, 0.96); for FA, OR=0.714 (95% Cl 0.57, 0.88); for WMH, OR=1.89 (95%Cl 1.33, 2.69). Voxel-wise analyses and patterns of peak significance showed non-specific patterns for white matter measures. Loss of GMV was most significant in the bilateral insula and anterior cingulate cortex. This study supports a cerebrovascular pattern for depressive symptoms in older adults. The localization of gray matter changes to the insula, a watershed area and a hub of affective circuits, suggests an etiological pathway from ischemia to increased depressive burden. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Tudorascu, Dana L.] Univ Pittsburgh, Dept Internal Med, Pittsburgh, PA 15213 USA. [Tudorascu, Dana L.] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15213 USA. [Rosano, Caterina; Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Venkatraman, Vijay K.] Univ Calif San Diego, Sch Med, Dept Neurosci, San Diego, CA 92103 USA. [Tudorascu, Dana L.; MacCloud, Rebecca L.; Aizenstein, Howard J.] Univ Pittsburgh, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. [Harris, Tamara] NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat Neurol & EpidemioL & Biostat, San Francisco, CA 94143 USA. [Aizenstein, Howard J.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15213 USA. [Tudorascu, Dana L.; Aizenstein, Howard J.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. RP Tudorascu, DL (reprint author), Univ Pittsburgh, Dept Internal Med, 200 Meyran Ave, Pittsburgh, PA 15213 USA. EM tudorascudl@upmc.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010 FU Healthy Brain and Resilience grant - National Institutes of Health/National Institutes of Aging [R01 AG29232-05, R01 AG037451-01]; National Institute of Mental Health [R01 MH086498] FX This work was supported by the Healthy Brain and Resilience grant funded by the National Institutes of Health/National Institutes of Aging, R01 AG29232-05, R01 AG037451-01 and National Institute of Mental Health R01 MH086498. NR 43 TC 4 Z9 4 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 EI 1872-7506 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD NOV 30 PY 2014 VL 224 IS 2 BP 73 EP 80 DI 10.1016/j.pscychresns.2014.08.009 PG 8 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AR8LN UT WOS:000343826800001 PM 25205441 ER PT J AU Willette, AA Calhoun, VD Egan, JM Kapogiannis, D AF Willette, Auriel A. Calhoun, Vince D. Egan, Josephine M. Kapogiannis, Dimitrios CA Alzheimer's Dis Neuroimaging Initi TI Prognostic classification of mild cognitive impairment and Alzheimer's disease: MRI independent component analysis SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Data reduction; MCI; AD; Alzheimer's disease neuroimaging initiative ID NEUROIMAGING INITIATIVE ADNI; BASE-LINE; COMPOSITE SCORE; CSF BIOMARKERS; DIAGNOSIS; ATROPHY; CONVERSION; PATTERNS; RISK; MCI AB Identifying predictors of mild cognitive impairment (MCI) and Alzheimer's disease (AD) can lead to more accurate diagnosis and facilitate clinical trial participation. We identified 320 participants (93 cognitively normal or CN, 162 MCI, 65 AD) with baseline magnetic resonance imaging (MRI) data, cerebrospinal fluid biomarkers, and cognition data in the Alzheimer's Disease Neuroimaging Initiative database. We used independent component analysis (ICA) on structural MR images to derive 30 matter covariance patterns (ICs) across all participants. These ICs were used in iterative and stepwise discriminant classifier analyses to predict diagnostic classification at 24 months for CN vs. MCI, CN vs. AD, MCI vs. AD, and stable MCI (MCI-S) vs. MCI progression to AD (MCI-P). Models were cross-validated with a "leave-10-out" procedure. For CN vs. MCI, 84.7% accuracy was achieved based on cognitive performance measures, ICs, p-tau(181p), and ApoE epsilon 4 status. For CN vs. AD, 94.8% accuracy was achieved based on cognitive performance measures, ICs, and p-tau(181p). For MCI vs. AD and MCI-S vs. MCI-P, models achieved 83.1% and 80.3% accuracy, respectively, based on cognitive performance measures. ICs, and p-tau(181p). ICA-derived MRI biomarkers achieve excellent diagnostic accuracy for MCI conversion, which is little improved by CSF biomarkers and ApoE epsilon 4 status. Published by Elsevier Ireland Ltd. C1 [Willette, Auriel A.; Kapogiannis, Dimitrios] NIA, Neurosci Lab, Ctr Biomed Res, Baltimore, MD 21224 USA. [Calhoun, Vince D.] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA. [Calhoun, Vince D.] Mind Res Network, Albuquerque, NM 87131 USA. [Egan, Josephine M.] NIA, Clin Invest Lab, Baltimore, MD 21225 USA. RP Kapogiannis, D (reprint author), NIA, Neurosci Lab, Ctr Biomed Res, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM kapogiannisd@mail.nih.gov FU Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; DOD ADNI (Department of Defense) [W81XWH-12-2-0012]; National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research; NIH, National Institute on Aging FX Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc.; Biogen ldec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.: Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 51 TC 12 Z9 12 U1 1 U2 15 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 EI 1872-7506 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD NOV 30 PY 2014 VL 224 IS 2 BP 81 EP 88 DI 10.1016/j.pscychresns.2014.08.005 PG 8 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AR8LN UT WOS:000343826800002 PM 25194437 ER PT J AU Adleman, NE Yi, JY Deveney, CM Guyer, AE Leibenluft, E Brotman, MA AF Adleman, Nancy E. Yi, Jennifer Y. Deveney, Christen M. Guyer, Amanda E. Leibenluft, Ellen Brotman, Melissa A. TI Increased intrasubject variability in response time in unaffected preschoolers at familial risk for bipolar disorder SO PSYCHIATRY RESEARCH LA English DT Article DE Population at risk; Bipolar disorder; Endophenotype ID SUSTAINED ATTENTION; EUTHYMIC PATIENTS; WORKING-MEMORY; CHILDREN; PARENTS; METAANALYSIS; PERFORMANCE; PARADIGM; DEFICITS; ADHD AB Increased intrasubject variability in response time (ISVRT) is evident in healthy preschoolers at familial risk for bipolar disorder, suggesting it may be an endophenotype. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Adleman, Nancy E.] Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. [Adleman, Nancy E.; Yi, Jennifer Y.; Deveney, Christen M.; Leibenluft, Ellen; Brotman, Melissa A.] NIMH, Emot & Dev Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Deveney, Christen M.] Wellesley Coll, Dept Psychol, Wellesley, MA 02181 USA. [Guyer, Amanda E.] Univ Calif Davis, Ctr Mind & Brain, Davis, CA 95616 USA. RP Adleman, NE (reprint author), Catholic Univ Amer, OBoyle Hall 310, Washington, DC 20064 USA. EM adleman@cua.edu RI Brotman, Melissa/H-7409-2013 FU NIMH, NIH; NARSAD FX This research was supported by the Intramural Research Program of the NIMH, NIH, and a NARSAD Young Investigator Grant (A.E.G.). We thank the staff of the Emotion and Development Branch at NIMH and subjects and families for their participation. NR 20 TC 5 Z9 5 U1 0 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD NOV 30 PY 2014 VL 219 IS 3 BP 687 EP 689 DI 10.1016/j.psychres.2014.06.047 PG 3 WC Psychiatry SC Psychiatry GA AP2KR UT WOS:000341901600043 PM 25041984 ER PT J AU Gery, I AF Gery, Igal TI The definition of lymphocyte activating factor: giving a Helping Hand to Serendipity SO FRONTIERS IN IMMUNOLOGY LA English DT Editorial Material DE interleukin-1; lymphocyte activating factor; cytokines; macrophages; thymocytes ID DELAYED HYPERSENSITIVITY; POTENTIATION; VITRO; MITOGENS; MEDIATOR(S); RESPONSES; MECHANISM; CELLS C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Gery, I (reprint author), NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM geryi@nei.nih.gov NR 14 TC 0 Z9 0 U1 0 U2 1 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD NOV 28 PY 2014 VL 5 AR 610 DI 10.3389/fimmu.2014.00610 PG 2 WC Immunology SC Immunology GA CI1VD UT WOS:000354532100001 PM 25506345 ER PT J AU Sun, GH Fu, LZ Shi, YB AF Sun, Guihong Fu, Liezhen Shi, Yun-Bo TI Epigenetic regulation of thyroid hormone-induced adult intestinal stem cell development during anuran metamorphosis SO CELL AND BIOSCIENCE LA English DT Review DE Thyroid hormone receptor; Stem cell; Metamorphosis; Xenopus laevis and tropicalis; Histone methylation; Histone acetylation; Intestine ID RECEPTOR-MEDIATED TRANSCRIPTION; ARGININE METHYLTRANSFERASE 1; EFFECTOR NUCLEASES TALENS; TARGETED GENE DISRUPTION; XENOPUS-LAEVIS; AMPHIBIAN METAMORPHOSIS; HISTONE H3; POSTEMBRYONIC DEVELOPMENT; COREPRESSOR COMPLEX; CO-REPRESSOR AB Epigenetic modifications of histones are emerging as key factors in gene regulation by diverse transcription factors. Their roles during vertebrate development and pathogenesis are less clear. The causative effect of thyroid hormone (T3) on amphibian metamorphosis and the ability to manipulate this process for molecular and genetic studies have led to the demonstration that T3 receptor (TR) is necessary and sufficient for Xenopus metamorphosis, a process that resembles the postembryonic development (around birth) in mammals. Importantly, analyses during metamorphosis have provided some of the first in vivo evidence for the involvement of histone modifications in gene regulation by TR during vertebrate development. Furthermore, expression and functional studies suggest that various histone modifying epigenetic enzymes likely participate in multiple steps during the formation of adult intestinal stem cells during metamorphosis. The similarity between intestinal remodeling and the maturation of the mammalian intestine around birth when T3 levels are high suggests conserved roles for the epigenetic enzymes in mammalian adult intestinal stem cell development and/ or proliferation. C1 [Sun, Guihong] Wuhan Univ, Sch Basic Med Sci, Wuhan 430072, Peoples R China. [Fu, Liezhen; Shi, Yun-Bo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, PCRM, NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, PCRM, NIH, 18 Lib Dr, Bethesda, MD 20892 USA. EM Shi@helix.nih.gov FU intramural Research Program of NICHD; NIH; National Natural Science Foundation of China [31370187, 30870113] FX This work was supported by the intramural Research Program of NICHD, NIH and National Natural Science Foundation of China (Grant No. 31370187 and 30870113). NR 120 TC 6 Z9 6 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD NOV 28 PY 2014 VL 4 AR 73 DI 10.1186/2045-3701-4-73 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AZ8LT UT WOS:000348468000001 PM 25937894 ER PT J AU Steffen, LM Van Horn, L Daviglus, ML Zhou, X Reis, JP Loria, CM Jacobs, DR Duffey, KJ AF Steffen, Lyn M. Van Horn, Linda Daviglus, Martha L. Zhou, Xia Reis, Jared P. Loria, Catherine M. Jacobs, David R. Duffey, Kiyah J. TI A modified Mediterranean diet score is associated with a lower risk of incident metabolic syndrome over 25 years among young adults: the CARDIA (Coronary Artery Risk Development in Young Adults) study SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE Metabolic syndrome; Mediterranean dietary pattern; Prospective studies; African Americans ID BLOOD-PRESSURE; CARDIOVASCULAR-DISEASE; PRIMARY PREVENTION; LIPID PROFILE; US ADULTS; OLIVE OIL; ADHERENCE; HEALTH; METAANALYSIS; CONSUMPTION AB The Mediterranean diet has been reported to be inversely associated with incident metabolic syndrome (MetSyn) among older adults; however, this association has not been studied in young African American and white adults. The objective of the present study was to evaluate the association of a modified Mediterranean diet (mMedDiet) score with the 25-year incidence of the MetSyn in 4713 African American and white adults enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study. A diet history questionnaire was used to assess dietary intake at baseline, year 7 and year 20 and a mMedDiet score was created. Cardiovascular risk factors were measured at multiple examinations over 25 years. The MetSyn was defined according to the National Cholesterol Education Program Adult Treatment Panel III (ATP III) criteria. Cox proportional-hazards regression analysis was use to evaluate associations for incident MetSyn across the mMedDiet score categories adjusting for demographic characteristics, lifestyle factors and BMI. Higher mMedDiet scores represented adherence to a dietary pattern rich in fruit, vegetables, whole grains, nuts and fish, but poor in red and processed meat and snack foods. The incidence of MetSyn components (abdominal obesity, elevated TAG concentrations and low HDL-cholesterol concentrations) was lower in those with higher mMedDiet scores than in those with lower scores. Furthermore, the incidence of the MetSyn was lower across the five mMedDiet score categories; the hazard ratios and 95% CI from category 1 to category 5 were 1.0; 0.94 (0.76, 1.15); 0.84 (0.68, 1.04); 0.73 (0.58, 0.92); and 0.72 (0.54, 0.96), respectively (P-trend = 0.005). These findings suggest that the risk of developing the MetSyn is lower when consuming a diet rich in fruit, vegetables, whole grains, nuts and fish. C1 [Steffen, Lyn M.; Zhou, Xia; Jacobs, David R.] Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, Minneapolis, MN 55454 USA. [Van Horn, Linda] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Daviglus, Martha L.] Univ Illinois, Coll Med, Chicago, IL USA. [Reis, Jared P.; Loria, Catherine M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Duffey, Kiyah J.] Virginia Tech, Dept Human Nutr Foods & Exercise, Blacksburg, VA USA. RP Steffen, LM (reprint author), Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, 1300 South Second St,Suite 300, Minneapolis, MN 55454 USA. EM steffen@umn.edu FU National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health [N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-95095, N01-HC-45134] FX The CARDIA study was supported by contracts N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-95095, and N01-HC-45134 from the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health. Drs Loria and Reis, who are employed by the NHLBI, contributed to the study design, conduct of the study, interpretation of the findings, and preparation of the manuscript. NR 43 TC 23 Z9 23 U1 0 U2 19 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 EI 1475-2662 J9 BRIT J NUTR JI Br. J. Nutr. PD NOV 28 PY 2014 VL 112 IS 10 BP 1654 EP 1661 DI 10.1017/S0007114514002633 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AX7MW UT WOS:000347100900009 PM 25234439 ER PT J AU Ronzone, E Wesolowski, J Bauler, LD Bhardwaj, A Hackstadt, T Paumet, F AF Ronzone, Erik Wesolowski, Jordan Bauler, Laura D. Bhardwaj, Anshul Hackstadt, Ted Paumet, Fabienne TI An alpha-Helical Core Encodes the Dual Functions of the Chlamydial Protein IncA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OCCUPY NONFUSOGENIC INCLUSIONS; MEMBRANE-FUSION; SNARE COMPLEX; COILED-COIL; CRYSTAL-STRUCTURE; TRACHOMATIS; SPECIFICITY; PSITTACI; CELLS; MODEL AB Chlamydia is an intracellular bacterium that establishes residence within parasitophorous compartments (inclusions) inside host cells. Chlamydial inclusions are uncoupled from the endolysosomal pathway and undergo fusion with cellular organelles and with each other. To do so, Chlamydia expresses proteins on the surface of the inclusion using a Type III secretion system. These proteins, termed Incs, are located at the interface between host and pathogen and carry out the functions necessary for Chlamydia survival. Among these Incs, IncA plays a critical role in both protecting the inclusion from lysosomal fusion and inducing the homotypic fusion of inclusions. Within IncA are two regions homologous to eukaryotic SNARE (soluble N-ethylmaleimide-sensitive factor attachment receptor) domains referred to as SNARE-like domain 1 (SLD1) and SNARE-like domain 2 (SLD2). Using a multidisciplinary approach, we have discovered the functional core of IncA that retains the ability to both inhibit SNARE-mediated fusion and promote the homotypic fusion of Chlamydia inclusions. Circular dichroism and analytical ultracentrifugation experiments show that this core region is composed almost entirely of alpha-helices and assembles into stable homodimers in solution. Altogether, we propose that both IncA functions are encoded in a structured core domain that encompasses SLD1 and part of SLD2. C1 [Ronzone, Erik; Wesolowski, Jordan; Paumet, Fabienne] Thomas Jefferson Univ, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA. [Bhardwaj, Anshul] Thomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA. [Bauler, Laura D.; Hackstadt, Ted] NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Paumet, F (reprint author), Thomas Jefferson Univ, Dept Microbiol & Immunol, 233 S 10th St,BLSB Rm 750, Philadelphia, PA 19107 USA. EM fabienne.paumet@jefferson.edu FU National Institutes of Health, NCI, Cancer Center Support Grant [P30 CA56036] FX We thank Drs. Gino Cingolani, John Pascal, and Michael Root for critical discussion and advice during the course of this study. Research in this paper includes work carried out at the Sydney Kimmel Cancer Center X-ray Crystallography and Molecular Interaction Facility and Nucleic Acid Facility, which are supported in part by National Institutes of Health, NCI, Cancer Center Support Grant P30 CA56036. NR 52 TC 4 Z9 4 U1 0 U2 5 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 NOV 28 PY 2014 VL 289 IS 48 BP 33469 EP 33480 DI 10.1074/jbc.M114.592063 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU5HC UT WOS:000345636600035 PM 25324548 ER PT J AU Brennan-Laun, SE Li, XL Ezelle, HJ Venkataraman, T Blackshear, PJ Wilson, GM Hassel, BA AF Brennan-Laun, Sarah E. Li, Xiao-Ling Ezelle, Heather J. Venkataraman, Thiagarajan Blackshear, Perry J. Wilson, Gerald M. Hassel, Bret A. TI RNase L Attenuates Mitogen-stimulated Gene Expression via Transcriptional and Post-transcriptional Mechanisms to Limit the Proliferative Response SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AU-RICH ELEMENTS; ANTIVIRAL INNATE IMMUNITY; PROTEIN-KINASE PKR; HUMAN COLON-CANCER; MESSENGER-RNA; 2-5A-DEPENDENT RNASE; GROWTH-FACTOR; TNF-ALPHA; TRISTETRAPROLIN EXPRESSION; 3'-UNTRANSLATED REGION AB The cellular response to mitogens is tightly regulated via transcriptional and post-transcriptional mechanisms to rapidly induce genes that promote proliferation and efficiently attenuate their expression to prevent malignant growth. RNase L is an endoribonuclease that mediates diverse antiproliferative activities, and tristetraprolin (TTP) is a mitogen-induced RNA-binding protein that directs the decay of proliferation-stimulatory mRNAs. In light of their roles as endogenous proliferative constraints, we examined the mechanisms and functional interactions of RNase Land TTP to attenuate a mitogenic response. Mitogen stimulation of RNase L-deficient cells significantly increased TTP transcription and the induction of other mitogen-induced mRNAs. This regulation corresponded with elevated expression of serum-response factor (SRF), a master regulator of mitogen-induced transcription. RNase L destabilized the SRF transcript and formed a complex with SRF mRNA in cells providing a mechanism by which RNase L down-regulates SRF-induced genes. TTP and RNase L proteins interacted in cells suggesting that RNase L is directed to cleave TTP bound RNAs as a mechanism of substrate specificity. Consistent with their concerted function in RNA turnover, the absence of either RNase Lor TTP stabilized SRF mRNA, and a subset of established TTP targets was also regulated by RNase L. RNase L deficiency enhanced mitogen-induced proliferation demonstrating its functional role in limiting the mitogenic response. Our findings support a model of feedback regulation in which RNase L and TTP target SRF mRNA and SRF-induced transcripts. Accordingly, meta-analysis revealed an enrichment of RNase L and TTP targets among SRF-regulated genes suggesting that the RNase L/TTP axis represents a viable target to inhibit SRF-driven proliferation in neoplastic diseases. C1 [Brennan-Laun, Sarah E.; Ezelle, Heather J.; Wilson, Gerald M.; Hassel, Bret A.] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Brennan-Laun, Sarah E.; Ezelle, Heather J.; Venkataraman, Thiagarajan; Hassel, Bret A.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Wilson, Gerald M.] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Li, Xiao-Ling] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Ezelle, Heather J.; Hassel, Bret A.] Baltimore Vet Affairs Med Ctr, Res Serv, Baltimore, MD 21201 USA. [Blackshear, Perry J.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Hassel, BA (reprint author), Univ Maryland, Sch Med, Dept Microbiol & Immunol, 685 W Baltimore St,HSF I 380, Baltimore, MD 21201 USA. EM bhassel@som.umaryland.edu OI Venkataraman, Thiagarajan/0000-0003-0921-6345 FU National Institutes of Health [AI077556]; NCI [T32CA154274]; Veterans Affairs Merit Award FX This work was supported, in whole or in part, by National Institutes of Health Grant AI077556 (to B. A. H.) and NCI T32 Cancer Biology Training Grant T32CA154274 from NCI (to S. E. B.-L.). This work was also supported by a Veterans Affairs Merit Award (to B. A. H.). NR 117 TC 5 Z9 5 U1 1 U2 3 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 NOV 28 PY 2014 VL 289 IS 48 BP 33629 EP 33643 DI 10.1074/jbc.M114.589556 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU5HC UT WOS:000345636600048 PM 25301952 ER PT J AU Berezhkovskii, AM Szabo, A Greives, N Zhou, HX AF Berezhkovskii, Alexander M. Szabo, Attila Greives, Nicholas Zhou, Huan-Xiang TI Multidimensional reaction rate theory with anisotropic diffusion SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID ACTIVATED RATE-PROCESSES; CHEMICAL-REACTIONS; METASTABLE STATE; KRAMERS PROBLEM; POLAR-SOLVENTS; DECAY; SOLVATION; FRICTION; COMPLEX; MOTION AB An analytical expression is derived for the rate constant that describes diffusive transitions between two deep wells of a multidimensional potential. The expression, in contrast to the Kramers-Langer formula for the rate constant, is valid even when the diffusion is highly anisotropic. Our approach is based on a variational principle for the reactive flux and uses a trial function for the splitting probability or commitor. The theoretical result is validated by Brownian dynamics simulations. (C) 2014 AIP Publishing LLC. C1 [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20819 USA. [Szabo, Attila] NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20819 USA. [Greives, Nicholas; Zhou, Huan-Xiang] Florida State Univ, Dept Phys, Tallahassee, FL 32306 USA. [Greives, Nicholas; Zhou, Huan-Xiang] Florida State Univ, Inst Mol Biophys, Tallahassee, FL 32306 USA. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20819 USA. RI Zhou, Huan-Xiang/M-5170-2016; Szabo, Attila/H-3867-2012 OI Zhou, Huan-Xiang/0000-0001-9020-0302; FU Intramural Research Program of the National Institutes of Health (NIH); Center for Information Technology; National Institute of Diabetes and Digestive and Kidney Diseases; NIH [GM058187] FX This study was supported by the Intramural Research Program of the National Institutes of Health (NIH), Center for Information Technology, and National Institute of Diabetes and Digestive and Kidney Diseases, and by Grant No. GM058187 from the NIH. NR 21 TC 5 Z9 5 U1 5 U2 27 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD NOV 28 PY 2014 VL 141 IS 20 AR 204106 DI 10.1063/1.4902243 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA AU5IZ UT WOS:000345641400007 PM 25429932 ER PT J AU Sun, CL Li, J Wang, X Duan, WJ Zhang, TY Ito, Y AF Sun, Changlei Li, Jia Wang, Xiao Duan, Wenjuan Zhang, Tianyou Ito, Yoichiro TI Preparative separation of quaternary ammonium alkaloids from Coptis chinensis Franch by pH-zone-refining counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE pH-zone-refining counter-current; chromatography; Coptis chinensis Franch; Quaternary ammonium alkaloids ID BERBERINE; MECHANISM; ACIDS; PURIFICATION; RATS AB pH-zone-refining counter-current chromatography was successfully applied to the preparative separation of five quaternary ammonium alkaloids from the crude extract of Coptis chinensis Franch. The separation was performed with a two-phase solvent system composed of chloroform-methanol-water (4:3:3, v/v), where the upper aqueous stationary phase was added with 60 mM of hydrochloric acid and the lower organic mobile phase with 5 mM of triethylamine. From 1.0 g of crude extract, 5.4 mg of columbamine at 96.6% purity, 6.1 mg of jateorhizine at 98.8% purity, 58.3 mg of coptisine at 99.5% purity, 25.6 mg of palmatine at 98.4% purity and 503.9 mg of berberine at 99.5% purity were obtained. The purities of the isolated alkaloids were analyzed by HPLC and the chemical structures were identified by electrospray ionization-mass spectrometry and H-1 NMR. (C) 2014 Elsevier B.V. All rights reserved. C1 [Sun, Changlei; Wang, Xiao; Duan, Wenjuan; Zhang, Tianyou] Shandong Acad Sci, Shandong Anal & Test Ctr, Jinan 250014, Shandong, Peoples R China. [Sun, Changlei; Li, Jia] Shandong Univ Tradit Chinese Med, Coll Pharm, Jinan 250355, Shandong, Peoples R China. [Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Wang, X (reprint author), Shandong Acad Sci, Shandong Anal & Test Ctr, 19 Keyuan St, Jinan 250014, Shandong, Peoples R China. EM wangx@sdas.org; itoy@nhlbi.nih.gov FU Natural Science Foundation of China [20872083]; Key Science and Technology Program of Shandong Province FX Financial support from the Natural Science Foundation of China (20872083) and the Key Science and Technology Program of Shandong Province are gratefully acknowledged. NR 31 TC 8 Z9 9 U1 8 U2 44 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD NOV 28 PY 2014 VL 1370 BP 156 EP 161 DI 10.1016/j.chroma.2014.10.043 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AU6PO UT WOS:000345724800019 PM 25454140 ER PT J AU Khoury, MJ Ioannidis, JPA AF Khoury, Muin J. Ioannidis, John P. A. TI Big data meets public health SO SCIENCE 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 20850 USA. [Ioannidis, John P. A.] Stanford Univ, Stanford Prevent Res Ctr, Palo Alto, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Meta Res Innovat Ctr Stanford, Palo Alto, CA 94305 USA. RP Khoury, MJ (reprint author), Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA 30333 USA. EM muk1@cdc.gov; jioannid@stanford.edu FU Intramural CDC HHS [CC999999] NR 12 TC 40 Z9 47 U1 21 U2 99 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 NOV 28 PY 2014 VL 346 IS 6213 BP 1054 EP 1055 DI 10.1126/science.aaa2709 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU7EK UT WOS:000345763400019 PM 25430753 ER PT J AU Babu, TM Levine, M Fitzgerald, T Luke, C Sangster, MY Jin, H Topham, D Katz, J Treanor, J Subbarao, K AF Babu, Tara M. Levine, Min Fitzgerald, Theresa Luke, Catherine Sangster, Mark Y. Jin, Hong Topham, David Katz, Jacqueline Treanor, John Subbarao, Kanta TI Live attenuated H7N7 influenza vaccine primes for a vigorous antibody response to inactivated H7N7 influenza vaccine SO VACCINE LA English DT Article DE Influenza; H7N7; Pandemic; Priming; Live attenuated vaccine ID VIRUS-VACCINE; HEALTHY-ADULTS; ANTIGENIC VARIANT; YOUNG-CHILDREN; A VIRUS; H5N1; IMMUNOGENICITY; SAFETY; PROTECTION; EFFICACY AB Background: H7 influenza viruses have emerged as potential pandemic threat. We evaluated the safety and immunogenicity of two candidate H7 pandemic live attenuated influenza vaccines (pLAIV) and their ability to prime for responses to an unadjuvanted H7 pandemic inactivated influenza vaccine (pIIV). Methods: Healthy seronegative adults received two doses of A/Netherlands/219/03 (H7N7) or one dose of A/chicken/British Columbia/CN-6/04 (H7N3) pLAIV all given as 10(7.5) 50% tissue culture infective doses (TCID50) intranasally. A subset of subjects received one 45 mu g dose of H7N7 pIIV containing the A/Mallard/Netherlands/12/2000 HA intramuscularly 18-24 months after pLAIV. Viral shedding was assessed by culture and real-time polymerase chain reaction (rRT-PCR), B cell responses following pLAIV were evaluated by ELISPOT and flow cytometry. Serum antibody was assessed by hemagglutination-inhibition (HAI), microneutralization (MN) and ELISA assays after each vaccine. Results: Serum HAI or MN responses were not detected in any subject following one or two doses of either H7 pLAIV, although some subjects had detectable H7 specific B cells after vaccination. However, 10/13 subjects primed with two doses of H7N7 pLAIV responded to a subsequent dose of the homologous H7N7 pIIV with high titer HAI and MN antibody that cross-reacted with both North American and Eurasian lineage H7 viruses, including H7N9. In contrast, nave subjects and recipients of a single dose of the mismatched H7N3 pLAIV did not develop HAI or MN antibody after plIV. Conclusions: While pLAIVs did not elicit detectable serum MN or HAI antibody, strain-specific pLAIV priming established long term immune memory that was cross-reactive with other H7 influenza strains. Understanding the mechanisms underlying priming by pLAIV may aid in pandemic vaccine development. (C) 2014 Published by Elsevier Ltd. C1 [Babu, Tara M.; Fitzgerald, Theresa; Treanor, John] Univ Rochester, Med Ctr, Div Infect Dis, Rochester, NY 14642 USA. [Levine, Min; Katz, Jacqueline] Ctr Dis Control & Prevent, Influenza Div, Atlanta, GA USA. [Luke, Catherine; Subbarao, Kanta] NIH, Infect Dis Lab, Bethesda, MD 20892 USA. [Jin, Hong] MedImmune LLC, Gaithersburg, MD USA. [Sangster, Mark Y.; Topham, David] Univ Rochester, Med Ctr, David Smith Ctr Immunol & Vaccine Biol, Rochester, NY 14642 USA. RP Treanor, J (reprint author), Univ Rochester, Med Ctr, Div Infect Dis, 601 Elmwood Ave, Rochester, NY 14642 USA. EM John_Treanor@urmc.rochester.edu OI Babu, Tara/0000-0001-7093-4077 FU Division of Intramural Research, NIAID, NIH; Biomedical Advanced Research and Development Authority, US Department of Health and Human Services [HHSN272200900026C] FX This study was supported in part by the Division of Intramural Research, NIAID, NIH and by the Biomedical Advanced Research and Development Authority, US Department of Health and Human Services (under contract # HHSN272200900026C). Preliminary results of this study were presented at the Options for Control of Influenza meeting in Cape Town, South Africa September 2013. NR 33 TC 21 Z9 22 U1 2 U2 7 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 NOV 28 PY 2014 VL 32 IS 50 BP 6798 EP 6804 DI 10.1016/j.vaccine.2014.09.070 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AU8BY UT WOS:000345822800011 PM 25446831 ER PT J AU Etemad, B Gonzalez, OA White, L Laeyendecker, O Kirk, GD Mehta, S Sagar, M AF Etemad, Behzad Gonzalez, Oscar A. White, Laura Laeyendecker, Oliver Kirk, Gregory D. Mehta, Shruti Sagar, Manish TI Characterization of HIV-1 envelopes in acutely and chronically infected injection drug users SO RETROVIROLOGY LA English DT Article DE HIV-1; Envelope; Transmission; Receptor; Replication; Injection drug use; Dendritic cells; Selection; Interferon ID HUMAN-IMMUNODEFICIENCY-VIRUS; TRANS-INFECTION; HETEROSEXUAL TRANSMISSION; NEUTRALIZATION SENSITIVITY; INTEGRIN ALPHA(4)BETA(7); TYPE-1 INFECTION; BREAST-MILK; SUBTYPE-B; T-CELLS; RECEPTOR AB Background: Mucosally acquired human immunodeficiency virus type 1 (HIV-1) infection results from a limited number of variants, and these infecting strains potentially have unique properties, such as increased susceptibility to entry blockers, relative interferon-alpha (IFN-alpha) resistance, and replication differences in some primary cells. There is no data about the phenotypic properties of HIV-1 envelope variants found early after acquisition among subjects infected through injection drug use (IDU). For the first time, we compared the characteristics of virus envelopes among injection drug users sampled prior to seroconversion (HIV RNA+/Ab-), within 1 year (early), and more than 2 years (chronic) after estimated acquisition. Results: Virus envelopes from 7 HIV RNA+/Ab- subjects possessed lower genetic diversity and divergence compared to 7 unrelated individuals sampled during the chronic phase of disease. Replication competent recombinant viruses incorporating the HIV RNA+/Ab- as compared to the chronic phase envelopes were significantly more sensitive to a CCR5 receptor inhibitor and IFN-alpha and showed a statistical trend toward greater sensitivity to a fusion blocker. The early as compared to chronic infection envelopes also demonstrated a statistical trend or significantly greater sensitivity to CCR5 and fusion inhibitor and IFN-alpha. The HIV RNA+/Ab- as compared to chronic envelope viruses replicated to a lower extent in mature monocyte derived dendritic cells - CD4+ T cell co-cultures, but there were no significant replication differences in other primary cells among the viruses with envelopes from the 3 different stages of infection. Conclusions: Similar to mucosal acquisition, HIV-1 envelope quasispecies present in injection drug users prior to seroconversion have unique phenotypic properties compared to those circulating during the chronic phase of disease. C1 [Etemad, Behzad; Gonzalez, Oscar A.; Sagar, Manish] Boston Univ, Sch Med, Boston, MA 02118 USA. [White, Laura] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Laeyendecker, Oliver; Kirk, Gregory D.; Mehta, Shruti] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Laeyendecker, Oliver] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Kirk, Gregory D.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Sagar, M (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA. EM msagar@bu.edu OI Laeyendecker, Oliver/0000-0002-6429-4760 FU NIH [AI077473, AI102774] FX We thank all the subjects who have contributed samples for these studies as part of the ALIVE cohort. This study was supported by NIH grants AI077473 (MS) and AI102774 (MS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 6 Z9 6 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD NOV 28 PY 2014 VL 11 AR 106 DI 10.1186/s12977-014-0106-8 PG 15 WC Virology SC Virology GA AU6IL UT WOS:000345706900001 PM 25430652 ER PT J AU Li, JZ Heisey, A Ahmed, H Wang, HY Zheng, L Carrington, M Wrin, T Schooley, RT Lederman, MM Kuritzkes, DR AF Li, Jonathan Z. Heisey, Andrea Ahmed, Hayat Wang, Hongying Zheng, Lu Carrington, Mary Wrin, Terri Schooley, Robert T. Lederman, Michael M. Kuritzkes, Daniel R. CA ACTG A5197 Study Team TI Relationship of HIV reservoir characteristics with immune status and viral rebound kinetics in an HIV therapeutic vaccine study SO AIDS LA English DT Article DE analytic treatment interruption; HIV; reservoir; therapeutic vaccine ID ACTIVE ANTIRETROVIRAL THERAPY; STRUCTURED TREATMENT INTERRUPTIONS; VIRUS TYPE-1 RNA; T-CELL RESPONSES; NEUTRALIZING ANTIBODIES; PCR ASSAY; INFECTION; PLASMA; DNA; NONPROGRESSORS AB Objectives: The objective of this study is to evaluate the impact of therapeutic HIV vaccination on the HIV reservoir and assess the relationship of the viral reservoir with HIV-specific immune status and viral rebound kinetics. Design: A retrospective analysis of ACTG A5197, a randomized, placebo-controlled trial of a therapeutic rAd5 HIV-1 gag vaccine. Methods: Participants received vaccine/placebo at weeks 0, 4 and 26 prior to a 16-week analytic treatment interruption (ATI) at week 38. Cell-associated HIV-1 RNA and DNA (CA-RNA and CA-DNA) and HIV-1 residual viremia were quantified at weeks 0, 8 and 38. HIV-specific CD4(+)/CD8(+) activity was assessed by an intracellular cytokine staining assay. Results: At study entry, CA-RNA and CA-DNA levels were correlated inversely with the numbers of HIV-specific CD4(+) interferon-g producing cells (CA-RNA: r = -0.23, P = 0.03 and CA-DNA: r = -0.28, P < 0.01, N = 93). Therapeutic HIV vaccination induced HIV-specific CD4(+) activity, but did not significantly affect levels of CA-RNA or CA-DNA. Vaccine recipients with undetectable residual viremia at week 8 had higher frequencies of HIV-specific CD4(+) and CD8(+) interferon-g producing cells (undetectable versus detectable residual viremia: 277 versus 161 CD4(+) cells/10(6) lymphocytes, P = 0.03 and 1326 versus 669 CD8(+) cells/10 6 lymphocytes, P = 0.04). Pre-ATI CARNA and CA-DNA were associated with post-ATI plasma HIV set point (CA-RNA: r = 0.51, P < 0.01 and CA-DNA: r = 0.47, P < 0.01). Conclusion: Vaccine-induced T-cell responses were associated with a modest transient effect on residual viremia, but more potent immune responses and/or combination treatment with latency-reversing agents are needed to reduce the HIV reservoir. HIV reservoir measures may act as biomarkers of post-ATI viral rebound kinetics. C1 [Li, Jonathan Z.; Heisey, Andrea; Ahmed, Hayat; Kuritzkes, Daniel R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Wang, Hongying; Zheng, Lu] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Carrington, Mary] Frederick Natl Lab Canc Res, Leidos Biomed Res Inst, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD USA. [Carrington, Mary] MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA. [Carrington, Mary] Harvard Univ, Cambridge, MA 02138 USA. [Wrin, Terri] Monogram Biosci, La Jolla, CA USA. [Schooley, Robert T.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Lederman, Michael M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Li, JZ (reprint author), Brigham & Womens Hosp, Div Infect Dis, 65 Landsdowne St,Rm 421, Cambridge, MA 02139 USA. EM Jli22@partners.org FU Harvard University Center for AIDS Research [NIAID 5P30AI060354-08]; National Institutes of Health (NIH) [UM1 AI068634, UM1 AI068636]; federal funds from the Frederick National Laboratory for Cancer Research [HHSN261200800001E]; Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research; Abbott; Avexa; Bristol-Myers Squibb; Gilead; GlaxoSmithKline; Merck; ViiV Healthcare FX This work was supported in part by a grant from the Harvard University Center for AIDS Research (to Dr Li, NIAID 5P30AI060354-08), National Institutes of Health (NIH) grants UM1 AI068634 (Statistical and Data Management Center of the AIDS Clinical Trials Group), UM1 AI068636 (AIDS Clinical Trials Group) and a subcontract from UM1 AI068636 to the Harvard Virology Support Laboratory (to Dr Kuritzkes). Merck provided the A5197 study vaccine and performed the assays characterizing HIV-specific T-cell activity. The NAb assays were performed by Monogram Biosciences. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. 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. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research.; J.Z.L. has served as a consultant for Therapy Edge, Quest Diagnostics and SeraCare Life Sciences. D. R. K. has served as a consultant to and/or has received research grant support from Abbott, Avexa, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck and ViiV Healthcare; he has also received speaking honoraria from Gilead and ViiV. NR 37 TC 13 Z9 13 U1 1 U2 4 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 NOV 28 PY 2014 VL 28 IS 18 BP 2649 EP 2657 DI 10.1097/QAD.0000000000000478 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AT9XO UT WOS:000345277300002 PM 25254301 ER PT J AU Ou, O Huppi, K Chakka, S Gehlhaus, K Dubois, W Patel, J Chen, J Mackiewicz, M Jones, TL Pitt, JJ Martin, SE Goldsmith, P Simmons, JK Mock, BA Caplen, NJ AF Ou, Oliver Huppi, Konrad Chakka, Sirisha Gehlhaus, Kristen Dubois, Wendy Patel, Jyoti Chen, Jinqiu Mackiewicz, Mark Jones, Tamara L. Pitt, Jason J. Martin, Scott E. Goldsmith, Paul Simmons, John K. Mock, Beverly A. Caplen, Natasha J. TI Loss-of-function RNAi screens in breast cancer cells identify AURKB, PLK1, PIK3R1, MAPK12, PRKD2, and PTK6 as sensitizing targets of rapamycin activity SO CANCER LETTERS LA English DT Article DE Rapamycin; Breast cancer; RNAi screen; HDAC inhibition ID HISTONE DEACETYLASE INHIBITORS; ESTROGEN-RECEPTOR; MAMMALIAN TARGET; MTOR INHIBITION; HDAC INHIBITORS; CARCINOMA; TEMSIROLIMUS; MECHANISMS; AURORA; POLO-LIKE-KINASE-1 AB The use of molecularly targeted drugs as single agents has shown limited utility in many tumor types, largely due to the complex and redundant nature of oncogenic signaling networks. Targeting of the PI3K/AKT/mTOR pathway through inhibition of mTOR in combination with aromatase inhibitors has seen success in particular sub-types of breast cancer and there is a need to identify additional synergistic combinations to maximize the clinical potential of mTOR inhibitors. We have used loss-of-function RNAi screens of the mTOR inhibitor rapamycin to identify sensitizers of mTOR inhibition. RNAi screens conducted in combination with rapamycin in multiple breast cancer cell lines identified six genes, AURKB, PLK1, PIK3R1, MAPK12, PRKD2, and PTK6 that when silenced, each enhanced the sensitivity of multiple breast cancer lines to rapamycin. Using selective pharmacological agents we confirmed that inhibition of AURKB or PLK1 synergizes with rapamycin. Compound-associated gene expression data suggested histone deacetylation (HDAC) inhibition as a strategy for reducing the expression of several of the rapamycin-sensitizing genes, and we tested and validated this using the HDAC inhibitor entinostat in vitro and in vivo. Our findings indicate new approaches for enhancing the efficacy of rapamycin including the use of combining its application with HDAC inhibition. Published by Elsevier Ireland Ltd. C1 [Ou, Oliver; Huppi, Konrad; Chakka, Sirisha; Gehlhaus, Kristen; Mackiewicz, Mark; Jones, Tamara L.; Pitt, Jason J.; Caplen, Natasha J.] NIH, Genet Branch, Bethesda, MD 20892 USA. [Dubois, Wendy; Patel, Jyoti; Simmons, John K.; Mock, Beverly A.] NIH, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Chen, Jinqiu; Goldsmith, Paul] NCI, Off Sci & Technol Partnerships, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Martin, Scott E.] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. RP Caplen, NJ (reprint author), NIH, Genet Branch, Bldg 10, Bethesda, MD 20892 USA. EM ncaplen@mail.nih.gov RI Mock, Beverly/B-3110-2015; Caplen, Natasha/H-2768-2016 OI Mock, Beverly/0000-0003-2479-4549; Caplen, Natasha/0000-0002-0001-9460 FU National Cancer Institute, Center for Cancer Research [ZIA BC 010939] FX This research was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research (ZO1 Number: ZIA BC 010939). We thank Dr. Jeffery Green (LCGB, CCR) for the kind gift of MDA-MB-231-luc cells, Dr. Christine Tomlinson for assistance in establishing the MDA-MB-231-luc model, and Dr. Mark Simpson (LCGB, CCR) for initial help with the animal experiments and Michelle Herrmann (Office of Science and Technology Partnerships, CCR) for assistance with protein assays. Syndax Pharmaceuticals and the National Cancer Institute, NIH generously provided Entinostat. NR 47 TC 5 Z9 5 U1 1 U2 9 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 NOV 28 PY 2014 VL 354 IS 2 BP 336 EP 347 DI 10.1016/j.canlet.2014.08.043 PG 12 WC Oncology SC Oncology GA AS2RP UT WOS:000344127600015 PM 25193464 ER PT J AU van der Waart, AB van de Weem, NMP Maas, F Kramer, CSM Kester, MGD Falkenburg, JHF Schaap, N Jansen, JH van der Voort, R Gattinoni, L Hobo, W Dolstra, H AF van der Waart, Anniek B. van de Weem, Noortje M. P. Maas, Frans Kramer, Cynthia S. M. Kester, Michel G. D. Falkenburg, J. H. Frederik Schaap, Nicolaas Jansen, Joop H. van der Voort, Robbert Gattinoni, Luca Hobo, Willemijn Dolstra, Harry TI Inhibition of Akt signaling promotes the generation of superior tumor-reactive T cells for adoptive immunotherapy SO BLOOD LA English DT Article ID MINOR HISTOCOMPATIBILITY ANTIGENS; VERSUS-HOST-DISEASE; STEM-CELL; TRANSCRIPTION FACTORS; MEMORY CELLS; TRANSPLANTATION; DIFFERENTIATION; EFFECTOR; EXPRESSION; LYMPHOCYTES AB Effective T-cell therapy against cancer is dependent on the formation of long-lived, stem cell-like T cells with the ability to self-renew and differentiate into potent effector cells. Here, we investigated the in vivo existence of stem cell-like antigen-specific T cells in allogeneic stem cell transplantation (allo-SCT) patients and their ex vivo generation for additive treatment posttransplant. Early after allo-SCT, CD8(+) stem cell memory T cells targeting minor histocompatibility antigens (MiHAs) expressed by recipient tumor cells were not detectable, emphasizing the need for improved additive MiHA-specific T-cell therapy. Importantly, MiHA-specific CD8(+) T cells with an early CCR7(+)CD62L(+)CD45RO(+)CD27(+)CD28(+)CD95(+) memory-like phenotype and gene signature could be expanded from naive precursors by inhibiting Akt signaling during ex vivo priming and expansion. This resulted in a MiHA-specific CD8(+) T-cell population containing a high proportion of stem cell-like T cells compared with terminal differentiated effector T cells in control cultures. Importantly, these Akt-inhibited MiHA-specific CD8(+) T cells showed a superior expansion capacity in vitro and in immunodeficient mice and induced a superior antitumor effect in intrafemural multiple myeloma-bearing mice. These findings provide a rationale for clinical exploitation of ex vivo-generated Akt-inhibited MiHA-specific CD8(+) T cells in additive immunotherapy to prevent or treat relapse in allo-SCT patients. C1 [van der Waart, Anniek B.; van de Weem, Noortje M. P.; Maas, Frans; Kramer, Cynthia S. M.; Jansen, Joop H.; van der Voort, Robbert; Hobo, Willemijn; Dolstra, Harry] Radboud Univ Nijmegen, Med Ctr, Dept Lab Med, Hematol Lab, NL-6500 HB Nijmegen, Netherlands. [Kester, Michel G. D.; Falkenburg, J. H. Frederik] Leiden Univ, Med Ctr, Dept Hematol, Lab Expt Hematol, Leiden, Netherlands. [Schaap, Nicolaas] Radboud Univ Nijmegen, Med Ctr, Dept Hematol, NL-6500 HB Nijmegen, Netherlands. [Gattinoni, Luca] NCI, NIH, Bethesda, MD 20892 USA. RP Dolstra, H (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Lab Med, Hematol Lab, Geert Grootepl 8,POB 9101, NL-6500 HB Nijmegen, Netherlands. EM harry.dolstra@radboudumc.nl RI Gattinoni, Luca/A-2281-2008; Dolstra, H./L-4276-2015; Schaap, N.P.M./L-4625-2015; Hobo, Willemijn/O-1667-2015; van der Waart, Anniek/O-4185-2015; Jansen, J.H./H-8054-2014 OI Gattinoni, Luca/0000-0003-2239-3282; Hobo, Willemijn/0000-0002-8206-8185; NR 44 TC 24 Z9 24 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 NOV 27 PY 2014 VL 124 IS 23 BP 3490 EP 3500 DI 10.1182/blood-2014-05-578583 PG 11 WC Hematology SC Hematology GA AY3DQ UT WOS:000347465100021 PM 25336630 ER PT J AU Horak, M Petralia, RS Kaniakova, M Sans, N AF Horak, Martin Petralia, Ronald S. Kaniakova, Martina Sans, Nathalie TI ER to synapse trafficking of NMDA receptors SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Review DE glutamate receptor; excitatory neurotransmission; ion channel; internalization; intracellular trafficking; subcellular compartment ID D-ASPARTATE RECEPTORS; ENDOPLASMIC-RETICULUM RETENTION; CAMKII-DEPENDENT PHOSPHORYLATION; CELL-SURFACE EXPRESSION; DENSITY PROTEIN PSD-95; LONG-TERM POTENTIATION; CASEIN KINASE 2; SUBUNIT COMPOSITION; AMPA RECEPTORS; HIPPOCAMPAL SYNAPSES AB Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. There are three distinct subtypes of ionotropic glutamate receptors (GluRs) that have been identified including 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid receptors (AMPARs), N-methyl-D-aspartate receptors (NMDARs) and kainate receptors. The most common GluRs in mature synapses are AMPARs that mediate the fast excitatory neurotransmission and NMDARs that mediate the slow excitatory neurotransmission. There have been large numbers of recent reports studying how a single neuron regulates synaptic numbers and types of AMPARs and NMDARs. Our current research is centered primarily on NMDARs and, therefore, we will focus in this review on recent knowledge of molecular mechanisms occurring (1) early in the biosynthetic pathway of NMDARs, (2) in the transport of NMDARs after their release from the endoplasmic reticulum (ER); and (3) at the plasma membrane including excitatory synapses. Because a growing body of evidence also indicates that abnormalities in NMDAR functioning are associated with a number of human psychiatric and neurological diseases, this review together with other chapters in this issue may help to enhance research and to gain further knowledge of normal synaptic physiology as well as of the etiology of many human brain diseases. C1 [Horak, Martin; Kaniakova, Martina] Acad Sci Czech Republic, Vvi, Inst Physiol, Prague 14220 4, Czech Republic. [Petralia, Ronald S.] Natl Inst Deafness & Other Commun Disprders, Adv Imaging core, NIH, Bethesda, MD USA. [Sans, Nathalie] INSERM, U862, Bordeaux, France. [Sans, Nathalie] Univ Bordeaux, U862, Bordeaux, France. RP Horak, M (reprint author), Acad Sci Czech Republic, Vvi, Inst Physiol, Videnska 1083, Prague 14220 4, Czech Republic. EM mhorak@biomed.cas.cz; nathalie.sans@inserm.fr RI Kaniakova, Martina/C-2593-2012; Horak, Martin/F-9819-2010 FU Grant Agency of the Czech Republic [14-09220P, 14-02219S]; Marie Curie International Reintegration Grant [PIRG-GA-2010-276827]; Research Project of the AS CR RVO [67985823]; BIOCEV-Biotechnology and Biomedicine Centre of Academy of Sciences; Charles University in Vestec; European Regional Development Fund; INSERM; Neurocampus program; Mossy PCP [ANR-12-BSV4-0016-01]; NIDCD/NIH FX This work was supported by the projects from the Grant Agency of the Czech Republic (14-09220P, Martina Kaniakova; 14-02219S, Martin Horak), Marie Curie International Reintegration Grant (PIRG-GA-2010-276827; Martin Horak), Research Project of the AS CR RVO: 67985823 and BIOCEV-Biotechnology and Biomedicine Centre of Academy of Sciences and Charles University in Vestec, project supported from European Regional Development Fund (Martin Horak). This work was also supported by INSERM, the Neurocampus program and the Mossy PCP ANR-12-BSV4-0016-01 grants (to Nathalie Sans). Ronald S. Petralia was supported by the Intramural Research Program of NIDCD/NIH. NR 195 TC 9 Z9 9 U1 2 U2 22 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD NOV 27 PY 2014 VL 8 AR 394 DI 10.3389/fncel.2014.00394 PG 18 WC Neurosciences SC Neurosciences & Neurology GA AX2MO UT WOS:000346778300001 PM 25505872 ER PT J AU Hutchins, BI Wray, S AF Hutchins, B. Ian Wray, Susan TI Capture of microtubule plus-ends at the actin cortex promotes axophilic neuronal migration by enhancing microtubule tension in the leading process SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Article DE neuronal migration; neuronal migration disorders; microtubules; IP3 receptors; EB1; super resolution microscopy; actin cytoskeleton ID CORTICAL INTERNEURONS; MULTIPOLAR MIGRATION; RADIAL MIGRATION; CEREBRAL-CORTEX; CENTROSOME; MOVEMENT; DYNAMICS; MOTILITY; FLOW; TRANSLOCATION AB Microtubules are a critical part of neuronal polarity and leading process extension, thus microtubule movement plays an important role in neuronal migration. However, the dynamics of microtubules during the forward movement of the nucleus into the leading process (nucleokinesis) is unclear and may be dependent on the cell type and mode of migration used. In particular, little is known about cytoskeletal changes during axophilic migration, commonly used in anteroposterior neuronal migration. We recently showed that leading process actin flow in migrating GnRH neurons is controlled by a signaling cascade involving IP3 receptors, CaMKK, AMPK, and RhoA. In the present study, microtubule dynamics were examined in GnRH neurons. Failure of the migration of these cells leads to the neuroendocrine disorder Kallmann Syndrome. Microtubules translocated forward along the leading process shaft during migration, but reversed direction and moved toward the nucleus when migration stalled. Blocking calcium release through IP3 receptors halted migration and induced the same reversal of microtubule translocation, while blocking cortical actin flow prevented microtubules from translocating toward the distal leading process. Super-resolution imaging revealed that microtubule plus-end tips are captured at the actin cortex through calcium-dependent mechanisms. This work shows that cortical actin flow draws the microtubule network forward through calcium-dependent capture in order to promote nucleokinesis, revealing a novel mechanism engaged by migrating neurons to facilitate movement. C1 [Hutchins, B. Ian; Wray, Susan] NINDS, Cellular & Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Hutchins, B. Ian] NIGMS, Postdoctoral Res Associate Program, NIH, Bethesda, MD 20892 USA. RP Wray, S (reprint author), NINDS, Cellular & Dev Neurobiol Sect, NIH, 35 Convent Dr,Bldg 35,Rm 3A1012, Bethesda, MD 20892 USA. EM wrays@ninds.nih.gov RI Hutchins, Ian/A-5713-2009; OI Hutchins, Ian/0000-0001-7657-552X; wray, susan/0000-0001-7670-3915 FU Intramural Research Program of NINDS, NIH [ZIA NS002824-21]; Postdoctoral Research Associate Program of NIGMS, NIH FX This work was supported by the Intramural Research Program of NINDS, NIH (ZIA NS002824-21 to Susan Wray), and a postdoctoral fellowship from the Postdoctoral Research Associate Program of NIGMS, NIH (B. Ian Hutchins). We thank Dr. Carolyn Smith and the NINDS Light Imaging Facility for training and use of the STED microscope, and Dr. Ellen Flannery for thoughtful comments on the manuscript. NR 36 TC 4 Z9 4 U1 2 U2 6 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD NOV 27 PY 2014 VL 8 AR 400 DI 10.3389/fncel.2014.00400 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AX2MR UT WOS:000346778600001 PM 25505874 ER PT J AU Swineford, LB Thurm, A Baird, G Wetherby, AM Swedo, S AF Swineford, Lauren B. Thurm, Audrey Baird, Gillian Wetherby, Amy M. Swedo, Susan TI Social (pragmatic) communication disorder: a research review of this new DSM-5 diagnostic category SO JOURNAL OF NEURODEVELOPMENTAL DISORDERS LA English DT Review DE Social communication disorder; Pragmatic language impairment; Autism spectrum disorder; DSM-5 ID AUTISM SPECTRUM DISORDERS; LANGUAGE USE INVENTORY; GENETIC ARCHITECTURE; QUALITATIVE ASPECTS; IMPAIRMENT; CHILDREN; CHECKLIST; DEFICITS; PARENTS; ADHD AB Social (pragmatic) communication disorder (SCD) is a new diagnostic category in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5). The purpose of this review is to describe and synthesize the relevant literature from language and autism spectrum disorder (ASD) research relating to pragmatic language impairment and other previously used terms that relate to SCD. The long-standing debate regarding how social communication/pragmatic impairments overlap and/or differ from language impairments, ASD, and other neurodevelopmental disorders is examined. The possible impact of the addition of SCD diagnostic category and directions for future research are also discussed. C1 [Swineford, Lauren B.; Thurm, Audrey; Swedo, Susan] NIMH, Pediat & Dev Neurosci Branch, Bethesda, MD 20892 USA. [Baird, Gillian] Kings Hlth Partners Paediat Neurosci St Thomos Ho, Guys & St Thomas NHS Fdn Trust, London SE1 5HE, England. [Wetherby, Amy M.] Florida State Univ, Dept Clin Sci, Tallahassee, FL 32303 USA. RP Swineford, LB (reprint author), NIMH, Pediat & Dev Neurosci Branch, 10 Ctr Dr MSC 1255,Bldg 10,Room 1C250, Bethesda, MD 20892 USA. EM swinefordlb@mail.nih.gov FU National Institute of Mental Health (NIMH) FX This research was supported by the Intramural Program of the National Institute of Mental Health (NIMH). The views expressed in this paper do not necessarily represent the views of the NIMH, NIH, HHS, or the United States Government. NR 56 TC 9 Z9 9 U1 5 U2 42 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 NOV 27 PY 2014 VL 6 AR 41 DI 10.1186/1866-1955-6-41 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AW1EB UT WOS:000346032200001 PM 25484991 ER PT J AU Mukherjee, M Ge, G Zhang, N Edwards, DG Sumazin, P Sharan, S Rao, PH Medina, D Pati, D AF Mukherjee, M. Ge, G. Zhang, N. Edwards, D. G. Sumazin, P. Sharan, S. K. Rao, P. H. Medina, D. Pati, D. TI MMTV-Espl1 transgenic mice develop aneuploid, estrogen receptor alpha (ER alpha)-positive mammary adenocarcinomas SO ONCOGENE LA English DT Article DE Separase; Espl1; aneuploidy; p53; cohesin; mammary tumor animal model ID HUMAN BREAST-CANCER; CHROMOSOMAL INSTABILITY; MOLECULAR CHARACTERIZATION; CLONAL EVOLUTION; GENE-EXPRESSION; TUMORS; TUMORIGENESIS; SEPARASE; CELLS; PROTEIN AB Separase, a protease encoded by the ESPL1 gene, cleaves the chromosomal cohesin during mitosis. Separase protein and transcripts are overexpressed in a wide range of human cancers. To investigate the physiological consequence of Separase overexpression in animals, we have generated a transgenic MMTV-Espl1 mouse model that overexpresses Separase protein in the mammary glands. MMTV-Espl1 mice in a C57BL/6 genetic background develop aggressive, highly aneuploid and estrogen receptor alpha-positive (ER alpha-) mammary adenocarcinomas with an 80% penetrance. The mammary tumors caused by overexpression of Separase, alone or combined with p53 heterozygosity, in mammary epithelium mimic several aspects of the most aggressive forms of human breast cancer, including high levels of genetic instability, cell cycle defects, poor differentiation, distant metastasis and metaplasia. Histopathologically, MMTV-Espl1 tumors are highly heterogeneous showing features of both luminal as well as basal subtypes of breast cancers, with aggressive disease phenotype. In addition to aneuploidy, Separase overexpression results in chromosomal instability (CIN) including premature chromatid separation (PCS), lagging chromosomes, anaphase bridges, micronuclei, centrosome amplification, multinucleated cells, gradual accumulation of DNA damage and progressive loss of tumor suppressors p53 and cadherin gene loci. These results suggest that Separase-overexpressing mammary cells are not only susceptible to chromosomal missegregation-induced aneuploidy but also other genetic instabilities including DNA damage and loss of key tumor suppressor gene loci, which in combination can initiate tumorigenesis and disease progression. C1 [Mukherjee, M.; Ge, G.; Zhang, N.; Sumazin, P.; Rao, P. H.; Pati, D.] Texas Childrens Canc Ctr, Dep Pediat Hematol Oncol, Houston, TX USA. [Edwards, D. G.; Medina, D.; Pati, D.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Sharan, S. K.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Pati, D (reprint author), Baylor Coll Med, Dept Pediat, 6621 Fannin St,MC3-3320 1102 Bates St, Houston, TX 77030 USA. EM pati@bcm.edu FU National Cancer Institute [1RO1 CA109330, 1RO1 CA109478] FX This study was supported by the grants from the National Cancer Institute (1RO1 CA109330 and 1RO1 CA109478) to D. Pati. NR 50 TC 10 Z9 10 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD NOV 27 PY 2014 VL 33 IS 48 BP 5511 EP 5522 DI 10.1038/onc.2013.493 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AW1ZO UT WOS:000346087900004 PM 24276237 ER PT J AU Khrenova, MG Savitsky, AP Topol, IA Nemukhin, AV AF Khrenova, Maria G. Savitsky, Alexander P. Topol, Igor A. Nemukhin, Alexander V. TI Exploration of the Zinc Finger Motif in Controlling Activity of Matrix Metalloproteinases SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID NUCLEOCAPSID PROTEIN NCP7; MOLECULAR-DYNAMICS; QM/MM; PEPTIDE; BINDING; MODEL; METALLOENZYMES; INHIBITORS; MECHANISM; ONIOM AB Discovering ways to control the activity of matrix metalloproteinases (MMPs), zinc-dependent enzymes capable of degrading extracellular matrix proteins, is an important field of cancer research. We report here a novel strategy for assembling MMP inhibitors on the basis of oligopeptide ligands by exploring the pattern known as the zinc finger motif. Advanced molecular modeling tools were used to characterize the structural binding motifs of experimentally tested MMP inhibitors, as well as those of newly proposed peptidomimetics, in their zinc-containing active sites. The results of simulations based on the quantum mechanics/molecular mechanics (QM/MM) approach and Car-Parrinello molecular dynamics with QM/MM potentials demonstrate that, upon binding of Regasepin1, a known MMP-9 inhibitor, the Zn2+(His(3)) structural element is rearranged to the Zn2+(Cys(2)His(2)) zinc finger motif, in which two Cys residues are borrowed from the ligand. Following consideration of the crystal structure of MMP-2 with its inhibitor, the oligopeptide APP-IP, we proposed a new peptidomimetic with two replacements in the substrate, Tyr3Cys and Asp6Cys. Simulations show that this peptide variant blocks an enzyme active site by the Zn2+(Cys(2)His(2)) zinc finger construct. Similarly, a natural substrate of MMP-2, Ace-Gln-Gly similar to Ile-Ala-Gly-Nme, can be converted to an inhibiting compound by two replacements, Ile by Cys and Gly by the d isomer of Cys, favoring formation of the zinc finger motif. C1 [Khrenova, Maria G.; Savitsky, Alexander P.] Russian Acad Sci, AN Bach Inst Biochem, Moscow 119071, Russia. [Khrenova, Maria G.; Nemukhin, Alexander V.] Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119991, Russia. [Topol, Igor A.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Informat Syst Program, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. [Nemukhin, Alexander V.] Russian Acad Sci, NM Emanuel Inst Biochem Phys, Moscow 119334, Russia. RP Topol, IA (reprint author), Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Informat Syst Program, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. EM Igor.Topol@fnlcr.nih.gov RI Khrenova, Maria/I-4829-2014; Savitsky, Alexander/O-9799-2015; Nemukhin, Alexander/P-9662-2015; OI Khrenova, Maria/0000-0001-7117-3089 FU Russian Science Foundation [14-03-00124]; Dynasty Foundation Fellowship; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX A.N. and M.K. thank the Russian Science Foundation (Project No. 14-03-00124) for support of this study. M.K. acknowledges stipend support from the Dynasty Foundation Fellowship. We acknowledge the use of supercomputer resources of the Lomonosov Moscow State University39 and of the Joint Supercomputer Center of the Russian Academy of Sciences. LT. thanks the staff and administration of the Advanced Biomedical Computing Center for their partial support of the project with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. 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 39 TC 3 Z9 3 U1 0 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD NOV 27 PY 2014 VL 118 IS 47 SI SI BP 13505 EP 13512 DI 10.1021/jp5088702 PG 8 WC Chemistry, Physical SC Chemistry GA AU6OU UT WOS:000345722900025 PM 25375834 ER PT J AU Chertow, DS Kleine, C Edwards, JK Scaini, R Giuliani, R Sprecher, A AF Chertow, Daniel S. Kleine, Christian Edwards, Jeffrey K. Scaini, Roberto Giuliani, Ruggero Sprecher, Armand TI Ebola Virus Disease in West Africa - Clinical Manifestations and Management SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Chertow, Daniel S.; Kleine, Christian; Edwards, Jeffrey K.; Scaini, Roberto; Giuliani, Ruggero; Sprecher, Armand] Liberia Mission, Med Sans Frontieres, Brussels, Belgium. [Chertow, Daniel S.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Kleine, Christian] JW Goethe Univ Hosp, Dept Infect Dis & Trop Med, Frankfurt, Germany. RP Chertow, DS (reprint author), Liberia Mission, Med Sans Frontieres, Brussels, Belgium. NR 4 TC 119 Z9 128 U1 2 U2 34 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 NOV 27 PY 2014 VL 371 IS 22 BP 2054 EP 2057 DI 10.1056/NEJMp1413084 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA AU4KP UT WOS:000345580000003 PM 25372854 ER PT J AU Lacro, RV Dietz, HC Sleeper, LA Yetman, AT Bradley, TJ Colan, SD Pearson, GD Tierney, ESS Levine, JC Atz, AM Benson, DW Braverman, AC Chen, S De Backer, J Gelb, BD Grossfeld, PD Klein, GL Lai, WW Liou, A Loeys, BL Markham, LW Olson, AK Paridon, SM Pemberton, VL Pierpont, ME Pyeritz, RE Radojewski, E Roman, MJ Sharkey, AM Stylianou, MP Wechsler, SB Young, LT Mahony, L AF Lacro, R. V. Dietz, H. C. Sleeper, L. A. Yetman, A. T. Bradley, T. J. Colan, S. D. Pearson, G. D. Tierney, E. S. Selamet Levine, J. C. Atz, A. M. Benson, D. W. Braverman, A. C. Chen, S. De Backer, J. Gelb, B. D. Grossfeld, P. D. Klein, G. L. Lai, W. W. Liou, A. Loeys, B. L. Markham, L. W. Olson, A. K. Paridon, S. M. Pemberton, V. L. Pierpont, M. E. Pyeritz, R. E. Radojewski, E. Roman, M. J. Sharkey, A. M. Stylianou, M. P. Wechsler, S. Burns Young, L. T. Mahony, L. CA Pediat Heart Network Investigators TI Atenolol versus Losartan in Children and Young Adults with Marfan's Syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID AORTIC-ROOT DILATION; CLINICAL-TRIAL; DOUBLE-BLIND; BLOCKADE; RECEPTOR; THERAPY; GROWTH; MULTICENTER; PROGRESSION; DILATATION AB BACKGROUND Aortic-root dissection is the leading cause of death in Marfan's syndrome. Studies suggest that with regard to slowing aortic-root enlargement, losartan may be more effective than beta-blockers, the current standard therapy in most centers. METHODS We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfan's syndrome. The primary outcome was the rate of aortic-root enlargement, expressed as the change in the maximum aortic-root-diameter z score indexed to body-surface area (hereafter, aortic-root z score) over a 3-year period. Secondary outcomes included the rate of change in the absolute diameter of the aortic root; the rate of change in aortic regurgitation; the time to aortic dissection, aortic-root surgery, or death; somatic growth; and the incidence of adverse events. RESULTS From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean [+/- SD] age, 11.5 +/- 6.5 years in the atenolol group and 11.0 +/- 6.2 years in the losartan group), who had an aorticroot z score greater than 3.0. The baseline-adjusted rate of change (+/- SE) in the aortic-root z score did not differ significantly between the atenolol group and the losartan group (-0.139 +/- 0.013 and -0.107 +/- 0.013 standard-deviation units per year, respectively; P = 0.08). Both slopes were significantly less than zero, indicating a decrease in the degree of aortic-root dilatation relative to body-surface area with either treatment. The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups. CONCLUSIONS Among children and young adults with Marfan's syndrome who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aorticroot dilatation between the two treatment groups over a 3-year period. C1 [Lacro, R. V.; Colan, S. D.; Tierney, E. S. Selamet; Levine, J. C.] Boston Childrens Hosp, Boston, MA 02115 USA. [Dietz, H. C.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Sleeper, L. A.; Colan, S. D.; Chen, S.; Klein, G. L.] New England Res Inst, Watertown, MA 02172 USA. [Yetman, A. T.] Primary Childrens Med Ctr, Salt Lake City, UT USA. [Yetman, A. T.] Univ Utah, Salt Lake City, UT USA. [Bradley, T. J.; Radojewski, E.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Pearson, G. D.; Pemberton, V. L.; Stylianou, M. P.] NHLBI, NIH, Bethesda, MD 20892 USA. [Atz, A. M.] Med Univ S Carolina, Charleston, SC USA. [Benson, D. W.] Cincinnati Childrens Med Ctr, Cincinnati, OH USA. [Braverman, A. C.; Sharkey, A. M.] Washington Univ, Sch Med, St Louis, MO 63130 USA. [De Backer, J.; Loeys, B. L.] Ghent Univ Hosp, Ghent, Belgium. [Gelb, B. D.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Lai, W. W.] Childrens Hosp New York, New York, NY USA. [Roman, M. J.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Grossfeld, P. D.] Univ Calif San Diego, Rady Childrens Hosp, San Diego, CA 92103 USA. [Liou, A.] Texas Childrens Hosp, Houston, TX 77030 USA. [Markham, L. W.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Olson, A. K.] Seattle Childrens Hosp, Seattle, WA USA. [Paridon, S. M.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Pyeritz, R. E.] Univ Penn, Philadelphia, PA 19104 USA. [Pierpont, M. E.] Childrens Hosp & Clin Minnesota, Minneapolis, MN USA. [Wechsler, S. Burns] Duke Univ, Med Ctr, Durham, NC USA. [Young, L. T.] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL USA. [Mahony, L.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Lacro, RV (reprint author), Boston Childrens Hosp, Dept Cardiol, 300 Longwood Ave, Boston, MA 02115 USA. EM ron.lacro@cardio.chboston.org OI Loeys, Bart/0000-0003-3703-9518 FU National Heart, Lung, and Blood Institute FX Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00429364. NR 28 TC 85 Z9 88 U1 1 U2 21 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 NOV 27 PY 2014 VL 371 IS 22 BP 2061 EP 2071 DI 10.1056/NEJMoa1404731 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AU4KP UT WOS:000345580000005 PM 25405392 ER PT J AU Stitziel, NO Won, HH Morrison, AC Peloso, GM Do, R Lange, LA Fontanillas, P Gupta, N Duga, S Goel, A Farrall, M Saleheen, D Ferrario, P Konig, I Asselta, R Merlini, PA Marziliano, N Notarangelo, MF Schick, U Auer, P Assimes, TL Reilly, M Wilensky, R Rader, DJ Hovingh, GK Meitinger, T Kessler, T Kastrati, A Laugwitz, KL Siscovick, D Rotter, JI Hazen, SL Tracy, R Cresci, S Spertus, J Jackson, R Schwartz, SM Natarajan, P Crosby, J Muzny, D Ballantyne, C Rich, SS O'Donnell, CJ Abecasis, G Sunyaev, S Nickerson, DA Buring, JE Ridker, PM Chasman, DI Austin, E Ye, Z Kullo, IJ Weeke, PE Shaffer, CM Bastarache, LA Denny, JC Roden, DM Palmer, C Deloukas, P Lin, DY Tang, ZZ Erdmann, J Schunkert, H Danesh, J Marrugat, J Elosua, R Ardissino, D McPherson, R Watkins, H Reiner, AP Wilson, JG Altshuler, D Gibbs, RA Lander, ES Boerwinkle, E Gabriel, S Kathiresan, S AF Stitziel, Nathan O. Won, Hong-Hee Morrison, Alanna C. Peloso, Gina M. Do, Ron Lange, Leslie A. Fontanillas, Pierre Gupta, Namrata Duga, Stefano Goel, Anuj Farrall, Martin Saleheen, Danish Ferrario, Paola Koenig, Inke Asselta, Rosanna Merlini, Piera A. Marziliano, Nicola Notarangelo, Maria Francesca Schick, Ursula Auer, Paul Assimes, Themistocles L. Reilly, Muredach Wilensky, Robert Rader, Daniel J. Hovingh, G. Kees Meitinger, Thomas Kessler, Thorsten Kastrati, Adnan Laugwitz, Karl-Ludwig Siscovick, David Rotter, Jerome I. Hazen, Stanley L. Tracy, Russell Cresci, Sharon Spertus, John Jackson, Rebecca Schwartz, Stephen M. Natarajan, Pradeep Crosby, Jacy Muzny, Donna Ballantyne, Christie Rich, Stephen S. O'Donnell, Christopher J. Abecasis, Goncalo Sunyaev, Shamil Nickerson, Deborah A. Buring, Julie E. Ridker, Paul M. Chasman, Daniel I. Austin, Erin Ye, Zi Kullo, Iftikhar J. Weeke, Peter E. Shaffer, Christian M. Bastarache, Lisa A. Denny, Joshua C. Roden, Dan M. Palmer, Colin Deloukas, Panos Lin, Dan-Yu Tang, Zheng-zheng Erdmann, Jeanette Schunkert, Heribert Danesh, John Marrugat, Jaume Elosua, Roberto Ardissino, Diego McPherson, Ruth Watkins, Hugh Reiner, Alex P. Wilson, James G. Altshuler, David Gibbs, Richard A. Lander, Eric S. Boerwinkle, Eric Gabriel, Stacey Kathiresan, Sekar TI Inactivating Mutations in NPC1L1 and Protection from Coronary Heart Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID INTESTINAL CHOLESTEROL ABSORPTION; MYOCARDIAL-INFARCTION; GENETIC-VARIANTS; EZETIMIBE; DESIGN; RISK; TRIAL; LDL; ASSOCIATION; SIMVASTATIN AB BACKGROUND Ezetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann-Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug. METHODS We sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease. RESULTS With sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P = 0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P = 0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%). CONCLUSIONS Naturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease. C1 [Stitziel, Nathan O.; Cresci, Sharon] Washington Univ, Sch Med, Dept Med, Div Cardiovasc, St Louis, MO 63130 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO 63130 USA. [Cresci, Sharon] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Won, Hong-Hee; Peloso, Gina M.; Do, Ron; Natarajan, Pradeep; Altshuler, David; Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Won, Hong-Hee; Peloso, Gina M.; Do, Ron; Natarajan, Pradeep; Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [O'Donnell, Christopher J.; Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Won, Hong-Hee; Peloso, Gina M.; Do, Ron; Natarajan, Pradeep; O'Donnell, Christopher J.; Altshuler, David; Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Sunyaev, Shamil] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Buring, Julie E.; Ridker, Paul M.; Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Won, Hong-Hee; Peloso, Gina M.; Do, Ron; Fontanillas, Pierre; Gupta, Namrata; Natarajan, Pradeep; Sunyaev, Shamil; Altshuler, David; Lander, Eric S.; Gabriel, Stacey; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Morrison, Alanna C.; Crosby, Jacy; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Muzny, Donna; Gibbs, Richard A.; Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Ballantyne, Christie] Baylor Coll Med, Sect Atherosclerosis & Vasc Med, Houston, TX 77030 USA. [Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Lin, Dan-Yu] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Duga, Stefano; Asselta, Rosanna] Univ Milan, Dipartimento Biotecnol Med & Med Traslaz, Milan, Italy. [Merlini, Piera A.; Marziliano, Nicola; Notarangelo, Maria Francesca; Ardissino, Diego] Azienda Osped Univ Parma, Parma, Italy. [Merlini, Piera A.; Ardissino, Diego] Assoc Studio Trombosi Cardiol, Pavia, Italy. [Goel, Anuj; Farrall, Martin; Watkins, Hugh] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England. [Goel, Anuj; Farrall, Martin; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Danesh, John] Univ Cambridge, Cambridge, England. [Deloukas, Panos] Wellcome Trust Sanger Inst, Cambridge, England. [Palmer, Colin] Univ Dundee, Med Res Inst, Dundee, Scotland. [Deloukas, Panos] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England. [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Saleheen, Danish] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Reilly, Muredach; Wilensky, Robert] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Saleheen, Danish] Ctr Noncommunicable Dis, Karachi, Pakistan. [Ferrario, Paola; Koenig, Inke] Med Univ Lubeck, Inst Med Biometrie & Stat, D-23538 Lubeck, Germany. [Buring, Julie E.] Med Univ Lubeck, Inst Integrat & Expt Genom, D-23538 Lubeck, Germany. [Buring, Julie E.] DZHK German Res Ctr Cardiovasc Res Partner Site H, Lubeck, Germany. [Meitinger, Thomas] Helmholtz Zentrum, Inst Humangenet, Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Klinikum Rechts Isar, Inst Humangenet, D-80290 Munich, Germany. [Laugwitz, Karl-Ludwig] Tech Univ Munich, Klinikum Rechts Isar, Med Klin, D-80290 Munich, Germany. [Kessler, Thorsten; Kastrati, Adnan; Schunkert, Heribert] Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany. [Meitinger, Thomas; Kastrati, Adnan; Laugwitz, Karl-Ludwig; Schunkert, Heribert] Partner Site Munich Heart Alliance, German Ctr Cardiovasc Res DZHK, Munich, Germany. [Schick, Ursula; Schwartz, Stephen M.; Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Siscovick, David] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Siscovick, David] Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98195 USA. [Schwartz, Stephen M.; Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Nickerson, Deborah A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Auer, Paul] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA. [Assimes, Themistocles L.] Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA. [Assimes, Themistocles L.] Stanford Univ, Div Cardiovasc Med, Stanford, CA 94305 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Hovingh, G. Kees] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Hazen, Stanley L.] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA. [Jackson, Rebecca] Ohio State Univ, Dept Med, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [Tracy, Russell] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Tracy, Russell] Univ Vermont, Coll Med, Dept Biochem, Burlington, VT 05405 USA. [Spertus, John] Univ Missouri Kansas City, St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Abecasis, Goncalo] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Austin, Erin; Ye, Zi; Kullo, Iftikhar J.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. [Weeke, Peter E.; Shaffer, Christian M.; Denny, Joshua C.; Roden, Dan M.] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Bastarache, Lisa A.; Denny, Joshua C.] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37235 USA. [Roden, Dan M.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN USA. [Tang, Zheng-zheng] Vanderbilt Univ, Dept Biostat, Nashville, TN 37235 USA. [Weeke, Peter E.] Rigshosp, Copenhagen Univ Hosp, Mol Cardiol Lab, Dept Cardiol, DK-2100 Copenhagen, Denmark. [Deloukas, Panos] King Abdulaziz Univ, Jeddah 21413, Saudi Arabia. [Marrugat, Jaume; Elosua, Roberto] Inst Hosp Mar Invest Med IMIM, Grp Epidemiol & Genet Cardiovasc, Barcelona, Spain. [McPherson, Ruth] Univ Ottawa Heart Inst, Div Cardiol, Ottawa, ON, Canada. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS USA. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 185 Cambridge St,CPZN 5-252, Boston, MA 02114 USA. EM skathiresan@partners.org RI Palmer, Colin/C-7053-2008; Meitinger, Thomas/O-1318-2015; Kessler, Thorsten/O-7426-2015; Deloukas, Panos/B-2922-2013; Study, GoDARTS/K-9448-2016; Konig, Inke/A-4544-2009; Erdmann, Jeanette/P-7513-2014; OI Watkins, Hugh/0000-0002-5287-9016; Assimes, Themistocles/0000-0003-2349-0009; Palmer, Colin/0000-0002-6415-6560; Deloukas, Panos/0000-0001-9251-070X; Asselta, Rosanna/0000-0001-5351-0619; ELOSUA, ROBERTO/0000-0001-8235-0095; Natarajan, Pradeep/0000-0001-8402-7435; Erdmann, Jeanette/0000-0002-4486-6231; Stitziel, Nathan/0000-0002-4963-8211; Duga, Stefano/0000-0003-3457-1410 FU National Institutes of Health FX Funded by the National Institutes of Health and others. NR 38 TC 137 Z9 139 U1 6 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 NOV 27 PY 2014 VL 371 IS 22 BP 2072 EP 2082 DI 10.1056/NEJMoa1405386 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AU4KP UT WOS:000345580000006 ER PT J AU Wang, AJ Smith, A Li, YF Urban, JF Ramalingam, TR Wynn, TA Lu, NH Shea-Donohue, T Yang, ZH Zhao, AP AF Wang, An-Jiang Smith, Allen Li, Yanfei Urban, Joseph F., Jr. Ramalingam, Thirumalai R. Wynn, Thomas A. Lu, Nonghua Shea-Donohue, Terez Yang, Zhonghan Zhao, Aiping TI Genetic deletion of IL-25 (IL-17E) confers resistance to dextran sulfate sodium-induced colitis in mice SO CELL AND BIOSCIENCE LA English DT Article DE IL-25; Colitis; DSS; Mice; IL-13; IL-33 ID INFLAMMATORY-BOWEL-DISEASE; TNBS-INDUCED COLITIS; NK-T-CELLS; ULCERATIVE-COLITIS; CROHNS-DISEASE; INTESTINAL FUNCTION; HELMINTH EXPULSION; RECOMBINANT IL-25; CYTOKINE; EXPRESSION AB Background: IL-25 is emerging as a key regulator of inflammation in the intestinal mucosa because of its ability to promote type 2 while suppressing Th1 and Th17 responses. Several previous studies reported inconsistent results on the role of exogenous IL-25 in development of colonic inflammation and none were performed in animals with a genetic deletion of IL-25. We investigated the contribution of endogenous IL-25 to DSS-induced colitis using mice deficient in IL-25. Results: Mice were exposed to DSS in drinking water ad libitum either for seven days (acute) or for three cycles of seven days with DSS followed by 14 days without DSS (chronic) to induce colitis, respectively. The loss of body weight, appearance of diarrhea and bloody stools, and shortening of colon length were significantly less pronounced in IL-25(-/-) mice compared to WT mice after exposure to acute DSS. Histological examination showed that DSS-treated IL-25(-/-) mice had only mild inflammation in the colon, while severe inflammation developed in DSS-treated WT mice. A significant up-regulation of IL-33 was observed in acute DSS-treated WT but not in the IL-25(-/-) mice. There was significantly lower expression of pro-inflammatory cytokines in the colon of acute DSS-treated IL-25(-/-) compared to WT mice. IL-25(-/-) mice were also partially protected from chronic DSS challenge especially during the first 2 cycles of DSS exposure. In contrast to IL-25(-/-) mice, IL-13(-/-) mice were more susceptible to DSS-induced colitis. Finally, stimulation of T84 colonic epithelial cells with IL-25 up-regulated the expression of IL-33 and several pro-inflammatory cytokines. Conclusions: These data indicate that endogenous IL-25 acts as a pro-inflammatory factor in DSS-induced colitis, which is unlikely to be mediated by IL-13 but possibly the induction of IL-33 and other pro-inflammatory mediators from colonic epithelial cells. The present study suggests that IL-25 may contribute to the pathogenesis of inflammatory bowel disease in at least a subgroup of patients. C1 [Wang, An-Jiang; Li, Yanfei; Shea-Donohue, Terez; Yang, Zhonghan; Zhao, Aiping] Univ Maryland, Sch Med, Dept Radiat Oncol, MSTF, Baltimore, MD 21201 USA. [Wang, An-Jiang; Li, Yanfei; Shea-Donohue, Terez; Yang, Zhonghan; Zhao, Aiping] Univ Maryland, Sch Med, Dept Med, MSTF, Baltimore, MD 21201 USA. [Wang, An-Jiang; Lu, Nonghua] Nanchang Univ, Dept Gastroenterol & Hepatol, Affiliated Hosp 1, Nanchang 330006, Peoples R China. [Smith, Allen; Urban, Joseph F., Jr.] ARS, USDA, Beltsville Human Nutr Res Ctr, Diet Genom & Immunol Lab, Beltsville, MD 20705 USA. [Ramalingam, Thirumalai R.; Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Yang, Zhonghan] Sun Yat Sen Univ, Zhongshan Med Sch, Dept Biochem, Guangzhou 510080, Guangdong, Peoples R China. RP Yang, ZH (reprint author), Univ Maryland, Sch Med, Dept Radiat Oncol, MSTF, 10 S Pine St,Room 7 00D, Baltimore, MD 21201 USA. EM yangzhh@mail.sysu.edu.cn; azhao@mbrc.umaryland.edu OI Urban, Joseph/0000-0002-1590-8869 FU NIH [R01-DK083418, R01-AI/DK49316]; USDA CRIS project [1235-51000-055]; Intramural Research Program of the NIH/NIAID; Twelfth Five Year Plan for National Major New Drug Creation Program [2011ZX09302-007-03]; National Nature Science Foundation of China [81370945] FX This work was supported by NIH grants R01-DK083418 (AZ), R01-AI/DK49316 (TS-D), USDA CRIS project #1235-51000-055 (AS, JFU), The Intramural Research Program of the NIH/NIAID (TAW), The Twelfth Five Year Plan for National Major New Drug Creation Program #2011ZX09302-007-03 (NL), and National Nature Science Foundation of China Grant 81370945 (ZY). NR 44 TC 2 Z9 2 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD NOV 26 PY 2014 VL 4 AR 72 DI 10.1186/2045-3701-4-72 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CS6MW UT WOS:000362194500001 PM 25937893 ER PT J AU Lee, KI Im, W Pastor, RW AF Lee, Kyu Il Im, Wonpil Pastor, Richard W. TI Langevin dynamics simulations of charged model phosphatidylinositol lipids in the presence of diffusion barriers: toward an atomic level understanding of corralling of PIP2 by protein fences in biological membranes SO BMC BIOPHYSICS LA English DT Article DE Phosphotidylinositol 4,5-bisphosphate; Protein fence; Diffusion relaxation; Actin; Human septin; Yeast septin ID MOLECULAR-DYNAMICS; BROWNIAN DYNAMICS; PHOSPHOINOSITIDES; ELECTROSTATICS; ORGANIZATION; MECHANISMS; BILAYERS; BINDING; MARCKS; SEPTIN AB Background: The polyvalent acidic lipid phosphatidylinositol, 4,5-bisphosphate (PIP2)is important for many cellular functions. It has been suggested that different pools of PIP2 exist in the cytoplasmic leaflet of the plasma membrane, and that such pooling could play a role in the regulation of PIP2. The mechanism of fencing, however, is not understood. Results: This study presents the results of Langevin dynamics simulations of PIP2 to elucidate some of the molecular level considerations that must be applied to models for fencing. For each simulation, a pool of PIP2 (modeled as charged spheres) was placed in containments with boundaries modeled as a single row of rods (steric or electrostatic) or rigid protein filaments. It is shown that even a small gap (20 angstrom, which is 1.85 times larger than the diameter of a PIP2 sphere) leads to poor steric blocking, and that electrostatic blockage is only effective at very high charge density. Filaments of human septin, yeast septin, and actin also failed to provide adequate blockage when placed on the membrane surface. The two septins do provide high blockage consistent with experiment and with phenomenological considerations of permeability when they are buried 9 angstrom and 12 angstrom below the membrane surface, respectively. In contrast, burial does not improve blockage by the "arch-shaped" actin filaments. Free energy estimates using implicit membrane-solvent models indicate that burial of the septins to about 10 angstrom can be achieved without penetration of charged residues into the hydrophobic region of the membrane. Conclusions: These results imply that a functioning fence assembled from protein filaments must either be buried well below the membrane surface, have more than a single row, or contain additional components that fill small gaps in the filaments. C1 [Lee, Kyu Il; Im, Wonpil] Univ Kansas, Dept Mol Biosci, Lawrence, KS 66045 USA. [Lee, Kyu Il; Im, Wonpil] Univ Kansas, Ctr Bioinformat, Lawrence, KS 66045 USA. [Pastor, Richard W.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Im, W (reprint author), Univ Kansas, Dept Mol Biosci, Lawrence, KS 66045 USA. EM wonpil@ku.edu; pastorr@nhlbi.nih.gov FU National Science Foundation [NSF MCB-1157677]; XSEDE Resources [TG-MCB070009]; Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute FX We gratefully acknowledge Stuart McLaughlin for motivating the present study, and for helpful comments on the manuscript. This work was supported by the National Science Foundation (NSF MCB-1157677 to WI), XSEDE Resources (TG-MCB070009 to WI), and the Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute (to RWP). NR 34 TC 2 Z9 2 U1 0 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2046-1682 J9 BMC BIOPHYS JI BMC Biophys. PD NOV 26 PY 2014 VL 7 AR 13 DI 10.1186/s13628-014-0013-3 PG 10 WC Biophysics SC Biophysics GA AW7MP UT WOS:000346448400001 PM 25774289 ER PT J AU Rudd, ML Mohamed, H Price, JC O'Hara, AJ Le Gallo, M Urick, ME Cruz, P Zhang, SY Hansen, NF Godwin, AK Sgroi, DC Wolfsberg, TG Mullikin, JC Merino, MJ Bell, DW AF Rudd, Meghan L. Mohamed, Hassan Price, Jessica C. O'Hara, Andrea J. Le Gallo, Matthieu Urick, Mary Ellen Cruz, Pedro Zhang, Suiyuan Hansen, Nancy F. Godwin, Andrew K. Sgroi, Dennis C. Wolfsberg, Tyra G. Mullikin, James C. Merino, Maria J. Bell, Daphne W. CA NISC Comparative Sequencing TI Mutational analysis of the tyrosine kinome in serous and clear cell endometrial cancer uncovers rare somatic mutations in TNK2 and DDR1 SO BMC CANCER LA English DT Article DE Endometrial; Cancer; Mutation; TNK2; ACK1; DDR1; Copy number; Tyrosine kinase; Tyrosine kinome ID DISCOIDIN DOMAIN RECEPTOR-1; CHRONIC MYELOID-LEUKEMIA; LUNG-CANCER; EGF RECEPTOR; KINASE ACK1; CARCINOMA; MIGRATION; GENOMICS; COMPLEX; GROWTH AB Background: Endometrial cancer (EC) is the 8(th) leading cause of cancer death amongst American women. Most ECs are endometrioid, serous, or clear cell carcinomas, or an admixture of histologies. Serous and clear ECs are clinically aggressive tumors for which alternative therapeutic approaches are needed. The purpose of this study was to search for somatic mutations in the tyrosine kinome of serous and clear cell ECs, because mutated kinases can point to potential therapeutic targets. Methods: In a mutation discovery screen, we PCR amplified and Sanger sequenced the exons encoding the catalytic domains of 86 tyrosine kinases from 24 serous, 11 clear cell, and 5 mixed histology ECs. For somatically mutated genes, we next sequenced the remaining coding exons from the 40 discovery screen tumors and sequenced all coding exons from another 72 ECs (10 clear cell, 21 serous, 41 endometrioid). We assessed the copy number of mutated kinases in this cohort of 112 tumors using quantitative real time PCR, and we used immunoblotting to measure expression of these kinases in endometrial cancer cell lines. Results: Overall, we identified somatic mutations in TNK2 (tyrosine kinase non-receptor, 2) and DDR1 (discoidin domain receptor tyrosine kinase 1) in 5.3% (6 of 112) and 2.7% (3 of 112) of ECs. Copy number gains of TNK2 and DDR1 were identified in another 4.5% and 0.9% of 112 cases respectively. Immunoblotting confirmed TNK2 and DDR1 expression in endometrial cancer cell lines. Three of five missense mutations in TNK2 and one of two missense mutations in DDR1 are predicted to impact protein function by two or more in silico algorithms. The TNK2(P761Rfs)*(72) frameshift mutation was recurrent in EC, and the DDR1(R570Q) missense mutation was recurrent across tumor types. Conclusions: This is the first study to systematically search for mutations in the tyrosine kinome in clear cell endometrial tumors. Our findings indicate that high-frequency somatic mutations in the catalytic domains of the tyrosine kinome are rare in clear cell ECs. We uncovered ten new mutations in TNK2 and DDR1 within serous and endometrioid ECs, thus providing novel insights into the mutation spectrum of each gene in EC. C1 [Rudd, Meghan L.; Mohamed, Hassan; Price, Jessica C.; O'Hara, Andrea J.; Le Gallo, Matthieu; Urick, Mary Ellen; Bell, Daphne W.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Mullikin, James C.; NISC Comparative Sequencing] NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. [Cruz, Pedro; Zhang, Suiyuan; Hansen, Nancy F.; Wolfsberg, Tyra G.; Mullikin, James C.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66160 USA. [Sgroi, Dennis C.] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA. [Sgroi, Dennis C.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Merino, Maria J.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bell, DW (reprint author), NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. EM belldaph@mail.nih.gov FU Intramural Program of the National Human Genome Research Institute, National Institutes of Health; Ovarian Cancer Research Fund; Avon Foundation; National Institute of Health [R01CA112021]; Department of Defense Breast Cancer Research Program [W81XWH-04-1-0606]; NCI SPORE in breast cancer at Massachusetts General Hospital; NIH [R01CA140323] FX We thank Niraj Travedi for advice on statistical analyses. Funded in part by the Intramural Program of the National Human Genome Research Institute, National Institutes of Health (DWB, JGW, and JCM), by NIH R01CA140323 and the Ovarian Cancer Research Fund (AKG), The Avon Foundation (DCS), National Institute of Health (R01CA112021, DCS), The Department of Defense Breast Cancer Research Program (W81XWH-04-1-0606, DCS), and the NCI SPORE in breast cancer at Massachusetts General Hospital (DCS). NR 60 TC 1 Z9 1 U1 0 U2 3 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 NOV 26 PY 2014 VL 14 AR 884 DI 10.1186/1471-2407-14-884 PG 9 WC Oncology SC Oncology GA AU9SC UT WOS:000345934000001 PM 25427824 ER PT J AU Wu, H Wang, W Naiyer, N Fichtenbaum, E Qualley, DF McCauley, MJ Gorelick, RJ Rouzina, I Musier-Forsyth, K Williams, MC AF Wu, Hao Wang, Wei Naiyer, Nada Fichtenbaum, Eric Qualley, Dominic F. McCauley, Micah J. Gorelick, Robert J. Rouzina, Ioulia Musier-Forsyth, Karin Williams, Mark C. TI Single aromatic residue location alters nucleic acid binding and chaperone function of FIV nucleocapsid protein SO VIRUS RESEARCH LA English DT Article DE Nucleocapsid protein; Feline immunodeficiency virus; Nucleic acid chaperone; Single-molecule stretching; Zinc fingers; Aromatic residues ID IMMUNODEFICIENCY-VIRUS TYPE-1; PLUS-STRAND TRANSFER; GENOMIC RNA DIMERIZATION; RETROVIRAL GAG PROTEINS; ZINC-FINGER; REVERSE TRANSCRIPTION; STEM-LOOP; SECONDARY STRUCTURE; PACKAGING SIGNAL; AMINO-ACIDS AB Feline immunodeficiency virus (FIV) is a retrovirus that infects domestic cats, and is an excellent animal model for human immunodeficiency virus type 1 (HIV-1) pathogenesis. The nucleocapsid (NC) protein is critical for replication in both retroviruses. FIV NC has several structural features that differ from HIV-1 NC. While both NC proteins have a single conserved aromatic residue in each of the two zinc fingers, the aromatic residue on the second finger of FIV NC is located on the opposite C-terminal side relative to its location in HIV-1 NC. In addition, whereas HIV-1 NC has a highly charged cationic N-terminal tail and a relatively short C-terminal extension, the opposite is true for FIV NC. To probe the impact of these differences on the nucleic acid (NA) binding and chaperone properties of FIV NC, we carried out ensemble and single-molecule assays with wild-type (WT) and mutant proteins. The ensemble studies show that FIV NC binding to DNA is strongly electrostatic, with a higher effective charge than that observed for HIV-1 NC. The C-terminal basic domain contributes significantly to the NA binding capability of FIV NC. In addition, the non-electrostatic component of DNA binding is much weaker for FIV NC than for HIV-1 NC. Mutation of both aromatic residues in the zinc fingers to Ala (F12A/W44A) further increases the effective charge of FIV NC and reduces its non-electrostatic binding affinity. Interestingly, switching the location of the C-terminal aromatic residue to mimic the HIV-1 NC sequence (N31W/W44A) reduces the effective charge of FIV NC and increases its non-electrostatic binding affinity to values similar to HIV-1 NC. Consistent with the results of these ensemble studies, single-molecule DNA stretching studies show that while WT FIV NC has reduced stacking capability relative to HIV-1 NC, the aromatic switch mutant recovers the ability to intercalate between the DNA bases. Our results demonstrate that altering the position of a single aromatic residue switches the binding mode of FIV NC from primarily electrostatic binding to more non-electrostatic binding, conferring upon it NA interaction properties comparable to that of HIV-1 NC. (C) 2014 Elsevier B.V. All rights reserved. C1 [Wu, Hao; McCauley, Micah J.; Williams, Mark C.] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Wang, Wei; Naiyer, Nada; Fichtenbaum, Eric; Qualley, Dominic F.; Musier-Forsyth, Karin] Ohio State Univ, Dept Chem & Biochem, Ctr Retrovirus Res, Columbus, OH 43210 USA. [Wang, Wei; Naiyer, Nada; Fichtenbaum, Eric; Qualley, Dominic F.; Musier-Forsyth, Karin] Ohio State Univ, Ctr RNA Biol, Columbus, OH 43210 USA. [Gorelick, Robert J.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Rouzina, Ioulia] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. RP Williams, MC (reprint author), Northeastern Univ, Dept Phys, Boston, MA 02115 USA. EM musier@chemistry.ohio-state.edu; mark@neu.edu OI Williams, Mark C./0000-0003-3219-376X FU National Institutes of Health [GM065056, GM072462]; National Science Foundation [MCB-1243883]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Cancer Institute, National Institutes of Health (Leidos Biomedical Research, Inc.) FX This work was supported by the National Institutes of Health [GM065056 to K.M.-F. and GM072462 to M.C.W.] and the National Science Foundation [MCB-1243883 to M.C.W]. This project was also supported by the National Cancer Institute, National Institutes of Health [contract no. HHSN261200800001E with Leidos Biomedical Research, Inc. to R.J.G.]. 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. We thank Drs. Lawrence Mathes and Kathleen Hays (Ohio State University) for the DNA plasmid encoding FIV Gag. We also thank Donald G. Johnson and Catherine V. Hixson of the AIDS and Cancer Virus Program for their assistance in cloning, and producing and purifying several of the recombinant proteins used in this study. NR 78 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 EI 1872-7492 J9 VIRUS RES JI Virus Res. PD NOV 26 PY 2014 VL 193 SI SI BP 39 EP 51 DI 10.1016/j.virusres.2014.06.002 PG 13 WC Virology SC Virology GA AU2ZA UT WOS:000345481700005 PM 24915282 ER PT J AU Wu, TY Gorelick, RJ Levin, JG AF Wu, Tiyun Gorelick, Robert J. Levin, Judith G. TI Selection of fully processed HIV-1 nucleocapsid protein is required for optimal nucleic acid chaperone activity in reverse transcription SO VIRUS RESEARCH LA English DT Article DE HIV-1; Nucleocapsid precursor proteins; Assembly intermediates; Nucleic acid chaperone; Reverse transcription; Roadblock mechanism ID IMMUNODEFICIENCY-VIRUS TYPE-1; PRIMER BINDING-SITE; STRONG-STOP DNA; IN-VITRO; STRAND TRANSFER; ZINC-FINGER; POSTTRANSLATIONAL MODIFICATIONS; RETROVIRAL REPLICATION; ORDERED AGGREGATION; MUTATIONAL ANALYSIS AB The mature HIV-1 nucleocapsid protein (NCp7) is generated by sequential proteolytic cleavage of precursor proteins containing additional C-terminal peptides: NCp15 (NCp7-spacer peptide 2 (SP2)-p6); and NCp9 (NCp7-SP2). Here, we compare the nucleic acid chaperone activities of the three proteins, using reconstituted systems that model the annealing and elongation steps in tRNA(LYs3)-primed (-) strong-stop DNA synthesis and subsequent minus-strand transfer. The maximum levels of annealing are similar for all of the proteins, but there are important differences in their ability to facilitate reverse transcriptase (RT)-catalyzed DNA extension. Thus, at low concentrations, NCp9 has the greatest activity, but with increasing concentrations, DNA synthesis is significantly reduced. This finding reflects NCp9's strong nucleic acid binding affinity (associated with the highly basic SP2 domain) as well as its slow dissociation kinetics, which together limit the ability of RT to traverse the nucleic acid template. NCp15 has the poorest activity of the three proteins due to its acidic p6 domain. Indeed, mutants with alanine substitutions for the acidic residues in p6 have improved chaperone function. Collectively, these data can be correlated with the known biological properties of NCp9 and NCp15 mutant virions and help to explain why mature NC has evolved as the critical cofactor for efficient virus replication and long-term viral fitness. (C) 2014 Elsevier B.V. All rights reserved. C1 [Wu, Tiyun; Levin, Judith G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Viral Gene Regulat, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Gorelick, Robert J.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick, MD 21702 USA. RP Levin, JG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Viral Gene Regulat, Program Genom Differentiat, NIH, Bldg 6B,Room 216,6 Ctr Dr, Bethesda, MD 20892 USA. EM levinju@mail.nih.gov FU Intramural Research Program at the National Institutes of Health (Eunice Kennedy Shriver National Institute of Child Health and Human Development); National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Leidos Biomedical Research Inc. FX We thank Donald G. Johnson, William J. Bosche, and Catherine V. Hixon for preparing the expression constructs and recombinant proteins used in this study. We also thank Christopher P. Jones and Karin Musier-Forsyth for the RNA 105 and tRNALys3 clones. We are indebted to Mithun Mitra for advice on the aggregation and fluorescence anisotropy assays, to Wei Wang, Ioulia Rouzina, and Karin Musier-Forsyth for generously sharing their results prior to publication, and to all of these colleagues for stimulating and valuable discussion. This work was supported in part by the Intramural Research Program at the National Institutes of Health (Eunice Kennedy Shriver National Institute of Child Health and Human Development [T.W. and J.G.L.]). This project has also been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E with Leidos Biomedical Research Inc. (R.J.G.). NR 66 TC 4 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 EI 1872-7492 J9 VIRUS RES JI Virus Res. PD NOV 26 PY 2014 VL 193 SI SI BP 52 EP 64 DI 10.1016/j.virusres.2014.06.004 PG 13 WC Virology SC Virology GA AU2ZA UT WOS:000345481700006 PM 24954787 ER PT J AU Nair, S Rein, A AF Nair, Smita Rein, Alan TI Antiretroviral restriction factors in mice SO VIRUS RESEARCH LA English DT Article DE Murine leukemia virus; Retrovirus; Fv1 restriction; APOBEC3; Tetherin ID MURINE LEUKEMIA-VIRUS; LOCUS AFFECTING RESISTANCE; GLYCOSYLATED GAG PROTEIN; REPLICATION IN-VIVO; FV-1 GENE-PRODUCT; INHIBITS HIV-1; VPU PROTEIN; REVERSE TRANSCRIPTION; CAPSID PROTEIN; HUMAN APOBEC3G AB One of the most exciting areas in contemporary retrovirus research is the discovery of "restriction factors". These are cellular proteins that act after virus entry to inhibit infection by or replication of retroviruses (and other viruses and intracellular pathogens). We briefly discuss here three antiretroviral restriction factors in mice: Fv1, APOBEC3, and tetherin, touching on both biological and molecular aspects of these restriction systems. Published by Elsevier B.V. C1 [Nair, Smita; Rein, Alan] NCI, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Rein, A (reprint author), NCI, 1050 Boyles St Frederick, Frederick, MD 21702 USA. EM reina@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 80 TC 3 Z9 3 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 EI 1872-7492 J9 VIRUS RES JI Virus Res. PD NOV 26 PY 2014 VL 193 SI SI BP 130 EP 134 DI 10.1016/j.virusres.2014.07.002 PG 5 WC Virology SC Virology GA AU2ZA UT WOS:000345481700012 PM 25018022 ER PT J AU Hosseini, P Matthews, BF AF Hosseini, Parsa Matthews, Benjamin F. TI Regulatory interplay between soybean root and soybean cyst nematode during a resistant and susceptible reaction SO BMC PLANT BIOLOGY LA English DT Article DE Soybean; Soybean cyst nematode; SCN; Transcription factor binding site ID GENE-EXPRESSION; HETERODERA-GLYCINES; TRANSCRIPTION FACTORS; SIGNAL-TRANSDUCTION; DEFENSE RESPONSES; OXIDATIVE STRESS; FEEDING CELLS; KNOT NEMATODE; JASMONIC ACID; BIOTIC STRESS AB Background: Plant-parasitic nematodes (PPNs) are obligate parasites that feed on the roots of living host plants. Often, these nematodes can lay hundreds of eggs, each capable of surviving without a host for as long as 12 years. When it comes to wreaking havoc on agricultural yield, few nematodes can compare to the soybean cyst nematode (SCN). Quantifying soybean (Glycinemax) transcription factor binding sites (TFBSs) during a late-stage SCN resistant and susceptible reaction can shed light onto the systematic interplay between host and pathogen, thereby elucidating underlying cis-regulatory mechanisms. Results: We sequenced the soybean root transcriptome at 6 and 8 days upon independent inoculation with a virulent and avirulent SCN population. Genes such as beta-1,4 glucanase, chalcone synthase, superoxide dismutase and various heat shock proteins (HSPs) exhibited reaction-specific expression profiles. Several likely defense-response genes candidates were also identified which are believed to confer SCN resistance. To explore magnitude of TFBS representation during SCN pathogenesis, a multivariate statistical software identified 46 over-represented TFBSs which capture soybean regulatory dynamics across both reactions. Conclusions: Our results reveal a set of soybean TFBSs which are over-represented solely throughout a resistant and susceptible SCN reaction. This set furthers our understanding of soybean cis-regulatory dynamics by providing reaction-specific levels of over-representation at 6 and 8 days after inoculation (dai) with SCN. C1 [Hosseini, Parsa] George Mason Univ, Sch Syst Biol, Manassas, VA 20110 USA. [Hosseini, Parsa] Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, NIH, Bethesda, MD 20894 USA. [Hosseini, Parsa; Matthews, Benjamin F.] USDA, Soybean Genom & Improvement Lab, Beltsville, MD 20705 USA. RP Hosseini, P (reprint author), George Mason Univ, Sch Syst Biol, Manassas, VA 20110 USA. EM parsa.hosseini@nih.gov FU United States Department of Agriculture - Soybean Genomics and Improvement Laboratory (USDA - SGIL); Intramural Research Program of the National Institutes of Health, National Library of Medicine FX We wish to thank the United States Department of Agriculture - Soybean Genomics and Improvement Laboratory (USDA - SGIL) for research funding and support. Our appreciations go out to Ivan Ovcharenko for advice on GO enrichment analysis and TFBS over-representation derivation. We wish to thank Arianne Tremblay for overseeing cDNA derivation and RNA extraction. We wish to thank Margaret H. MacDonald for inoculation of soybean roots with SCN. We also wish to thank Patrick Gillevet and James Willett for numerous thought-provoking discussions. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 66 TC 3 Z9 4 U1 3 U2 31 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2229 J9 BMC PLANT BIOL JI BMC Plant Biol. PD NOV 25 PY 2014 VL 14 AR 300 DI 10.1186/s12870-014-0300-9 PG 10 WC Plant Sciences SC Plant Sciences GA AX4WK UT WOS:000346929300001 PM 25421055 ER PT J AU Bulea, TC Prasad, S Kilicarslan, A Contreras-Vidal, JL AF Bulea, Thomas C. Prasad, Saurabh Kilicarslan, Atilla Contreras-Vidal, Jose L. TI Sitting and standing intention can be decoded from scalp EEG recorded prior to movement execution SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE EEG; electroencephalography; movement-related cortical potentials; classification; brain-machine; interface; mobile neuroimaging; lower extremity ID BRAIN-COMPUTER INTERFACES; INDEPENDENT COMPONENT ANALYSIS; SINGLE-TRIAL EEG; NONINVASIVE ELECTROENCEPHALOGRAPHIC SIGNALS; HUMAN VOLUNTARY MOVEMENT; TREADMILL WALKING; CORTICAL POTENTIALS; MOTOR IMAGERY; FEATURE-SELECTION; CLASSIFICATION AB Low frequency signals recorded from non-invasive electroencephalography (EEG), in particular movement-related cortical potentials (MRPs), are associated with preparation and execution of movement and thus present a target for use in brain-machine interfaces. We investigated the ability to decode movement intent from delta-band (0.1-4 Hz) EEG recorded immediately before movement execution in healthy volunteers. We used data from epochs starting 1.5 s before movement onset to classify future movements into one of three classes: stand-up, sit-down, or quiet. We assessed classification accuracy in both externally triggered and self-paced paradigms. Movement onset was determined from electromyography (EMG) recordings synchronized with EEG signals. We employed an artifact subspace reconstruction (ASR) algorithm to eliminate high amplitude noise before building our time-embedded EEG features. We applied local Fisher's discriminant analysis to reduce the dimensionality of our spatio-temporal features and subsequently used a Gaussian mixture model classifier for our three class problem. Our results demonstrate significantly better than chance classification accuracy (chance level = 33.3%) for the self-initiated (78.0 2.6%) and triggered (74.7 5.7%) paradigms. Surprisingly, we found no significant difference in classification accuracy between the self-paced and cued paradigms when using the full set of non-peripheral electrodes. However, accuracy was significantly increased for self-paced movements when only electrodes over the primary motor area were used. Overall, this study demonstrates that delta-band EEG recorded immediately before movement carries discriminative information regarding movement type. Our results suggest that EEG-based classifiers could improve lower-limb neuroprostheses and neurorehabilitation techniques by providing earlier detection of movement intent, which could be used in robot-assisted strategies for motor training and recovery of function. C1 [Bulea, Thomas C.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bethesda, MD 20892 USA. [Bulea, Thomas C.; Prasad, Saurabh; Kilicarslan, Atilla; Contreras-Vidal, Jose L.] Univ Houston, Dept Elect & Comp Engn, Lab Noninvas Brain Machine Interface Syst, Houston, TX USA. RP Bulea, TC (reprint author), NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, CRC, Bldg 10,Room 1-1469,10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. EM thomas.bulea@nih.gov FU NIH Clinical Center, NINDS [R01N5075889]; NSF [IIS-1302339] FX The authors thank Recep Ozdemir, Yongtian He and Shahriar Iqbal for assistance during the experiments. This research was funded in part by the intramural research program at the NIH Clinical Center, NINDS R01N5075889, and NSF IIS-1302339. NR 83 TC 0 Z9 0 U1 4 U2 13 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD NOV 25 PY 2014 VL 8 DI 10.3389/fnins.2014.00376 PG 19 WC Neurosciences SC Neurosciences & Neurology GA AW8UW UT WOS:000346537800001 ER PT J AU Kannan, S Rogozin, IB Koonin, EV AF Kannan, Sivakumar Rogozin, Igor B. Koonin, Eugene V. TI MitoCOGs: clusters of orthologous genes from mitochondria and implications for the evolution of eukaryotes SO BMC EVOLUTIONARY BIOLOGY LA English DT Article DE Mitochondria; Genome evolution; Gene loss; Gene transfer; Introns; Clusters of orthologous genes ID HORIZONTAL TRANSFER; FLOWERING PLANTS; INTRON EVOLUTION; YEAST MITOCHONDRIAL; GENOME EVOLUTION; ORIGIN; PROTEINS; SEQUENCE; PHYLOGENY; PROTEOME AB Background: Mitochondria are ubiquitous membranous organelles of eukaryotic cells that evolved from an alpha-proteobacterial endosymbiont and possess a small genome that encompasses from 3 to 106 genes. Accumulation of thousands of mitochondrial genomes from diverse groups of eukaryotes provides an opportunity for a comprehensive reconstruction of the evolution of the mitochondrial gene repertoire. Results: Clusters of orthologous mitochondrial protein-coding genes (MitoCOGs) were constructed from all available mitochondrial genomes and complemented with nuclear orthologs of mitochondrial genes. With minimal exceptions, the mitochondrial gene complements of eukaryotes are subsets of the superset of 66 genes found in jakobids. Reconstruction of the evolution of mitochondrial genomes indicates that the mitochondrial gene set of the last common ancestor of the extant eukaryotes was slightly larger than that of jakobids. This superset of mitochondrial genes likely represents an intermediate stage following the loss and transfer to the nucleus of most of the endosymbiont genes early in eukaryote evolution. Subsequent evolution in different lineages involved largely parallel transfer of ancestral endosymbiont genes to the nuclear genome. The intron density in nuclear orthologs of mitochondrial genes typically is nearly the same as in the rest of the genes in the respective genomes. However, in land plants, the intron density in nuclear orthologs of mitochondrial genes is almost 1.5-fold lower than the genomic mean, suggestive of ongoing transfer of functional genes from mitochondria to the nucleus. Conclusions: The MitoCOGs are expected to become an important resource for the study of mitochondrial evolution. The nearly complete superset of mitochondrial genes in jakobids likely represents an intermediate stage in the evolution of eukaryotes after the initial, extensive loss and transfer of the endosymbiont genes. In addition, the bacterial multi-subunit RNA polymerase that is encoded in the jakobid mitochondrial genomes was replaced by a single-subunit phage-type RNA polymerase in the rest of the eukaryotes. These results are best compatible with the rooting of the eukaryotic tree between jakobids and the rest of the eukaryotes. The land plants are the only eukaryotic branch in which the gene transfer from the mitochondrial to the nuclear genome appears to be an active, ongoing process. C1 [Kannan, Sivakumar; Rogozin, Igor B.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU US Department of Health and Human Services FX We thank Koonin group members for useful discussions. The authors' research is supported by intramural funds of the US Department of Health and Human Services (to the national Library of Medicine). NR 112 TC 11 Z9 11 U1 4 U2 24 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD NOV 25 PY 2014 VL 14 AR 237 DI 10.1186/s12862-014-0237-5 PG 16 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA AU6JX UT WOS:000345710600001 PM 25421434 ER PT J AU Lai, GY Weinstein, SJ Albanes, D Taylor, PR Virtamo, J McGlynn, KA Freedman, ND AF Lai, G. Y. Weinstein, S. J. Albanes, D. Taylor, P. R. Virtamo, J. McGlynn, K. A. Freedman, N. D. TI Association of serum alpha-tocopherol, beta-carotene, and retinol with liver cancer incidence and chronic liver disease mortality SO BRITISH JOURNAL OF CANCER LA English DT Article DE micronutrients; serum; prospective cohort; liver cancer; chronic liver disease ID HEPATOCELLULAR-CARCINOMA; VITAMIN-A; OXIDATIVE STRESS; FOLLOW-UP; RISK-FACTORS; CIRRHOSIS; ANTIOXIDANTS; PREVENTION; PLASMA; TRIAL AB Background: Micronutrients may influence the development or progression of liver cancer and liver disease. We evaluated the association of serum alpha-tocopherol, beta-carotene, and retinol with incident liver cancer and chronic liver disease (CLD) mortality in a prospective cohort of middle-aged Finnish male smokers. Methods: Baseline and 3-year follow-up serum were available from 29 046 and 22 805 men, respectively. After 24 years of follow-up, 208 men were diagnosed with liver cancer and 237 died from CLD. Hazards ratios and 95% confidence intervals were calculated for highest vs lowest quartiles from multivariate proportional hazards models. Results: Higher beta-carotene and retinol levels were associated with less liver cancer (beta-carotene: 0.35, 0.22-0.55, P-trend <0.0001; retinol: 0.58, 0.39-0.85, P-trend = 0.0009) and CLD mortality (beta-carotene: 0.47, 0.30-0.75, P-trend = 0.001; retinol: 0.55, 0.38-0.78, P-trend = 0.0007). alpha-Tocopherol was associated with CLD mortality (0.63, 0.40-0.99, P-trend = 0.06), but not with liver cancer (1.06, 0.64-1.74, P-trend = 0.77). Participants with higher levels of beta-carotene and retinol, but not alpha-tocopherol, at both baseline and year 3 had lower risk of each outcome than those with lower levels. Conclusions: Our findings suggest that higher concentrations of beta-carotene and retinol are associated with incident liver cancer and CLD. However, such data do not indicate that supplementation should be considered for these diseases. C1 [Lai, G. Y.] NCI, Canc Prevent Div, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Lai, G. Y.; Weinstein, S. J.; Albanes, D.; Freedman, N. D.] NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Bethesda, MD 20892 USA. [Taylor, P. R.] NCI, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, Bethesda, MD 20892 USA. [Virtamo, J.] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [McGlynn, K. A.] NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, Bethesda, MD 20892 USA. RP Lai, GY (reprint author), NCI, Canc Prevent Div, Canc Prevent Fellowship Program, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM laigy@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; Freedman, Neal/B-9741-2015 OI Freedman, Neal/0000-0003-0074-1098 FU Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services; US Public Health Service [N01-CN-45165, N01-RC-45035, N01-RC-37004] FX We thank all individuals for their participation in this study. This research was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and US Public Health Service contracts (N01-CN-45165, N01-RC-45035, and N01-RC-37004). The sponsor reviewed and approved final submission but had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation of the manuscript. NR 47 TC 4 Z9 4 U1 1 U2 8 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 NOV 25 PY 2014 VL 111 IS 11 BP 2163 EP 2171 DI 10.1038/bjc.2014.365 PG 9 WC Oncology SC Oncology GA AU4QW UT WOS:000345597700017 PM 25314058 ER PT J AU Mattson, MP Allison, DB Fontana, L Harvie, M Longo, VD Malaisse, WJ Mosley, M Notterpek, L Ravussin, E Scheer, FAJL Seyfried, TN Varady, KA Panda, S AF Mattson, Mark P. Allison, David B. Fontana, Luigi Harvie, Michelle Longo, Valter D. Malaisse, Willy J. Mosley, Michael Notterpek, Lucia Ravussin, Eric Scheer, Frank A. J. L. Seyfried, Thomas N. Varady, Krista A. Panda, Satchidananda TI Meal frequency and timing in health and disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE metabolism; circadian rhythm; time-restricted feeding; feeding behavior; obesity ID HIGH-FAT DIET; RANDOMIZED CONTROLLED-TRIAL; WEIGHT-LOSS; CALORIE RESTRICTION; CIRCADIAN CLOCK; ENERGY RESTRICTION; FOOD RESTRICTION; OVERWEIGHT WOMEN; RISK MARKERS; MOUSE MODEL AB Although major research efforts have focused on how specific components of foodstuffs affect health, relatively little is known about a more fundamental aspect of diet, the frequency and circadian timing of meals, and potential benefits of intermittent periods with no or very low energy intakes. The most common eating pattern in modern societies, three meals plus snacks every day, is abnormal from an evolutionary perspective. Emerging findings from studies of animal models and human subjects suggest that intermittent energy restriction periods of as little as 16 h can improve health indicators and counteract disease processes. The mechanisms involve a metabolic shift to fat metabolism and ketone production, and stimulation of adaptive cellular stress responses that prevent and repair molecular damage. As data on the optimal frequency and timing of meals crystalizes, it will be critical to develop strategies to incorporate those eating patterns into health care policy and practice, and the lifestyles of the population. C1 NIA, Lab Neurosci, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Dept Neurosci, Sch Med, Baltimore, MD 21205 USA. [Allison, David B.] Univ Alabama Birmingham, Nutr & Obes Res Ctr, Birmingham, AL 35294 USA. [Fontana, Luigi] Washington Univ, Dept Med, St Louis, MO 63130 USA. [Fontana, Luigi] Univ Brescia, Dept Clin & Expt Sci, I-25123 Brescia, Italy. [Fontana, Luigi] CEINGE Biotecnol Avanzate, I-80145 Naples, Italy. [Harvie, Michelle] Univ S Manchester Hosp, Genesis Breast Canc Prevent Ctr, Manchester M23 9LT, Lancs, England. [Longo, Valter D.] Univ So Calif, Longev Inst, Davis Sch Gerontol, Los Angeles, CA 90089 USA. [Longo, Valter D.] Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. [Malaisse, Willy J.] Free Univ Brussels, Lab Expt Hormonol, B-1070 Brussels, Belgium. [Mosley, Michael] British Broadcasting Corp, London W1A 1AA, England. [Notterpek, Lucia] Univ Florida, McKnight Brain Inst, Coll Med, Dept Neurosci, Gainesville, FL 32610 USA. [Ravussin, Eric] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Scheer, Frank A. J. L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Scheer, Frank A. J. L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Seyfried, Thomas N.] Boston Coll, Dept Biol, Chestnut Hill, MA 02467 USA. [Varady, Krista A.] Univ Illinois, Dept Kinesiol & Nutr, Chicago, IL 60612 USA. [Panda, Satchidananda] Salk Inst Biol Studies, Reg Biol Lab, La Jolla, CA 92037 USA. RP Mattson, MP (reprint author), NIA, Lab Neurosci, Baltimore, MD 21224 USA. EM mark.mattson@nih.gov; panda@salk.edu OI Seyfried, Thomas/0000-0003-1491-3989; Allison, David/0000-0003-3566-9399 FU National Institute on Aging Intramural Research Program; Glenn Foundation for Medical Research; NIH [P30DK056336, P01AG034906, R01NS041012, P30DK072476, R01DK099512, R01NS055195, R01HL106228, R01DK091618]; European Union [FP7-SSH-2012-1, 320333]; Genesis Breast Cancer Prevention, UK; Belgian Foundation for Scientific Medical Research Grant [3.4520.07] FX This article incorporates information from a workshop on "Eating Patterns and Disease," which can be viewed at videocast.nih.gov/summary.asp?Live=13746&bhcp=1, and was supported by the National Institute on Aging Intramural Research Program and the Glenn Foundation for Medical Research. Relevant research in the authors' laboratories are supported by NIH intramural support (to M. P. M.); NIH Grants P30DK056336 (to D. B. A.), P01AG034906 (to V. D. L.), R01NS041012 (to L.N.), P30DK072476 (to E. R.), R01DK099512 (to F.A.J.L.S.), R01NS055195 (to T.N.S.), R01HL106228 (to K. A. V.), and R01DK091618 (to S. P.); the European Union's Seventh Framework Programme MOPACT [mobilising the potential of active ageing in Europe; FP7-SSH-2012-1 Grant 320333 (to L. F.)]; a grant from Genesis Breast Cancer Prevention, UK (to M. H.); and Belgian Foundation for Scientific Medical Research Grant 3.4520.07 (to W.J.M.). NR 86 TC 44 Z9 44 U1 13 U2 94 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 NOV 25 PY 2014 VL 111 IS 47 BP 16647 EP 16653 DI 10.1073/pnas.1413965111 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU5QX UT WOS:000345662700019 PM 25404320 ER PT J AU Xu, ZX Lefevre, GM Gavrilova, O St Claire, MBF Riddick, G Felsenfeld, G AF Xu, Zhixiong Lefevre, Gaelle M. Gavrilova, Oksana St Claire, Mark B. Foster Riddick, Gregory Felsenfeld, Gary TI Mapping of long-range INS promoter interactions reveals a role for calcium-activated chloride channel ANO1 in insulin secretion SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chloride channel; diabetes; insulin secretion ID PANCREATIC BETA-CELLS; DEPENDENT DIABETES-MELLITUS; HUMAN GENOME; CHROMATIN INTERACTIONS; SUSCEPTIBILITY LOCUS; ELECTRICAL-ACTIVITY; DROSOPHILA GENOME; CYSTIC-FIBROSIS; CHROMOSOME 11Q; TMEM16A AB We used circular chromatin conformation capture (4C) to identify a physical contact in human pancreatic islets between the region near the insulin (INS) promoter and the ANO1 gene, lying 68 Mb away on human chromosome 11, which encodes a Ca2+-dependent chloride ion channel. In response to glucose, this contact was strengthened and ANO1 expression increased, whereas inhibition of INS gene transcription by INS promoter targeting siRNA decreased ANO1 expression, revealing a regulatory effect of INS promoter on ANO1 expression. Knockdown of ANO1 expression caused decreased insulin secretion in human islets, establishing a physical proximity-dependent feedback loop involving INS transcription, ANO1 expression, and insulin secretion. To explore a possible role of ANO1 in insulin metabolism, we carried out experiments in Ano1(+/-) mice. We observed reduced serum insulin levels and insulin-to-glucose ratios in high-fat diet-fed Ano1(+/-) mice relative to Ano1(+/+) mice fed the same diet. Our results show that determination of long-range contacts within the nucleus can be used to detect novel and physiologically relevant mechanisms. They also show that networks of long-range physical contacts are important to the regulation of insulin metabolism. C1 [Xu, Zhixiong; Lefevre, Gaelle M.; Gavrilova, Oksana; St Claire, Mark B. Foster; Riddick, Gregory; Felsenfeld, Gary] NIDDK, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM gary.felsenfeld@nih.gov FU NIDDK FX We thank Tatyana Chanturiya and Ruifeng Teng [National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Mouse Metabolic Core] and Huiyan Lu and Jennifer Portas (NIDDK Laboratory of Animal Sciences) for their technical assistance. We thank Dr. A. S. Verkman for providing ANO1 inhibitors and activators. We also thank Dr. Jason Rock for kindly providing Ano1+/- mice. This work was supported by the NIDDK's Intramural Research Program. NR 45 TC 6 Z9 6 U1 0 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 NOV 25 PY 2014 VL 111 IS 47 BP 16760 EP 16765 DI 10.1073/pnas.1419240111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU5QX UT WOS:000345662700037 PM 25385647 ER PT J AU Romano, A Inbar, E Debrabant, A Charmoy, M Lawyer, P Ribeiro-Gomes, F Barhoumi, M Grigg, M Shaik, J Dobson, D Beverley, SM Sacks, DL AF Romano, Audrey Inbar, Ehud Debrabant, Alain Charmoy, Melanie Lawyer, Phillip Ribeiro-Gomes, Flavia Barhoumi, Mourad Grigg, Michael Shaik, Jahangheer Dobson, Deborah Beverley, Stephen M. Sacks, David L. TI Cross-species genetic exchange between visceral and cutaneous strains of Leishmania in the sand fly vector SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Leishmania; genetic exchange; sand fly ID POPULATION-STRUCTURE; OLD-WORLD; A2 GENE; DONOVANI; INFECTION; INFANTUM; HYBRIDIZATION; CHROMOSOME; EVOLUTION; SURVIVAL AB Genetic exchange between Leishmania major strains during their development in the sand fly vector has been experimentally shown. To investigate the possibility of genetic exchange between different Leishmania species, a cutaneous strain of L. major and a visceral strain of Leishmania infantum, each bearing a different drug-resistant marker, were used to coinfect Lutzomyia longipalpis sand flies. Eleven double-drug-resistant progeny clones, each the product of an independent mating event, were generated and submitted to genotype and phenotype analyses. The analysis of multiple allelic markers across the genome suggested that each progeny clone inherited at least one full set of chromosomes from each parent, with loss of heterozygosity at some loci, and uniparental retention of maxicircle kinetoplast DNA. Hybrids with DNA contents of approximately 2n, 3n, and 4n were observed. In vivo studies revealed clear differences in the ability of the hybrids to produce pathology in the skin or to disseminate to and grow in the viscera, suggesting polymorphisms and differential inheritance of the gene(s) controlling these traits. The studies, to our knowledge, represent the first experimental confirmation of cross-species mating in Leishmania, opening the way toward genetic linkage analysis of important traits and providing strong evidence that genetic exchange is responsible for the generation of the mixed-species genotypes observed in natural populations. C1 [Romano, Audrey; Inbar, Ehud; Charmoy, Melanie; Lawyer, Phillip; Ribeiro-Gomes, Flavia; Barhoumi, Mourad; Grigg, Michael; Sacks, David L.] NIAID, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. [Debrabant, Alain] US FDA, Div Emerging & Transfus Transmitted Dis, Off Blood Res & Review, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Shaik, Jahangheer; Dobson, Deborah; Beverley, Stephen M.] Washington Univ, Dept Mol Microbiol, Sch Med, St Louis, MO 63110 USA. RP Sacks, DL (reprint author), NIAID, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. EM dsacks@nih.gov RI Ribeiro-Gomes, Flavia/F-7609-2015; OI Beverley, Stephen/0000-0001-5319-0811 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); NIH [AI-R01-29646] FX We thank Kim Beacht for assistance with the animal studies. This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); and by NIH Grant AI-R01-29646 (to S.M.B.). NR 39 TC 6 Z9 6 U1 3 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 NOV 25 PY 2014 VL 111 IS 47 BP 16808 EP 16813 DI 10.1073/pnas.1415109111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU5QX UT WOS:000345662700045 PM 25385616 ER PT J AU Brooke, CB Ince, WL Wei, JJ Bennink, JR Yewdell, JW AF Brooke, Christopher B. Ince, William L. Wei, Jiajie Bennink, Jack R. Yewdell, Jonathan W. TI Influenza A virus nucleoprotein selectively decreases neuraminidase gene-segment packaging while enhancing viral fitness and transmissibility SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE influenza virus; genome segmentation; genome packaging; nucleoprotein; host adaptation ID HUMAN AIRWAY EPITHELIUM; RIBONUCLEOPROTEIN COMPLEXES; DELETERIOUS MUTATIONS; FUNCTIONAL BALANCE; HEMAGGLUTININ; REASSORTMENT; PARTICLES; RECOMBINATION; ADAPTATION; RESISTANCE AB The influenza A virus (IAV) genome is divided into eight distinct RNA segments believed to be copackaged into virions with nearly perfect efficiency. Here, we describe a mutation in IAV nucleoprotein (NP) that enhances replication and transmission in guinea pigs while selectively reducing neuraminidase (NA) gene segment packaging into virions. We show that incomplete IAV particles lacking gene segments contribute to the propagation of the viral population through multiplicity reactivation under conditions of widespread coinfection, which we demonstrate commonly occurs in the upper respiratory tract of guinea pigs. NP also dramatically altered the functional balance of the viral glycoproteins on particles by selectively decreasing NA expression. Our findings reveal novel functions for NP in selective control of IAV gene packaging and balancing glycoprotein expression and suggest a role for incomplete gene packaging during host adaptation and transmission. C1 [Brooke, Christopher B.; Ince, William L.; Wei, Jiajie; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM jyewdell@niaid.nih.gov FU Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health FX This work was funded by the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health. NR 37 TC 10 Z9 10 U1 0 U2 9 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 NOV 25 PY 2014 VL 111 IS 47 BP 16854 EP 16859 DI 10.1073/pnas.1415396111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU5QX UT WOS:000345662700053 PM 25385602 ER PT J AU He, Y Fisher, R Chowdhury, S Sultana, I Pereira, CP Bray, M Reed, JL AF He, Yong Fisher, Robert Chowdhury, Soma Sultana, Ishrat Pereira, Claudia P. Bray, Mike Reed, Jennifer L. TI Vaccinia Virus Induces Rapid Necrosis in Keratinocytes by a STAT3-Dependent Mechanism SO PLOS ONE LA English DT Article ID CELL-DEATH; STAT3 ACTIVATION; PROTEIN; PHOSPHORYLATION; INFLAMMATION; NECROPTOSIS; MITOCHONDRIA; APOPTOSIS; KINASE AB Rationale: Humans with a dominant negative mutation in STAT3 are susceptible to severe skin infections, suggesting an essential role for STAT3 signaling in defense against cutaneous pathogens. Methods: To focus on innate antiviral defenses in keratinocytes, we used a standard model of cutaneous infection of severe combined immunodeficient mice with the current smallpox vaccine, ACAM-2000. In parallel, early events post-infection with the smallpox vaccine ACAM-2000 were investigated in cultured keratinocytes of human and mouse origin. Results: Mice treated topically with a STAT3 inhibitor (Stattic) developed larger vaccinia lesions with higher virus titers and died more rapidly than untreated controls. Cultured human and murine keratinocytes infected with ACAM-2000 underwent rapid necrosis, but when treated with Stattic or with inhibitors of RIP1 kinase or caspase-1, they survived longer, produced higher titers of virus, and showed reduced activation of type I interferon responses and inflammatory cytokines release. Treatment with inhibitors of RIP1 kinase and STAT3, but not caspase-1, also reduced the inflammatory response of keratinocytes to TLR ligands. Vaccinia growth properties in Vero cells, which are known to be defective in some antiviral responses, were unaffected by inhibition of RIP1K, caspase-1, or STAT3. Conclusions: Our findings indicate that keratinocytes suppress the replication and spread of vaccinia virus by undergoing rapid programmed cell death, in a process requiring STAT3. These data offer a new framework for understanding susceptibility to skin infection in patients with STAT3 mutations. Interventions which promote prompt necroptosis/pyroptosis of infected keratinocytes may reduce risks associated with vaccination with live vaccinia virus. C1 [He, Yong; Fisher, Robert; Chowdhury, Soma; Sultana, Ishrat; Pereira, Claudia P.; Reed, Jennifer L.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. RP Reed, JL (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM jennifer.reed@fda.hhs.gov FU Medical Countermeasures Initiative and Modernization of Science - Food and Drug Administration, Center for Biologics Evaluation and Research FX This work was supported by Medical Countermeasures Initiative and Modernization of Science funding awarded by the Food and Drug Administration, Center for Biologics Evaluation and Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 2 Z9 2 U1 1 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 NOV 24 PY 2014 VL 9 IS 11 AR e113690 DI 10.1371/journal.pone.0113690 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AX2IM UT WOS:000346766900066 PM 25419841 ER PT J AU Keadle, SK Shiroma, EJ Freedson, PS Lee, IM AF Keadle, Sarah Kozey Shiroma, Eric J. Freedson, Patty S. Lee, I-Min TI Impact of accelerometer data processing decisions on the sample size, wear time and physical activity level of a large cohort study SO BMC PUBLIC HEALTH LA English DT Article DE Physical activity; Measurement; Exposure assessment; Behavioral epidemiology; Sedentary behavior ID RANDOMIZED CONTROLLED-TRIAL; LOW-DOSE ASPIRIN; PRIMARY PREVENTION; CARDIOVASCULAR-DISEASE; SEDENTARY BEHAVIOR; WOMENS HEALTH; UNITED-STATES; NONWEAR TIME; SELF-REPORT; ALGORITHMS AB Background: Accelerometers objectively assess physical activity (PA) and are currently used in several large-scale epidemiological studies, but there is no consensus for processing the data. This study compared the impact of wear-time assessment methods and using either vertical (V)-axis or vector magnitude (VM) cut-points on accelerometer output. Methods: Participants (7,650 women, mean age 71.4 y) were mailed an accelerometer (ActiGraph GT3X+), instructed to wear it for 7 days, record dates and times the monitor was worn on a log, and return the monitor and log via mail. Data were processed using three wear-time methods (logs, Troiano or Choi algorithms) and V-axis or VM cut-points. Results: Using algorithms alone resulted in "mail-days" incorrectly identified as "wear-days" (27-79% of subjects had >7-days of valid data). Using only dates from the log and the Choi algorithm yielded: 1) larger samples with valid data than using log dates and times, 2) similar wear-times as using log dates and times, 3) more wear-time (V, 48.1 min more; VM, 29.5 min more) than only log dates and Troiano algorithm. Wear-time algorithm impacted sedentary time (similar to 30-60 min lower for Troiano vs. Choi) but not moderate-to-vigorous (MV) PA time. Using V-axis cut-points yielded similar to 60 min more sedentary time and similar to 10 min less MVPA time than using VM cut-points. Conclusions: Combining log-dates and the Choi algorithm was optimal, minimizing missing data and researcher burden. Estimates of time in physical activity and sedentary behavior are not directly comparable between V-axis and VM cut-points. These findings will inform consensus development for accelerometer data processing in ongoing epidemiologic studies. C1 [Keadle, Sarah Kozey] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Keadle, Sarah Kozey] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Shiroma, Eric J.; Lee, I-Min] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Shiroma, Eric J.; Lee, I-Min] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, Boston, MA 02115 USA. [Freedson, Patty S.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Dept Kinesiol, Amherst, MA 01003 USA. RP Keadle, SK (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM sarah.keadle@nih.gov OI Keadle, Sarah/0000-0002-9569-9306 FU National Institutes of Health [CA154647] FX This research was supported by research grant CA154647 from the National Institutes of Health. NR 39 TC 9 Z9 9 U1 2 U2 17 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 NOV 24 PY 2014 VL 14 AR 1210 DI 10.1186/1471-2458-14-1210 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AU1EK UT WOS:000345363600001 PM 25421941 ER PT J AU Zhang, MS Arnaoutov, A Dasso, M AF Zhang, Michael Shaofei Arnaoutov, Alexei Dasso, Mary TI RanBP1 Governs Spindle Assembly by Defining Mitotic Ran-GTP Production SO DEVELOPMENTAL CELL LA English DT Article ID XENOPUS EGG EXTRACTS; NUCLEAR TRANSPORT; BINDING-PROTEIN; MICROTUBULE ASTERS; CELL-CYCLE; BOUND RAN; RCC1; MITOSIS; CHROMATIN; GRADIENT AB Accurate control of the Ras-related nuclear protein (Ran) GTPase cycle depends on the regulated activity of regulator of chromosome condensation 1 (RCC1), Ran's nucleotide exchange factor. RanBP1 has been characterized as a coactivator of the Ran GTPase-activating protein RanGAP1. RanBP1 can also form a stable complex with Ran and RCC1, although the dynamics and function of this complex remain poorly understood. Here, we show that formation of the heterotrimeric RCC1/Ran/RanBP1 complex in M phase Xenopus egg extracts controls both RCC1's enzymatic activity and partitioning between the chromatin-bound and soluble pools of RCC1. This mechanism is critical for spatial control of Ran-guanosine triphosphate (GTP) gradients that guide mitotic spindle assembly. Moreover, phosphorylation of RanBP1 drives changes in the dynamics of chromatin-bound RCC1 pools at the metaphase-anaphase transition. Our findings reveal an important mitotic role for RanBP1, controlling the spatial distribution and magnitude of mitotic Ran-GTP production and thereby ensuring accurate execution of Ran-dependent mitotic events. C1 [Zhang, Michael Shaofei; Arnaoutov, Alexei; Dasso, Mary] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Dasso, M (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM dassom@mail.nih.gov OI Dasso, Mary/0000-0002-5410-1371 FU NICHD [HD008740] FX This study was supported by NICHD project HD008740. NR 39 TC 10 Z9 10 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD NOV 24 PY 2014 VL 31 IS 4 BP 393 EP 404 DI 10.1016/j.devcel.2014.10.014 PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA AU3UZ UT WOS:000345540200006 PM 25458009 ER PT J AU Ionan, AC Polley, MYC McShane, LM Dobbin, KK AF Ionan, Alexei C. Polley, Mei-Yin C. McShane, Lisa M. Dobbin, Kevin K. TI Comparison of confidence interval methods for an intra-class correlation coefficient (ICC) SO BMC MEDICAL RESEARCH METHODOLOGY LA English DT Article DE Confidence interval; Credible interval; Generalized confidence interval; Intraclass correlation coefficient; Modified large sample ID ASSESSING AGREEMENT; RELIABILITY; VARIANCE; MODELS; BAYES; SAMPLE AB Background: The intraclass correlation coefficient (ICC) is widely used in biomedical research to assess the reproducibility of measurements between raters, labs, technicians, or devices. For example, in an inter-rater reliability study, a high ICC value means that noise variability (between-raters and within-raters) is small relative to variability from patient to patient. A confidence interval or Bayesian credible interval for the ICC is a commonly reported summary. Such intervals can be constructed employing either frequentist or Bayesian methodologies. Methods: This study examines the performance of three different methods for constructing an interval in a two-way, crossed, random effects model without interaction: the Generalized Confidence Interval method (GCI), the Modified Large Sample method (MLS), and a Bayesian method based on a noninformative prior distribution (NIB). Guidance is provided on interval construction method selection based on study design, sample size, and normality of the data. We compare the coverage probabilities and widths of the different interval methods. Results: We show that, for the two-way, crossed, random effects model without interaction, care is needed in interval method selection because the interval estimates do not always have properties that the user expects. While different methods generally perform well when there are a large number of levels of each factor, large differences between the methods emerge when the number of one or more factors is limited. In addition, all methods are shown to lack robustness to certain hard-to-detect violations of normality when the sample size is limited. Conclusions: Decision rules and software programs for interval construction are provided for practical implementation in the two-way, crossed, random effects model without interaction. All interval methods perform similarly when the data are normal and there are sufficient numbers of levels of each factor. The MLS and GCI methods outperform the NIB when one of the factors has a limited number of levels and the data are normally distributed or nearly normally distributed. None of the methods work well if the number of levels of a factor are limited and data are markedly non-normal. The software programs are implemented in the popular R language. C1 [Ionan, Alexei C.] Univ Georgia, Dept Stat, Athens, GA 30602 USA. [Polley, Mei-Yin C.; McShane, Lisa M.] NCI, Biometr Res Branch, Rockville, MD USA. [Dobbin, Kevin K.] Univ Georgia, Dept Epidemiol & Biostat, Athens, GA 30602 USA. RP Dobbin, KK (reprint author), Univ Georgia, Dept Epidemiol & Biostat, Athens, GA 30602 USA. EM dobbinke@uga.edu FU Georgia Research Alliance's Distinguished Cancer Scholars Program FX Ionan and Dobbin were supported in part by a grant from the Georgia Research Alliance's Distinguished Cancer Scholars Program. NR 41 TC 3 Z9 4 U1 4 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2288 J9 BMC MED RES METHODOL JI BMC Med. Res. Methodol. PD NOV 22 PY 2014 VL 14 AR 121 DI 10.1186/1471-2288-14-121 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AW7JA UT WOS:000346439300001 PM 25417040 ER PT J AU Fu, YL Liu, H Ng, L Kim, JW Hao, H Swaroop, A Forrest, D AF Fu, Yulong Liu, Hong Ng, Lily Kim, Jung-Woong Hao, Hong Swaroop, Anand Forrest, Douglas TI Feedback Induction of a Photoreceptor-specific Isoform of Retinoid-related Orphan Nuclear Receptor beta by the Rod Transcription Factor NRL SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-FATE; CONE PHOTORECEPTORS; MOUSE RETINA; DIFFERENTIATION FACTOR; GENES; NR2E3; CRX; DEGENERATION; EXPRESSION; AMACRINE AB Vision requires the generation of cone and rod photoreceptors that function in daylight and dim light, respectively. The neural retina leucine zipper factor (NRL) transcription factor critically controls photoreceptor fates as it stimulates rod differentiation and suppresses cone differentiation. However, the controls over NRL induction that balance rod and cone fates remain unclear. We have reported previously that the retinoid-related orphan receptor beta gene (Rorb) is required for Nrl expression and other retinal functions. We show that Rorb differentially expresses two isoforms: ROR beta 2 in photoreceptors and ROR beta 1 in photoreceptors, progenitor cells, and other cell types. Deletion of ROR beta 2 or ROR beta 1 increased the cone: rod ratio similar to 2-fold, whereas deletion of both isoforms in Rorb(-/-) mice produced almost exclusively cone-like cells at the expense of rods, suggesting that both isoforms induce Nrl. Electroporation of either ROR beta isoform into retinal explants from Rorb(-/-) neonates reactivated Nrl and rod genes but, in Nrl(-/-) explants, failed to reactivate rod genes, indicating that NRL is the effector for both ROR beta isoforms in rod differentiation. Unexpectedly, ROR beta 2 expression was lost in Nrl(-/-) mice. Moreover, NRL-activated the ROR beta 2-specific promoter of Rorb, indicating that NRL activates Rorb, its own inducer gene. We suggest that feedback activation between Nrl and Rorb genes reinforces the commitment to rod differentiation. C1 [Fu, Yulong; Liu, Hong; Ng, Lily; Forrest, Douglas] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Kim, Jung-Woong; Hao, Hong; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. RP Forrest, D (reprint author), NIDDK, Lab Endocrinol & Receptor Biol, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM forrestd@niddk.nih.gov FU NIDDK; NEI at the National Institutes of Health; KaroBio Foundation FX This work was supported, in whole or in part, by the intramural research programs of the NIDDK (to D. F.) and NEI (to A. S.) at the National Institutes of Health. This work was also supported by the KaroBio Foundation (to D. F.). NR 54 TC 3 Z9 3 U1 0 U2 2 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 NOV 21 PY 2014 VL 289 IS 47 DI 10.1074/jbc.M114.605774 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU0SO UT WOS:000345335000007 PM 25296752 ER PT J AU Gahl, RF He, Y Yu, SQ Tjandra, N AF Gahl, Robert F. He, Yi Yu, Shiqin Tjandra, Nico TI Conformational Rearrangements in the Pro-apoptotic Protein, Bax, as It Inserts into Mitochondria A CELLULAR DEATH SWITCH SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FLUORESCENCE CORRELATION SPECTROSCOPY; BCL-2 FAMILY; PORE; TRANSLOCATION; CYTOSOL; OLIGOMERIZE; MEMBRANES; BCL-X(L); BINDING; HELIX AB The B-cell lymphoma 2 (Bcl-2) family of proteins regulates the activation of apoptosis through the mitochondria pathway. Pro-and anti-apoptotic members of this family keep each other in check until the correct time to commit to apoptosis. The point of no return for this commitment is the permeabilization of the outer mitochondrial membrane. Translocation of the pro-apoptotic member, Bax, from the cytosol to the mitochondria is the molecular signature of this event. We employed a novel method to reliably detect Forster resonance energy transfer (FRET) between pairs of fluorophores to identify intra-molecular conformational changes and inter-molecular contacts in Bax as this translocation occurs in live cells. In the cytosol, our FRET measurement indicated that the C-terminal helix is exposed instead of tucked away in the core of the protein. In addition fluorescence correlation spectroscopy (FCS) showed that cytosolic Bax diffuses much slower than expected, suggesting possible complex formation or transient membrane interaction. Cross-linking the C-terminal helix (alpha 9) to helix alpha 4 reduced the potential of those interactions to occur. After translocation, our FRET measurements showed that Bax molecules form homo-oligomers in the mitochondria through two distinct interfaces involving the BH3 domain (helix alpha 2) and the C-terminal helix. These findings have implications for possible contacts with other Bcl-2 proteins necessary for the regulation of apoptosis. C1 [Gahl, Robert F.; He, Yi; Yu, Shiqin; Tjandra, Nico] NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), 50 South Dr,Bldg 50,Rm 3503, Bethesda, MD 20892 USA. EM tjandran@nhlbi.nih.gov FU Intramural Research Program of the National Institutes of Health, NHLBI FX This work was supported by the Intramural Research Program of the National Institutes of Health, NHLBI. NR 36 TC 14 Z9 14 U1 1 U2 10 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 NOV 21 PY 2014 VL 289 IS 47 DI 10.1074/jbc.M114.593897 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU0SO UT WOS:000345335000040 PM 25315775 ER PT J AU Ginsburg, DS Anlembom, TE Wang, JN Patel, SR Li, B Hinnebusch, AG AF Ginsburg, Daniel S. Anlembom, Timi Elvuchio Wang, Jianing Patel, Sanket R. Li, Bing Hinnebusch, Alan G. TI NuA4 Links Methylation of Histone H3 Lysines 4 and 36 to Acetylation of Histones H4 and H3 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSCRIPTIONAL ACTIVATOR GCN4P; POL II CTD; SACCHAROMYCES-CEREVISIAE; SAGA COMPLEX; GENOME-WIDE; H2B MONOUBIQUITINATION; CRYPTIC TRANSCRIPTION; DEACETYLASE COMPLEX; CODING REGIONS; GENE DELETION AB Cotranscriptional methylation of histone H3 lysines 4 and 36 by Set1 and Set2, respectively, stimulates interaction between nucleosomes and histone deacetylase complexes to block cryptic transcription in budding yeast. We previously showed that loss of all H3K4 and H3K36 methylation in a set1 Delta set2 Delta mutant reduces interaction between native nucleosomes and the NuA4 lysine acetyltransferase (KAT) complex. We now provide evidence that NuA4 preferentially binds H3 tails mono- and dimethylated on H3K4 and di- and trimethylated on H3K36, an H3 methylation pattern distinct from that recognized by the RPD3C(S) and Hos2/Set3 histone deacetylase complexes (HDACs). Loss of H3K4 or H3K36 methylation in set1 Delta or set2 Delta mutants reduces NuA4 interaction with bulk nucleosomes in vitro and in vivo, and reduces NuA4 occupancy of transcribed coding sequences at particular genes. We also provide evidence that NuA4 acetylation of lysine residues in the histone H4 tail stimulates SAGA interaction with nucleosomes and its recruitment to coding sequences and attendant acetylation of histone H3 in vivo. Thus, H3 methylation exerts opposing effects of enhancing nucleosome acetylation by both NuA4 and SAGA as well as stimulating nucleosome deacetylation by multiple HDACs to maintain the proper level of histone acetylation in transcribed coding sequences. C1 [Ginsburg, Daniel S.; Anlembom, Timi Elvuchio; Wang, Jianing; Patel, Sanket R.] LIU Post, Dept Biomed Sci, Brookville, NY 11548 USA. [Li, Bing] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA. [Hinnebusch, Alan G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Ginsburg, DS (reprint author), Dept Biomed Sci, 720 Northern Blvd, Brookville, NY 11548 USA. EM daniel.ginsburg@liu.edu FU National Institutes of Health Intramural Research Program; LIU Post Campus Faculty Research Committee; National Institutes of Health [R01GM090077]; Welch Foundation [I-1713] FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program and the LIU Post Campus Faculty Research Committee.; W.A. "Tex" Moncrief, Jr. Scholar in Medical Research and supported by National Institutes of Health Grant R01GM090077 and Welch Foundation Grant I-1713. NR 54 TC 9 Z9 9 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 NOV 21 PY 2014 VL 289 IS 47 DI 10.1074/jbc.M114.585588 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU0SO UT WOS:000345335000023 PM 25301943 ER PT J AU Miyazaki, T Kim, YS Yoon, J Wang, H Suzuki, T Morse, HC AF Miyazaki, Takuya Kim, Yong-Soo Yoon, Jeongheon Wang, Hongsheng Suzuki, Teruhiko Morse, Herbert C., III TI The 3 '-5 ' DNA Exonuclease TREX1 Directly Interacts with Poly(ADP-ribose) Polymerase-1 (PARP1) during the DNA Damage Response SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FAMILIAL CHILBLAIN LUPUS; AICARDI-GOUTIERES-SYNDROME; MEDIATED CELL-DEATH; GENE; GRANZYME; PROTEIN; ACTIVATION; MUTATIONS; SET; ERYTHEMATOSUS AB The main function of the 3'-5' DNA exonuclease TREX1 is to digest cytosolic single-stranded DNA to prevent activation of cell-intrinsic responses to immunostimulatory DNA. TREX1 translocates to the nucleus following DNA damage with its nuclear activities being less well defined. Although mutations in human TREX1 have been linked to autoimmune/inflammatory diseases, the mechanisms contributing to the pathogenesis of these diseases remain incompletely understood. Here, using mass spectrometry and co-immunoprecipitation assays and in vivo overexpression models, we show that TREX1 interacts with poly(ADP-ribose) polymerase-1 (PARP1), a nuclear enzyme involved in the DNA damage response. Two zinc finger domains at the amino terminus of PARP1 were required for the interaction with TREX1 that occurs after nuclear translocation of TREX1 in response to DNA damage. Functional studies suggested that TREX1 may contribute to stabilization of PARP1 levels in the DNA damage response and its activity. These results provide new insights into the mechanisms of single-stranded DNA repair following DNA damage and alterations induced by gene mutations. C1 [Miyazaki, Takuya; Kim, Yong-Soo; Yoon, Jeongheon; Wang, Hongsheng; Morse, Herbert C., III] NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Suzuki, Teruhiko] Tokyo Metropolitan Inst Med Sci, Stem Cell Project Grp, Tokyo 1568506, Japan. RP Morse, HC (reprint author), NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, 5640 Fishers Lane, Rockville, MD 20852 USA. EM hmorse@niaid.nih.gov OI Morse, Herbert/0000-0002-9331-3705 FU National Institutes of Health Intramural Research Program of the NIAID FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of the NIAID. NR 39 TC 5 Z9 5 U1 1 U2 8 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 NOV 21 PY 2014 VL 289 IS 47 DI 10.1074/jbc.M114.547331 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU0SO UT WOS:000345335000014 PM 25278026 ER PT J AU Prustel, T Meier-Schellersheim, M AF Pruestel, Thorsten Meier-Schellersheim, Martin TI Rate coefficients, binding probabilities, and related quantities for area reactivity models SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID DIFFUSION-INFLUENCED REACTION AB We further develop the general theory of the area reactivity model that describes the diffusion-influenced reaction of an isolated receptor-ligand pair in terms of a generalized Feynman-Kac equation and that provides an alternative to the classical contact reactivity model. Analyzing both the irreversible and reversible reaction, we derive the equation of motion of the survival probability as well as several relationships between single pair quantities and the reactive flux at the encounter distance. Building on these relationships, we derive the equation of motion of the many-particle survival probability for irreversible pseudo-first-order reactions. Moreover, we show that the usual definition of the rate coefficient as the reactive flux is deficient in the area reactivity model. Numerical tests for our findings are provided through Brownian Dynamics simulations. We calculate exact and approximate expressions for the irreversible rate coefficient and show that this quantity behaves differently from its classical counterpart. Furthermore, we derive approximate expressions for the binding probability as well as the average lifetime of the bound state and discuss on-and off-rates in this context. Throughout our approach, we point out similarities and differences between the area reactivity model and its classical counterpart, the contact reactivity model. The presented analysis and obtained results provide a theoretical framework that will facilitate the comparison of experiment and model predictions. C1 [Pruestel, Thorsten; Meier-Schellersheim, Martin] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. RP Prustel, T (reprint author), NIAID, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM prustelt@niaid.nih.gov; mms@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases. NR 22 TC 2 Z9 2 U1 0 U2 5 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD NOV 21 PY 2014 VL 141 IS 19 AR 194115 DI 10.1063/1.4901115 PG 14 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA AU3LM UT WOS:000345514700015 PM 25416882 ER PT J AU Nyenswah, T Fahnbulleh, M Massaquoi, M Nagbe, T Bawo, L Falla, JD Kohar, H Gasasira, A Nabeth, P Yett, S Gergonne, B Casey, S Espinosa, B McCoy, A Feldman, H Hensley, L Baily, M Fields, B Lo, T Lindblade, K Mott, J Boulanger, L Christie, A Wang, SS Montgomery, J Mahoney, F AF Nyenswah, Tolbert Fahnbulleh, Miatta Massaquoi, Moses Nagbe, Thomas Bawo, Luke Falla, James Dorbor Kohar, Henry Gasasira, Alex Nabeth, Pierre Yett, Sheldon Gergonne, Bernadette Casey, Sean Espinosa, Benjamin McCoy, Andrea Feldman, Heinz Hensley, Lisa Baily, Mark Fields, Barry Lo, Terrence Lindblade, Kim Mott, Josh Boulanger, Lucy Christie, Athalia Wang, Susan Montgomery, Joel Mahoney, Frank TI Ebola Epidemic - Liberia, March-October 2014 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID DISEASE OUTBREAK; VIRUS DISEASE C1 [Nyenswah, Tolbert; Fahnbulleh, Miatta; Massaquoi, Moses; Nagbe, Thomas; Bawo, Luke; Falla, James Dorbor; Kohar, Henry] Minist Hlth & Social Welf, Monrovia, Liberia. [Gasasira, Alex; Nabeth, Pierre] World Hlth Org, Geneva, Switzerland. [Yett, Sheldon] United Nations Childrens Fund, New York, NY USA. [Gergonne, Bernadette] Medecins Sans Frontieres, Geneva, Switzerland. [Casey, Sean] Int Med Corps, Los Angeles, CA USA. [Espinosa, Benjamin; McCoy, Andrea] US Navy, Pentagon, AR USA. [Feldman, Heinz; Hensley, Lisa] Natl Inst Hlth, Bethesda, MD USA. [Baily, Mark] US Army Med Res Inst Infect Dis, Ft Detroit, MD USA. [Fields, Barry; Lo, Terrence; Lindblade, Kim; Mott, Josh; Boulanger, Lucy; Christie, Athalia; Wang, Susan; Montgomery, Joel; Mahoney, Frank] CDC, Atlanta, GA 30333 USA. RP Mahoney, F (reprint author), CDC, Atlanta, GA 30333 USA. EM fmahoney@cdc.gov NR 5 TC 15 Z9 16 U1 0 U2 14 PU CENTER DISEASE CONTROL & PREVENTION PI ATLANTA PA MAILSTOP E-90, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD NOV 21 PY 2014 VL 63 IS 46 BP 1082 EP 1086 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AU3LO UT WOS:000345514900009 PM 25412068 ER PT J AU Nyenswah, T Fahnbulleh, M Ketah, F Massaquoi, M Nagbe, T Bawo, L Falla, JD Kohar, H Gasasira, A Nabeth, P Popowitz, H Yett, S Hurum, L Sailly, L Casey, S Espinosa, B Mccoy, A Feldman, H Hensley, L Baily, M Pendarvis, J Fields, B Lo, T Quin, J Aberle-Grasse, J Lindblade, K Mott, J Boulanger, L Christie, A Wang, SS Montgomery, J Mahoney, F AF Nyenswah, Tolbert Fahnbulleh, Miatta Ketah, Francis Massaquoi, Moses Nagbe, Thomas Bawo, Luke Falla, James Dorbor Kohar, Henry Gasasira, Alex Nabeth, Pierre Popowitz, Heather Yett, Sheldon Hurum, Lindis Sailly, Laurence Casey, Sean Espinosa, Benjamin McCoy, Andrea Feldman, Heinz Hensley, Lisa Baily, Mark Pendarvis, Justin Fields, Barry Lo, Terrence Quin, Jin Aberle-Grasse, John Lindblade, Kim Mott, Josh Boulanger, Lucy Christie, Athalia Wang, Susan Montgomery, Joel Mahoney, Frank TI Ebola Epidemic - Liberia, March-October 2014 (vol 63, pg 1082, 2014) SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Correction C1 [Nyenswah, Tolbert; Fahnbulleh, Miatta; Ketah, Francis; Massaquoi, Moses; Nagbe, Thomas; Bawo, Luke; Falla, James Dorbor; Kohar, Henry] Minist Hlth & Social Welf, Monrovia, Liberia. [Gasasira, Alex; Nabeth, Pierre] World Hlth Org, Geneva, Switzerland. [Popowitz, Heather; Yett, Sheldon] United Nations Childrens Fund, New York, NY USA. [Hurum, Lindis; Sailly, Laurence] Medecins Sans Frontieres, Geneva, Switzerland. [Casey, Sean] Int Med Corps, Los Angeles, CA USA. [Espinosa, Benjamin; McCoy, Andrea] US Navy, Pentagon, AR USA. [Feldman, Heinz; Hensley, Lisa] Natl Inst Hlth, Atlanta, GA USA. [Baily, Mark] US Army Med Res Inst Infect Dis, Ft Detroit, MD USA. [Pendarvis, Justin] US Agcy Int Dev, Washington, DC 20523 USA. [Fields, Barry; Lo, Terrence; Quin, Jin; Aberle-Grasse, John; Lindblade, Kim; Mott, Josh; Boulanger, Lucy; Christie, Athalia; Wang, Susan; Montgomery, Joel; Mahoney, Frank] CDC, Atlanta, GA 30333 USA. RP Nyenswah, T (reprint author), Minist Hlth & Social Welf, Monrovia, Liberia. NR 1 TC 2 Z9 2 U1 0 U2 3 PU CENTER DISEASE CONTROL & PREVENTION PI ATLANTA PA MAILSTOP E-90, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD NOV 21 PY 2014 VL 63 IS 46 BP 1094 EP 1094 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AU3LO UT WOS:000345514900012 ER PT J AU Belkaid, Y Segre, JA AF Belkaid, Yasmine Segre, Julia A. TI Dialogue between skin microbiota and immunity SO SCIENCE LA English DT Review ID PROPIONIBACTERIUM-ACNES; STAPHYLOCOCCUS-EPIDERMIDIS; ANTIMICROBIAL PEPTIDES; DENDRITIC CELLS; GUT MICROBIOTA; COLONIZATION RESISTANCE; NONPATHOGENIC BACTERIA; INTESTINAL MICROBIOTA; ATOPIC-DERMATITIS; GENOME SEQUENCE AB Human skin, the body's largest organ, functions as a physical barrier to bar the entry of foreign pathogens, while concomitantly providing a home to myriad commensals. Over a human's life span, keratinized skin cells, immune cells, and microbes all interact to integrate the processes of maintaining skin's physical and immune barrier under homeostatic healthy conditions and also under multiple stresses, such as wounding or infection. In this Review, we explore the intricate interactions of microbes and immune cells on the skin surface and within associated appendages to regulate this orchestrated maturation in the context of both host physiological changes and environmental challenges. C1 [Belkaid, Yasmine] NIAID, Program Barrier Immun & Repair, NIH, Bethesda, MD 20892 USA. [Belkaid, Yasmine] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Segre, Julia A.] NHGRI, Microbial Genom Sect, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. RP Belkaid, Y (reprint author), NIAID, Program Barrier Immun & Repair, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ybelkaid@niaid.nih.gov; jsegre@nhgri.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, and National Human Genome Research Institute, National Institutes of Health. We thank A. Byrd, V. Ridaura, and T. Hand for discussion about the manuscript and help with the preparation of the figures. We apologize to our colleagues tor riot having cited all papers relevant to this expanding field because of space constraints. NR 67 TC 63 Z9 65 U1 13 U2 75 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 NOV 21 PY 2014 VL 346 IS 6212 BP 954 EP 959 DI 10.1126/science.1260144 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU6EL UT WOS:000345696000034 PM 25414304 ER PT J AU Rasmussen, AL Okumura, A Ferris, MT Green, R Feldmann, F Kelly, SM Scott, DP Safronetz, D Haddock, E LaCasse, R Thomas, MJ Sova, P Carter, VS Weiss, JM Miller, DR Shaw, GD Korth, MJ Heise, MT Baric, RS de Villena, FPM Fedlmann, H Katze, MG AF Rasmussen, Angela L. Okumura, Atsushi Ferris, Martin T. Green, Richard Feldmann, Friederike Kelly, Sara M. Scott, Dana P. Safronetz, David Haddock, Elaine LaCasse, Rachel Thomas, Matthew J. Sova, Pavel Carter, Victoria S. Weiss, Jeffrey M. Miller, Darla R. Shaw, Ginger D. Korth, Marcus J. Heise, Mark T. Baric, Ralph S. de Villena, Fernando Pardo-Manuel Fedlmann, Heinz Katze, Michael G. TI Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance SO SCIENCE LA English DT Article ID GUINEA-PIGS; ZAIRE-EBOLAVIRUS; VIRUS-INFECTION; COAGULATION; PATHWAY; MOUSE; MALFORMATIONS; OUTBREAK; CELLS; MICE AB Existing mouse models of lethal Ebola virus infection do not reproduce hallmark symptoms of Ebola hemorrhagic fever, neither delayed blood coagulation and disseminated intravascular coagulation nor death fromshock, thus restricting pathogenesis studies to nonhuman primates. Here we show that mice from the Collaborative Cross panel of recombinant inbred mice exhibit distinct disease phenotypes after mouse-adapted Ebola virus infection. Phenotypes range from complete resistance to lethal disease to severe hemorrhagic fever characterized by prolonged coagulation times and 100% mortality. Inflammatory signaling was associated with vascular permeability and endothelial activation, and resistance to lethal infection arose by induction of lymphocyte differentiation and cellular adhesion, probably mediated by the susceptibility allele Tek. These data indicate that genetic background determines susceptibility to Ebola hemorrhagic fever. C1 [Rasmussen, Angela L.; Okumura, Atsushi; Green, Richard; Kelly, Sara M.; Thomas, Matthew J.; Sova, Pavel; Carter, Victoria S.; Weiss, Jeffrey M.; Korth, Marcus J.; Katze, Michael G.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Ferris, Martin T.; Miller, Darla R.; Shaw, Ginger D.; Heise, Mark T.; de Villena, Fernando Pardo-Manuel] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Feldmann, Friederike; Scott, Dana P.; LaCasse, Rachel] NIAID, Rocky Mt Vet Branch, NIH, Rocky Mt Labs, Hamilton, MT USA. [Okumura, Atsushi; Safronetz, David; Haddock, Elaine; Fedlmann, Heinz] NIAID, Virol Lab, NIH, Rocky Mt Labs, Hamilton, MT USA. [Heise, Mark T.; Baric, Ralph S.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC USA. [Katze, Michael G.] Washington Natl Primate Res Ctr, Seattle, WA USA. RP Katze, MG (reprint author), Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. EM honey@uw.edu RI Okumura, Atsushi/E-8012-2015; OI Okumura, Atsushi/0000-0002-7779-3059; Rasmussen, Angela/0000-0001-9462-3169 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [U54 AI081680, U19 AI109761, U19 AI100625]; Office of the Director, National Institutes of Health [P51 OD010425]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This study was supported in part by awards U54 AI081680, U19 AI109761, and U19 AI100625 from the National Institute of Allergy and Infectious Diseases, National Institutes of Health; P51 OD010425 from the Office of the Director, National Institutes of Health; and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. Microarray data have been deposited with the Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo) (accession number GSE57214), and raw data can be obtained at https://www.ccebola.org/project/Supplemental/begin.view. Mice were developed by the Collaborative Cross Consortium, an international consortium of researchers who designed, planned, and implemented the Collaborative Cross project. Initial animals were provided by the Jackson Laboratory, and CC lines were developed independently at the Oak Ridge National Laboratories in Tennessee, USA; Tel Aviv University, Israel; and Geniad, Ltd., Australia. CC lines are currently produced and distributed at the University of North Carolina, Chapel Hill. A.L.R. designed the study, performed functional analysis of microarray data, and wrote the manuscript; A.O. performed infections, veterinary examinations, and necropsies and assessed phenotype, collected and processed samples, and titrated virus from organs by focus-forming assay; M.T.F., M.T.H., F.P.-M.V., and R.S.B. established systems for designing and breeding CC-RIX mouse populations and utilizing them for virus pathogenesis studies and contributed to strain selection and data analysis; R.G. performed microarray data normalization, batch correction, and differential expression analysis; S.M.K. and J.M.W. performed target preparation and hybridization of microarrays; R.L. coordinated veterinary care for experimental animals; D.P.S. performed histopathological staining and analyzed the histopathology data; F.F., D.S., and E.H. assisted with mouse procedures in high biocontainment; M.J.T. and R.G. performed sequencing and subsequent analysis of viral RNA; A.F. performed functional analysis of microarray data; P.S. quantified viral RNA by quantitative polymerase chain reaction; M.J.K. edited the manuscript; and H.F. and M.G.K. contributed significantly to study design, provided space and infrastructure for the experiments and analysis, assisted in data analysis, and edited the manuscript. NR 27 TC 58 Z9 62 U1 4 U2 79 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 NOV 21 PY 2014 VL 346 IS 6212 BP 987 EP 991 DI 10.1126/science.1259595 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU6EL UT WOS:000345696000042 PM 25359852 ER PT J AU Fowler, BJ Gelfand, BD Kim, Y Kerur, N Tarallo, V Hirano, Y Amarnath, S Fowler, DH Radwan, M Young, MT Pittman, K Kubes, P Agarwal, HK Parang, K Hinton, DR Bastos-Carvalho, A Li, SJ Yasuma, T Mizutani, T Yasuma, R Wright, C Ambati, J AF Fowler, Benjamin J. Gelfand, Bradley D. Kim, Younghee Kerur, Nagaraj Tarallo, Valeria Hirano, Yoshio Amarnath, Shoba Fowler, Daniel H. Radwan, Marta Young, Mark T. Pittman, Keir Kubes, Paul Agarwal, Hitesh K. Parang, Keykavous Hinton, David R. Bastos-Carvalho, Ana Li, Shengjian Yasuma, Tetsuhiro Mizutani, Takeshi Yasuma, Reo Wright, Charles Ambati, Jayakrishna TI Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity SO SCIENCE LA English DT Article ID VERSUS-HOST-DISEASE; P2X(7) RECEPTOR; MACULAR DEGENERATION; INFLAMMASOME ACTIVATION; CASPASE-1 ACTIVATION; NLRP3 INFLAMMASOME; P2X7 RECEPTOR; ATP RELEASE; INTERLEUKIN-18; PATHOGENESIS AB Nucleoside reverse transcriptase inhibitors (NRTIs) are mainstay therapeutics for HIV that block retrovirus replication. Alu (an endogenous retroelement that also requires reverse transcriptase for its life cycle)-derived RNAs activate P2X7 and the NLRP3 inflammasome to cause cell death of the retinal pigment epithelium in geographic atrophy, a type of age-related macular degeneration. We found that NRTIs inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented caspase-1 activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease, and sterile liver inflammation. Our findings suggest that NRTIs are ripe for drug repurposing in P2X7-driven diseases. C1 [Fowler, Benjamin J.; Gelfand, Bradley D.; Kim, Younghee; Kerur, Nagaraj; Tarallo, Valeria; Hirano, Yoshio; Bastos-Carvalho, Ana; Li, Shengjian; Yasuma, Tetsuhiro; Mizutani, Takeshi; Yasuma, Reo; Wright, Charles; Ambati, Jayakrishna] Univ Kentucky, Dept Ophthalmol & Visual Sci, Lexington, KY 40536 USA. [Fowler, Benjamin J.; Ambati, Jayakrishna] Univ Kentucky, Dept Physiol, Lexington, KY 40536 USA. [Gelfand, Bradley D.] Univ Kentucky, Dept Microbiol Immunol & Human Genet, Lexington, KY 40536 USA. [Gelfand, Bradley D.] Univ Kentucky, Dept Biomed Engn, Lexington, KY 40536 USA. [Tarallo, Valeria] CNR, Inst Genet & Biophys, Angiogenesis Lab, I-80125 Naples, Italy. [Amarnath, Shoba; Fowler, Daniel H.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Radwan, Marta; Young, Mark T.] Cardiff Univ, Sch Biosci, Cardiff CF10 3AX, S Glam, Wales. [Pittman, Keir; Kubes, Paul] Univ Calgary, Immunol Res Grp, Calgary, AB T2N 4N1, Canada. [Agarwal, Hitesh K.; Parang, Keykavous] Chapman Univ, Sch Pharm, Irvine, CA 92618 USA. [Hinton, David R.] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA. [Hinton, David R.] Univ So Calif, Keck Sch Med, Dept Ophthalmol, Los Angeles, CA 90033 USA. RP Ambati, J (reprint author), Univ Kentucky, Dept Ophthalmol & Visual Sci, Lexington, KY 40536 USA. EM jamba2@email.uky.edu OI Young, Mark/0000-0002-9615-9002; Tarallo, Valeria/0000-0002-6920-4402 FU NIH [DP1GM114862, R01EY018350, R01EY018836, R01EY020672, R01EY022238, R01EY024068, T32HL091812, UL1RR033173, K99EY024336]; Doris Duke Distinguished Clinical Scientist Award; Burroughs Wellcome Fund Clinical Scientist Award in Translational Research; Ellison Medical Foundation Senior Scholar in Aging Award; Foundation Fighting Blindness Individual Investigator Research Award; Harrington Discovery Institute Scholar-Innovator Award; Dr. E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair; Research to Prevent Blindness departmental unrestricted grant; Programme for Advanced Medical Education - Fundacao Calouste Gulbenkian; Programme for Advanced Medical Education - Fundacao Champalimaud; Programme for Advanced Medical Education - Ministerio da Saude; Programme for Advanced Medical Education - Fundacao para a Ciencia e Tecnologia, Portugal; Bayer Global Ophthalmology Research Award; Alcon Japan Research award; Beckman Initiative for Macular Research; American Heart Association; International Retinal Research Foundation (IRRF); Fight for Sight postdoctoral award; Loris and David Rich Postdoctoral Scholar Award (IRRF); Center for Cancer Research, National Cancer Institute; Biotechnology and Biological Sciences Research Council (BBSRC) grant [BB/J017345/1]; NIH grants [P30EY003040, R01EY001545]; Arnold and Mabel Beckman Foundation; Alberta Innovates Health Solutions Graduate Studentship; BBSRC FX We thank B. K. Ambati, K. Ambati, A. M. Adams, A. M. Rao, and G. S. Rao for discussions; L. Toll, G. R. Pattison R. King, L. Xu, M. McConnell, C. Payne, D. Robertson, G. Botzet, and J. May for technical assistance; G. Dubyak for discussions and providing the HEK293-P2X7 cell line; and the University of Kentucky Viral Core (COBRE) for providing lentivirus-GFP. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. J.A. and B.J.F. are listed as inventors on a patent application for the therapeutic use of NRTIs and chemical derivatives filed by their employer, the University of Kentucky. J.A. is a cofounder of iVeena, Inc., which has licensed the technology described in this work. J.A. was supported by NIH grants (DP1GM114862, R01EY018350, R01EY018836, R01EY020672, R01EY022238, and R01EY024068), Doris Duke Distinguished Clinical Scientist Award, Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, Ellison Medical Foundation Senior Scholar in Aging Award, Foundation Fighting Blindness Individual Investigator Research Award, Harrington Discovery Institute Scholar-Innovator Award, Dr. E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair, and Research to Prevent Blindness departmental unrestricted grant; B. J. F. by NIH T32HL091812 and UL1RR033173; A. B. C. by the Programme for Advanced Medical Education (sponsored by Fundacao Calouste Gulbenkian, Fundacao Champalimaud, Ministerio da Saude and Fundacao para a Ciencia e Tecnologia, Portugal) and Bayer Global Ophthalmology Research Award; Y.H. by Alcon Japan Research award; N.K. by Beckman Initiative for Macular Research and NIH K99EY024336; B. D. G. by American Heart Association and International Retinal Research Foundation (IRRF); T.Y. by Fight for Sight postdoctoral award; and C. W. by The Loris and David Rich Postdoctoral Scholar Award (IRRF). D. H. F and S. A. are supported by the Center for Cancer Research, National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. M. T.Y. and M. R. are supported by Biotechnology and Biological Sciences Research Council (BBSRC) grant BB/J017345/1. D. R. H. is supported by NIH grants P30EY003040 and R01EY001545 and by the Arnold and Mabel Beckman Foundation. K.P. is supported by an Alberta Innovates Health Solutions Graduate Studentship, and M.R. by the BBSRC. me-d4T is available from the University of Kentucky via a Materials Transfer Agreement. NR 40 TC 41 Z9 44 U1 7 U2 23 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 NOV 21 PY 2014 VL 346 IS 6212 BP 1000 EP 1003 DI 10.1126/science.1261754 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU6EL UT WOS:000345696000045 PM 25414314 ER PT J AU Kulkarni, RA Meier, JL AF Kulkarni, Rhushikesh A. Meier, Jordan L. TI Chemical Cryptology of Cancer's Histone Code SO CHEMISTRY & BIOLOGY LA English DT Editorial Material ID B-CELL LYMPHOMA; EZH2; INHIBITION AB Somatic mutations in non-Hodgkin's lymphoma frequently activate EZH2, a protein methyltransferase responsible for H3K27 trimethylation. In this issue of Chemistry and Biology, Bradley and coworkers describe a new set of EZH2 inhibitors amenable to probing the targetable role of H3K27 trimethylation in lymphoma. C1 [Kulkarni, Rhushikesh A.; Meier, Jordan L.] NCI, Chem Biol Lab, Frederick, MD 21702 USA. RP Meier, JL (reprint author), NCI, Chem Biol Lab, Frederick, MD 21702 USA. EM jordan.meier@nih.gov RI Meier, Jordan/N-2608-2014 NR 12 TC 0 Z9 0 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 EI 1879-1301 J9 CHEM BIOL JI Chem. Biol. PD NOV 20 PY 2014 VL 21 IS 11 BP 1419 EP 1421 DI 10.1016/j.chembiol.2014.11.003 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU3IW UT WOS:000345506900001 PM 25457120 ER PT J AU Navarro, G Aguinaga, D Moreno, E Hradsky, J Reddy, PP Cortes, A Mallol, J Casado, V Mikhaylova, M Kreutz, MR Lluis, C Canela, EI McCormick, PJ Ferre, S AF Navarro, Gemma Aguinaga, David Moreno, Estefania Hradsky, Johannes Reddy, Pasham P. Cortes, Antoni Mallol, Josefa Casado, Vicent Mikhaylova, Marina Kreutz, Michael R. Lluis, Carme Canela, Enric I. McCormick, Peter J. Ferre, Sergi TI Intracellular Calcium Levels Determine Differential Modulation of Allosteric Interactions within G Protein-Coupled Receptor Heteromers SO CHEMISTRY & BIOLOGY LA English DT Article ID ADENOSINE A(2A) RECEPTORS; DOPAMINE-D-2 RECEPTORS; D2 DOPAMINE; NEURONS; CELLS; STIMULATION; STRIATUM; ANTIGEN; NCS-1 AB The pharmacological significance of the adenosine A(2A) receptor (A(2A)R)-dopamine D-2 receptor (D2R) heteromer is well established and it is being considered as an important target for the treatment of Parkinson's disease and other neuropsychiatric disorders. However, the physiological factors that control its distinctive biochemical properties are still unknown. We demonstrate that different intracellular Ca2+ levels exert a differential modulation of A(2A)R-D2R heteromer-mediated adenylyl-cyclase and MAPK signaling in striatal cells. This depends on the ability of low and high Ca2+ levels to promote a selective interaction of the heteromer with the neuronal Ca2+-binding proteins NCS-1 and calneuron-1, respectively. These Ca2+-binding proteins differentially modulate allosteric interactions within the A(2A)R-D2R heteromer, which constitutes a unique cellular device that integrates extracellular (adenosine and dopamine) and intracellular (Ca+2) signals to produce a specific functional response. C1 [Navarro, Gemma; Aguinaga, David; Moreno, Estefania; Cortes, Antoni; Mallol, Josefa; Casado, Vicent; Lluis, Carme; Canela, Enric I.; McCormick, Peter J.] Univ Barcelona, Fac Biol, Dept Biochem & Mol Biol, Ctr Invest Biomed Red Enfermedades Neurodegenerat, E-08028 Barcelona, Spain. [Navarro, Gemma; Aguinaga, David; Moreno, Estefania; Cortes, Antoni; Mallol, Josefa; Casado, Vicent; Lluis, Carme; Canela, Enric I.; McCormick, Peter J.] Univ Barcelona, Inst Biomed, E-08028 Barcelona, Spain. [Hradsky, Johannes; Reddy, Pasham P.; Mikhaylova, Marina; Kreutz, Michael R.] Leibniz Inst Neurobiol, Res Grp Neuroplast, D-39118 Magdeburg, Germany. [Mikhaylova, Marina] Univ Utrecht, NL-3584 Utrecht, Netherlands. [McCormick, Peter J.] Univ E Anglia, Sch Pharm, Norwich NR4 7TJ, Norfolk, England. [Ferre, Sergi] NIDA, Integrat Neurobiol Sect, Intramural Res Program, US Dept HHS,NIH, Baltimore, MD 21224 USA. RP Navarro, G (reprint author), Univ Barcelona, Fac Biol, Dept Biochem & Mol Biol, Ctr Invest Biomed Red Enfermedades Neurodegenerat, E-08028 Barcelona, Spain. EM dimartts@hotmail.com; sferre@intra.nida.nih.gov RI Casado, Vicent/K-1660-2014; Canela, Enric I./M-8726-2013; McCormick, Peter/E-7387-2012; OI Canela, Enric I./0000-0003-4992-7440; McCormick, Peter/0000-0002-2225-5181; Ferre, Sergi/0000-0002-1747-1779 FU National Institute on Drug Abuse; Spanish "Ministerio de Ciencia y Tecnologia" [SAF2011-23813]; Government of Catalonia [2009-SGR-12]; CIBERNED [CB06/05/0064]; German Research Foundation [SFB779/TPB8, DFG Kr1879/3-1]; Leibniz Foundation (Pakt f. Forschung); European Molecular Biology Organization Long-Term Fellowship [EMBO ALTF 884-2011]; European Commission [GA-2010-267146]; Marie Curie Actions (Intra-European Fellowship); "Ramon y Cajal" Fellowship FX This work was supported by the intramural funds of the National Institute on Drug Abuse, from the Spanish "Ministerio de Ciencia y Tecnologia" (SAF2011-23813), the Government of Catalonia (2009-SGR-12), CIBERNED (CB06/05/0064), the German Research Foundation (SFB779/TPB8, DFG Kr1879/3-1), the Leibniz Foundation (Pakt f. Forschung), a European Molecular Biology Organization Long-Term Fellowship (to M.M., EMBO ALTF 884-2011), the European Commission (EMBOCOFUND2010, GA-2010-267146), a Marie Curie Actions (Intra-European Fellowship), and a "Ramon y Cajal" Fellowship (to P.J.M.). NR 28 TC 9 Z9 10 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 EI 1879-1301 J9 CHEM BIOL JI Chem. Biol. PD NOV 20 PY 2014 VL 21 IS 11 BP 1546 EP 1556 DI 10.1016/j.chembiol.2014.10.004 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU3IW UT WOS:000345506900015 PM 25457181 ER PT J AU Zhu, YZ Wu, Y Luo, Y Zou, Y Ma, BY Zhang, QW AF Zhu, Yuzhen Wu, Ying Luo, Yin Zou, Yu Ma, Buyong Zhang, Qingwen TI R102Q Mutation Shifts the Salt-Bridge Network and Reduces the Structural Flexibility of Human Neuronal Calcium Sensor-1 Protein SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID EF-HAND MOTIFS; DOPAMINE-RECEPTOR; WATER MODELS; BINDING; STABILITY; RECOGNITION; MEMORY; NCS-1; ROLES; MYRISTOYLATION AB Neuronal calcium sensor-1 (NCS-1) protein has a variety of different neuronal functions and interacts with multiple binding partners mostly through a large solvent-exposed hydrophobic crevice (HC). A single R102Q mutation in human NCS-1 protein was demonstrated to be associated with autism disease. Solution NMR study reported that this R102Q mutant had long-range chemical shift effects on the HC and the C-terminal tail (L3). To understand the influence of the R102Q mutation on the HC and L3 of NCS-1, we have investigated the conformational dynamics and the structural flexibility of wild type (WT) NCS-1 and its R102Q mutant by conducting extensive all-atom molecular dynamics (MD) simulations. On the basis of six independent 450 ns MD simulations, we have found that the R102Q mutation in NCS-1 protein (1) dramatically reduces the flexibility of loops L2 and L3, (2) facilitates L3 in a more extended state to occupy the hydrophobic crevice to a larger extent, (3) significantly affects the intersegment salt bridges, and (4) changes the subspace of the free energy landscape of NCS-1 protein. Analysis of the salt bridge network in both WT and the R102Q variant demonstrates that the R102Q-mutation-induced salt bridge alternations play a critical role on the reduced flexibility of L2 and L3. These results reveal the important role of salt bridges on the structural properties of NCS-1 protein and that R102Q mutation disables the dynamic relocation of C-terminus, which may block the binding of NCS-1 protein to its receptors. This study may provide structural insights into the autistic spectrum disorder associated with R102Q mutation. C1 [Zhu, Yuzhen; Wu, Ying; Zou, Yu; Zhang, Qingwen] Shanghai Univ Sport, Coll Phys Educ & Training, Shanghai 200438, Peoples R China. [Luo, Yin] Fudan Univ, Dept Phys, Shanghai 200433, Peoples R China. [Ma, Buyong] NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. RP Zhang, QW (reprint author), Shanghai Univ Sport, Coll Phys Educ & Training, 399 Chang Hai Rd, Shanghai 200438, Peoples R China. EM zqw@sus.edu.cn RI Ma, Buyong/F-9491-2011; OI Ma, Buyong/0000-0002-7383-719X; Zhang, Qingwen/0000-0002-8885-1066 FU NCI, NIH [HHSN261200800001E] FX We thank Drs. Guanghong Wei and Cong Guo for helpful discussion. B.M acknowledges the financial support from NCI, NIH, under contract number HHSN261200800001E. NR 59 TC 5 Z9 5 U1 0 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD NOV 20 PY 2014 VL 118 IS 46 BP 13112 EP 13122 DI 10.1021/jp507936a PG 11 WC Chemistry, Physical SC Chemistry GA AU2ST UT WOS:000345468600009 PM 25343687 ER PT J AU Insel, TR Landis, S AF Insel, Thomas R. Landis, Story TI Allison Doupe (1954-2014) OBITUARY SO NATURE LA English DT Biographical-Item C1 [Insel, Thomas R.] NIMH, Bethesda, MD 20892 USA. [Landis, Story] US Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. RP Insel, TR (reprint author), NIMH, Bethesda, MD 20892 USA. EM tinsel@mail.nih.gov; landiss@ninds.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 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 NOV 20 PY 2014 VL 515 IS 7527 BP 344 EP 344 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU7HE UT WOS:000345770600027 PM 25409820 ER PT J AU Yue, F Cheng, Y Breschi, A Vierstra, J Wu, WS Ryba, T Sandstrom, R Ma, ZH Davis, C Pope, BD Shen, Y Pervouchine, DD Djebali, S Thurman, RE Kaul, R Rynes, E Kirilusha, A Marinov, GK Williams, BA Trout, D Amrhein, H Fisher-Aylor, K Antoshechkin, I DeSalvo, G See, LH Fastuca, M Drenkow, J Zaleski, C Dobin, A Prieto, P Lagarde, J Bussotti, G Tanzer, A Denas, O Li, KW Bender, MA Zhang, MH Byron, R Groudine, MT McCleary, D Pham, L Ye, Z Kuan, S Edsall, L Wu, YC Rasmussen, MD Bansal, MS Kellis, M Keller, CA Morrissey, CS Mishra, T Jain, D Dogan, N Harris, RS Cayting, P Kawli, T Boyle, AP Euskirchen, G Kundaje, A Lin, S Lin, Y Jansen, C Malladi, VS Cline, MS Erickson, DT Kirkup, VM Learned, K Sloan, CA Rosenbloom, KR De Sousa, BL Beal, K Pignatelli, M Flicek, P Lian, J Kahveci, T Lee, D Kent, WJ Santos, MR Herrero, J Notredame, C Johnson, A Vong, S Lee, K Bates, D Neri, F Diegel, M Canfield, T Sabo, PJ Wilken, MS Reh, TA Giste, E Shafer, A Kutyavin, T Haugen, E Dunn, D Reynolds, AP Neph, S Humbert, R Hansen, RS De Bruijn, M Selleri, L Rudensky, A Josefowicz, S Samstein, R Eichler, EE Orkin, SH Levasseur, D Papayannopoulou, T Chang, KH Skoultchi, A Gosh, S Disteche, C Treuting, P Wang, Y Weiss, MJ Blobel, GA Cao, X Zhong, S Wang, T Good, PJ Lowdon, RF Adams, LB Zhou, XQ Pazin, MJ Feingold, EA Wold, B Taylor, J Mortazavi, A Weissman, SM Stamatoyannopoulos, JA Snyder, MP Guigo, R Gingeras, TR Gilbert, DM Hardison, RC Beer, MA Ren, B AF Yue, Feng Cheng, Yong Breschi, Alessandra Vierstra, Jeff Wu, Weisheng Ryba, Tyrone Sandstrom, Richard Ma, Zhihai Davis, Carrie Pope, Benjamin D. Shen, Yin Pervouchine, Dmitri D. Djebali, Sarah Thurman, Robert E. Kaul, Rajinder Rynes, Eric Kirilusha, Anthony Marinov, Georgi K. Williams, Brian A. Trout, Diane Amrhein, Henry Fisher-Aylor, Katherine Antoshechkin, Igor DeSalvo, Gilberto See, Lei-Hoon Fastuca, Meagan Drenkow, Jorg Zaleski, Chris Dobin, Alex Prieto, Pablo Lagarde, Julien Bussotti, Giovanni Tanzer, Andrea Denas, Olgert Li, Kanwei Bender, M. A. Zhang, Miaohua Byron, Rachel Groudine, Mark T. McCleary, David Pham, Long Ye, Zhen Kuan, Samantha Edsall, Lee Wu, Yi-Chieh Rasmussen, Matthew D. Bansal, Mukul S. Kellis, Manolis Keller, Cheryl A. Morrissey, Christapher S. Mishra, Tejaswini Jain, Deepti Dogan, Nergiz Harris, Robert S. Cayting, Philip Kawli, Trupti Boyle, Alan P. Euskirchen, Ghia Kundaje, Anshul Lin, Shin Lin, Yiing Jansen, Camden Malladi, Venkat S. Cline, Melissa S. Erickson, Drew T. Kirkup, Vanessa M. Learned, Katrina Sloan, Cricket A. Rosenbloom, Kate R. De Sousa, Beatriz Lacerda Beal, Kathryn Pignatelli, Miguel Flicek, Paul Lian, Jin Kahveci, Tamer Lee, Dongwon Kent, W. James Santos, Miguel Ramalho Herrero, Javier Notredame, Cedric Johnson, Audra Vong, Shinny Lee, Kristen Bates, Daniel Neri, Fidencio Diegel, Morgan Canfield, Theresa Sabo, Peter J. Wilken, Matthew S. Reh, Thomas A. Giste, Erika Shafer, Anthony Kutyavin, Tanya Haugen, Eric Dunn, Douglas Reynolds, Alex P. Neph, Shane Humbert, Richard Hansen, R. Scott De Bruijn, Marella Selleri, Licia Rudensky, Alexander Josefowicz, Steven Samstein, Robert Eichler, Evan E. Orkin, Stuart H. Levasseur, Dana Papayannopoulou, Thalia Chang, Kai-Hsin Skoultchi, Arthur Gosh, Srikanta Disteche, Christine Treuting, Piper Wang, Yanli Weiss, Mitchell J. Blobel, Gerd A. Cao, Xiaoyi Zhong, Sheng Wang, Ting Good, Peter J. Lowdon, Rebecca F. Adams, Leslie B. Zhou, Xiao-Qiao Pazin, Michael J. Feingold, Elise A. Wold, Barbara Taylor, James Mortazavi, Ali Weissman, Sherman M. Stamatoyannopoulos, John A. Snyder, Michael P. Guigo, Roderic Gingeras, Thomas R. Gilbert, David M. Hardison, Ross C. Beer, Michael A. Ren, Bing CA Mouse ENCODE Consortium TI A comparative encyclopedia of DNA elements in the mouse genome SO NATURE LA English DT Article ID TRANSCRIPTION FACTOR-BINDING; EMBRYONIC STEM-CELLS; PERVASIVE TRANSCRIPTION; CHROMATIN INTERACTIONS; EVOLUTIONARY DYNAMICS; TRANSPOSABLE ELEMENTS; ENCODE DATA; LANDSCAPE; GENE; EXPRESSION AB The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases. C1 [Yue, Feng; Shen, Yin; McCleary, David; Pham, Long; Ye, Zhen; Kuan, Samantha; Edsall, Lee; Ren, Bing] Ludwig Inst Canc Res, La Jolla, CA 92093 USA. [Yue, Feng; Shen, Yin; McCleary, David; Pham, Long; Ye, Zhen; Kuan, Samantha; Edsall, Lee; Ren, Bing] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. [Yue, Feng] Penn State Univ, Coll Med, Dept Biochem & Mol Biol, Hershey, PA 17033 USA. [Cheng, Yong; Ma, Zhihai; Cayting, Philip; Kawli, Trupti; Boyle, Alan P.; Euskirchen, Ghia; Kundaje, Anshul; Lin, Shin; Lin, Yiing; Malladi, Venkat S.; Erickson, Drew T.; Sloan, Cricket A.; Snyder, Michael P.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Breschi, Alessandra; Pervouchine, Dmitri D.; Djebali, Sarah; Prieto, Pablo; Lagarde, Julien; Bussotti, Giovanni; Tanzer, Andrea; Notredame, Cedric; Guigo, Roderic] Ctr Genom Regulat, Barcelona 08003, Catalonia, Spain. [Breschi, Alessandra; Pervouchine, Dmitri D.; Djebali, Sarah; Prieto, Pablo; Lagarde, Julien; Bussotti, Giovanni; Tanzer, Andrea; Notredame, Cedric; Guigo, Roderic] UPF, Barcelona 08003, Catalonia, Spain. [Vierstra, Jeff; Sandstrom, Richard; Thurman, Robert E.; Kaul, Rajinder; Rynes, Eric; Johnson, Audra; Vong, Shinny; Lee, Kristen; Bates, Daniel; Neri, Fidencio; Diegel, Morgan; Canfield, Theresa; Sabo, Peter J.; Giste, Erika; Shafer, Anthony; Kutyavin, Tanya; Haugen, Eric; Dunn, Douglas; Reynolds, Alex P.; Neph, Shane; Humbert, Richard; Hansen, R. Scott; Eichler, Evan E.; Stamatoyannopoulos, John A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Wu, Weisheng; Keller, Cheryl A.; Morrissey, Christapher S.; Mishra, Tejaswini; Jain, Deepti; Dogan, Nergiz; Harris, Robert S.; Hardison, Ross C.] Penn State Univ, Huck Inst,Life Sci, Ctr Comparat Genom & Bioinformat, University Pk, PA 16802 USA. [Ryba, Tyrone; Pope, Benjamin D.; Gilbert, David M.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. [Davis, Carrie; See, Lei-Hoon; Fastuca, Meagan; Drenkow, Jorg; Zaleski, Chris; Dobin, Alex; Gingeras, Thomas R.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Kirilusha, Anthony; Marinov, Georgi K.; Williams, Brian A.; Trout, Diane; Amrhein, Henry; Fisher-Aylor, Katherine; Antoshechkin, Igor; DeSalvo, Gilberto; Wold, Barbara] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Tanzer, Andrea] Univ Vienna, Fac Chem, Dept Theoret Chem, A-1090 Vienna, Austria. [Denas, Olgert; Li, Kanwei; Taylor, James] Emory Univ, O Wayne Rollins Res Ctr, Dept Biol, Atlanta, GA 30322 USA. [Denas, Olgert; Li, Kanwei; Taylor, James] Emory Univ, O Wayne Rollins Res Ctr, Dept Math & Comp Sci, Atlanta, GA 30322 USA. [Bender, M. A.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Bender, M. A.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Zhang, Miaohua; Byron, Rachel; Groudine, Mark T.] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. [Groudine, Mark T.] Univ Washington, Dept Radiat Oncol, Seattle, WA 98195 USA. [Wu, Yi-Chieh; Rasmussen, Matthew D.; Bansal, Mukul S.; Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Kellis, Manolis] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Jansen, Camden; Mortazavi, Ali] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92697 USA. [Cline, Melissa S.; Kirkup, Vanessa M.; Learned, Katrina; Rosenbloom, Kate R.; Kent, W. James] Univ Calif Santa Cruz, Sch Engn, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [De Sousa, Beatriz Lacerda; Santos, Miguel Ramalho] Univ Calif San Francisco, Dept Obstet Gynecol, San Francisco, CA 94143 USA. [De Sousa, Beatriz Lacerda; Santos, Miguel Ramalho] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [De Sousa, Beatriz Lacerda; Santos, Miguel Ramalho] Univ Calif San Francisco, Ctr Reprod Sci, San Francisco, CA 94143 USA. [Beal, Kathryn; Pignatelli, Miguel; Flicek, Paul; Herrero, Javier; Levasseur, Dana] European Bioinformat Inst, European Mol Biol Lab, Cambridge CB10 1SD, England. [Lian, Jin; Weissman, Sherman M.] Yale Univ, Dept Genet, New Haven, CT 06520 USA. [Kahveci, Tamer] Univ Florida, Gainesville, FL 32611 USA. [Lee, Dongwon; Beer, Michael A.] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Lee, Dongwon; Beer, Michael A.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21205 USA. [Herrero, Javier] UCL, UCL Canc Inst, Bill Lyons Informat Ctr, London WC1E 6DD, England. [Wilken, Matthew S.; Reh, Thomas A.; Wang, Yanli] Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. [De Bruijn, Marella] Univ Oxford, MRC Mol Haemotol Unit, Oxford OX3 9DS, England. [Selleri, Licia] Weill Cornell Med Coll, Dept Cell & Dev Biol, New York, NY 10065 USA. [Rudensky, Alexander; Josefowicz, Steven; Samstein, Robert] Mem Sloan Kettering Canc Ctr, Program Immunol, HHMI & Ludwig Ctr, New York, NY 10065 USA. [Orkin, Stuart H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Cambridge, MA 02138 USA. [Levasseur, Dana] Univ Iowa, Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. [Papayannopoulou, Thalia; Chang, Kai-Hsin] Univ Washington, Dept Med, Div Hematol, Seattle, WA 98195 USA. [Skoultchi, Arthur; Gosh, Srikanta] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. [Disteche, Christine] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Treuting, Piper] Univ Washington, Dept Comparat Med, Seattle, WA 98195 USA. [Wang, Yanli] Penn State Univ, Bioinformat & Genom Program, University Pk, PA 16802 USA. [Weiss, Mitchell J.] St Jude Childrens Res Hosp, Dept Hematol, Memphis, TN 38105 USA. [Blobel, Gerd A.] Childrens Hosp Philadelphia, Div Hematol, Philadelphia, PA 19104 USA. [Blobel, Gerd A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Cao, Xiaoyi; Zhong, Sheng] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Wang, Ting] Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, Dept Genet, St Louis, MO 63108 USA. [Good, Peter J.; Lowdon, Rebecca F.; Adams, Leslie B.; Zhou, Xiao-Qiao; Pazin, Michael J.; Feingold, Elise A.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Ren, B (reprint author), Ludwig Inst Canc Res, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM jstam@u.washington.edu; mpsnyder@stanford.edu; roderic.guigo@crg.cat; gingeras@cshl.edu; gilbert@bio.fsu.edu; ross@bx.psu.edu; mbeer@jhu.edu; biren@ucsd.edu RI Taylor, James/F-1026-2011; Ma, Zhihai/E-7130-2015; Prieto Barja, Pablo/H-2035-2015; Cao, Xiaoyi/D-4646-2017; Djebali, Sarah/O-9817-2014; cheng, yong/I-4270-2012; Pervouchine, Dmitri/H-5252-2015; Guigo, Roderic/D-1303-2010; Kumar, Swathi/I-7941-2015; Tanzer, Andrea/L-3147-2015; Fisher, Andrew/A-1113-2016; Boyle, Alan/I-1848-2014; Notredame, Cedric/G-3868-2010 OI Pazin, Michael/0000-0002-7561-3640; Samstein, Robert/0000-0001-6860-2401; Edsall, Lee Elizabeth/0000-0002-0326-2829; Herrero, Javier/0000-0001-7313-717X; Haugen, Eric/0000-0001-7444-8981; Flicek, Paul/0000-0002-3897-7955; Zhou, Xiao-Qiao/0000-0002-0724-5153; Bussotti, Giovanni/0000-0002-4078-7413; Taylor, James/0000-0001-5079-840X; Prieto Barja, Pablo/0000-0002-1615-3998; Cao, Xiaoyi/0000-0001-7222-5450; Djebali, Sarah/0000-0002-0599-1267; Pervouchine, Dmitri/0000-0003-0543-9760; Guigo, Roderic/0000-0002-5738-4477; Kumar, Swathi/0000-0002-2770-5145; Tanzer, Andrea/0000-0003-2873-4236; Boyle, Alan/0000-0002-2081-1105; Notredame, Cedric/0000-0003-1461-0988 FU National Institutes of Health [R01HG003991, 1U54HG007004, 3RC2HG005602, GM083337, GM085354, F31CA165863, RC2HG005573, R01DK065806]; Spanish Plan Nacional [BIO2011-26205]; ERC [BIO2011-26205, 294653]; National Science Foundation Graduate Research Fellowship [DGE-071824]; Wellcome Trust [095908]; NHGRI [U01HG004695]; [R01HD043997-09]; [F32HL110473]; [K99HL119617] FX This work is funded by grants R01HG003991 (B. R.), 1U54HG007004 (T. R. G.), 3RC2HG005602 (M. P. S.), GM083337 and GM085354 (D. M. G.), F31CA165863 (B. D. P.), RC2HG005573 and R01DK065806 (R. C. H.) from the National Institutes of Health, and BIO2011-26205 from the Spanish Plan Nacional and ERC 294653 (to R. G.). J.V. is supported by a National Science Foundation Graduate Research Fellowship under grant no. DGE-071824. K. B., M. P., J.H. and P. F. acknowledge the Wellcome Trust (grant number 095908), the NHGRI (grant number U01HG004695) and the European Molecular Biology Laboratory. We thank G. Hon for helping the analysis of high-throughput enhancer validation. L. S. is supported by R01HD043997-09. S. L. was supported by grants F32HL110473 and K99HL119617. NR 71 TC 197 Z9 199 U1 10 U2 58 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 NOV 20 PY 2014 VL 515 IS 7527 BP 355 EP + DI 10.1038/nature13992 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU7HE UT WOS:000345770600034 PM 25409824 ER PT J AU Vassilopoulos, A Chisholm, C Lahusen, T Zheng, H Deng, CX AF Vassilopoulos, A. Chisholm, C. Lahusen, T. Zheng, H. Deng, C-X TI A critical role of CD29 and CD49f in mediating metastasis for cancer-initiating cells isolated from a Brca1-associated mouse model of breast cancer SO ONCOGENE LA English DT Article DE CD29; CD49f; CSCs; EMT; cancer metastasis ID EPITHELIAL-MESENCHYMAL TRANSITION; STEM-CELLS; BRCA1; IDENTIFICATION; SUSCEPTIBILITY; EXPRESSION; MECHANISMS; SIGNATURE; MARKERS; REPAIR AB Cancer metastasis is a lethal problem that claims the lives of over 90% of cancer patients. In this study, we have investigated metastatic potential of cancer stem cells (CSCs) isolated from mammary tumors of a Brca1-mutant mouse model. Our data indicated that CSCs, which are enriched in CD24(+)CD29(+)/CD49f(+) cell population, displayed much higher migration ability than CD24(-)CD29(-)/CD49f (-) cells in tissue culture and enhanced metastatic potential in allograft-nude mice. CD24(+)CD29(+) cells maintained the ability to differentiate and reconstitute heterogeneity in the metastatic tumors whereas CD24(-)CD29(-) cells could not. Corresponding to their enhanced metastatic ability, CD24(+)CD29(+) cells exhibited features of the epithelial to mesenchymal transition. Finally, using short hairpin RNA to knock down CD29 and/or CD49f in metastatic cancer cells, we demonstrated that while acute knockdown of CD29 or CD49f alone slightly decreased cell migration ability, knockdown of both genes generated a profound effect to block their migration, revealing an overlapping, yet critical function of both genes in the migration of CSCs. Our findings indicate that in addition to serving as markers of CSCs, CD29 and CD49f may also serve as potential therapeutic targets for cancer metastasis. C1 [Vassilopoulos, A.; Chisholm, C.; Lahusen, T.; Zheng, H.; Deng, C-X] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. EM chuxiad@bdg10.niddk.nih.gov RI deng, chuxia/N-6713-2016 FU Intramural Research Program of the National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health, USA FX We thank members of the Deng lab for critical reading of the manuscript. This work was supported by the Intramural Research Program of the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, USA. NR 47 TC 11 Z9 12 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD NOV 20 PY 2014 VL 33 IS 47 BP 5477 EP 5482 DI 10.1038/onc.2013.516 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AT7MG UT WOS:000345120700010 PM 24317509 ER PT J AU Perez, EA Romond, EH Suman, VJ Jeong, JH Sledge, G Geyer, CE Martino, S Rastogi, P Gralow, J Swain, SM Winer, EP Colon-Otero, G Davidson, NE Mamounas, E Zujewski, JA Wolmark, N AF Perez, Edith A. Romond, Edward H. Suman, Vera J. Jeong, Jong-Hyeon Sledge, George Geyer, Charles E., Jr. Martino, Silvana Rastogi, Priya Gralow, Julie Swain, Sandra M. Winer, Eric P. Colon-Otero, Gerardo Davidson, Nancy E. Mamounas, Eleftherios Zujewski, Jo Anne Wolmark, Norman TI Trastuzumab Plus Adjuvant Chemotherapy for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Planned Joint Analysis of Overall Survival From NSABP B-31 and NCCTG N9831 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID FOLLOW-UP; TRIAL; DOXORUBICIN; PACLITAXEL AB Purpose Positive interim analysis findings from four large adjuvant trials evaluating trastuzumab in patients with early-stage human epidermal growth factor receptor 2 (HER2) -positive breast cancer were first reported in 2005. One of these reports, the joint analysis of North Central Cancer Treatment Group NCCTG N9831 (Combination Chemotherapy With or Without Trastuzumab in Treating Women With HER2-Overexpressing Breast Cancer) and the National Surgical Adjuvant Breast and Bowel Project NSABP B-31 (Doxorubicin and Cyclophosphamide Plus Paclitaxel With or Without Trastuzumab in Treating Women With Node-Positive Breast Cancer That Overexpresses HER2), was updated in 2011. We now report the planned definitive overall survival (OS) results from this joint analysis along with updates on the disease-free survival (DFS) end point. Methods In all, 4,046 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials. The required number of events for the definitive statistical analysis for OS (710 events) was reached in September 2012. Updated analyses of overall DFS and related subgroups were also performed. Results Median time on study was 8.4 years. Adding trastuzumab to chemotherapy led to a 37% relative improvement in OS (hazard ratio [HR], 0.63; 95% CI, 0.54 to 0.73; P < .001) and an increase in 10-year OS rate from 75.2% to 84%. These results were accompanied by an improvement in DFS of 40% (HR, 0.60; 95% CI, 0.53 to 0.68; P < .001) and increase in 10-year DFS rate from 62.2% to 73.7%. All patient subgroups benefited from addition of this targeted anti-HER2 agent. Conclusion The addition of trastuzumab to paclitaxel after doxorubicin and cyclophosphamide in early-stage HER2-positive breast cancer results in a substantial and durable improvement in survival as a result of a sustained marked reduction in cancer recurrence. (C) 2014 by American Society of Clinical Oncology C1 [Perez, Edith A.; Colon-Otero, Gerardo] Mayo Clin, Jacksonville, FL 32224 USA. [Mamounas, Eleftherios] Univ Florida, Hlth Canc Ctr Orlando Hlth, Orlando, FL USA. [Romond, Edward H.] Univ Kentucky, Lexington, KY USA. [Suman, Vera J.] Mayo Clin, Rochester, MN USA. [Jeong, Jong-Hyeon; Rastogi, Priya] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Davidson, Nancy E.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15260 USA. [Wolmark, Norman] Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. [Sledge, George] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Martino, Silvana] Angeles Clin & Res Inst, Santa Monica, CA USA. [Geyer, Charles E., Jr.] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA. [Gralow, Julie] Univ Washington, Seattle Canc Care Alliance, Seattle, WA USA. [Swain, Sandra M.] MedStar Washington Hosp Ctr, Washington, DC USA. [Winer, Eric P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Zujewski, Jo Anne] NIH, Rockville, MD USA. RP Perez, EA (reprint author), Mayo Clin, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM perez.edith@mayo.edu OI Jeong, Jong/0000-0003-0596-2201; Swain, Sandra/0000-0002-1320-3830 FU National Institutes of Health [U10-CA25224, CA129949]; National Surgical Adjuvant Breast and Bowel Project [U10-CA12027, U10-CA69651, U10-CA37377, U10-CA69974]; Breast Cancer Research Foundation; Genentech [35-03]; Cancer and Leukemia Group B FX Supported by Grants No. U10-CA25224 and CA129949 from the National Institutes of Health; Grants No. U10-CA12027, U10-CA69651, U10-CA37377, and U10-CA69974 from the National Surgical Adjuvant Breast and Bowel Project; by the Breast Cancer Research Foundation; and by Grant No. 35-03 from Genentech. P.A.K. received research funding from Cancer and Leukemia Group B. NR 11 TC 118 Z9 125 U1 1 U2 9 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 20 PY 2014 VL 32 IS 33 BP 3744 EP + DI 10.1200/JCO.2014.55.5730 PG 10 WC Oncology SC Oncology GA AT3US UT WOS:000344861400010 PM 25332249 ER PT J AU Lin, YJ Chang, JS Liu, X Tsang, HY Lin, TH Liao, CC Huang, SM Chien, WK Chen, JH Wu, JY Chen, CH Chang, LC Lin, CW Ho, TJ Tsai, FJ AF Lin, Ying-Ju Chang, Jeng-Sheng Liu, Xiang Tsang, Hsinyi Lin, Ting-Hsu Liao, Chiu-Chu Huang, Shao-Mei Chien, Wen-Kuei Chen, Jin-Hua Wu, Jer-Yuarn Chen, Chien-Hsiun Chang, Li-Ching Lin, Cheng-Wen Ho, Tsung-Jung Tsai, Fuu-Jen TI Genetic variants of glutamate receptor gene family in Taiwanese Kawasaki disease children with coronary artery aneurysms SO CELL AND BIOSCIENCE LA English DT Article DE KD; GRIK1; Single nucleotide polymorphism; CAA ID GENOME-WIDE ASSOCIATION; JUVENILE ABSENCE EPILEPSY; SUSCEPTIBILITY LOCI; GRIK1 POLYMORPHISM; HEAVY DRINKERS; HAN CHINESE; ACTIVATION; AUTOANTIBODIES; SCHIZOPHRENIA; TOPIRAMATE AB Background: Patients with Kawasaki disease (KD), a pediatric systemic vasculitis, may develop coronary artery aneurysm (CAA) as a complication. To investigate the role of glutamate receptors in KD and its CAA development, we performed genetic association studies. Methods and results: We examined the whole family of glutamate receptors by genetic association studies in a Taiwanese cohort of 262 KD patients. We identified glutamate receptor ionotropic, kainate 1 (GRIK1) as a novel susceptibility locus associated with CAA formation in KD. Statistically significant differences were noted for factors like fever duration, 1st Intravenous immunoglobulin (IVIG) used time (number of days after the first day of fever) and the GRIK1 (rs466013, rs425507, and rs38700) genetic variants. This significant association persisted even after using multivariate regression analysis (Full model: for rs466013: odds ratio = 2.12; 95% CI = 1.22-3.65; for rs425507: odds ratio = 2.16; 95% CI = 1.26-3.76; for rs388700: odds ratio = 2.16; 95% CI = 1.26-3.76). Conclusions: We demonstrated that GRIK1 polymorphisms are associated CAA formation in KD, even when adjusted for fever duration and IVIG used time, and may also serve as a genetic marker for the CAA formation in KD. C1 [Lin, Ying-Ju; Lin, Ting-Hsu; Liao, Chiu-Chu; Huang, Shao-Mei; Tsai, Fuu-Jen] China Med Univ Hosp, Dept Med Res, Taichung, Taiwan. [Lin, Ying-Ju; Wu, Jer-Yuarn; Chen, Chien-Hsiun; Ho, Tsung-Jung; Tsai, Fuu-Jen] China Med Univ, Sch Chinese Med, Taichung, Taiwan. [Chang, Jeng-Sheng] China Med Univ Hosp, Dept Pediat, Taichung, Taiwan. [Liu, Xiang; Tsang, Hsinyi] NIAID, NIH, Bethesda, MD 20892 USA. [Chien, Wen-Kuei; Chen, Jin-Hua] China Med Univ, Ctr Biostat, Taichung, Taiwan. [Chien, Wen-Kuei; Chen, Jin-Hua] Taipei Med Univ, Ctr Biostat, Taipei, Taiwan. [Chien, Wen-Kuei; Chen, Jin-Hua] Taipei Med Univ, Sch Publ Hlth, Taipei, Taiwan. [Wu, Jer-Yuarn; Chen, Chien-Hsiun; Chang, Li-Ching] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Lin, Cheng-Wen] China Med Univ, Dept Med Lab Sci & Biotechnol, Taichung, Taiwan. [Ho, Tsung-Jung] China Med Univ, Beigang Hosp, Div Chinese Med, Taichung, Yunlin County, Taiwan. [Ho, Tsung-Jung] China Med Univ, Tainan Municipal An Nan Hosp, Div Chinese Med, Tainan, Taiwan. [Tsai, Fuu-Jen] Asia Univ, Taichung, Taiwan. RP Tsai, FJ (reprint author), China Med Univ Hosp, Dept Med Res, Taichung, Taiwan. EM d0704@mail.cmuh.org.tw RI Liu, Xiang/F-5731-2014; Tsai, Fuu-Jen/J-4140-2015 FU CMU [CMU100-S-01]; CMUH [DMR-103-039]; Republic of China National Science Council [NSC100-2320-B-039-012-MY3] FX Financial support for this research was provided by CMU (CMU100-S-01), CMUH (DMR-103-039), and the Republic of China National Science Council (NSC100-2320-B-039-012-MY3). NR 53 TC 0 Z9 0 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD NOV 19 PY 2014 VL 4 AR 67 DI 10.1186/2045-3701-4-67 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AX2YU UT WOS:000346809000001 PM 25485088 ER PT J AU Cai, YY Yu, SQ Postnikova, EN Mazur, S Bernbaum, JG Burk, R Zhang, TF Radoshitzky, SR Muller, MA Jordan, I Bollinger, L Hensley, LE Jahrling, PB Kuhn, JH AF Cai, Yingyun Yu, Shulqing Postnikova, Elena N. Mazur, Steven Bernbaum, John G. Burk, Robin Zhang, Tengfei Radoshitzky, Sheli R. Mueller, Marcel A. Jordan, Ingo Bollinger, Laura Hensley, Lisa E. Jahrling, Peter B. Kuhn, Jens H. TI CD26/DPP4 Cell-Surface Expression in Bat Cells Correlates with Bat Cell Susceptibility to Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Infection and Evolution of Persistent Infection SO PLOS ONE LA English DT Article ID TO-HUMAN TRANSMISSION; DROMEDARY CAMELS; SAUDI-ARABIA; VIRUS; EMERGENCE; RECEPTOR; USAGE AB Middle East respiratory syndrome coronavirus (MERS-CoV) is a recently isolated betacoronavirus identified as the etiologic agent of a frequently fatal disease in Western Asia, Middle East respiratory syndrome. Attempts to identify the natural reservoirs of MERS-CoV have focused in part on dromedaries. Bats are also suspected to be reservoirs based on frequent detection of other betacoronaviruses in these mammals. For this study, ten distinct cell lines derived from bats of divergent species were exposed to MERS-CoV. Plaque assays, immunofluorescence assays, and transmission electron microscopy confirmed that six bat cell lines can be productively infected. We found that the susceptibility or resistance of these bat cell lines directly correlates with the presence or absence of cell surface-expressed CD26/DPP4, the functional human receptor for MERS-CoV. Human anti-CD26/DPP4 antibodies inhibited infection of susceptible bat cells in a dose-dependent manner. Overexpression of human CD26/DPP4 receptor conferred MERS-CoV susceptibility to resistant bat cell lines. Finally, sequential passage of MERS-CoV in permissive bat cells established persistent infection with concomitant downregulation of CD26/DPP4 surface expression. Together, these results imply that bats indeed could be among the MERS-CoV host spectrum, and that cellular restriction of MERS-CoV is determined by CD26/DPP4 expression rather than by downstream restriction factors. C1 [Cai, Yingyun; Yu, Shulqing; Postnikova, Elena N.; Mazur, Steven; Bernbaum, John G.; Burk, Robin; Zhang, Tengfei; Bollinger, Laura; Hensley, Lisa E.; Jahrling, Peter B.; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 21702 USA. [Radoshitzky, Sheli R.] US Army Med Res Inst, Frederick, MD USA. [Mueller, Marcel A.] Univ Bonn, Med Ctr, Inst Virol, Bonn, Germany. [Jordan, Ingo] ProBioGen AG, Berlin, Germany. RP Kuhn, JH (reprint author), NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 21702 USA. EM kuhnjens@mail.nih.gov RI Kuhn, Jens H./B-7615-2011; OI Kuhn, Jens H./0000-0002-7800-6045; Jordan, Ingo/0000-0003-2711-7252; Mueller, Marcel/0000-0003-2242-5117 FU US Department of Health and Human Services [HHSN272200700016I]; Hartmut Hoffmann-Berling International Graduate School of Molecular & Cellular Biology (HBIGS), Heidelberg, Germany FX YC, SY, ENP, SM, RB, TZ, LB, and JHK performed this work for the US Department of Health and Human Services under contract number HHSN272200700016I (Battelle Memorial Institute). RB was supported by the Hartmut Hoffmann-Berling International Graduate School of Molecular & Cellular Biology (HBIGS), Heidelberg, Germany. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 4 Z9 5 U1 0 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 NOV 19 PY 2014 VL 9 IS 11 AR e112060 DI 10.1371/journal.pone.0112060 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU3SG UT WOS:000345533200012 PM 25409519 ER PT J AU Khan, I Suhasini, AN Banerjee, T Sommers, JA Kaplan, DL Kuper, J Kisker, C Brosh, RM AF Khan, Irfan Suhasini, Avvaru N. Banerjee, Taraswi Sommers, Joshua A. Kaplan, Daniel L. Kuper, Jochen Kisker, Caroline Brosh, Robert M., Jr. TI Impact of Age-Associated Cyclopurine Lesions on DNA Repair Helicases SO PLOS ONE LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; WARSAW BREAKAGE SYNDROME; XERODERMA-PIGMENTOSUM; ESCHERICHIA-COLI; REPLICATION-FORK; HUMAN-CELLS; BIOCHEMICAL-CHARACTERIZATION; SUBSTRATE-SPECIFICITY; TRANSLESION SYNTHESIS; GENOMIC STABILITY AB 8,5' cyclopurine deoxynucleosides (cPu) are locally distorting DNA base lesions corrected by nucleotide excision repair (NER) and proposed to play a role in neurodegeneration prevalent in genetically defined Xeroderma pigmentosum (XP) patients. In the current study, purified recombinant helicases from different classifications based on sequence homology were examined for their ability to unwind partial duplex DNA substrates harboring a single site-specific cPu adduct. Superfamily (SF) 2 RecQ helicases (RECQ1, BLM, WRN, RecQ) were inhibited by cPu in the helicase translocating strand, whereas helicases from SF1 (UvrD) and SF4 (DnaB) tolerated cPu in either strand. SF2 Fe-S helicases (FANCJ, DDX11 (ChlR1), DinG, XPD) displayed marked differences in their ability to unwind the cPu DNA substrates. Archaeal Thermoplasma acidophilum XPD (taXPD), homologue to the human XPD helicase involved in NER DNA damage verification, was impeded by cPu in the non-translocating strand, while FANCJ was uniquely inhibited by the cPu in the translocating strand. Sequestration experiments demonstrated that FANCJ became trapped by the translocating strand cPu whereas RECQ1 was not, suggesting the two SF2 helicases interact with the cPu lesion by distinct mechanisms despite strand-specific inhibition for both. Using a protein trap to simulate single-turnover conditions, the rate of FANCJ or RECQ1 helicase activity was reduced 10-fold and 4.5-fold, respectively, by cPu in the translocating strand. In contrast, single-turnover rates of DNA unwinding by DDX11 and UvrD helicases were only modestly affected by the cPu lesion in the translocating strand. The marked difference in effect of the translocating strand cPu on rate of DNA unwinding between DDX11 and FANCJ helicase suggests the two Fe-S cluster helicases unwind damaged DNA by distinct mechanisms. The apparent complexity of helicase encounters with an unusual form of oxidative damage is likely to have important consequences in the cellular response to DNA damage and DNA repair. C1 [Khan, Irfan; Suhasini, Avvaru N.; Banerjee, Taraswi; Sommers, Joshua A.; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Kaplan, Daniel L.] Florida State Univ, Coll Med, Dept Biomed Sci, Tallahassee, FL USA. [Kuper, Jochen; Kisker, Caroline] Univ Wurzburg, Inst Biol Struct, Rudolf Virchow Ctr Expt Biomed, D-97070 Wurzburg, Germany. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov OI Kaplan, Daniel/0000-0003-2760-7745 FU Intramural Research program of the National Institutes of Health, National Institute on Aging; Fanconi Anemia Research Fund; Deutsche Forschungsgemeinschaft [Forschungszentrum FZ82, KI-562/2] FX This work was supported by the Intramural Research program of the National Institutes of Health, National Institute on Aging and by the Fanconi Anemia Research Fund (to R. M. B.) and through the Deutsche Forschungsgemeinschaft (Forschungszentrum FZ82 and KI-562/2 to C. K.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 7 Z9 7 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 NOV 19 PY 2014 VL 9 IS 11 AR e113293 DI 10.1371/journal.pone.0113293 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU3SG UT WOS:000345533200092 PM 25409515 ER PT J AU Singh, PK Bourque, G Craig, NL Dubnau, JT Feschotte, C Flasch, DA Gunderson, KL Malik, HS Moran, JV Peters, JE Slotkin, RK Levin, HL AF Singh, Parmit Kumar Bourque, Guillaume Craig, Nancy L. Dubnau, Josh T. Feschotte, Cedric Flasch, Diane A. Gunderson, Kevin L. Malik, Harmit Singh Moran, John V. Peters, Joseph E. Slotkin, R. Keith Levin, Henry L. TI Mobile genetic elements and genome evolution 2014 SO MOBILE DNA LA English DT Editorial Material AB The Mobile Genetic Elements and Genome Evolution conference was hosted by Keystone Symposia in Santa Fe, NM USA, 9 March through 14 March 2014. The goal of this conference was to bring together scientists from around the world who study transposable elements in diverse organisms and researchers who study the impact these elements have on genome evolution. The meeting included over 200 scientists who participated through poster presentations, short talks selected from abstracts, and invited speakers. The talks were organized into eight sessions and two workshops. The topics varied from diverse mechanisms of mobilization to the evolution of genomes and their defense strategies against transposable elements. C1 [Singh, Parmit Kumar; Levin, Henry L.] Natl Inst Hlth, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Bourque, Guillaume] McGill Univ, Montreal, PQ, Canada. [Bourque, Guillaume] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Craig, Nancy L.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Craig, Nancy L.; Malik, Harmit Singh; Moran, John V.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Dubnau, Josh T.] Cold Spring Harbor Lab, Cold Spring on Hudson, NY USA. [Feschotte, Cedric] Univ Utah, Sch Med, Dept Human Genet, Salt Lake City, UT USA. [Flasch, Diane A.; Moran, John V.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Gunderson, Kevin L.] Illumina Inc, San Diego, CA USA. [Malik, Harmit Singh] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98104 USA. [Peters, Joseph E.] Cornell Univ, Dept Microbiol, Ithaca, NY USA. [Slotkin, R. Keith] Ohio State Univ, Dept Mol Genet, Columbus, OH 43210 USA. RP Levin, HL (reprint author), Natl Inst Hlth, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. EM levinh@mail.nih.gov OI Peters, Joseph/0000-0001-8309-3297 NR 0 TC 4 Z9 4 U1 2 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1759-8753 J9 MOBILE DNA-UK JI Mob. DNA PD NOV 18 PY 2014 VL 5 AR 26 DI 10.1186/1759-8753-5-26 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA AZ8OE UT WOS:000348474100001 ER PT J AU Kadri, SS Danner, RL AF Kadri, Sameer S. Danner, Robert L. TI Review: In sepsis, the effect of resuscitation with crystalloid and colloid fluids on mortality varies Commentary SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID CRITICALLY-ILL ADULTS; KIDNEY INJURY; ASSOCIATION; ALBUMIN; SALINE C1 [Kadri, Sameer S.; Danner, Robert L.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Kadri, SS (reprint author), NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 4 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 NOV 18 PY 2014 VL 161 IS 10 AR JC12 DI 10.7326/0003-4819-161-10-201411180-02012 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AX9TT UT WOS:000347245600022 PM 25402533 ER PT J AU Mehta, RG Hawthorne, M Mehta, RR Torres, KEO Peng, XJ McCormick, DL Kopelovich, L AF Mehta, Rajendra G. Hawthorne, Michael Mehta, Rajeshwari R. Torres, Karen E. O. Peng, Xinjian McCormick, David L. Kopelovich, Levy TI Differential Roles of ER alpha and ER beta in Normal and Neoplastic Development in the Mouse Mammary Gland SO PLOS ONE LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; ESTROGEN-RECEPTOR BETA; BREAST-CANCER CELLS; EXPRESSION; LIGAND; GPR30; GENE AB The present experiments were performed to determine the roles of estrogen receptors alpha and beta (ER alpha and ER beta) in normal and neoplastic development in the mouse mammary gland. In wild-type mice, in vivo administration of estradiol (E) + progesterone (P) stimulated mammary ductal growth and alveolar differentiation. Mammary glands from mice in which the ER beta gene has been deleted (beta ERKO mice) demonstrated normal ductal growth and differentiation in response to E + P. By contrast, mammary glands from mice in which the ERa gene has been deleted (alpha ERKO mice) demonstrated only rudimentary ductal structures that did not differentiate in response to E + P. EGF demonstrates estrogen-like activity in the mammary glands of aERKO mice: treatment of alpha ERKO mice with EGF + P (without E) supported normal mammary gland development, induced expression of progesterone receptor (PR), and increased levels of G-protein-coupled receptor (GPR30) protein. Mammary gland development in beta ERKO mice treated with EGF + P was comparable to that of wild-type mice receiving EGF + P; EGF had no statistically significant effects on the induction of PR or expression of GPR30 in mammary glands harvested from either wild-type mice or beta ERKO mice. In vitro exposure of mammary glands to 7,12-imethylbenz[a] anthracene (DMBA) induced preneoplastic mammary alveolar lesions (MAL) in glands from wild-type mice and beta ERKO mice, but failed to induce MAL in mammary glands from alpha ERKO mice. Microarray analysis of DMBA-treated mammary glands identified 28 functional pathways whose expression was significantly different in alpha ERKO mice versus both beta ERKO and wild-type mice; key functions that were differentially expressed in alpha ERKO mice included cell division, cell proliferation, and apoptosis. The data demonstrate distinct roles for ER alpha and ER beta in normal and neoplastic development in the mouse mammary gland, and suggest that EGF can mimic the ER alpha-mediated effects of E in this organ. C1 [Mehta, Rajendra G.; Hawthorne, Michael; Mehta, Rajeshwari R.; Peng, Xinjian; McCormick, David L.] IIT Res Inst, Chicago, IL USA. [Torres, Karen E. O.] GenUs Biosyst, Northbrook, IL USA. [Kopelovich, Levy] NCI, Canc Prevent Div, Rockville, MD USA. RP Mehta, RG (reprint author), IIT Res Inst, Chicago, IL USA. EM RMehta@iitri.org FU Division of Cancer Prevention, National Cancer Institute (NCI), Bethesda, Maryland [NO1-CN-43301]; Division of Cancer Prevention Branch, NCI FX Funding provided by Division of Cancer Prevention, National Cancer Institute (NCI), Bethesda, Maryland NO1-CN-43301 (RGM) and LK, Division of Cancer Prevention Branch, NCI. 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 4 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 NOV 18 PY 2014 VL 9 IS 11 AR e113175 DI 10.1371/journal.pone.0113175 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AX7UZ UT WOS:000347121300089 PM 25405629 ER PT J AU Talley, AK Healy, SA Finney, OC Murphy, SC Kublin, J Salas, CJ Lundebjerg, S Gilbert, P Van Voorhis, WC Whisler, J Wang, RB Ockenhouse, CF Heppner, DG Kappe, SH Duffy, PE AF Talley, Angela K. Healy, Sara A. Finney, Olivia C. Murphy, Sean C. Kublin, James Salas, Carola J. Lundebjerg, Susan Gilbert, Peter Van Voorhis, Wesley C. Whisler, John Wang, Ruobing Ockenhouse, Chris F. Heppner, D. Gray Kappe, Stefan H. Duffy, Patrick E. TI Safety and Comparability of Controlled Human Plasmodium falciparum Infection by Mosquito Bite in Malaria-Naive Subjects at a New Facility for Sporozoite Challenge SO PLOS ONE LA English DT Article ID TO-BLOOD INOCULA; HUMAN VOLUNTEERS; VACCINES; IMMUNITY; UPDATE; COHORT; VIVAX; CELLS; MODEL; RATES AB Background: Controlled human malaria infection (CHMI) studies which recapitulate mosquito-borne infection are a critical tool to identify protective vaccine and drug candidates for advancement to field trials. In partnership with the Walter Reed Army Institute of Research, the CHMI model was established at the Seattle Biomedical Research Institute's Malaria Clinical Trials Center (MCTC). Activities and reagents at both centers were aligned to ensure comparability and continued safety of the model. To demonstrate successful implementation, CHMI was performed in six healthy malaria-naive volunteers. Methods: All volunteers received NF54 strain Plasmodium falciparum by the bite of five infected Anopheles stephensi mosquitoes under controlled conditions and were monitored for signs and symptoms of malaria and for parasitemia by peripheral blood smear. Subjects were treated upon diagnosis with chloroquine by directly observed therapy. Immunological (T cell and antibody) and molecular diagnostic (real-time quantitative reverse transcriptase polymerase chain reaction [qRT-PCR]) assessments were also performed. Results: All six volunteers developed patent parasitemia and clinical malaria. No serious adverse events occurred during the study period or for six months post-infection. The mean prepatent period was 11.2 days (range 9-14 days), and geometric mean parasitemia upon diagnosis was 10.8 parasites/mu L (range 2-69) by microscopy. qRT-PCR detected parasites an average of 3.7 days (range 2-4 days) earlier than blood smears. All volunteers developed antibodies to the blood-stage antigen merozoite surface protein 1 (MSP-1), which persisted up to six months. Humoral and cellular responses to pre-erythrocytic antigens circumsporozoite protein (CSP) and liver-stage antigen 1 (LSA-1) were limited. Conclusion: The CHMI model was safe, well tolerated and characterized by consistent prepatent periods, pre-symptomatic diagnosis in 3/6 subjects and adverse event profiles as reported at established centers. The MCTC can now evaluate candidates in the increasingly diverse vaccine and drug pipeline using the CHMI model. C1 [Talley, Angela K.; Finney, Olivia C.; Lundebjerg, Susan; Whisler, John; Wang, Ruobing; Kappe, Stefan H.] Seattle Biomed Res Inst, Malaria Clin Trials Ctr, Seattle, WA 98109 USA. [Healy, Sara A.; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Bethesda, MD 20892 USA. [Murphy, Sean C.] Univ Washington, Med Ctr, Dept Lab Med, Seattle, WA 98195 USA. [Kublin, James; Gilbert, Peter] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Salas, Carola J.] US Naval Med Res Unit 6, Lima, Peru. [Van Voorhis, Wesley C.] Univ Washington, Med Ctr, Dept Med, Seattle, WA 98195 USA. [Ockenhouse, Chris F.; Heppner, D. Gray] Walter Reed Army Inst Res, US Mil Malaria Vaccine Program, Silver Spring, MD USA. RP Duffy, PE (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM patrick.duffy@nih.gov FU PATH Malaria Vaccine Initiative (MVI); United States Department of Defense; Intramural Research Program of National Institute of Allergy and Infectious Diseases, National Institutes of Health; Global Emerging Infections Surveillance and Response System of the United States Department of Defense (AFHSC/GEIS) [847705.82000.256B.B0016] FX Funding for the initial MCTC infrastructure and for this clinical trial funding was provided by the PATH Malaria Vaccine Initiative (MVI) and the United States Department of Defense. MVI staff (Florence Kaltovich and Cynthia Lee) provided technical support on the chemistry, manufacturing, and control section of the IND application and the clinical operations aspects associated with this study, the latter through MVI's clinical quality assurance consultants at The Total Approach. C. F. O. is now employed by MVI/PATH and contributed to the review of the manuscript. This work was also supported by the Intramural Research Program of National Institute of Allergy and Infectious Diseases, National Institutes of Health (S. A. H., P. E. D.), and the Global Emerging Infections Surveillance and Response System of the United States Department of Defense (AFHSC/GEIS) under work unit number 847705.82000.256B.B0016 (C. J. S.). The authors have no conflicts that affect their adherence to all PLOS ONE policies on sharing data and materials. NR 27 TC 6 Z9 7 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 NOV 18 PY 2014 VL 9 IS 11 AR e109654 DI 10.1371/journal.pone.0109654 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AX7UZ UT WOS:000347121300006 PM 25405724 ER PT J AU White, MT Karl, S Battle, KE Hay, SI Mueller, I Ghani, AC AF White, Michael T. Karl, Stephan Battle, Katherine E. Hay, Simon I. Mueller, Ivo Ghani, Azra C. TI Modelling the contribution of the hypnozoite reservoir to Plasmodium vivax transmission SO ELIFE LA English DT Article ID NEW-GUINEAN CHILDREN; MATHEMATICAL-MODEL; MALARIA TRANSMISSION; G6PD DEFICIENCY; FALCIPARUM; INFECTION; RELAPSE; ELIMINATION; PARASITE; IMMUNITY AB Plasmodium vivax relapse infections occur following activation of latent liver-stages parasites (hypnozoites) causing new blood-stage infections weeks to months after the initial infection. We develop a within-host mathematical model of liver-stage hypnozoites, and validate it against data from tropical strains of P. vivax. The within-host model is embedded in a P. vivax transmission model to demonstrate the build-up of the hypnozoite reservoir following new infections and its depletion through hypnozoite activation and death. The hypnozoite reservoir is predicted to be over-dispersed with many individuals having few or no hypnozoites, and some having intensely infected livers. Individuals with more hypnozoites are predicted to experience more relapses and contribute more to onwards P. vivax transmission. Incorporating hypnozoite killing drugs such as primaquine into first-line treatment regimens is predicted to cause substantial reductions in P. vivax transmission as individuals with the most hypnozoites are more likely to relapse and be targeted for treatment. C1 [White, Michael T.; Ghani, Azra C.] Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis Epidemiol, Ctr Outbreak Anal & Modelling, MRC, London, England. [Karl, Stephan; Mueller, Ivo] Walter & Eliza Hall Inst Med Res, Dept Infect & Immun, Melbourne, Australia. [Karl, Stephan; Mueller, Ivo] Univ Melbourne, Dept Med Biol, Melbourne, Vic, Australia. [Battle, Katherine E.; Hay, Simon I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. [Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Mueller, Ivo] Ctr Recerca Salut Int Barcelona, Barcelona, Spain. RP White, MT (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis Epidemiol, Ctr Outbreak Anal & Modelling, MRC, London, England. EM m.white08@imperial.ac.uk RI Ghani, Azra/B-8560-2009; Hay, Simon/F-8967-2015; OI Hay, Simon/0000-0002-0611-7272; Battle, Katherine/0000-0003-2401-2615 FU Wellcome Trust; Medical Research Council; National Health and Medical Research Council FX Medical Research Council Population Health Scientist Fellowship Michael T White; National Health and Medical Research Council Senior Research Fellowship Ivo Mueller; National Health and Medical Research Council Research Fellowship Stephan Karl; Wellcome Trust Senior Research Fellowship Katherine E Battle, Simon I Hay; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 56 TC 20 Z9 20 U1 1 U2 5 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD NOV 18 PY 2014 VL 3 AR e04692 DI 10.7554/eLife.04692 PG 19 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AU5HW UT WOS:000345638500004 ER PT J AU Jones, CP Ferre-D'Amare, AR AF Jones, Christopher P. Ferre-D'Amare, Adrian R. TI Crystal structure of a c-di-AMP riboswitch reveals an internally pseudo-dimeric RNA SO EMBO JOURNAL LA English DT Article DE cyclic di-AMP; riboregulation; riboswitch; small-angle X-ray scattering; X-ray crystallography ID X-RAY-SCATTERING; LIGAND-BINDING; BACILLUS-SUBTILIS; YDAO RIBOSWITCH; GMP RIBOSWITCH; MACROMOLECULAR STRUCTURES; STREPTOCOCCUS-PNEUMONIAE; BACTERIAL 2ND-MESSENGER; TERTIARY INTERACTIONS; GLYCINE RIBOSWITCH AB Cyclic diadenosine monophosphate (c-di-AMP) is a second messenger that is essential for growth and homeostasis in bacteria. A recently discovered c-di-AMP-responsive riboswitch controls the expression of genes in a variety of bacteria, including important pathogens. To elucidate the molecular basis for specific binding of c-di-AMP by a gene-regulatory mRNA domain, we have determined the co-crystal structure of this riboswitch. Unexpectedly, the structure reveals an internally pseudo-symmetric RNA in which two similar three-helix-junction elements associate head-to-tail, creating a trough that cradles two c-di-AMP molecules making quasiequivalent contacts with the riboswitch. The riboswitch selectively binds c-di-AMP and discriminates exquisitely against other cyclic dinucleotides, such as c-di-GMP and cyclic-AMP-GMP, via interactions with both the backbone and bases of its cognate second messenger. Small-angle X-ray scattering experiments indicate that global folding of the riboswitch is induced by the two bound cyclic dinucleotides, which bridge the two symmetric three-helix domains. This structural reorganization likely couples c-di-AMP binding to gene expression. C1 [Jones, Christopher P.; Ferre-D'Amare, Adrian R.] NHLBI, Biochem & Biophys Ctr, Bethesda, MD 20892 USA. RP Ferre-D'Amare, AR (reprint author), NHLBI, Biochem & Biophys Ctr, Bldg 10, Bethesda, MD 20892 USA. EM adrian.ferre@nih.gov FU U.S. Department of Energy; intramural program of the NHLBI, NIH; National Institutes of Health FX We thank the staff at beamlines 5.0.1, 5.0.2, and 8.2.1 of the ALS for crystallographic data collection, G. Piszczek (National Heart, Lung and Blood Institute, NHLBI) for ITC support, Y.-X. Wang and X. Fang (National Cancer Institute) and the staff of APS beamline 12-ID-C for SAXS support, N. Baird, K. Collins, M. Lau, A. Roll-Mecak, K. Warner, and J. Zhang for discussions. This work was partly conducted at the ALS on the BCSB beamlines which are supported by the National Institutes of Health. Use of ALS and APS and was supported by the U.S. Department of Energy. This work was supported in part by the intramural program of the NHLBI, NIH. NR 69 TC 19 Z9 19 U1 0 U2 10 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 NOV 18 PY 2014 VL 33 IS 22 BP 2692 EP 2703 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AU0FP UT WOS:000345299300010 PM 25271255 ER PT J AU Gottesman, MM Hanover, JA Jakoby, W AF Gottesman, Michael M. Hanover, John A. Jakoby, William TI Gil Ashwell, 1916-2014 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material C1 [Gottesman, Michael M.] NCI, Cell Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Hanover, John A.; Jakoby, William] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, Bldg 37, Bethesda, MD 20892 USA. EM mgottesman@nih.gov NR 3 TC 0 Z9 0 U1 0 U2 1 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 NOV 18 PY 2014 VL 111 IS 46 BP 16232 EP 16233 DI 10.1073/pnas.1417238111 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT7ZL UT WOS:000345153300019 PM 25385634 ER PT J AU Du, N Kwon, H Li, P West, EE Oh, J Liao, W Yu, ZX Ren, M Leonard, WJ AF Du, Ning Kwon, Hyokjoon Li, Peng West, Erin E. Oh, Jangsuk Liao, Wei Yu, Zuxi Ren, Min Leonard, Warren J. TI EGR2 is critical for peripheral naive T-cell differentiation and the T-cell response to influenza SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE EGR2; T cells; differentiation; RNA-Seq; influenza ID TRANSCRIPTION FACTORS; GROWTH; INFLAMMATION; EXPRESSION; MEMORY; NOTCH AB Early growth response 2 (EGR2) transcription factor negatively regulates T-cell activation, in contrast to the positive regulation of this process by EGR1. Here, we unexpectedly found that EGR2 promotes peripheral naive T-cell differentiation, with delayed T-cell receptor-induced proliferation in naive T cells from Egr2 conditional knockout (CKO) mice and decreased production of IFN-gamma, IL-4, IL-9, and IL-17A in cells subjected to T-helper differentiation. Moreover, genes that promote T-cell activation, including Tbx21 and Notch1, had decreased expression in Egr2 CKO T cells and are direct EGR2 target genes. Following influenza infection, Egr2 CKO mice had delayed viral clearance, more weight loss, and more severe pathological changes in the lung than did WT and Egr1 KO mice, with decreased production of effector cytokines, increased infiltration of antigen-specific memory-precursor CD8(+) T cells, and lower numbers of lung-resident memory CD8(+) T cells. Thus, unexpectedly, EGR2 can function as a positive regulator that is essential for naive T-cell differentiation and in vivo T-cell responses to a viral infection. C1 [Du, Ning; Kwon, Hyokjoon; Li, Peng; West, Erin E.; Oh, Jangsuk; Liao, Wei; Ren, Min; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Du, Ning; Kwon, Hyokjoon; Li, Peng; West, Erin E.; Oh, Jangsuk; Liao, Wei; Ren, Min; Leonard, Warren J.] NHLBI, Ctr Immunol, NIH, Bethesda, MD 20892 USA. [Yu, Zuxi] NHLBI, Pathol Core, NIH, Bethesda, MD 20892 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health FX We thank J.-X. Lin and R. Spolski (NHLBI) for critical comments, S. Epstein (Food and Drug Administration) for PR8 and X-79 strains of influenza virus, J. Zhu and Y. Wakabayashi (NHLBI DNA Sequencing Core) for excellent services, and NHLBI Flow Cytometry Core Facility for cell sorting and sample analysis. This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health. NR 24 TC 2 Z9 2 U1 1 U2 5 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 NOV 18 PY 2014 VL 111 IS 46 BP 16484 EP 16489 DI 10.1073/pnas.1417215111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT7ZL UT WOS:000345153300065 PM 25368162 ER PT J AU Thomas, C Ye, FQ Irfanoglu, MO Modi, P Saleem, KS Leopold, DA Pierpaoli, C AF Thomas, Cibu Ye, Frank Q. Irfanoglu, M. Okan Modi, Pooja Saleem, Kadharbatcha S. Leopold, David A. Pierpaoli, Carlo TI Anatomical accuracy of brain connections derived from diffusion MRI tractography is inherently limited SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE diffusion MRI; tractography; white matter; tracer; validation ID LIVING HUMAN BRAIN; WHITE-MATTER; FIBER PATHWAYS; MACAQUE MONKEYS; TENSOR; CORTEX; RESOLUTION; ARCHITECTURE; TRACKING; PROJECT AB Tractography based on diffusion-weighted MRI (DWI) is widely used for mapping the structural connections of the human brain. Its accuracy is known to be limited by technical factors affecting in vivo data acquisition, such as noise, artifacts, and data undersampling resulting from scan time constraints. It generally is assumed that improvements in data quality and implementation of sophisticated tractography methods will lead to increasingly accurate maps of human anatomical connections. However, assessing the anatomical accuracy of DWI tractography is difficult because of the lack of independent knowledge of the true anatomical connections in humans. Here we investigate the future prospects of DWI-based connectional imaging by applying advanced tractography methods to an ex vivo DWI dataset of the macaque brain. The results of different tractography methods were compared with maps of known axonal projections from previous tracer studies in the macaque. Despite the exceptional quality of the DWI data, none of the methods demonstrated high anatomical accuracy. The methods that showed the highest sensitivity showed the lowest specificity, and vice versa. Additionally, anatomical accuracy was highly dependent upon parameters of the tractography algorithm, with different optimal values for mapping different pathways. These results suggest that there is an inherent limitation in determining long-range anatomical projections based on voxel-averaged estimates of local fiber orientation obtained from DWI data that is unlikely to be overcome by improvements in data acquisition and analysis alone. C1 [Thomas, Cibu; Irfanoglu, M. Okan; Modi, Pooja; Pierpaoli, Carlo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Pediat Imaging & Tissue Sci, Bethesda, MD 20892 USA. [Thomas, Cibu; Irfanoglu, M. Okan; Pierpaoli, Carlo] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Ye, Frank Q.; Leopold, David A.] NINDS, Neurophysiol Imaging Facil, NIMH, Bethesda, MD 20892 USA. [Ye, Frank Q.; Leopold, David A.] NEI, Bethesda, MD 20892 USA. [Ye, Frank Q.; Leopold, David A.] NIMH, Sect Cognit Neurophysiol & Imaging, Neuropsychol Lab, Bethesda, MD 20892 USA. [Saleem, Kadharbatcha S.] NIMH, Sect Cognit Neurosci, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Thomas, C (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Pediat Imaging & Tissue Sci, Bethesda, MD 20892 USA. EM cibu.thomas@nih.gov OI Leopold, David/0000-0002-1345-6360 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Mental Health Intramural Programs; Department of Defense in the Center for Neuroscience and Regenerative Medicine FX We thank Drs. Peter Basser, Elizabeth Hutchinson, Alexandru Avram, Danping Liu, and Neda Sadeghi for useful comments and discussion. Special thanks go to Dr. Afonso Silva for providing the MRI scanner time and instrument support. This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and National Institute of Mental Health Intramural Programs. Salary support for C. T. and M.O.I. was provided by funding from the Department of Defense in the Center for Neuroscience and Regenerative Medicine. NR 63 TC 94 Z9 94 U1 1 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 NOV 18 PY 2014 VL 111 IS 46 BP 16574 EP 16579 DI 10.1073/pnas.1405672111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT7ZL UT WOS:000345153300080 PM 25368179 ER PT J AU Zhang, HY Gao, M Liu, QR Bi, GH Li, X Yang, HJ Gardner, EL Wu, J Xi, ZX AF Zhang, Hai-Ying Gao, Ming Liu, Qing-Rong Bi, Guo-Hua Li, Xia Yang, Hong-Ju Gardner, Eliot L. Wu, Jie Xi, Zheng-Xiong TI Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cannabinoid; CB2 receptor; JWH133; dopamine; cocaine ID VENTRAL TEGMENTAL AREA; MESSENGER-RNA EXPRESSION; DORSAL-HORN NEURONS; MU-OPIOID RECEPTOR; RAT CNS; IMMUNOHISTOCHEMICAL LOCALIZATION; PREFRONTAL CORTEX; NEUROPATHIC RATS; KNOCKOUT MICE; BRAIN AB Cannabinoid CB2 receptors (CB(2)Rs) have been recently reported to modulate brain dopamine (DA)-related behaviors; however, the cellular mechanisms underlying these actions are unclear. Here we report that CB(2)Rs are expressed in ventral tegmental area (VTA) DA neurons and functionally modulate DA neuronal excitability and DA-related behavior. In situ hybridization and immunohistochemical assays detected CB2 mRNA and CB2R immunostaining in VTA DA neurons. Electrophysiological studies demonstrated that activation of CB(2)Rs by JWH133 or other CB2R agonists inhibited VTA DA neuronal firing in vivo and ex vivo, whereas microinjections of JWH133 into the VTA inhibited cocaine self-administration. Importantly, all of the above findings observed in WT or CB1-/- mice are blocked by CB2R antagonist and absent in CB2-/- mice. These data suggest that CB2R-mediated reduction of VTA DA neuronal activity may underlie JWH133's modulation of DA-regulated behaviors. C1 [Zhang, Hai-Ying; Liu, Qing-Rong; Bi, Guo-Hua; Yang, Hong-Ju; Gardner, Eliot L.; Xi, Zheng-Xiong] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Gao, Ming; Wu, Jie] St Josephs Hosp, Barrow Neurol Inst, Div Neurol, Phoenix, AZ 85013 USA. [Gao, Ming; Wu, Jie] St Josephs Hosp, Barrow Neurol Inst, Dept Neurobiol, Phoenix, AZ 85013 USA. [Li, Xia] Univ Calif San Diego, Sch Med, Dept Psychiat, La Jolla, CA 92093 USA. [Wu, Jie] Univ Arizona, Coll Med, Dept Basic Med Sci, Phoenix, AZ 85004 USA. [Wu, Jie] Shantou Univ, Coll Med, Dept Physiol, Shantou 210854, Guangdong, Peoples R China. RP Wu, J (reprint author), St Josephs Hosp, Barrow Neurol Inst, Div Neurol, Phoenix, AZ 85013 USA. EM jie.wu@dignityhealth.org; zxi@intra.nida.nih.gov RI Liu, Qing-Rong/A-3059-2012; OI Liu, Qing-Rong/0000-0001-8477-6452; Zhang, Haiying/0000-0003-0593-5940; Xi, Zheng-Xiong/0000-0001-6482-8104 FU National Institute on Drug Abuse, National Institutes of Health; Barrow Neuroscience Foundation; Barrow Neurological Institute-Bristol-Myers Squibb FX We thank Dr. Yavin Shaham for his critical reading and comments on the manuscript, Dr. Ken Mackie (Indiana University Bloomington) for advice and counsel during the performance of this research, and Dr. Scott Steffensen (Brigham Young University Provo) for providing GAD67-GFP transgenic mice. This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. The electrophysiological studies were supported by the Barrow Neuroscience Foundation (M. G.) and the Barrow Neurological Institute-Bristol-Myers Squibb Seed Fund (J.W.). NR 58 TC 43 Z9 43 U1 1 U2 12 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 NOV 18 PY 2014 VL 111 IS 46 BP E5007 EP E5015 DI 10.1073/pnas.1413210111 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT7ZL UT WOS:000345153300016 PM 25368177 ER PT J AU Meyerson, JR Rao, P Kumar, J Chittori, S Banerjee, S Pierson, J Mayer, ML Subramaniam, S AF Meyerson, Joel R. Rao, Prashant Kumar, Janesh Chittori, Sagar Banerjee, Soojay Pierson, Jason Mayer, Mark L. Subramaniam, Sriram TI Self-assembled monolayers improve protein distribution on holey carbon cryo-EM supports SO SCIENTIFIC REPORTS LA English DT Article ID CRYOELECTRON MICROSCOPY; ELECTRON CRYOMICROSCOPY; SPECIMENS; ADSORPTION; SURFACES; GRAPHENE; GRIDS; TEM AB Poor partitioning of macromolecules into the holes of holey carbon support grids frequently limits structural determination by single particle cryo-electron microscopy (cryo-EM). Here, we present a method to deposit, on gold-coated carbon grids, a self-assembled monolayer whose surface properties can be controlled by chemical modification. We demonstrate the utility of this approach to drive partitioning of ionotropic glutamate receptors into the holes, thereby enabling 3D structural analysis using cryo-EM methods. C1 [Meyerson, Joel R.; Rao, Prashant; Banerjee, Soojay; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kumar, Janesh; Chittori, Sagar; Mayer, Mark L.] NICHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Pierson, Jason] FEI Co, Hillsboro, OR 97124 USA. RP Meyerson, JR (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM joel.meyerson@nih.gov; ss1@nih.gov OI Chittori, Sagar/0000-0003-1417-6552 FU NCI; NICHD; NIH; IATAP program at NIH; NIH-FEI Living Lab for Structural Biology FX This work was supported by the intramural programs of the NCI, and NICHD, NIH, and IATAP program at NIH and the NIH-FEI Living Lab for Structural Biology. We thank Y.J. Eun for expert assistance with self-assembled monolayer design and chemistry, L. Earl for discussions on the manuscript, and S. Fellini, S. Chacko and their colleagues for continued support with use of the Biowulf cluster for computing at NIH. NR 20 TC 11 Z9 11 U1 4 U2 25 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 NOV 18 PY 2014 VL 4 AR 7084 DI 10.1038/srep07084 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU0FM UT WOS:000345298900003 PM 25403871 ER PT J AU Beinart, R Zhang, YY Lima, JAC Bluemke, DA Soliman, EZ Heckbert, SR Post, WS Guallar, E Nazarian, S AF Beinart, Roy Zhang, Yiyi Lima, Joao A. C. Bluemke, David A. Soliman, Elsayed Z. Heckbert, Susan R. Post, Wendy S. Guallar, Eliseo Nazarian, Saman TI The QT Interval Is Associated With Incident Cardiovascular Eventse The MESA Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiovascular disease; coronary heart disease; heart failure; myocardial infarction; QT interval; stroke ID CORONARY-HEART-DISEASE; PROLONGED VENTRICULAR REPOLARIZATION; SUDDEN-DEATH; MYOCARDIAL-INFARCTION; GENERAL-POPULATION; ATHEROGENIC DIET; PROGNOSTIC VALUE; CARDIAC DEATH; RISK PROFILE; CORRECTED QT AB BACKGROUND Prolonged heart rate-corrected QT interval on electrocardiograms (ECGs) is associated with increased risk of myocardial infarction and cardiovascular disease (CVD)-related deaths in patients with prevalent coronary heart disease. OBJECTIVES This study sought to examine the prognostic association between the baseline QT interval and incident cardiovascular events in individuals without prior known CVD. METHODS The corrected baseline 12-lead ECG QT interval duration (QT(corr)) was determined by adjustment for age, sex, race/ethnicity, and RR interval duration in 6,273 participants in MESA (Multi-Ethnic Study of Atherosclerosis). Cox proportional hazards models adjusting for demographic and clinical risk factors were used to examine the association of baseline QTcorr with incident cardiovascular events. RESULTS The mean age at enrollment was 61.7 +/- 10 years, and 53.4% of participants were women. Cardiovascular events occurred in 291 participants over a mean follow-up of 8.0 +/- 1.7 years. Each 10-ms increase in the baseline QT(corr) was associated with incident heart failure (hazard ratio [HR]: 1.25; 95% CI: 1.14 to 1.37), CVD events (HR: 1.12; 95% CI: 1.05 to 1.20), and stroke (HR: 1.19; 95% CI: 1.07 to 1.32) after adjustment for CVD risk factors and potential confounders. There was no evidence of interaction with sex or ethnicity. CONCLUSIONS The QT interval was associated with incident cardiovascular events in middle-aged and older adults without prior CVD. C1 [Beinart, Roy; Lima, Joao A. C.; Post, Wendy S.; Nazarian, Saman] Johns Hopkins Univ, Div Cardiol, Baltimore, MD 21287 USA. [Beinart, Roy] Tel Aviv Univ, Leviev Heart Ctr, Chaim Sheba Med Ctr, IL-69978 Tel Aviv, Israel. [Zhang, Yiyi; Guallar, Eliseo; Nazarian, Saman] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21287 USA. [Bluemke, David A.] NIH, Bethesda, MD 20892 USA. [Soliman, Elsayed Z.] Wake Forest Sch Med, Epidemiol Cardiol Res Ctr, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Soliman, Elsayed Z.] Wake Forest Sch Med, Dept Internal Med, Cardiol Sect, Winston Salem, NC USA. [Heckbert, Susan R.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Nazarian, S (reprint author), Johns Hopkins Univ, Div Cardiol, 600 North Wolfe St,Carnegie 592A, Baltimore, MD 21287 USA. EM snazarian@jhmi.edu RI zhang, yiyi/J-2592-2012 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC95169]; NIH [K23HL089333, R01HL116280]; Biosense Webster, Inc FX MESA (Multi-Ethnic Study of Atherosclerosis) was funded by grants N01-HC-95159 through N01-HC95169 from the National Heart, Lung, and Blood Institute. The contents of this paper are the responsibility of the authors and do not necessarily represent the official views of the National Institute of Health (NIH). Dr. Nazarian is funded by NIH grants K23HL089333 and R01HL116280; is a scientific advisor to Biosense Webster Inc.; and is the principal investigator for research funding to Johns Hopkins University from Biosense Webster, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. P. E. Shah, MD, served as Guest Editor for this article. NR 41 TC 12 Z9 14 U1 0 U2 5 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 NOV 18 PY 2014 VL 64 IS 20 BP 2111 EP 2119 DI 10.1016/j.jacc.2014.08.039 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AT0HK UT WOS:000344617400007 PM 25457400 ER PT J AU Malley, JD Malley, KG Moore, JH AF Malley, James D. Malley, Karen G. Moore, Jason H. TI O brave new world that has such machines in it SO BIODATA MINING LA English DT Editorial Material ID PROBABILITY MACHINES C1 [Malley, James D.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. [Malley, Karen G.] Malley Res Programming Inc, Rockville, MD USA. [Moore, Jason H.] Dartmouth Coll, Geisel Sch Med, Inst Quantitat Biomed Sci, Dept Genet, Lebanon, NH 03756 USA. [Moore, Jason H.] Dartmouth Coll, Geisel Sch Med, Inst Quantitat Biomed Sci, Dept Community & Family Med, Lebanon, NH 03756 USA. RP Moore, JH (reprint author), Dartmouth Coll, Geisel Sch Med, Inst Quantitat Biomed Sci, Dept Genet, One Med Ctr Dr, Lebanon, NH 03756 USA. EM jason.h.moore@dartmouth.edu NR 3 TC 0 Z9 0 U1 1 U2 2 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 NOV 17 PY 2014 VL 7 AR 26 DI 10.1186/1756-0381-7-26 PG 2 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AW1DB UT WOS:000346029700001 PM 25780388 ER PT J AU Hoos, MD Vitek, MP Ridnour, LA Wilson, J Jansen, M Everhart, A Wink, DA Colton, CA AF Hoos, Michael D. Vitek, Michael P. Ridnour, Lisa A. Wilson, Joan Jansen, Marilyn Everhart, Angela Wink, David A. Colton, Carol A. TI The impact of human and mouse differences in NOS2 gene expression on the brain's redox and immune environment SO MOLECULAR NEURODEGENERATION LA English DT Article DE NOS2; Mouse models; Neurodegeneration; Redox; Inflammation; Nitric oxide ID NITRIC-OXIDE SYNTHASE; NF-KAPPA-B; GENOME-WIDE ASSOCIATION; ALZHEIMERS-DISEASE; A-BETA; OXIDATIVE STRESS; TRANSGENIC MICE; PERITONEAL-MACROPHAGES; SPECIES-DIFFERENCES; CYTOKINE INDUCTION AB Background: Mouse models are used in the study of human disease. Despite well-known homologies, the difference in immune response between mice and humans impacts the application of data derived from mice to human disease outcomes. Nitric oxide synthase-2 (NOS2) is a key gene that displays species-specific outcomes via altered regulation of the gene promoter and via post-transcriptional mechanisms in humans that are not found in mice. The resulting levels of NO produced by activation of human NOS2 are different from the levels of NO produced by mouse Nos2. Since both tissue redox environment and immune responsiveness are regulated by the level of NO and its interactions, we investigated the significance of mouse and human differences on brain oxidative stress and on immune activation in HuNOS2(tg)/mNos2(-/-) mice that express the entire human NOS2 gene and that lack a functional mNos2 compared to wild type (WT) mice that express normal mNos2. Methods/results: Similarly to human, brain tissue from HuNOS2(tg)/mNos2(-/-) mice showed the presence of a NOS2 gene 3' UTR binding site. We also identified miRNA-939, the binding partner for this site, in mouse brain lysates and further demonstrated reduced levels of nitric oxide (NO) typical of the human immune response on injection with lipopolysaccharide (LPS). HuNOS2(tg)/mNos2(-/-) brain samples were probed for characteristic differences in redox and immune gene profiles compared to WT mice using gene arrays. Selected genes were also compared against mNos2(-/-) brain lysates. Reconstitution of the human NOS2 gene significantly altered genes that encode multiple anti-oxidant proteins, oxidases, DNA repair, mitochondrial proteins and redox regulated immune proteins. Expression levels of typical pro-inflammatory, anti-inflammatory and chemokine genes were not significantly different with the exception of increased TNFa and Ccr1 mRNA expression in the HuNOS2(tg)/mNos2(-/-) mice compared to WT or mNos2(-/-) mice. Conclusions: NO is a principle factor in establishing the tissue redox environment and changes in NO levels impact oxidative stress and immunity, both of which are primary characteristics of neurodegenerative diseases. The HuNOS2(tg)/mNos2(-/-) mice provide a potentially useful mechanism to address critical species-specific immune differences that can impact the study of human diseases. C1 [Hoos, Michael D.] Stonybrook Hlth Sci, Dept Neurosurg, Stony Brook, NY 11794 USA. [Vitek, Michael P.; Wilson, Joan; Jansen, Marilyn; Everhart, Angela; Colton, Carol A.] Duke Univ, Med Ctr, Dept Neurol, Durham, NC 27710 USA. [Ridnour, Lisa A.; Wink, David A.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Colton, CA (reprint author), Duke Univ, Med Ctr, Dept Neurol, Durham, NC 27710 USA. EM Carol.Colton@duke.edu NR 70 TC 4 Z9 4 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD NOV 17 PY 2014 VL 9 AR 50 DI 10.1186/1750-1326-9-50 PG 15 WC Neurosciences SC Neurosciences & Neurology GA AU9SH UT WOS:000345934500001 PM 25403885 ER PT J AU Klein, F Nogueira, L Nishimura, Y Phad, G West, AP Halper-Stromberg, A Horwitz, JA Gazumyan, A Liu, C Eisenreich, TR Lehmann, C Fatkenheuer, G Williams, C Shingai, M Martin, MA Bjorkman, PJ Seaman, MS Zolla-Pazner, S Hedestam, GBK Nussenzweig, MC AF Klein, Florian Nogueira, Lilian Nishimura, Yoshiaki Phad, Ganesh West, Anthony P., Jr. Halper-Stromberg, Ariel Horwitz, Joshua A. Gazumyan, Anna Liu, Cassie Eisenreich, Thomas R. Lehmann, Clara Faetkenheuer, Gerd Williams, Constance Shingai, Masashi Martin, Malcolm A. Bjorkman, Pamela J. Seaman, Michael S. Zolla-Pazner, Susan Hedestam, Gunilla B. Karlsson Nussenzweig, Michel C. TI Enhanced HIV-1 immunotherapy by commonly arising antibodies that target virus escape variants SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID BROADLY NEUTRALIZING ANTIBODIES; SIMIAN IMMUNODEFICIENCY VIRUS; HUMORAL IMMUNE-RESPONSES; BINDING-SITE ANTIBODIES; V3 LOOP; ENVELOPE PROTEIN; RHESUS-MONKEYS; HUMANIZED MICE; TYPE-1 SF162; B-CELLS AB Antibody-mediated immunotherapy is effective in humanized mice when combinations of broadly neutralizing antibodies (bNAbs) are used that target nonoverlapping sites on the human immunodeficiency virus type 1 (HIV-1) envelope. In contrast, single bNAbs can control simian-human immunodeficiency virus (SHIV) infection in immune-competent macaques, suggesting that the host immune response might also contribute to the control of viremia. Here, we investigate how the autologous antibody response in intact hosts can contribute to the success of immunotherapy. We find that frequently arising antibodies that normally fail to control HIV-1 infection can synergize with passively administered bNAbs by preventing the emergence of bNAb viral escape variants. C1 [Klein, Florian; Nogueira, Lilian; Halper-Stromberg, Ariel; Horwitz, Joshua A.; Gazumyan, Anna; Liu, Cassie; Eisenreich, Thomas R.; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Nishimura, Yoshiaki; Shingai, Masashi; Martin, Malcolm A.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Phad, Ganesh; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, SE-17177 Stockholm, Sweden. [West, Anthony P., Jr.; Bjorkman, Pamela J.] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Bjorkman, Pamela J.] CALTECH, Howard Hughes Med Inst, Pasadena, CA 91125 USA. [Lehmann, Clara; Faetkenheuer, Gerd] Univ Hosp Cologne, Dept Internal Med 1, D-50924 Cologne, Germany. [Williams, Constance; Zolla-Pazner, Susan] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Seaman, Michael S.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. [Zolla-Pazner, Susan] Vet Affairs Med Ctr, Res Serv, New York, NY 10010 USA. RP Klein, F (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. EM fklein@rockefeller.edu OI Phad, Ganesh E/0000-0002-0047-6899 FU Stavros Niarchos Foundation; Robert Mapplethorpe Foundation; Swedish Research Council; International AIDS Vaccine Initiative; Karolinska Institutet; Federal Ministry of Education and Research (Bundesministerium fur Bildung und Forschung, BMBF) [01KI1017]; German Centre for Infection Research (DZIF), partner site Bonn-Cologne, Cologne, Germany; Bill and Melinda Gates Foundation; Comprehensive Antibody Vaccine Immune Monitoring Consortium Grant [1032144]; Collaboration for AIDS Vaccine Discovery Grants [1040753, 38619]; National Center for Advancing Translational Sciences (NCATS) [UL1 TR000043]; CHAVI-ID [UM1AI100663]; National Institute of Allergy and Infectious Diseases, National Institutes of Health; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery [AI 100148-01]; National Institutes of Health [P01 AI100151, R01 HL59725]; Department of Veterans Affairs; [AI 100663-01] FX F. Klein was supported by the Stavros Niarchos Foundation and the Robert Mapplethorpe Foundation. G. B. Karlsson Hedestam and G. Phad were supported by grants from the Swedish Research Council, the International AIDS Vaccine Initiative and Karolinska Institutet. C. Lehmann was supported by the Federal Ministry of Education and Research (Bundesministerium fur Bildung und Forschung, BMBF) grant 01KI1017. C. Lehmann and G. Fatkenheuer were supported by the the German Centre for Infection Research (DZIF), partner site Bonn-Cologne, Cologne, Germany. This work was supported in part by the Bill and Melinda Gates Foundation with Comprehensive Antibody Vaccine Immune Monitoring Consortium Grant 1032144 (to M. S. Seaman) and Collaboration for AIDS Vaccine Discovery Grants 1040753 (to P.J. Bjorkman) and 38619 (to M. C. Nussenzweig). This work was also supported in part by grant #UL1 TR000043 from the National Center for Advancing Translational Sciences (NCATS), AI 100663-01 and CHAVI-ID Award UM1AI100663 (to M. C. Nussenzweig), the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (to M. A. Martin), Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, AI 100148-01 (to P.J. Bjorkman and M. C. Nussenzweig), and National Institutes of Health grant P01 AI100151 and R01 HL59725 (to S. Zolla-Pazner), and research funds from the Department of Veterans Affairs (to S. Zolla-Pazner). P.J. Bjorkman and M. C. Nussenzweig are Howard Hughes Medical Institute Investigators. NR 48 TC 35 Z9 35 U1 1 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD NOV 17 PY 2014 VL 211 IS 12 BP 2361 EP 2372 DI 10.1084/jem.20141050 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AT9TL UT WOS:000345268800009 PM 25385756 ER PT J AU Mirsoian, A Bouchlaka, MN Sckisel, GD Chen, MY Pai, CCS Maverakis, E Spencer, RG Fishbein, KW Siddiqui, S Monjazeb, AM Martin, B Maudsley, S Hesdorffer, C Ferrucci, L Longo, DL Blazar, BR Wiltrout, RH Taub, DD Murphy, WJ AF Mirsoian, Annie Bouchlaka, Myriam N. Sckisel, Gail D. Chen, Mingyi Pai, Chien-Chun Steven Maverakis, Emanuel Spencer, Richard G. Fishbein, Kenneth W. Siddiqui, Sana Monjazeb, Arta M. Martin, Bronwen Maudsley, Stuart Hesdorffer, Charles Ferrucci, Luigi Longo, Dan L. Blazar, Bruce R. Wiltrout, Robert H. Taub, Dennis D. Murphy, William J. TI Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ENDOCRINE ORGAN; TISSUE; OBESITY; CANCER AB Aging is a contributing factor in cancer occurrence. We recently demonstrated that systemic immunotherapy (IT) administration in aged, but not young, mice resulted in induction of rapid and lethal cytokine storm. We found that aging was accompanied by increases in visceral fat similar to that seen in young obese (ob/ob or diet-induced obese [DIO]) mice. Yet, the effects of aging and obesity on inflammatory responses to immunotherapeutics are not well defined. We determine the effects of adiposity on systemic IT tolerance in aged compared with young obese mice. Both young ob/ob- and DIO-generated proinflammatory cytokine levels and organ pathologies are comparable to those in aged ad libitum mice after IT, culminating in lethality. Young obese mice exhibited greater ratios of M1/M2 macrophages within the peritoneal and visceral adipose tissues and higher percentages of TNF+ macrophages in response to. CD40/IL-2 as compared with young lean mice. Macrophage depletion or TNF blockade in conjunction with. CD40/IL-2 prevented cytokine storms in young obese mice and protected from lethality. Calorie-restricted aged mice contain less visceral fat and displayed reduced cytokine levels, protection from organ pathology, and protection from lethality upon. CD40/IL-2 administration. Our data demonstrate that adiposity is a critical factor in the age-associated pathological responses to systemic anti-cancer IT. C1 [Mirsoian, Annie; Bouchlaka, Myriam N.; Sckisel, Gail D.; Pai, Chien-Chun Steven; Maverakis, Emanuel] Univ Calif Davis, Dept Dermatol, Sacramento, CA 95817 USA. [Chen, Mingyi] Univ Calif Davis, Dept Pathol & Lab Med, Sacramento, CA 95817 USA. [Monjazeb, Arta M.] Univ Calif Davis, Dept Radiat Oncol, Sacramento, CA 95817 USA. [Taub, Dennis D.; Murphy, William J.] Univ Calif Davis, Dept Dermatol & Internal Med, Sacramento, CA 95817 USA. [Spencer, Richard G.; Fishbein, Kenneth W.; Siddiqui, Sana; Martin, Bronwen; Maudsley, Stuart; Hesdorffer, Charles; Ferrucci, Luigi; Longo, Dan L.] NIA, Intramural Res Program, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Blazar, Bruce R.] Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. [Wiltrout, Robert H.] NCI, Frederick, MD 21702 USA. [Taub, Dennis D.] Vet Affairs Med Ctr, Hematol & Immunol Translat Res Ctr, Washington, DC 20422 USA. RP Murphy, WJ (reprint author), Univ Calif Davis, Dept Dermatol & Internal Med, Sacramento, CA 95817 USA. EM wmjmurphy@ucdavis.edu OI Bouchlaka, Myriam/0000-0003-2865-0817; Fishbein, Kenneth/0000-0002-6353-4603; Maverakis, Emanual/0000-0002-6294-6294 FU NIH [CA0905572, AG034874]; National Institute on Aging, NIH FX This work has been supported by NIH grants CA0905572 and AG034874 and by the Intramural Research Program of the National Institute on Aging, NIH. NR 16 TC 20 Z9 20 U1 1 U2 13 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 NOV 17 PY 2014 VL 211 IS 12 BP 2373 EP 2383 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AT9TL UT WOS:000345268800010 PM 25366964 ER PT J AU Cohen, SS Park, YY Signorello, LB Patel, AV Boggs, DA Kolonel, LN Kitahara, CM Knutsen, SF Gillanders, E Monroe, KR de Gonzalez, AB Bethea, TN Black, A Fraser, G Gapstur, S Hartge, P Matthews, CE Park, SY Purdue, MP Singh, P Harvey, C Blot, WJ Palmer, JR AF Cohen, Sarah S. Park, Yikyung Signorello, Lisa B. Patel, Alpa V. Boggs, Deborah A. Kolonel, Laurence N. Kitahara, Cari M. Knutsen, Synnove F. Gillanders, Elizabeth Monroe, Kristine R. de Gonzalez, Amy Berrington Bethea, Traci N. Black, Amanda Fraser, Gary Gapstur, Susan Hartge, Patricia Matthews, Charles E. Park, Song-Yi Purdue, Mark P. Singh, Pramil Harvey, Chinonye Blot, William J. Palmer, Julie R. TI A Pooled Analysis of Body Mass Index and Mortality among African Americans SO PLOS ONE LA English DT Article ID SELF-REPORTED HEIGHT; UNITED-STATES; US ADULTS; PROSPECTIVE COHORT; OBESITY; WEIGHT; ASSOCIATION; OVERWEIGHT; WHITE; WOMEN AB Pooled analyses among whites and East Asians have demonstrated positive associations between all-cause mortality and body mass index (BMI), but studies of African Americans have yielded less consistent results. We examined the association between BMI and all-cause mortality in a sample of African Americans pooled from seven prospective cohort studies: NIH-AARP, 1995-2009; Adventist Health Study 2, 2002-2008; Black Women's Health Study, 1995-2009; Cancer Prevention Study II, 1982-2008; Multiethnic Cohort Study, 1993-2007; Prostate, Lung, Colorectal and Ovarian Screening Trial, 1993-2009; Southern Community Cohort Study, 2002-2009. 239,526 African Americans (including 100,175 never smokers without baseline heart disease, stroke, or cancer), age 30-104 (mean 52) and 71% female, were followed up to 26.5 years (mean 11.7). Hazard ratios (HR) and 95% confidence intervals (CI) for mortality were derived from multivariate Cox proportional hazards models. Among healthy, never smokers (11,386 deaths), HRs (CI) for BMI 25-27.4, 27.5-29.9, 30-34.9, 35-39.9, 40-49.9, and 50-60 kg/m(2) were 1.02 (0.92-1.12), 1.06 (0.95-1.18), 1.32 (1.18-1.47), 1.54 (1.29-1.83), 1.93 (1.46-2.56), and 1.93 (0.80-4.69), respectively among men and 1.06 (0.99-1.15), 1.15 (1.06-1.25), 1.24 (1.15-1.34), 1.58 (1.43-1.74), 1.80 (1.60-2.02), and 2.31 (1.74-3.07) respectively among women (reference category 22.5-24.9). HRs were highest among those with the highest educational attainment, longest follow-up, and for cardiovascular disease mortality. Obesity was associated with a higher risk of mortality in African Americans, similar to that observed in pooled analyses of whites and East Asians. This study provides compelling evidence to support public health efforts to prevent excess weight gain and obesity in African Americans. C1 [Cohen, Sarah S.; Blot, William J.] Int Epidemiol Inst, Rockville, MD 20850 USA. [Cohen, Sarah S.] EpidStat Inst, Ann Arbor, MI USA. [Park, Yikyung; Kitahara, Cari M.; de Gonzalez, Amy Berrington; Black, Amanda; Hartge, Patricia; Matthews, Charles E.; Purdue, Mark P.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Signorello, Lisa B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Patel, Alpa V.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Boggs, Deborah A.; Bethea, Traci N.; Palmer, Julie R.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Kolonel, Laurence N.; Park, Song-Yi] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Knutsen, Synnove F.; Fraser, Gary] Loma Linda Univ, Sch Publ Hlth, Ctr Nutr Hlth Lifestyle & Dis Prevent, Loma Linda, CA 92350 USA. [Gillanders, Elizabeth] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Monroe, Kristine R.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Singh, Pramil] Loma Linda Univ, Sch Publ Hlth, Ctr Hlth Res, Loma Linda, CA 92350 USA. [Harvey, Chinonye] NCI, Epidemiol & Genom Res Program, NIH, Bethesda, MD 20892 USA. [Blot, William J.] Vanderbilt Univ, Med Ctr, Dept Med, Div Epidemiol, Nashville, TN 37235 USA. [Blot, William J.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. RP Cohen, SS (reprint author), Int Epidemiol Inst, Rockville, MD 20850 USA. EM sarah@epidstat.com RI matthews, Charles/E-8073-2015; Purdue, Mark/C-9228-2016; Kitahara, Cari/R-8267-2016; OI matthews, Charles/0000-0001-8037-3103; Purdue, Mark/0000-0003-1177-3108; Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute's (NCI) Intramural Research Program, Division of Cancer Epidemiology and Genetics (DCEG); Epidemiology and Genomics Research Program, Division of Cancer Control and Populations Sciences; Intramural Research Program of the National Cancer Institute, National Institutes of Health; National Cancer Institute [R01 CA94594, R01 CA058420, R37 CA54281, R01 CA092447, 3R01 CA092447-08S1]; American Cancer Society; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health FX This pooled analysis was supported by the National Cancer Institute's (NCI) Intramural Research Program, Division of Cancer Epidemiology and Genetics (DCEG) and the Epidemiology and Genomics Research Program, Division of Cancer Control and Populations Sciences. The NIH-AARP study is supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The Adventist Health Study 2 is funded by grant R01 CA94594 from the National Cancer Institute. The Black Women's Health Study is funded by grant R01 CA058420 from the National Cancer Institute. The Cancer Prevention Study II Nutrition Cohort is supported by the American Cancer Society. The authors thank all of the men and women in the Cancer Prevention Study II Nutrition Cohort for their many years of dedicated participation in the study. The Multiethnic Cohort Study (MEC) is funded by grant R37 CA54281 from the National Cancer Institute. The PLCO is supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. The PLCO investigators thank the Screening Center investigators and staff of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Mr. Tom Riley and staff, Information Management Services, Inc., Ms. Barbara O'Brien and staff, Westat, Inc. Most importantly, we acknowledge the study participants for their contributions to making this study possible. The Southern Community Cohort Study (SCCS) is funded by grant R01 CA092447 from the National Cancer Institute including special allocations from the American Recovery and Reinvestment Act (3R01 CA092447-08S1). The funding sources for this study did not participate in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, or the decision to submit the manuscript for publication. NR 23 TC 6 Z9 6 U1 0 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 NOV 17 PY 2014 VL 9 IS 11 AR e111980 DI 10.1371/journal.pone.0111980 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT8BL UT WOS:000345158700023 PM 25401742 ER PT J AU Eggert, T Medina-Echeverz, J Kapanadze, T Kruhlak, MJ Korangy, F Greten, TF AF Eggert, Tobias Medina-Echeverz, Jose Kapanadze, Tamar Kruhlak, Michael J. Korangy, Firouzeh Greten, Tim F. TI Tumor Induced Hepatic Myeloid Derived Suppressor Cells Can Cause Moderate Liver Damage SO PLOS ONE LA English DT Article ID COLONY-STIMULATING FACTOR; BEARING MICE; DENDRITIC CELLS; HEPATOCELLULAR-CARCINOMA; IMMUNE-RESPONSE; T-CELLS; INJURY; MECHANISMS; DIFFERENTIATION; INFLAMMATION AB Subcutaneous tumors induce the accumulation of myeloid derived suppressor cells (MDSC) not only in blood and spleens, but also in livers of these animals. Unexpectedly, we observed a moderate increase in serum transaminases in mice with EL4 subcutaneous tumors, which prompted us to study the relationship of hepatic MDSC accumulation and liver injury. MDSC were the predominant immune cell population expanding in livers of all subcutaneous tumor models investigated (RIL175, B16, EL4, CT26 and BNL), while liver injury was only observed in EL4 and B16 tumor-bearing mice. Elimination of hepatic MDSC in EL4 tumor-bearing mice using low dose 5-fluorouracil (5-FU) treatment reversed transaminase elevation and adoptive transfer of hepatic MDSC from B16 tumor-bearing mice caused transaminase elevation indicating a direct MDSC mediated effect. Surprisingly, hepatic MDSC from B16 tumor-bearing mice partially lost their damage-inducing potency when transferred into mice bearing non damage-inducing RIL175 tumors. Furthermore, MDSC expansion and MDSC-mediated liver injury further increased with growing tumor burden and was associated with different cytokines including GM-CSF, VEGF, interleukin-6, CCL2 and KC, depending on the tumor model used. In contrast to previous findings, which have implicated MDSC only in protection from T cell-mediated hepatitis, we show that tumor-induced hepatic MDSC themselves can cause moderate liver damage. C1 [Eggert, Tobias; Medina-Echeverz, Jose; Kapanadze, Tamar; Korangy, Firouzeh; Greten, Tim F.] NCI, Gastrointestinal Malignancy Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kapanadze, Tamar] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany. [Kruhlak, Michael J.] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Greten, TF (reprint author), NCI, Gastrointestinal Malignancy Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM tim.greten@nih.gov RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 FU National Institutes of Health intramural research program FX The underlying research reported in the study was funded by the National Institutes of Health intramural research program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 5 Z9 5 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 NOV 17 PY 2014 VL 9 IS 11 AR e112717 DI 10.1371/journal.pone.0112717 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT8BL UT WOS:000345158700065 PM 25401795 ER PT J AU Sato, K Choyke, PL Kobayashi, H AF Sato, Kazuhide Choyke, Peter L. Kobayashi, Hisataka TI Photoimmunotherapy of Gastric Cancer Peritoneal Carcinomatosis in a Mouse Model SO PLOS ONE LA English DT Article ID CYTOSINE-ANALOG CS-682; IN-VIVO; PANCREATIC-CANCER; ORTHOTOPIC MODEL; RISK-FACTORS; CELL-DEATH; EFFICACY; TUMORS; SURVIVAL; GROWTH AB Photoimmunotherapy (PIT) is a new cancer treatment that combines the specificity of antibodies for targeting tumors with the toxicity induced by photosensitizers after exposure to near infrared (NIR) light. We performed PIT in a model of disseminated gastric cancer peritoneal carcinomatosis and monitored efficacy with in vivo GFP fluorescence imaging. In vitro and in vivo experiments were conducted with a HER2-expressing, GFP-expressing, gastric cancer cell line (N87-GFP). A conjugate comprised of a photosensitizer, IR-700, conjugated to trastuzumab (tra-IR700), followed by NIR light was used for PIT. In vitro PIT was evaluated by measuring cytotoxicity with dead staining and a decrease in GFP fluorescence. In vivo PIT was evaluated in a disseminated peritoneal carcinomatosis model and a flank xenograft using tumor volume measurements and GFP fluorescence intensity. In vivo anti-tumor effects of PIT were confirmed by significant reductions in tumor volume (at day 15, p<0.0001 vs. control) and GFP fluorescence intensity (flank model: at day 3, PIT treated vs. control p<0.01 and peritoneal disseminated model: at day 3 PIT treated vs. control, p<0.05). Cytotoxic effects in vitro were shown to be dependent on the light dose and caused necrotic cell rupture leading to GFP release and a decrease in fluorescence intensity in vitro. Thus, loss of GFP fluorescence served as a useful biomarker of cell necrosis after PIT. C1 [Sato, Kazuhide; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov FU NIH Intramural program; JSPS FX This work was supported by the NIH Intramural program and JSPS Research Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 16 Z9 16 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 NOV 17 PY 2014 VL 9 IS 11 AR e113276 DI 10.1371/journal.pone.0113276 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT8BL UT WOS:000345158700128 PM 25401794 ER PT J AU George-Raizen, JB Shockley, KR Trojanowski, NF Lamb, AL Raizen, DM AF George-Raizen, Julia B. Shockley, Keith R. Trojanowski, Nicholas F. Lamb, Annesia L. Raizen, David M. TI Dynamically-expressed prion-like proteins form a cuticle in the pharynx of Caenorhabditis elegans SO BIOLOGY OPEN LA English DT Article DE C. elegans; molting; larvae; amyloid; cuticle; ABU/PQN; innate immunity; unfolded protein response ID GENE-EXPRESSION; C-ELEGANS; INNATE IMMUNITY; RESPONSE GENES; PROBE LEVEL; LIFE-SPAN; COLLAGEN; ANIMALS; REGIONS; PATHWAY AB In molting animals, a cuticular extracellular matrix forms the first barrier to infection and other environmental insults. In the nematode Caenorhabditis elegans there are two types of cuticle: a well-studied collagenous cuticle lines the body, and a poorly-understood chitinous cuticle lines the pharynx. In the posterior end of the pharynx is the grinder, a tooth-like cuticular specialization that crushes food prior to transport to the intestine for digestion. We here show that the grinder increases in size only during the molt. To gain molecular insight into the structure of the grinder and pharyngeal cuticle, we performed a microarray analysis to identify mRNAs increased during the molt. We found strong transcriptional induction during the molt of 12 of 15 previously identified abu genes encoding Prion-like (P) glutamine (Q) and asparagine (N) rich PQN proteins, as well as 15 additional genes encoding closely related PQN proteins. abu/pqn genes, which we name the abu/pqn paralog group (APPG) genes, were expressed in pharyngeal cells and the proteins encoded by two APPG genes we tested localized to the pharyngeal cuticle. Deleting the APPG gene abu-14 caused abnormal pharyngeal cuticular structures and knocking down other APPG genes resulted in abnormal cuticular function. We propose that APPG proteins promote the assembly and function of a unique cuticular structure. The strong developmental regulation of the APPG genes raises the possibility that such genes would be identified in transcriptional profiling experiments in which the animals' developmental stage is not precisely staged. C1 [George-Raizen, Julia B.; Trojanowski, Nicholas F.; Lamb, Annesia L.; Raizen, David M.] Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Shockley, Keith R.] NIEHS, Biostat Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Raizen, DM (reprint author), Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. EM raizen@mail.med.upenn.edu OI Trojanowski, Nicholas/0000-0001-7317-2266 FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences; National Heart Lung Blood Institute [T31HL07953]; National Institute for Neurological Diseases and Stroke [R01NS064030]; NARSAD Young Investigator Award; McCabe Fund for Biomedical Research from the University of Pennsylvania; National Institutes of Health Office of Research Infrastructure Programs [P40 OD010440] FX K.R.S. was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences; N.F.T. was supported by The National Heart Lung Blood Institute (T31HL07953); D.M.R. was supported by The National Institute for Neurological Diseases and Stroke (R01NS064030), a NARSAD Young Investigator Award, and a McCabe Fund for Biomedical Research from the University of Pennsylvania. Some strains were provided by the CGC, which is funded by National Institutes of Health Office of Research Infrastructure Programs (P40 OD010440). NR 51 TC 4 Z9 4 U1 0 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 2046-6390 J9 BIOL OPEN JI Biol. Open PD NOV 15 PY 2014 VL 3 IS 11 BP 1139 EP 1149 DI 10.1242/bio.20147500 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AZ2ZR UT WOS:000348098200015 PM 25361578 ER PT J AU Cui, YX Palii, SS Innes, CL Paules, RS AF Cui, Yuxia Palii, Stela S. Innes, Cynthia L. Paules, Richard S. TI Depletion of ATR selectively sensitizes ATM-deficient human mammary epithelial cells to ionizing radiation and DNA-damaging agents SO CELL CYCLE LA English DT Article DE ATM and Rad3-related (ATR); DNA damage response; G(2); M checkpoint; ionizing radiation; synthetic lethality ID EARLY EMBRYONIC LETHALITY; CANCER-CELLS; TARGETING ATR; ATAXIA-TELANGIECTASIA; INDUCED AUTOPHAGY; G(2) CHECKPOINT; TUMOR-CELLS; INHIBITION; APOPTOSIS; RESISTANCE AB DNA damage response (DDR) to double strand breaks is coordinated by 3 phosphatidylinositol 3-kinase-related kinase (PIKK) family members: the ataxia-telangiectasia mutated kinase (ATM), the ATM and Rad3-related (ATR) kinase and the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs). ATM and ATR are central players in activating cell cycle checkpoints and function as an active barrier against genome instability and tumorigenesis in replicating cells. Loss of ATM function is frequently reported in various types of tumors, thus placing more reliance on ATR for checkpoint arrest and cell survival following DNA damage. To investigate the role of ATR in the G(2)/M checkpoint regulation in response to ionizing radiation (IR), particularly when ATM is deficient, cell lines deficient of ATM, ATR, or both were generated using a doxycycline-inducible lentiviral system. Our data suggests that while depletion of ATR or ATM alone in wild-type human mammary epithelial cell cultures (HME-CCs) has little effect on radiosensitivity or IR-induced G2/M checkpoint arrest, depletion of ATR in ATM-deficient cells causes synthetic lethality following IR, which correlates with severe G(2)/M checkpoint attenuation. ATR depletion also inhibits IR-induced autophagy, regardless of the ATM status, and enhances IR-induced apoptosis particularly when ATM is deficient. Collectively, our results clearly demonstrate that ATR function is required for the IR-induced G(2)/M checkpoint activation and subsequent survival of cells with ATM deficiency. The synthetic lethal interaction between ATM and ATR in response to IR supports ATR as a therapeutic target for improved anti-cancer regimens, especially in tumors with a dysfunctional ATM pathway. C1 [Cui, Yuxia; Palii, Stela S.; Innes, Cynthia L.; Paules, Richard S.] Natl Inst Hlth Res, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Paules, RS (reprint author), Natl Inst Hlth Res, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. EM paules@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences [Z01ES021157] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01ES021157). NR 43 TC 2 Z9 2 U1 0 U2 3 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 NOV 15 PY 2014 VL 13 IS 22 BP 3541 EP 3550 DI 10.4161/15384101.2014.960729 PG 10 WC Cell Biology SC Cell Biology GA AZ6KM UT WOS:000348328800013 PM 25483091 ER PT J AU Liu, Z Li, Y Zhang, R Chen, Z Han, Y Su, C AF Liu, Z. Li, Y. Zhang, R. Chen, Z. Han, Y. Su, C. TI Circulating Tumor Cells in Peripheral and Pulmonary Venous Blood Predict Poor Long-term Survival in Surgically Resected Non-Small Cell Lung Cancer Patients SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Chicago Multidisciplinary Symposium in Thoracic Oncology CY OCT 30-NOV 01, 2014 CL Chicago, IL C1 [Liu, Z.; Li, Y.; Han, Y.; Su, C.] Capital Med Univ, Beijing Chest Hosp, Beijing, Peoples R China. [Zhang, R.] Capital Med Univ, Beijing Childrens Hosp, Beijing, Peoples R China. [Chen, Z.] NIDCD, Clin Genom Unit, Head & Neck Surg Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 15 PY 2014 VL 90 SU 5 MA 202 BP S49 EP S49 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AW6ZG UT WOS:000346413500104 ER PT J AU Rowe, L Krauze, A Hanson, J Yee, D AF Rowe, L. Krauze, A. Hanson, J. Yee, D. TI Dosimetry and Survival From an Adaptive Radiation Therapy Clinical Trial for Limited-Stage Small Cell Lung Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Chicago Multidisciplinary Symposium in Thoracic Oncology CY OCT 30-NOV 01, 2014 CL Chicago, IL C1 [Rowe, L.] Univ Alberta, Edmonton, AB, Canada. [Krauze, A.] NCI, NIH, Bethesda, MD 20892 USA. [Hanson, J.; Yee, D.] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 15 PY 2014 VL 90 SU 5 MA 251 BP S66 EP S66 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AW6ZG UT WOS:000346413500146 ER PT J AU Bharadwaj, G Benini, PGZ Basudhar, D Ramos-Colon, CN Johnson, GM Larriva, MM Keefer, LK Andrei, D Miranda, KM AF Bharadwaj, Gaurav Benini, Patricia G. Z. Basudhar, Debashree Ramos-Colon, Cyf N. Johnson, Gail M. Larriva, Marti M. Keefer, Larry K. Andrei, Daniela Miranda, Katrina M. TI Analysis of the HNO and NO donating properties of alicyclic amine diazeniumdiolates SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article DE Nitroxyl; Nitric oxide; Diazeniumdiolate; IPA/NO; Angeli's salt; Tamoxifen ID TRIOXODINITRATE ANGELIS SALT; DENSITY-FUNCTIONAL THEORY; NITRIC-OXIDE DONORS; NITROXYL HNO; AQUEOUS-SOLUTION; VASODILATING ACTIVITIES; ELECTRON-ACCEPTORS; RELAXING FACTOR; BREAST-CANCER; IN-VIVO AB Nitroxyl (HNO) donors have been shown to elicit a variety of pharmacological responses, ranging from tumoricidal effects to treatment of heart failure. Isopropylamine-based diazeniumdiolates have been shown to produce HNO on decomposition under physiological conditions. Herein, we report the synthesis and HNO release profiles of primary alicyclic amine-based diazeniumdiolates. These compounds extend the range of known diazeniumdiolate-based HNO donors. Acetoxymethyl ester-protected diazeniumdiolates were also synthesized to improve purification and cellular uptake. The acetoxymethyl derivative of cyclopentylamine diazeniumdiolate not only showed higher cytotoxicity toward cancer cells as compared to the parent anion but was also effective in combination with tamoxifen for targeting estrogen receptor alpha-negative breast cancer cells. (C) 2014 Elsevier Inc. All rights reserved. C1 [Bharadwaj, Gaurav; Benini, Patricia G. Z.; Basudhar, Debashree; Ramos-Colon, Cyf N.; Johnson, Gail M.; Larriva, Marti M.; Miranda, Katrina M.] Univ Arizona, Dept Chem & Biochem, Tucson, AZ 85721 USA. [Keefer, Larry K.; Andrei, Daniela] NCI, Biol Chem Lab, Frederick, MD 21702 USA. RP Miranda, KM (reprint author), Univ Arizona, Dept Chem & Biochem, Tucson, AZ 85721 USA. EM kmiranda@email.arizona.edu RI Keefer, Larry/N-3247-2014; OI Keefer, Larry/0000-0001-7489-9555; Miranda, Katrina/0000-0002-9175-5091 FU Intramural NIH HHS; NIGMS NIH HHS [R01 GM076247, R01-GM076247] NR 74 TC 4 Z9 4 U1 2 U2 21 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 EI 1089-8611 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD NOV 15 PY 2014 VL 42 BP 70 EP 78 DI 10.1016/j.niox.2014.08.013 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AU7XZ UT WOS:000345812900010 PM 25192820 ER PT J AU Miranda, K Debashree, B Cheng, R Bharadwaj, G Ridnour, L Wink, D AF Miranda, Katrina Debashree, Basudhar Cheng, Robert Bharadwaj, Gaurav Ridnour, Lisa Wink, David TI Nitrogen oxide releasing NSAIDs as anticancer agents SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract DE Nitric oxide; Nitroxyl; NSAID; Anticancer C1 [Miranda, Katrina; Debashree, Basudhar; Cheng, Robert; Ridnour, Lisa; Wink, David] NCI, Bethesda, MD 20892 USA. [Bharadwaj, Gaurav] Univ Arizona, Tucson, AZ 85721 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 EI 1089-8611 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD NOV 15 PY 2014 VL 42 MA 1922-2 BP 110 EP 111 DI 10.1016/j.niox.2014.09.038 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AU7XZ UT WOS:000345812900045 ER PT J AU Cheng, R Debashree, B Ridnour, L Wink, D Miranda, K AF Cheng, Robert Debashree, Basudhar Ridnour, Lisa Wink, David Miranda, Katrina TI Differentiating nitric oxide and nitroxyl associated gene expressions as their relates to cancer and treatment SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract DE Nitric oxide; NO; Diazeniumdiolate; HNO; Nitroxyl; Breast C1 [Cheng, Robert; Debashree, Basudhar; Ridnour, Lisa; Wink, David; Miranda, Katrina] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 1089-8603 EI 1089-8611 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD NOV 15 PY 2014 VL 42 MA P110 BP 117 EP 118 DI 10.1016/j.niox.2014.09.058 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AU7XZ UT WOS:000345812900065 ER PT J AU Ridnour, L Glynn, S Barasch, K Windhausen, A Sneha, D Dorsey, T Yfantis, H Lee, DH Heinecke, J Brueggemann, E Lizardo, M Khanna, C Ambs, S Wink, D Hines, H Switzer, C AF Ridnour, Lisa Glynn, Sharon Barasch, Kim Windhausen, Alisha Sneha, Dhanapal Dorsey, Tiffany Yfantis, Harris Lee, Dong H. Heinecke, Julie Brueggemann, Ernie Lizardo, Mike Khanna, Chand Ambs, Stephan Wink, David Hines, Harry Switzer, Chris TI Nitric oxide and breast cancer disease progression: Role of timp-1 in pro-survival signaling SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract DE Nitric oxide; Breast cancer; TIMP-1; CD63; PI3k; Akt; BAD; MMP-9 C1 [Ridnour, Lisa; Barasch, Kim; Windhausen, Alisha; Sneha, Dhanapal; Dorsey, Tiffany; Heinecke, Julie; Lizardo, Mike; Khanna, Chand; Ambs, Stephan; Wink, David; Switzer, Chris] NCI, Bethesda, MD 20892 USA. [Glynn, Sharon] NUI, Prostate Canc Inst, Galway, Ireland. [Yfantis, Harris; Lee, Dong H.] Baltimore VA Med Ctr, Baltimore, MD USA. [Brueggemann, Ernie; Hines, Harry] USAMRID, Ft Detrick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 EI 1089-8611 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD NOV 15 PY 2014 VL 42 MA P176 BP 139 EP 140 DI 10.1016/j.niox.2014.09.120 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AU7XZ UT WOS:000345812900127 ER PT J AU Tiso, M Schechter, A AF Tiso, Mauro Schechter, Alan TI Nitrate reduction by commensal gut bacteria under physiological conditions SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract DE Nitrate; Nitrite; Nitric oxide; Ammonia; Microbiota C1 [Tiso, Mauro] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Schechter, Alan] NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 EI 1089-8611 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD NOV 15 PY 2014 VL 42 MA P195 BP 145 EP 146 DI 10.1016/j.niox.2014.09.136 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AU7XZ UT WOS:000345812900143 ER PT J AU Cao, HB Duan, JB Lin, DD Shugart, YY Calhoun, V Wang, YP AF Cao, Hongbao Duan, Junbo Lin, Dongdong Shugart, Yin Yao Calhoun, Vince Wang, Yu-Ping TI Sparse representation based biomarker selection for schizophrenia with integrated analysis of fMRI and SNPs SO NEUROIMAGE LA English DT Review DE Sparse representations; SNP; fMRI; Variable selection; Schizophrenia ID MINIMIZATION; RECOVERY; VECTORS AB Integrative analysis of multiple data types can take advantage of their complementary information and therefore may provide higher power to identify potential biomarkers that would be missed using individual data analysis. Due to different natures of diverse data modality, data integration is challenging. Here we address the data integration problemby developing a generalized sparse model (GSM) using weighting factors to integrate multi-modality data for biomarker selection. As an example, we applied the GSM model to a joint analysis of two types of schizophrenia data sets: 759,075 SNPs and 153,594 functional magnetic resonance imaging (fMRI) voxels in 208 subjects (92 cases/116 controls). To solve this small-sample-large-variable problem, we developed a novel sparse representation based variable selection (SRVS) algorithm, with the primary aim to identify biomarkers associated with schizophrenia. To validate the effectiveness of the selected variables, we performed multivariate classification followed by a ten-fold cross validation. We compared our proposed SRVS algorithm with an earlier sparse model based variable selection algorithm for integrated analysis. In addition, we compared with the traditional statistics method for uni-variant data analysis (Chi-squared test for SNP data and ANOVA for fMRI data). Results showed that our proposed SRVS method can identify novel biomarkers that show stronger capability in distinguishing schizophrenia patients from healthy controls. Moreover, better classification ratios were achieved using biomarkers from both types of data, suggesting the importance of integrative analysis. (C) 2014 Elsevier Inc. All rights reserved. C1 [Cao, Hongbao; Shugart, Yin Yao] NIMH, Unit Stat Genom, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Duan, Junbo; Lin, Dongdong; Wang, Yu-Ping] Tulane Univ, Dept Biomed Engn, New Orleans, LA 70118 USA. [Duan, Junbo; Wang, Yu-Ping] Tulane Univ, Dept Biostat & Bioinformat, New Orleans, LA 70118 USA. [Calhoun, Vince] Mind Res Network, Albuquerque, NM USA. [Calhoun, Vince] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA. RP Wang, YP (reprint author), Tulane Univ, Dept Biomed Engn, New Orleans, LA 70118 USA. EM wyp@tulane.edu RI Lin, Dongdong/A-8337-2017 FU NIH [R01MH104680]; Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP, NIMH, NIH) [MH002930-03] FX This work has been partially supported by NIH R01MH104680. Drs. Cao and Shugart gratefully acknowledge the support of the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP, NIMH, NIH) (project number MH002930-03). NR 42 TC 7 Z9 7 U1 1 U2 13 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 NOV 15 PY 2014 VL 102 BP 220 EP 228 DI 10.1016/j.neuroimage.2014.01.021 PN 1 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AU1OQ UT WOS:000345390400020 PM 24530838 ER PT J AU Kundu, P Santin, MD Bandettini, PA Bullmore, ET Petiet, A AF Kundu, Prantik Santin, Mathieu D. Bandettini, Peter A. Bullmore, Edward T. Petiet, Alexandra TI Differentiating BOLD and non-BOLD signals in fMRI time series from anesthetized rats using multi-echo EPI at 11.7T SO NEUROIMAGE LA English DT Article ID INDEPENDENT COMPONENT ANALYSIS; STATE FUNCTIONAL CONNECTIVITY; BRAIN; CORTEX; CONTRAST; MRI AB The study of spontaneous brain activity using fMRI is central to mapping brain networks. However, current fMRI methodology has limitations in the study of small animal brain organization using ultra-high field fMRI experiments, as imaging artifacts are difficult to control and the relationship between classical neuroanatomy and spontaneous functional BOLD activity is not fully established. Challenges are especially prevalent during the fMRI study of individual rodent brains, which could be instrumental to studies of disease progression and pharmacology. A recent advance in fMRI methodology enables unbiased, accurate, and comprehensive identification of functional BOLD signals by interfacing multi-echo (ME) fMRI acquisition, NMR signal decay analysis, and independent components analysis (ICA), in a procedure called ME-ICA. Here we present a pilot study on the suitability of ME-ICA for ultra high field animal fMRI studies of spontaneous brain activity under anesthesia. ME-ICA applied to 11.7 T fMRI data of rats first showed robust performance in automatic high dimensionality estimation and ICA decomposition, similar to that previously reported for 3.0 T human data. ME sequence optimization for 11.7 T indicated that 3 echoes, 0.5 mm isotropic voxel size and TR=3s was adequate for sensitive and specific BOLD signal acquisition. Next, in seeking optimal inhaled isoflurane anesthesia dosage, we report that progressive increase in anesthesia goes with concomitant decrease in statistical complexity of "global" functional activity, as measured by the number of BOLD components, or degrees of freedom(DOF). Finally, BOLD functional connectivity maps for individual rodents at the component level show that spontaneous BOLD activity follows classical neuroanatomy, and seed-based analysis shows plausible cortical-cortical and cortical-subcortical functional interactions. (C) 2014 Published by Elsevier Inc. C1 [Kundu, Prantik; Bandettini, Peter A.] NIMH, Sect Funct Imaging Methods, Bethesda, MD 20892 USA. [Kundu, Prantik; Bullmore, Edward T.] Univ Cambridge, Behav Clin Neurosci Inst, Cambridge, England. [Santin, Mathieu D.; Petiet, Alexandra] Ctr Neuroimaging Res, Brain & Spine Inst, Paris, France. [Bandettini, Peter A.] NIMH, Funct MRI Core Facil, Bethesda, MD 20892 USA. [Bullmore, Edward T.] Cambridgeshire Peterborough NHS Fdn Trust, NIHR Cambridge Biomed Res Ctr, Cambridge, England. [Bullmore, Edward T.] GlaxoSmithKline, Alternat Discovery & Dev, ImmunoPsychiat, Stevenage, Herts, England. RP Kundu, P (reprint author), NIMH, Sect Funct Imaging Methods, Bethesda, MD 20892 USA. EM prantikk@gmail.com OI Kundu, Prantik/0000-0001-9367-3068; Bullmore, Edward/0000-0002-8955-8283 FU NIH-Cambridge Scholars Program FX P.K. was supported by the NIH-Cambridge Scholars Program. Data analysis was conducted in part using the NIH Helix and Biowulf resources. We also thank IHU and IPRIAC for their support for the 11.7 T MRI system. ETB is employed half-time by the University of Cambridge and half-time by GlaxoSmithKline (GSK); he holds stock in GSK. NR 29 TC 9 Z9 9 U1 2 U2 9 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 NOV 15 PY 2014 VL 102 BP 861 EP 874 DI 10.1016/j.neuroimage.2014.07.025 PN 2 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AU1PD UT WOS:000345391700059 PM 25064668 ER PT J AU Savoia, CP Liu, QH Zheng, YM Yadav, V Zhang, Z Wu, LG Wang, YX AF Savoia, Carlo P. Liu, Qing-Hua Zheng, Yun-Min Yadav, Vishal Zhang, Zhen Wu, Ling-Gang Wang, Yong-Xiao TI Calcineurin upregulates local Ca2+ signaling through ryanodine receptor-1 in airway smooth muscle cells SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE local calcium signaling; contraction ID PROTEIN-KINASE-C; ACTIVATED CHLORIDE CHANNELS; CALCIUM SPARKS; SARCOPLASMIC-RETICULUM; A-ALPHA; SKELETAL-MUSCLE; RELEASE; MYOCYTES; DEPOLARIZATION; CONTRACTION AB Local Ca2+ signals (Ca2+ sparks) play an important role in multiple cellular functions in airway smooth muscle cells (ASMCs). Protein kinase C is an element of is known to downregulate ASMC Ca2+ sparks and contraction; however, no complementary phosphatase has been shown to produce opposite effects. Here, we for the first time report that treatment with a specific calcineurin (CaN) autoinhibitory peptide (CAIP) to block CaN activity decreases, whereas application of nickel to activate CaN increases, Ca2+ sparks in both the presence and absence of extracellular Ca2+. Treatment with xestospogin-C to eliminate functional inositol 1,4,5-trisphosphate receptors does not prevent CAIP from inhibiting local Ca2+ signaling. However, high ryanodine treatment almost completely blocks spark formation and prevents the nickel-mediated increase in sparks. Unlike CAIP, the protein phosphatase 2A inhibitor endothall has no effect. Local Ca2+ signaling is lower in CaN catalytic subunit A alpha gene knockout (CaN-A alpha(-/-)) mouse ASMCs. The effects of CAIP and nickel are completely lost in CaN-A alpha(-/-) ASMCs. Neither CAIP nor nickel produces an effect on Ca2+ sparks in type 1 ryanodine receptor heterozygous knockout (RyR1(-/+)) mouse ASMCs. However, their effects are not altered in RyR2(-/+) or RyR3(-/-) mouse ASMCs. CaN inhibition decreases methacholine-induced contraction in isolated RyR1(+/+) but not RyR1(-/+) mouse tracheal rings. Supportively, muscarinic contractile responses are also reduced in CaN-A alpha(-/+) mouse tracheal rings. Taken together, these results provide novel evidence that CaN regulates ASMC Ca2+ sparks specifically through RyR1, which plays an important role in the control of Ca2+ signaling and contraction in ASMCs. C1 [Savoia, Carlo P.; Liu, Qing-Hua; Zheng, Yun-Min; Yadav, Vishal; Wang, Yong-Xiao] Albany Med Coll, Ctr Cardiovasc Sci, Albany, NY 12208 USA. [Liu, Qing-Hua] South Cent Univ Nationalities, Coll Life Sci, Inst Med Biol, Wuhan, Hubei, Peoples R China. [Zhang, Zhen; Wu, Ling-Gang] NINDS, Synapt Transmiss Sect, Bethesda, MD 20892 USA. RP Wang, YX (reprint author), Albany Med Coll, Ctr Cardiovasc Sci, MC-8,47 New Scotland Ave, Albany, NY 12208 USA. EM wangy@mail.amc.edu FU National Heart, Lung, and Blood Institute [R01-HL-071000]; American Heart Association Established Investigator Award [0340160N]; Scientist Development Grants [0730242N, 0630236N] FX This work was supported by National Heart, Lung, and Blood Institute Grant R01-HL-071000 (Y.-X. Wang), an American Heart Association Established Investigator Award 0340160N (Y.-X. Wang), as well as Scientist Development Grants 0730242N (Q.-H. Liu) and 0630236N (Y.-M. Zheng). NR 51 TC 2 Z9 2 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 EI 1522-1504 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD NOV 15 PY 2014 VL 307 IS 10 BP L781 EP L790 DI 10.1152/ajplung.00149.2014 PG 10 WC Physiology; Respiratory System SC Physiology; Respiratory System GA AT9LJ UT WOS:000345248600006 PM 25239916 ER PT J AU Qian, CQ Yu, X Pothayee, N Dodd, S Bouraoud, N Star, R Bennett, K Koretsky, A AF Qian, Chunqi Yu, Xin Pothayee, Nikorn Dodd, Stephen Bouraoud, Nadia Star, Robert Bennett, Kevin Koretsky, Alan TI Live nephron imaging by MRI SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE filtration; glomeruli; MRI; perfusion; renal tubules ID GLOMERULAR MORPHOLOGY; NUMBER; KIDNEYS; RAT; SENSITIVITY; DISEASE; MODEL; MICE; SIZE; NMR AB The local sensitivity of MRI can be improved with small MR detectors placed close to regions of interest. However, to maintain such sensitivity advantage, local detectors normally need to communicate with the external amplifier through cable connections, which prevent the use of local detectors as implantable devices. Recently, an integrated wireless amplifier was developed that can efficiently amplify and broadcast locally detected signals, so that the local sensitivity was enhanced without the need for cable connections. This integrated detector enabled the live imaging of individual glomeruli using negative contrast introduced by cationized ferritin, and the live imaging of renal tubules using positive contrast introduced by gadopentetate dimeglumine. Here, we utilized the high blood flow to image individual glomeruli as hyperintense regions without any contrast agent. These hyperintense regions were identified for pixels with signal intensities higher than the local average. Addition of Mn2+ allowed the simultaneous detection of both glomeruli and renal tubules: Mn2+ was primarily reabsorbed by renal tubules, which would be distinguished from glomeruli due to higher enhancement in T-1-weighted MRI. Dynamic studies of Mn2+ absorption confirmed the differential absorption affinity of glomeruli and renal tubules, potentially enabling the in vivo observation of nephron function. C1 [Qian, Chunqi; Yu, Xin; Pothayee, Nikorn; Dodd, Stephen; Bouraoud, Nadia; Koretsky, Alan] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Star, Robert] Natl Inst Diabet & Digest & Kidney Dis, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD USA. [Bennett, Kevin] Univ Hawaii, Dept Biol, Honolulu, HI 96822 USA. [Yu, Xin] Max Planck Inst Biol Cybernet, High Field Magnet Resonance Dept, D-72076 Tubingen, Germany. RP Qian, CQ (reprint author), NIH, 10 Ctr Dr,Rm 1D52, Bethesda, MD 20892 USA. EM qianc2@ninds.nih.gov RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU intramural research program of the National Institute of Neurological Disorder and Stroke FX This study was supported in part by the intramural research program of the National Institute of Neurological Disorder and Stroke. NR 22 TC 5 Z9 5 U1 1 U2 9 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD NOV 15 PY 2014 VL 307 IS 10 BP F1162 EP F1168 DI 10.1152/ajprenal.00326.2014 PG 7 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA AT9ME UT WOS:000345250600009 PM 25186296 ER PT J AU Han, LF Diehl, A Nguyen, NK Korangath, P Teo, WW Cho, SW Kominsky, S Huso, DL Feigenbaum, L Rein, A Argani, P Landberg, G Gessler, M Sukumar, S AF Han, Liangfeng Diehl, Adam Nguyen, Nguyen K. Korangath, Preethi Teo, Weiwen Cho, Soonweng Kominsky, Scott Huso, David L. Feigenbaum, Lionel Rein, Alan Argani, Pedram Landberg, Goran Gessler, Manfred Sukumar, Saraswati TI The Notch Pathway Inhibits TGF beta Signaling in Breast Cancer through HEYL-Mediated Crosstalk SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-BETA; MAMMARY-GLAND DEVELOPMENT; CONGENITAL HEART-DEFECTS; MESENCHYMAL TRANSITION; TARGET GENES; MOUSE HEY1; MICE; TRANSCRIPTION; ACTIVATION; RECEPTOR AB Acquired resistance to TGF beta is a key step in the early stages of tumorigenesis. Mutations in TGF beta signaling components are rare, and little is known about the development of resistance in breast cancer. On the other hand, an activated Notch pathway is known to play a substantial role in promoting breast cancer development. Here, we present evidence of crosstalk between these two pathways through HEYL. HEYL, a basic helix-loop-helix transcription factor and a direct target of Notch signaling, is specifically overexpressed in breast cancer. HEYL represses TGF beta activity by binding to TGF beta-activated Smads. HeyL(-/-) mice have defective mammary gland development with fewer terminal end buds. On the other hand, HeyL transgenic mice show accelerated mammary gland epithelial proliferation and 24% of multiparous mice develop mammary gland cancer. Therefore, repression of TGF beta signaling by Notch acting through HEYL may promote initiation of breast cancer. (C) 2014 AACR. C1 [Han, Liangfeng; Diehl, Adam; Nguyen, Nguyen K.; Korangath, Preethi; Teo, Weiwen; Cho, Soonweng; Sukumar, Saraswati] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Kominsky, Scott] Johns Hopkins Univ, Sch Med, Dept Orthopaed Surg, Baltimore, MD USA. [Huso, David L.] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD USA. [Feigenbaum, Lionel] Sci Applications Int Corp, Lab Anim Sci Program, Frederick, MD USA. [Rein, Alan] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Argani, Pedram] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Landberg, Goran] Univ Manchester, Manchester Acad Hlth Sci Ctr, Sch Canc, Breakthrough Breast Canc Unit, Manchester, Lancs, England. [Gessler, Manfred] Univ Wurzburg, Comprehens Canc Ctr Mainfraken, Dept Biochem, Wurzburg, Germany. [Sukumar, Saraswati] Univ Wurzburg, Theodor Boveri Inst, Wurzburg, Germany. RP Sukumar, S (reprint author), Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Breast Canc Program, 1650 Orleans St,Room 143, Baltimore, MD 21231 USA. EM saras@jhmi.edu FU Department of Defense predoctoral fellowship [W81XWH-04-1-0382]; DOD Center of Excellence [W81XWH-04-1-0595]; Susan G Komen Grant [SAC110050]; Intramural Research Program of the NIH, National Cancer Institute (NCI) Center for Cancer Research FX This work was supported by the Department of Defense predoctoral fellowship W81XWH-04-1-0382 (L. Han), the DOD Center of Excellence Grant W81XWH-04-1-0595 and Susan G Komen Grant SAC110050 (S. Sukumar). This work was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute (NCI) Center for Cancer Research. NR 32 TC 4 Z9 4 U1 0 U2 12 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 NOV 15 PY 2014 VL 74 IS 22 BP 6509 EP 6518 DI 10.1158/0008-5472.CAN-14-0816 PG 10 WC Oncology SC Oncology GA AT7PR UT WOS:000345130500014 PM 25217524 ER PT J AU Bates, SE AF Bates, Susan E. TI Central Nervous System Malignancies: What Next? SO CLINICAL CANCER RESEARCH LA English DT Editorial Material C1 NCI, Rockville, MD USA. RP Bates, SE (reprint author), NCI, Rockville, MD USA. FU Intramural NIH HHS [Z99 CA999999] NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 15 PY 2014 VL 20 IS 22 BP 5590 EP 5590 DI 10.1158/1078-0432.CCR-14-1258 PG 1 WC Oncology SC Oncology GA AT7PT UT WOS:000345130800004 PM 25398841 ER PT J AU Holkova, B Kmieciak, M Perkins, EB Bose, P Baz, RC Roodman, GD Stuart, RK Ramakrishnan, V Wan, W Peer, CJ Dawson, J Kang, L Honeycutt, C Tombes, MB Shrader, E Weir-Wiggins, C Wellons, M Sankala, H Hogan, KT Colevas, AD Doyle, LA Figg, WD Coppola, D Roberts, JD Sullivan, D Grant, S AF Holkova, Beata Kmieciak, Maciej Perkins, E. Brent Bose, Prithviraj Baz, Rachid C. Roodman, G. David Stuart, Robert K. Ramakrishnan, Viswanathan Wan, Wen Peer, Cody J. Dawson, Jana Kang, Loveleen Honeycutt, Connie Tombes, Mary Beth Shrader, Ellen Weir-Wiggins, Caryn Wellons, Martha Sankala, Heidi Hogan, Kevin T. Colevas, A. Dimitrios Doyle, L. Austin Figg, William D. Coppola, Domenico Roberts, John D. Sullivan, Daniel Grant, Steven TI Phase I Trial of Bortezomib (PS-341; NSC 681239) and "Nonhybrid" (Bolus) Infusion Schedule of Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory Indolent B-cell Neoplasms SO CLINICAL CANCER RESEARCH LA English DT Article ID KINASE INHIBITOR FLAVOPIRIDOL; CHRONIC LYMPHOCYTIC-LEUKEMIA; MULTIPLE-MYELOMA; INTERNATIONAL WORKSHOP; RESPONSE CRITERIA; DOWN-REGULATION; LYMPHOMA; APOPTOSIS; CANCER; MCL-1 AB Purpose: This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, Waldenstrom macroglobulinemia, and mantle cell lymphoma). Experimental Design: Patients received bortezomib (intravenous push), followed by alvocidib (1-hour infusion), on days 1, 4, 8, and 11 of a 21-day treatment cycle. Patients experiencing responses or stable disease continued on treatment at the investigator's discretion. A standard 3+3 dose-escalation design was used to identify the MTD based on DLTs, and pharmacokinetic and pharmacodynamic studies were conducted. Results: A total of 44 patients were enrolled, with 39 patients assessed for response. The MTD was established as 1.3 mg/m(2) for bortezomib and 40 mg/m2 for alvocidib. The most common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common nonhematologic toxicities included diarrhea, fatigue, and sensory neuropathy. Three complete remissions (8%) and 10 partial remissions (26%) were observed for a total response rate of 33%. Pharmacokinetic findings with the current dosing regimen were consistent with the comparable literature and the hybrid dosing regimen. Pharmacodynamic study results did not correlate with clinical responses. Conclusions: The combination of bortezomib and alvocidib is tolerable, and an MTD has been established for this schedule. The regimen appears to be efficacious in patients with relapsed/refractory multiple myeloma or indolent non-Hodgkin lymphoma. As the nonhybrid regimen is less cumbersome than the previous hybrid dosing schedule regimen, the current schedule is recommended for successor studies. (C) 2014 AACR. C1 [Holkova, Beata; Kmieciak, Maciej; Perkins, E. Brent; Bose, Prithviraj; Honeycutt, Connie; Tombes, Mary Beth; Shrader, Ellen; Weir-Wiggins, Caryn; Wellons, Martha; Sankala, Heidi; Hogan, Kevin T.; Grant, Steven] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA. [Holkova, Beata; Perkins, E. Brent; Bose, Prithviraj; Roberts, John D.; Grant, Steven] Virginia Commonwealth Univ, Dept Internal Med, Richmond, VA USA. [Baz, Rachid C.; Dawson, Jana; Coppola, Domenico; Sullivan, Daniel] H Lee Moffitt Canc Ctr & Res Inst, Chem Biol & Mol Med Program, Tampa, FL USA. [Roodman, G. David] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Stuart, Robert K.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Ramakrishnan, Viswanathan; Wan, Wen] Virginia Commonwealth Univ, Dept Biostat, Richmond, VA USA. [Peer, Cody J.; Figg, William D.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kang, Loveleen] James A Haley Vet Hosp, Tampa, FL 33612 USA. [Colevas, A. Dimitrios; Doyle, L. Austin] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD USA. [Grant, Steven] Virginia Commonwealth Univ, Dept Microbiol & Immunol, Richmond, VA 23298 USA. [Grant, Steven] Virginia Commonwealth Univ, Dept Biochem & Mol Biol, Richmond, VA USA. [Grant, Steven] Virginia Commonwealth Univ, Inst Mol Med, Richmond, VA USA. RP Holkova, B (reprint author), VCU Massey Canc Ctr, 401 Coll St,POB 980035, Richmond, VA 23298 USA. EM bholkova@mcvh-vcu.edu RI Figg Sr, William/M-2411-2016 FU NIH [NCI R01 CA93738, NCI R01 CA100866, NCI R21 CA110953, NCI R01 CA167708, NCI P50 CA130805, NCI P30 CA016059, NCI P30 CA76292, NCI N01, HHSN261201100100C, NCRR M01 RR000065, KL2TR000057]; Multiple Myeloma Research Foundation FX The study was supported by grants from the NIH [NCI R01 CA93738, NCI R01 CA100866, NCI R21 CA110953, NCI R01 CA167708, NCI P50 CA130805 (Lymphoma SPORE), NCI P30 CA016059 (Cancer Center Support Grant to Massey Cancer Center), NCI P30 CA76292 (Cancer Center Support Grant to H. Lee Moffitt Cancer Center & Research Institute), NCI N01 Contract HHSN261201100100C for the Southeast Phase 2 Consortium, NCRR M01 RR000065 (GCRC), and National Center for Advancing Translational Sciences KL2TR000057 (CTSA)] and an award from the Multiple Myeloma Research Foundation. NR 37 TC 8 Z9 9 U1 0 U2 4 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 NOV 15 PY 2014 VL 20 IS 22 BP 5652 EP 5662 DI 10.1158/1078-0432.CCR-14-0805 PG 11 WC Oncology SC Oncology GA AT7PT UT WOS:000345130800011 PM 25248382 ER PT J AU Misteli, T AF Misteli, Tom TI The long reach of telomeres SO GENES & DEVELOPMENT LA English DT Article DE chromatin; replicative aging; senescence; cancer; age-dependent gene expression; telomerase; chromosome looping AB The primary purpose of telomeres is to protect chromosome ends from erosion during cell division cycles. New observations suggest an additional function for telomeres, namely in gene silencing via formation of long-range chromatin interactions. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov NR 9 TC 3 Z9 3 U1 0 U2 17 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 NOV 15 PY 2014 VL 28 IS 22 BP 2445 EP 2446 DI 10.1101/gad.254573.114 PG 2 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA AT9TP UT WOS:000345269300001 PM 25403176 ER PT J AU Moran, TP Nakano, H Kondilis-Mangum, HD Wade, PA Cook, DN AF Moran, Timothy P. Nakano, Hideki Kondilis-Mangum, Hrisavgi D. Wade, Paul A. Cook, Donald N. TI Epigenetic Control of Ccr7 Expression in Distinct Lineages of Lung Dendritic Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTIGEN-PRESENTING CELLS; STEADY-STATE CONDITIONS; GENE-EXPRESSION; HUMAN GENOME; LYMPH-NODES; FLT3 LIGAND; MIGRATION; INFLAMMATION; TOLERANCE; RECRUITMENT AB Adaptive immune responses to inhaled allergens are induced following CCR7-dependent migration of precursor of dendritic cell (pre-DC)-derived conventional DCs (cDCs) from the lung to regional lymph nodes. However, monocyte-derived (moDCs) in the lung express very low levels of Ccr7 and consequently do not migrate efficiently to LN. To investigate the molecular mechanisms that underlie this dichotomy, we studied epigenetic modifications at the Ccr7 locus of murine cDCs and moDCs. When expanded from bone marrow precursors, moDCs were enriched at the Ccr7 locus for trimethylation of histone 3 lysine 27 (H3K27me3), a modification associated with transcriptional repression. Similarly, moDCs prepared from the lung also displayed increased levels of H3K27me3 at the Ccr7 promoter compared with migratory cDCs from that organ. Analysis of DC progenitors revealed that epigenetic modification of Ccr7 does not occur early during DC lineage commitment because monocytes and pre-DCs both had low levels of Ccr7-associated H3K27me3. Rather, Ccr7 is gradually silenced during the differentiation of monocytes to moDCs. Thus, epigenetic modifications of the Ccr7 locus control the migration and therefore the function of DCs in vivo. These findings suggest that manipulating epigenetic mechanisms might be a novel approach to control DC migration and thereby improve DC-based vaccines and treat inflammatory diseases of the lung. C1 [Moran, Timothy P.] Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. [Nakano, Hideki; Cook, Donald N.] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [Kondilis-Mangum, Hrisavgi D.; Wade, Paul A.] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Cook, DN (reprint author), NIEHS, NIH, 111 TW Alexander Dr,Bldg 101,Room E244, Res Triangle Pk, NC 27709 USA. EM cookd@niehs.nih.gov OI Moran, Timothy/0000-0002-6832-9772 FU National Institutes of Health [5 T32 AI 007062-34]; National Institute on Environmental Health Sciences FX This work was supported by National Institutes of Health Grant 5 T32 AI 007062-34 and by the Intramural Research Program of the National Institutes of Health and the National Institute on Environmental Health Sciences. NR 56 TC 3 Z9 3 U1 0 U2 0 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 NOV 15 PY 2014 VL 193 IS 10 BP 4904 EP 4913 DI 10.4049/jimmunol.1401104 PG 10 WC Immunology SC Immunology GA AT6BJ UT WOS:000345023400019 PM 25297875 ER PT J AU Kleaveland, KR Velikoff, M Yang, JB Agarwal, M Rippe, RA Moore, BB Kim, KK AF Kleaveland, Kathryn R. Velikoff, Miranda Yang, Jibing Agarwal, Manisha Rippe, Richard A. Moore, Bethany B. Kim, Kevin K. TI Fibrocytes Are Not an Essential Source of Type I Collagen during Lung Fibrosis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; IDIOPATHIC PULMONARY-FIBROSIS; CELLS INITIATE FIBROSIS; CIRCULATING FIBROCYTES; PSEUDOMONAS-AERUGINOSA; EXTRACELLULAR-MATRIX; TISSUE FIBROSIS; GENE-EXPRESSION; GROWTH-FACTOR; MYOFIBROBLASTS AB Progressive fibrosis involves accumulation of activated collagen-producing mesenchymal cells. Fibrocytes are hematopoietic-derived cells with mesenchymal features that potentially have a unique and critical function during fibrosis. Fibrocytes have been proposed as an important direct contributor of type I collagen deposition during fibrosis based largely on fate-mapping studies. To determine the functional contribution of hematopoietic cell-derived type I collagen to fibrogenesis, we use a double-transgenic system to specifically delete the type I collagen gene across a broad population of hematopoietic cells. These mice develop a robust fibrotic response similar to littermate genotype control mice injured with bleomycin indicating that fibrocytes are not a necessary source of type I collagen. Using collagen-promoter GFP mice, we find that fibrocytes express type I collagen. However, fibrocytes with confirmed deletion of the type I collagen gene have readily detectable intracellular type I collagen indicating that uptake of collagen from neighboring cells account for much of the fibrocyte collagen. Collectively, these results clarify several seemingly conflicting reports regarding the direct contribution of fibrocytes to collagen deposition. C1 [Kleaveland, Kathryn R.; Velikoff, Miranda; Yang, Jibing; Agarwal, Manisha; Moore, Bethany B.; Kim, Kevin K.] Univ Michigan, Dept Internal Med, Div Pulm & Crit Care Med, Ann Arbor, MI 48109 USA. [Rippe, Richard A.] NIAAA, NIH, Bethesda, MD 20892 USA. RP Kim, KK (reprint author), 109 Zina Pitcher Pl,BSRB 4061, Ann Arbor, MI 48109 USA. EM kevkim@med.umich.edu OI Moore, Bethany/0000-0003-3051-745X FU National Institutes of Health [R01 HL108904, R01 HL115618] FX This work was supported by National Institutes of Health Grants R01 HL108904 (to K.K.K.) and R01 HL115618 (to B.B.M.). NR 60 TC 15 Z9 15 U1 1 U2 7 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 NOV 15 PY 2014 VL 193 IS 10 BP 5229 EP 5239 DI 10.4049/jimmunol.1400753 PG 11 WC Immunology SC Immunology GA AT6BJ UT WOS:000345023400051 PM 25281715 ER PT J AU Che, N Li, X Zhang, L Liu, R Chen, HF Gao, X Shi, ST Chen, WJ Sun, LY AF Che, Nan Li, Xia Zhang, Lu Liu, Rui Chen, Haifeng Gao, Xiang Shi, Songtao Chen, Wanjun Sun, Lingyun TI Impaired B Cell Inhibition by Lupus Bone Marrow Mesenchymal Stem Cells Is Caused by Reduced CCL2 Expression SO JOURNAL OF IMMUNOLOGY LA English DT Article ID STROMAL CELLS; INDOLEAMINE 2,3-DIOXYGENASE; ERYTHEMATOSUS; TRANSPLANTATION; PROLIFERATION; DIFFERENTIATION; MICE; ACTIVATION; GENERATION; INDUCTION AB Mesenchymal stem cells (MSC) from healthy human and normal mice can inhibit normal B cell proliferation, differentiation, and Ab secretion in vitro. However, it remains unknown whether MSC from lupus-like mice and patients with systemic lupus erythematosus (SLE) exhibit the same immunoregulatory activity as normal MSC for B cell inhibition and, if not, what the underlying molecular mechanism would be. In this study, we showed that bone marrow-derived MSCs from lupus-like mice and SLE patients had an impairment in suppressing normal B cell proliferation and differentiation, which was caused by the reduction of CCL2 levels. Knockdown of CCL2 in normal MSC damaged their suppressive capacity for B cells. Conversely, overexpression of CCL2 in lupus MSCs restored their immunoregulatory ability for B cells in vitro and ameliorated the pathology of lupus nephritis and serological changes in MRL/lpr mice in vivo. Mechanistically, MSC-mediated B cell inhibition was dependent on matrix metalloproteinase proteolytic processing of CCL2. These findings reveal a novel function of CCL2 in B cell regulation by MSCs and suggest that CCL2 manipulation on MSCs may serve as a potential pathway for developing the more effective MSC-based therapy in autoimmune diseases associated with B cell activation, such as SLE. C1 [Che, Nan; Li, Xia; Zhang, Lu; Liu, Rui; Chen, Haifeng; Sun, Lingyun] Nanjing Univ, Affiliated Hosp, Nanjing Drum Tower Hosp, Sch Med,Dept Rheumatol & Immunol, Nanjing 210008, Jiangsu, Peoples R China. [Gao, Xiang] Nanjing Univ, Model Anim Res Ctr, Nanjing 210093, Jiangsu, Peoples R China. [Shi, Songtao] Univ So Calif, Ctr Craniofacial Mol Biol, Herman Ostrow Sch Dent, Los Angeles, CA 90033 USA. [Chen, Wanjun] Natl Inst Dent & Craniofacial Res, Mucosal Immunol Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Sun, LY (reprint author), Nanjing Univ, Affiliated Hosp, Nanjing Drum Tower Hosp, Sch Med,Dept Rheumatol & Immunol, 321 Zhongshan Rd, Nanjing 210008, Jiangsu, Peoples R China. EM lingyunsun2012@163.com FU National Natural Science Foundation of China [81273304]; Major International (Regional) Joint Research Project [81120108021]; Jiangsu Province Kejiao Xingwei Program; Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research FX This work was supported by the National Natural Science Foundation of China Grant 81273304, Major International (Regional) Joint Research Project 81120108021, the Jiangsu Province Kejiao Xingwei Program, and the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research (to W.C). NR 41 TC 11 Z9 11 U1 5 U2 11 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 NOV 15 PY 2014 VL 193 IS 10 BP 5306 EP 5314 DI 10.4049/jimmunol.1400036 PG 9 WC Immunology SC Immunology GA AT6BJ UT WOS:000345023400058 PM 25339674 ER PT J AU Nardo, L Lane, NE Parimi, N Cawthon, PM Fan, B Shepherd, J Cauley, J Zucker-Levin, A Murphy, RA Katzman, WB AF Nardo, Lorenzo Lane, Nancy E. Parimi, Neeta Cawthon, Peggy M. Fan, Bo Shepherd, John Cauley, Jane Zucker-Levin, Audrey Murphy, Rachel A. Katzman, Wendy B. TI Diffuse Idiopathic Skeletal Hyperostosis Association With Thoracic Spine Kyphosis A Cross-sectional Study for the Health Aging and Body Composition Study SO SPINE LA English DT Article DE Cobb angle; kyphosis; hyperkyphosis; diffuse idiopathic skeletal hyperostosis; DISH; aging; spine; computed tomography; spine ligament; race; bone metabolism ID ANTERIOR LONGITUDINAL LIGAMENT; COMMUNITY-DWELLING WOMEN; OLDER WOMEN; OSTEOPOROTIC FRACTURES; HYPER-OSTOSIS; ROTES-QUEROL; COBB ANGLE; HYPERKYPHOSIS; RELIABILITY; FORESTIER AB Study Design. A descriptive study of the association between diffuse idiopathic skeletal hyperostosis (DISH) and kyphosis. Objective. To investigate the association of DISH with Cobb angle of kyphosis in a large cohort of older subjects from the Health Aging and Body Composition Study. Summary of Background Data. DISH and thoracic kyphosis are well-defined radiographical findings in spines of older individuals. Characteristics of DISH (ossifications between vertebral segments) reflect changes of spine anatomy and physiology that may be associated with Cobb angle of kyphosis. Methods. Using data from 1172 subjects aged 70 to 79 years, we measured DISH and Cobb angle of kyphosis from computed tomographic lateral scout scans. Characteristics of participants with and without DISH were assessed using the. 2 and t tests. Association between DISH and Cobb angle was analyzed using linear regression. Cobb angle and DISH relationship was assessed at different spine levels (thoracic and lumbar). Results. DISH was identified on computed tomographic scout scan in 152 subjects with 101 cases in only the thoracic spine and 51 in both thoracic and lumbar spine segments. The mean Cobb angle of kyphosis in the analytic sample was 31.3 degrees (standard deviation = 11.2). The presence of DISH was associated with a greater Cobb angle of 9.1 degrees and 95% confidence interval (95% CI) (5.6-12.6) among African Americans and a Cobb angle of 2.9 degrees and 95% CI (0.5-5.2) among Caucasians compared with those with no DISH. DISH in the thoracic spine alone was associated with a greater Cobb angle of 10.6 degrees and 95% CI (6.5-14.7) in African Americans and a Cobb angle of 3.8 degrees and 95% CI (1.0-6.5) in Caucasians compared with those with no DISH. Conclusion. DISH is associated with greater Cobb angle of kyphosis, especially when present in the thoracic spine alone. The association of DISH with Cobb angle is stronger within the African American population. C1 [Nardo, Lorenzo] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. [Lane, Nancy E.] Univ Calif Davis, Ctr Musculoskeletal Hlth, Sch Med, Sacramento, CA 95817 USA. [Parimi, Neeta; Cawthon, Peggy M.] Calif Pacific Med Res Ctr, San Francisco, CA USA. [Fan, Bo; Shepherd, John] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94158 USA. [Cauley, Jane] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Zucker-Levin, Audrey] Univ Tennessee, Ctr Hlth Sci, Coll Allied Hlth Sci, Dept Phys Therapy, Memphis, TN 38163 USA. [Murphy, Rachel A.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Katzman, Wendy B.] Univ Calif San Francisco, Dept Phys Therapy & Rehabil Sci, San Francisco, CA 94158 USA. RP Katzman, WB (reprint author), Univ Calif San Francisco, Dept Phys Therapy & Rehabil Sci, 1500 Owens St Suite 400, San Francisco, CA 94158 USA. EM wendy.katzman@ucsf.edu RI Cauley, Jane/N-4836-2015; OI Cauley, Jane/0000-0003-0752-4408; Nardo, Lorenzo/0000-0002-0266-2708 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050, RO1 AG041921]; National Institute of Nursing Research (NINR) [R01-NR-012459]; NIH [AR043052, K24AR04884, P50 AR060752]; Office of Research in Women's Health; National Institute of Arthritis, Musculoskeletal, and Skin Diseases P50 [AR063043] FX National Institute on Aging (NIA) Contracts N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106; NIA grants R01-AG028050, RO1 AG041921; National Institute of Nursing Research (NINR) grant R01-NR-012459; NIH grants AR043052 and K24AR04884, P50 AR060752, Office of Research in Women's Health and the National Institute of Arthritis, Musculoskeletal, and Skin Diseases P50 grant AR063043 funds were received in support of this work. NR 26 TC 0 Z9 1 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD NOV 15 PY 2014 VL 39 IS 24 BP E1418 EP E1424 DI 10.1097/BRS.0000000000000615 PG 7 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA AT7QY UT WOS:000345133700003 PM 25387143 ER PT J AU Spitz, MR Lam, TK Schully, SD Khoury, MJ AF Spitz, Margaret R. Lam, Tram Kim Schully, Sheri D. Khoury, Muin J. TI The Next Generation of Large-Scale Epidemiologic Research: Implications for Training Cancer Epidemiologists SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE cancer epidemiologists; education; large-scale epidemiologic research ID POPULATION HEALTH; PUBLIC-HEALTH; TEAM SCIENCE; COLLABORATION; FUTURE AB There is expanding consensus on the need to modernize the training of cancer epidemiologists to accommodate rapidly emerging technological advancements and the digital age, which are transforming the practice of cancer epidemiology. There is also a growing imperative to extend cancer epidemiology research that is etiological to that which is applied and has the potential to affect individual and public health. Medical schools and schools of public health are recognizing the need to develop such integrated programs; however, we lack the data to estimate how many current training programs are effectively equipping epidemiology students with the knowledge and tools to design, conduct, and analyze these increasingly complex studies. There is also a need to develop new mentoring approaches to account for the transdisciplinary team-science environment that now prevails. With increased dialogue among schools of public health, medical schools, and cancer centers, revised competencies and training programs at predoctoral, doctoral, and postdoctoral levels must be developed. Continuous collection of data on the impact and outcomes of such programs is also recommended. C1 [Spitz, Margaret R.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Lam, Tram Kim; Schully, Sheri D.] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. RP Spitz, MR (reprint author), Baylor Coll Med, Dan L Duncan Canc Ctr, One Baylor Plaza, Houston, TX 77030 USA. EM spitz@bcm.edu NR 19 TC 5 Z9 5 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 NOV 15 PY 2014 VL 180 IS 10 BP 964 EP 967 DI 10.1093/aje/kwu256 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AT2OK UT WOS:000344773900002 PM 25234430 ER PT J AU Jankovic, N Geelen, A Streppel, MT de Groot, LCPGM Orfanos, P van den Hooven, EH Pikhart, H Boffetta, P Trichopoulou, A Bobak, M Bueno-de-Mesquita, HB Kee, F Franco, OH Park, Y Hallmans, G Tjonneland, A May, AM Pajak, A Malyutina, S Kubinova, R Amiano, P Kampman, E Feskens, EJ AF Jankovic, Nicole Geelen, Anouk Streppel, Martinette T. de Groot, Lisette C. P. G. M. Orfanos, Philippos van den Hooven, Edith H. Pikhart, Hynek Boffetta, Paolo Trichopoulou, Antonia Bobak, Martin Bueno-de-Mesquita, H. B. Kee, Frank Franco, Oscar H. Park, Yikyung Hallmans, Goran Tjonneland, Anne May, Anne M. Pajak, Andrzej Malyutina, Sofia Kubinova, Ruzena Amiano, Pilar Kampman, Ellen Feskens, Edith J. TI Adherence to a Healthy Diet According to the World Health Organization Guidelines and All-Cause Mortality in Elderly Adults From Europe and the United States SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE aging; cohort; Consortium on Health and Ageing: Network of Cohorts in Europe and the United States; diet; longevity; meta-analysis ID CARDIOVASCULAR-DISEASE; EPIC PROJECT; DESIGN; PREVENTION; COHORT; RISK; DETERMINANTS; RATIONALE; QUALITY; SCORES AB The World Health Organization (WHO) has formulated guidelines for a healthy diet to prevent chronic diseases and postpone death worldwide. Our objective was to investigate the association between the WHO guidelines, measured using the Healthy Diet Indicator (HDI), and all-cause mortality in elderly men and women from Europe and the United States. We analyzed data from 396,391 participants (42% women) in 11 prospective cohort studies who were 60 years of age or older at enrollment (in 1988-2005). HDI scores were based on 6 nutrients and 1 food group and ranged from 0 (least healthy diet) to 70 (healthiest diet). Adjusted cohort-specific hazard ratios were derived by using Cox proportional hazards regression and subsequently pooled using random-effects meta-analysis. During 4,497,957 person-years of follow-up, 84,978 deaths occurred. Median HDI scores ranged from 40 to 54 points across cohorts. For a 10-point increase in HDI score (representing adherence to an additional WHO guideline), the pooled adjusted hazard ratios were 0.90 (95% confidence interval (CI): 0.87, 0.93) for men and women combined, 0.89 (95% CI: 0.85, 0.92) for men, and 0.90 (95% CI: 0.85, 0.95) for women. These estimates translate to an increased life expectancy of 2 years at the age of 60 years. Greater adherence to the WHO guidelines is associated with greater longevity in elderly men and women in Europe and the United States. C1 [Jankovic, Nicole; Geelen, Anouk; Streppel, Martinette T.; de Groot, Lisette C. P. G. M.; Kampman, Ellen; Feskens, Edith J.] Wageningen Univ, Div Human Nutr, Dept Agrotechnol & Food Sci, NL-6700 EV Wageningen, Netherlands. [Orfanos, Philippos; Trichopoulou, Antonia] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece. [van den Hooven, Edith H.; Franco, Oscar H.] Univ Med Ctr Rotterdam, Dept Epidemiol, Erasmus Med Ctr, Rotterdam, Netherlands. [Pikhart, Hynek; Bobak, Martin] UCL, Res Dept Epidemiol & Publ Hlth, Inst Epidemiol & Hlth Care, London, England. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Mt Sinai Sch Med, Inst Translat Epidemiol, New York, NY USA. [Boffetta, Paolo; Trichopoulou, Antonia] Hellen Hlth Fdn, Athens, Greece. [Bueno-de-Mesquita, H. B.] Natl Inst Publ Hlth & Environm, Dept Determinants Chron Dis, NL-3720 BA Bilthoven, Netherlands. [Bueno-de-Mesquita, H. B.] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Bueno-de-Mesquita, H. B.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England. [Bueno-de-Mesquita, H. B.] Univ Malaya, Fac Med, Dept Social & Prevent Med, Kuala Lumpur, Malaysia. [Kee, Frank] Queens Univ Belfast, United Kingdom Clin Res Collaborat Ctr Excellence, Sch Med Dent & Biomed Sci, Belfast, Antrim, North Ireland. [Park, Yikyung] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Tjonneland, Anne] Danish Canc Soc Res Ctr, Copenhagen, Denmark. [May, Anne M.] Univ Med Ctr Utrecht, Dept Epidemiol, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Pajak, Andrzej] Jagiellonian Univ, Dept Epidemiol & Populat Studies, Fac Hlth Sci, Coll Med, Krakow, Poland. [Malyutina, Sofia] Russian Acad Med Sci, Inst Internal & Prevent Med, Survey Ctr, Siberian Branch, Novosibirsk, Russia. [Malyutina, Sofia] Novosibirsk State Med Univ, Novosibirsk, Russia. [Kubinova, Ruzena] Environm & Populat Hlth Monitoring Ctr, Natl Inst Publ Hlth, Prague, Czech Republic. [Amiano, Pilar] Basque Govt, Publ Hlth Div Gipuzkoa, Res Inst BioDonostia, San Sebastian, Spain. [Amiano, Pilar] Consortium Biomed Res Epidemiol & Publ Hlth CIBER, Madrid, Spain. RP Jankovic, N (reprint author), Wageningen Univ, Div Human Nutr, POB 8129, NL-6700 EV Wageningen, Netherlands. EM nicole.jankovic@wur.nl RI Geelen, Anouk/P-5041-2014; Kampman, E./H-8057-2014; OI Geelen, Anouk/0000-0003-1799-4075; Pikhart, Hynek/0000-0001-5277-4049; Feskens, Edith/0000-0001-5819-2488; Park, Yikyung/0000-0002-6281-489X FU Directorate-General for Research & Innovation in the European Commission [242244]; Regional Government of Andalucia, Spain; Regional Government of Asturias, Spain; Regional Government of Basque Country, Spain; Regional Government of Murcia, Spain; Regional Government of Navarra, Spain; Regional Government of Vasterbotten, Sweden; 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; Statistics Netherlands; Danish Cancer Society; Hellenic Health Foundation; Stavros Niarchos Foundation; Intramural Research Program of the National Institutes of Health; National Cancer Institute; Wellcome Trust [064947/Z/01/Z]; MacArthur Foundation; National Institute on Aging [1R01 AG23522]; Erasmus Medical Center; Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Genomics Initiative; Ministry of Education, Culture, and Science; Ministry of Health, Welfare, and Sports; European Commission; Municipality of Rotterdam FX This analysis was part of the Consortium on Health and Ageing (CHANCES) project funded in the FP7 framework programme of the Directorate-General for Research & Innovation in the European Commission (grant 242244). The CHANCES project is coordinated by the Hellenic Health Foundation, Greece. The included cohorts were financially supported by the Regional Governments of Andalucia, Asturias, Basque Country, Murcia, and Navarra, Spain; the Regional Government of Vasterbotten, Sweden; the Dutch Ministry of Public Health, Welfare, and Sports; the Netherlands Cancer Registry; LK Research Funds; Dutch Prevention Funds; Dutch Zorg Onderzoek Nederland; the World Cancer Research Fund; Statistics Netherlands; the Danish Cancer Society; the Hellenic Health Foundation; the Stavros Niarchos Foundation; the Intramural Research Program of the National Institutes of Health; the National Cancer Institute; the Wellcome Trust (grant 064947/Z/01/Z), the MacArthur Foundation; and the National Institute on Aging (grant 1R01 AG23522). The Rotterdam Elderly Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Netherlands Genomics Initiative; the Ministry of Education, Culture, and Science; the Ministry of Health, Welfare, and Sports; the European Commission; and the Municipality of Rotterdam. The Survey in Europe on Nutrition and the Elderly was a concerted action within the European Community Concerted Action on Nutrition and Health Programme of the European Union. NR 32 TC 21 Z9 23 U1 2 U2 18 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 NOV 15 PY 2014 VL 180 IS 10 BP 978 EP 988 DI 10.1093/aje/kwu229 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AT2OK UT WOS:000344773900004 PM 25318818 ER PT J AU Xiao, Q Keadle, SK Hollenbeck, AR Matthews, CE AF Xiao, Qian Keadle, Sarah K. Hollenbeck, Albert R. Matthews, Charles E. TI Sleep Duration and Total and Cause-Specific Mortality in a Large US Cohort: Interrelationships With Physical Activity, Sedentary Behavior, and Body Mass Index SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE body mass index; mortality; physical activity; sedentary behavior; sleep; sleep duration ID ALL-CAUSE MORTALITY; METAANALYSIS; HEALTH; ADULTS; WOMEN; OBESITY; WEIGHT; ASSOCIATION; DISEASE; STATES AB Both short and long durations of sleep are associated with higher mortality, but little is known about the interrelationship between sleep and other modifiable factors in relation to mortality. In the National Institutes of Health-AARP Diet and Health Study (1995-1996), we examined associations between sleep duration and total, cardiovascular disease (CVD), and cancer mortality among 239,896 US men and women aged 51-72 years who were free of cancer, CVD, and respiratory disease. We evaluated the influence of moderate-to-vigorous physical activity, television viewing, and body mass index (BMI; weight (kg)/height (m)(2)) on the sleep-mortality association and assessed their combined association with mortality. During an average of 14 years of follow-up, we identified 44,100 deaths. Compared with 7-8 hours of sleep per day, both shorter and longer sleep durations were associated with higher total and CVD mortality. We found a greater elevation in CVD mortality associated with shorter sleep among overweight and obese people, suggesting a synergistic interaction between sleep and BMI. People in the unhealthy categories of all 4 risk factors (sleep < 7 hours/day, moderate-to-vigorous physical activity a parts per thousand currency sign1 hour/week, television viewing a parts per thousand yen3 hours/day, and BMI a parts per thousand yen25) had significantly higher all-cause (relative risk (RR) = 1.42, 95% confidence interval (CI): 1.34, 1.52), CVD (RR = 1.90, 95% CI: 1.67, 2.17), and cancer (RR = 1.21, 95% CI: 1.09, 1.34) mortality. Short sleep duration may predict higher mortality, particularly CVD mortality, among overweight and obese people. C1 [Xiao, Qian; Keadle, Sarah K.; Matthews, Charles E.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Xiao, Q (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM qian.xiao@nih.gov RI matthews, Charles/E-8073-2015; OI matthews, Charles/0000-0001-8037-3103; Keadle, Sarah/0000-0002-9569-9306 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Department of Health and Human Services FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Department of Health and Human Services. NR 33 TC 24 Z9 26 U1 0 U2 17 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 NOV 15 PY 2014 VL 180 IS 10 BP 997 EP 1006 DI 10.1093/aje/kwu222 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AT2OK UT WOS:000344773900006 PM 25281691 ER PT J AU Joshi, AD Lindstrom, S Husing, A Barrdahl, M VanderWeele, TJ Campa, D Canzian, F Gaudet, MM Figueroa, JD Baglietto, L Berg, CD Buring, JE Chanock, SJ Chirlaque, MD Diver, WR Dossus, L Giles, GG Haiman, CA Hankinson, SE Henderson, BE Hoover, RN Hunter, DJ Isaacs, C Kaaks, R Kolonel, LN Krogh, V Le Marchand, L Lee, IM Lund, E McCarty, CA Overvad, K Peeters, PH Riboli, E Schumacher, F Severi, G Stram, DO Sund, M Thun, MJ Travis, RC Trichopoulos, D Willett, WC Zhang, SM Ziegler, RG Kraft, P AF Joshi, Amit D. Lindstrom, Sara Husing, Anika Barrdahl, Myrto VanderWeele, Tyler J. Campa, Daniele Canzian, Federico Gaudet, Mia M. Figueroa, Jonine D. Baglietto, Laura Berg, Christine D. Buring, Julie E. Chanock, Stephen J. Chirlaque, Maria-Dolores Diver, W. Ryan Dossus, Laure Giles, Graham G. Haiman, Christopher A. Hankinson, Susan E. Henderson, Brian E. Hoover, Robert N. Hunter, David J. Isaacs, Claudine Kaaks, Rudolf Kolonel, Laurence N. Krogh, Vittorio Le Marchand, Loic Lee, I-Min Lund, Eiliv McCarty, Catherine A. Overvad, Kim Peeters, Petra H. Riboli, Elio Schumacher, Fredrick Severi, Gianluca Stram, Daniel O. Sund, Malin Thun, Michael J. Travis, Ruth C. Trichopoulos, Dimitrios Willett, Walter C. Zhang, Shumin Ziegler, Regina G. Kraft, Peter CA BPC3 TI Additive Interactions Between Susceptibility Single-Nucleotide Polymorphisms Identified in Genome-Wide Association Studies and Breast Cancer Risk Factors in the Breast and Prostate Cancer Cohort Consortium SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE additive interactions; breast cancer; genome-wide association studies; single-nucleotide polymorphisms ID BASE-LINE CHARACTERISTICS; CONFIDENCE-INTERVALS; COMMON VARIANTS; CONFER SUSCEPTIBILITY; 14Q24.1 RAD51L1; LIFE-STYLE; LOCI; PREDICTION; ALLELES; HEALTH AB Additive interactions can have public health and etiological implications but are infrequently reported. We assessed departures from additivity on the absolute risk scale between 9 established breast cancer risk factors and 23 susceptibility single-nucleotide polymorphisms (SNPs) identified from genome-wide association studies among 10,146 non-Hispanic white breast cancer cases and 12,760 controls within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium. We estimated the relative excess risk due to interaction and its 95% confidence interval for each pairwise combination of SNPs and nongenetic risk factors using age- and cohort-adjusted logistic regression models. After correction for multiple comparisons, we identified a statistically significant relative excess risk due to interaction (uncorrected P = 4.51 x 10(-5)) between a SNP in the DNA repair protein RAD51 homolog 2 gene (RAD51L1; rs10483813) and body mass index (weight (kg)/height (m)(2)). We also compared additive and multiplicative polygenic risk prediction models using per-allele odds ratio estimates from previous studies for breast-cancer susceptibility SNPs and observed that the multiplicative model had a substantially better goodness of fit than the additive model. C1 [Joshi, Amit D.; Lindstrom, Sara; Hunter, David J.; Kraft, Peter] Harvard Univ, Program Genet Epidemiol & Stat Genet, Sch Publ Hlth, Boston, MA 02115 USA. [Husing, Anika; Barrdahl, Myrto; Kaaks, Rudolf] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Joshi, Amit D.; VanderWeele, Tyler J.; Trichopoulos, Dimitrios; Kraft, Peter] Harvard Univ, Dept Epidemiol, Sch Publ Hlth, Boston, MA 02115 USA. [Campa, Daniele] Univ Pisa, Dept Biol, Pisa, Italy. [VanderWeele, Tyler J.] Harvard Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02115 USA. [Campa, Daniele; Canzian, Federico] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Gaudet, Mia M.] Amer Canc Soc, Genet Epidemiol Unit, Atlanta, GA 30329 USA. [Figueroa, Jonine D.; Chanock, Stephen J.; Hoover, Robert N.; Ziegler, Regina G.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Baglietto, Laura; Giles, Graham G.; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic, Australia. [Baglietto, Laura; Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Sch Populat Hlth, Melbourne, Vic, Australia. [Berg, Christine D.] NCI, Div Canc Prevent, Bethesda, MD 20892 USA. [Buring, Julie E.; Lee, I-Min; Zhang, Shumin] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Buring, Julie E.; Lee, I-Min; Zhang, Shumin] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Chirlaque, Maria-Dolores] Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain. [Chirlaque, Maria-Dolores] Consorcio Invest Biomed Epidemiol & Salud Publ, Madrid, Spain. [Diver, W. Ryan; Thun, Michael J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Dossus, Laure] Inst Gustave Roussy, INSERM, Ctr Res Epidemiol & Populat Hlth, U1018, F-94805 Villejuif, France. [Dossus, Laure] Paris South Univ, Unite Mixte Rech Sante 1018, Villejuif, France. [Giles, Graham G.] Monash Univ, Fac Med, Melbourne, Vic 3004, Australia. [Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Stram, Daniel O.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hankinson, Susan E.] Univ Massachusetts, Div Biostat & Epidemiol, Sch Publ Hlth & Hlth Sci, Amherst, MA 01003 USA. [Isaacs, Claudine] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Kolonel, Laurence N.] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA. [Krogh, Vittorio] Fdn IRCCS Ist Nazl Tumori, Epidemiol & Prevent Unit, Milan, Italy. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Lund, Eiliv] Univ Tromso, Inst Community Med, Tromso, Norway. [McCarty, Catherine A.] Essentia Inst Rural Hlth, Duluth, MN USA. [Overvad, Kim] Aarhus Univ, Epidemiol Sect, Dept Publ Hlth, Aarhus, Denmark. [Peeters, Petra H.] Univ Med Ctr Utrecht, Dept Epidemiol, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Peeters, Petra H.; Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Fac Med, Dept Epidemiol & Biostat, London, England. [Sund, Malin] Umea Univ Hosp, Dept Surg, S-90185 Umea, Sweden. [Travis, Ruth C.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Trichopoulos, Dimitrios] Hellen Hlth Fdn, Athens, Greece. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Willett, Walter C.] Harvard Univ, Dept Nutr, Sch Publ Hlth, Boston, MA 02115 USA. RP Joshi, AD (reprint author), Harvard Univ, Dept Epidemiol, Sch Publ Hlth, 655 Huntington Ave,Bldg 2,Room 205, Boston, MA 02115 USA. EM ajoshi@hsph.harvard.edu RI Campa, Daniele/K-1617-2016; Krogh, Vittorio/K-2628-2016; OI Campa, Daniele/0000-0003-3220-9944; Krogh, Vittorio/0000-0003-0122-8624; Giles, Graham/0000-0003-4946-9099 FU National Cancer Institute, US National Institutes of Health [CA148065, U01-CA98233, U19-CA148065, U01-CA98710, U01-CA98216, U01-CA98758]; Intramural Research Program of the National Institutes of Health/National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This study was funded by the National Cancer Institute, US National Institutes of Health (grant CA148065 and cooperative agreements U01-CA98233 and U19-CA148065 to D.J.H., U01-CA98710 to M.J.T., U01-CA98216 to E. R. and R. K., and U01-CA98758 to B. E. H.) and the Intramural Research Program of the National Institutes of Health/National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 65 TC 6 Z9 6 U1 1 U2 10 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 NOV 15 PY 2014 VL 180 IS 10 BP 1018 EP 1027 DI 10.1093/aje/kwu214 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AT2OK UT WOS:000344773900008 PM 25255808 ER PT J AU Yeganova, L Kim, W Kim, S Wilbur, WJ AF Yeganova, Lana Kim, Won Kim, Sun Wilbur, W. John TI Retro: concept-based clustering of biomedical topical sets SO BIOINFORMATICS LA English DT Article AB Motivation: Clustering methods can be useful for automatically grouping documents into meaningful clusters, improving human comprehension of a document collection. Although there are clustering algorithms that can achieve the goal for relatively large document collections, they do not always work well for small and homogenous datasets. Methods: In this article, we present Retro-a novel clustering algorithm that extracts meaningful clusters along with concise and descriptive titles from small and homogenous document collections. Unlike common clustering approaches, our algorithm predicts cluster titles before clustering. It relies on the hypergeometric distribution model to discover key phrases, and generates candidate clusters by assigning documents to these phrases. Further, the statistical significance of candidate clusters is tested using supervised learning methods, and a multiple testing correction technique is used to control the overall quality of clustering. Results: We test our system on five disease datasets from OMIM (R) and evaluate the results based on MeSH (R) term assignments. We further compare our method with several baseline and state-of-the-art methods, including K-means, expectation maximization, latent Dirichlet allocation-based clustering, Lingo, OPTIMSRC and adapted GK-means. The experimental results on the 20-Newsgroup and ODP-239 collections demonstrate that our method is successful at extracting significant clusters and is superior to existing methods in terms of quality of clusters. Finally, we apply our system to a collection of 6248 topical sets from the HomoloGene (R) database, a resource in PubMed (R). Empirical evaluation confirms the method is useful for small homogenous datasets in producing meaningful clusters with descriptive titles. C1 [Yeganova, Lana; Kim, Won; Kim, Sun; Wilbur, W. John] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Yeganova, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM lana.yeganova@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 27 TC 3 Z9 3 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD NOV 15 PY 2014 VL 30 IS 22 BP 3240 EP 3248 DI 10.1093/bioinformatics/btu514 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA AT2OQ UT WOS:000344774600013 PM 25075115 ER PT J AU Kohut, SJ Hiranita, T Hong, SK Ebbs, AL Tronci, V Green, J Garces-Ramirez, L Chun, LE Mereu, M Newman, AH Katz, JL Tanda, G AF Kohut, Stephen J. Hiranita, Takato Hong, Soo-Kyung Ebbs, Aaron L. Tronci, Valeria Green, Jennifer Garces-Ramirez, Linda Chun, Lauren E. Mereu, Maddalena Newman, Amy H. Katz, Jonathan L. Tanda, Gianluigi TI Preference for Distinct Functional Conformations of the Dopamine Transporter Alters the Relationship between Subjective Effects of Cocaine and Stimulation of Mesolimbic Dopamine SO BIOLOGICAL PSYCHIATRY LA English DT Article DE ADHD; benztropine analogs; cocaine discrimination; dopamine microdialysis; drug abuse and addiction; nucleus accumbens shell ID UPTAKE INHIBITORS; BENZTROPINE ANALOGS; EXTRACELLULAR DOPAMINE; PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS; SQUIRREL-MONKEYS; MONOAMINE UPTAKE; ABUSE LIABILITY; BINDING; MICRODIALYSIS AB Background: Subjective effects of cocaine are mediated primarily by dopamine (DA) transporter (DAT) blockade. The present study assessed the hypothesis that different DAT conformational equilibria regulate differences in cocaine-like subjective effects and extracellular DA induced by diverse DA-uptake inhibitors (DUIs). Methods: The relationship between cocaine-like subjective effects and stimulation of mesolimbic DA levels by standard DUIs (cocaine, methylphenidate, WIN35,428) and atypical DUIs (benztropine analogs: AHN1-055, AHN2-005, JHW007) was investigated using cocaine discrimination and DA microdialysis procedures in rats. Results: All drugs stimulated DA levels with different maxima and time courses. Standard DUIs, which preferentially bind outward-facing DAT conformations, fully substituted for cocaine, consistently producing cocaine-like subjective effects at DA levels of 100-125% over basal values, regardless of dose or pretreatment time. The atypical DUIs, with DAT binding minimally affected by DAT conformation, produced inconsistent cocaine-like subjective effects. Full effects were obtained, if at all, only at a few doses and pretreatment times and at DA levels 600-700% greater than basal values. Importantly, the linear, time-independent, relationship between cocaine-like subjective effects and DA stimulation obtained with standard DUIs was not obtained with the atypical DUIs. Conclusions: These results suggest a time-related desensitization process underlying the reduced cocaine subjective effects of atypical DUIs that may be differentially induced by the binding modalities identified using molecular approaches. Since the DAT is the target of several drugs for treating neuropsychiatric disorders, such as attention-deficit/hyperactivity disorder, these results help to identify safe and effective medications with minimal cocaine-like subjective effects that contribute to abuse liability. C1 [Kohut, Stephen J.; Hiranita, Takato; Hong, Soo-Kyung; Ebbs, Aaron L.; Tronci, Valeria; Green, Jennifer; Garces-Ramirez, Linda; Chun, Lauren E.; Mereu, Maddalena; Katz, Jonathan L.; Tanda, Gianluigi] NIDA, Psychobiol Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH,US Dept HHS, Baltimore, MD 21224 USA. [Newman, Amy H.] NIDA, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH,US Dept HHS, Baltimore, MD 21224 USA. [Newman, Amy H.; Tanda, Gianluigi] NIDA, Medicat Dev Program, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH,US Dept HHS, Baltimore, MD 21224 USA. [Hong, Soo-Kyung] Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea. [Garces-Ramirez, Linda] Inst Politecn Nacl, Escuela Nacl Ciencias Biol, Mexico City, DF, Mexico. RP Tanda, G (reprint author), NIDA, Intramural Res Program, NIH, US Dept HHS,Medicat Dev Program, NIDA Suite 200,251 Bayview Blvd, Baltimore, MD 21224 USA. EM gtanda@mail.nih.gov RI Tanda, Gianluigi/B-3318-2009; OI Tanda, Gianluigi/0000-0001-9526-9878; Katz, Jonathan/0000-0002-1068-1159 FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services; Consejo Nacional de Ciencia y Tecnologia, Mexico; Japanese Society for the Promotion of Science; Research Fellowship for Japanese Biomedical and Behavioral Researchers at the National Institutes of Health FX This work was funded by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services.; Linda Garces-Ramirez was recipient of a scholarship from Consejo Nacional de Ciencia y Tecnologia, Mexico.; Takato Hiranita was supported in part by the Japanese Society for the Promotion of Science, Research Fellowship for Japanese Biomedical and Behavioral Researchers at the National Institutes of Health. NR 60 TC 5 Z9 5 U1 0 U2 10 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 NOV 15 PY 2014 VL 76 IS 10 BP 802 EP 809 DI 10.1016/j.biopsych.2014.03.031 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AT2AN UT WOS:000344733100008 PM 24853388 ER PT J AU Burotto, M Chiou, VL Lee, JM Kohn, EC AF Burotto, Mauricio Chiou, Victoria L. Lee, Jung-Min Kohn, Elise C. TI The MAPK Pathway Across Different Malignancies: A New Perspective SO CANCER LA English DT Review DE mitogen-activated protein kinase (MAPK); v-raf murine sarcoma viral oncogene homolog (BRAF); extracellular signal-regulated kinase (ERK); mitogen-activated protein kinase-kinase (MEK); signaling; melanoma; ovarian cancer; colorectal cancer ID CELL LUNG-CANCER; ACTIVATED PROTEIN-KINASE; BRAF V600E MUTATION; METASTATIC COLORECTAL-CANCER; RNA INTERFERENCE SCREEN; WILD-TYPE BRAF; ACQUIRED-RESISTANCE; POTENTIAL MECHANISM; MEK INHIBITION; OVARIAN-CANCER AB The mitogen-activated protein kinase/extracellular signal-regulated (MAPK/ERK) pathway is activated by upstream genomic events and/or activation of multiple signaling events in which information coalesces at this important nodal pathway point. This pathway is tightly regulated under normal conditions by phosphatases and bidirectional communication with other pathways, like the protein kinase B/mammalian target of rapamycin (AKT/m-TOR) pathway. Recent evidence indicates that the MAPK/ERK signaling node can function as a tumor suppressor as well as the more common pro-oncogenic signal. The effect that predominates depends on the intensity of the signal and the context or tissue in which the signal is aberrantly activated. Genomic profiling of tumors has revealed common mutations in MAPK/ERK pathway components, such as v-raf murine sarcoma viral oncogene homolog B1 (BRAF). Currently approved for the treatment of melanoma, inhibitors of BRAF kinase are being studied alone and in combination with inhibitors of the MAPK and other pathways to optimize the treatment of many tumor types. Therapies targeted toward MAPK/ERK components have various response rates when used in different solid tumors, such as colorectal cancer and ovarian cancer. Understanding the differential nature of activation of the MAPK/ERK pathway in each tumor type is critical in developing single and combination regimens, because different tumors have unique mechanisms of primary and secondary signaling and subsequent sensitivity to drugs. (C) 2014 American Cancer Society. C1 [Chiou, Victoria L.; Lee, Jung-Min; Kohn, Elise C.] NCI, Womens Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Kohn, Elise C.] NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diagnost, Bethesda, MD 20892 USA. RP Burotto, M (reprint author), Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM mauricio.burottopichun@nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA FX This work was supported by the Intramural Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA. NR 101 TC 61 Z9 67 U1 11 U2 54 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 NOV 15 PY 2014 VL 120 IS 22 BP 3446 EP 3456 DI 10.1002/cncr.28864 PG 11 WC Oncology SC Oncology GA AT0UT UT WOS:000344650900006 PM 24948110 ER PT J AU Gulati, R Tsodikov, A Etzioni, R Hunter-Merrill, RA Gore, JL Mariotto, AB Cooperberg, MR AF Gulati, Roman Tsodikov, Alex Etzioni, Ruth Hunter-Merrill, Rachel A. Gore, John L. Mariotto, Angela B. Cooperberg, Matthew R. TI Expected Population Impacts of Discontinued Prostate-Specific Antigen Screening SO CANCER LA English DT Article DE mass screening; models; statistical; prostate-specific antigen; prostatic neoplasms; surveillance ID RADICAL PROSTATECTOMY; CANCER MORTALITY; UNITED-STATES; FOLLOW-UP; MEN; TRIAL; US; OVERDIAGNOSIS; SURVEILLANCE; RECURRENCE AB BACKGROUND Prostate-specific antigen (PSA) screening for prostate cancer has high risks of overdiagnosis, particularly among older men, and reports from screening trials indicate that it saves few lives after 11 to 13 years of follow-up. New clinical guidelines recommend against PSA screening for all men or for men aged >70 years, but, to the authors' knowledge, the expected population effects of these guidelines have not been studied to date. METHODS Two models of prostate cancer natural history and diagnosis were previously developed using reconstructed PSA screening patterns and prostate cancer incidence in the United States. Assuming a survival benefit of PSA screening consistent with the screening trials, the authors used the models to predict incidence and mortality rates for the period from 2013 through 2025 under continued PSA screening and under discontinued PSA screening for all men or for men aged >70 years. RESULTS The models predicted that continuation of recent screening rates will overdiagnose 710,000 to 1,120,000 men (range between models) but will avoid 36,000 to 57,000 cancer deaths over the period 2013 through 2025. Discontinued screening for all men eliminated 100% of overdiagnoses but failed to prevent 100% of avoidable cancer deaths. Continued screening for men aged <70 years eliminated 64% to 66% of overdiagnoses but failed to prevent 36% to 39% of avoidable cancer deaths. CONCLUSIONS Discontinuing PSA screening for all men may generate many avoidable cancer deaths. Continuing PSA screening for men aged <70 years could prevent greater than one-half of these avoidable cancer deaths while dramatically reducing overdiagnoses compared with continued PSA screening for all ages. (c) 2014 American Cancer Society. C1 [Gulati, Roman; Etzioni, Ruth; Hunter-Merrill, Rachel A.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Tsodikov, Alex] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Gore, John L.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Mariotto, Angela B.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Cooperberg, Matthew R.] Univ Calif San Francisco, Dept Urol, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. RP Gulati, R (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,M2-B230, Seattle, WA 98109 USA. EM rgulati@fhcrc.org FU National Cancer Institute at the National Institutes of Health as part of the Cancer Intervention and Surveillance Modeling Network (CISNET) [U01CA157224] FX Supported by the National Cancer Institute at the National Institutes of Health (U01CA157224) as part of the Cancer Intervention and Surveillance Modeling Network (CISNET). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. The contents of the current study are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 53 TC 27 Z9 28 U1 1 U2 3 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 NOV 15 PY 2014 VL 120 IS 22 BP 3519 EP 3526 DI 10.1002/cncr.28932 PG 8 WC Oncology SC Oncology GA AT0UT UT WOS:000344650900014 PM 25065910 ER PT J AU Tortelli, B Fujiwara, H Bagel, JH Zhang, J Sidhu, R Jiang, XT Yanjanin, NM Shankar, RK Carillo-Carasco, N Heiss, J Ottinger, E Porter, FD Schaffer, JE Vite, CH Ory, DS AF Tortelli, Brett Fujiwara, Hideji Bagel, Jessica H. Zhang, Jessie Sidhu, Rohini Jiang, Xuntian Yanjanin, Nicole M. Shankar, Roopa Kanakatti Carillo-Carasco, Nuria Heiss, John Ottinger, Elizabeth Porter, Forbes D. Schaffer, Jean E. Vite, Charles H. Ory, Daniel S. TI Cholesterol homeostatic responses provide biomarkers for monitoring treatment for the neurodegenerative disease Niemann-Pick C1 (NPC1) SO HUMAN MOLECULAR GENETICS LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; LATE ENDOSOMES/LYSOSOMES; CYCLODEXTRIN OVERCOMES; NEURONAL CHOLESTEROL; CEREBROSPINAL-FLUID; MOUSE MODEL; PLASMA; BRAIN; MIGLUSTAT; TRANSPORT AB Niemann-Pick C1 (NPC1) disease is a rare, neurodegenerative lysosomal cholesterol storage disorder, typified by progressive cognitive and motor function impairment. Affected individuals usually succumb to the disease in adolescence. 2-Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) has emerged as a promising intervention that reduces lipid storage and prolongs survival in NPC1 disease animal models. A barrier to the development of HP-beta-CD and other treatments for NPC disease has been the lack of validated biochemical measures to evaluate efficacy. Here we explored whether cholesterol homeostatic responses resulting from HP-beta-CD-mediated redistribution of sequestered lysosomal cholesterol could provide biomarkers to monitor treatment. Upon direct CNS delivery of HP-beta-CD, we found increases in plasma 24(S)-HC in two independent NPC1 disease animal models, findings that were confirmed in humanNPC1 subjects receiving HP-beta-CD. Since circulating 24(S)-HC is almost exclusively CNS-derived, the increase in plasma 24(S)-HC provides a peripheral, non-invasive measure of the CNS effect of HP-beta-CD. Our findings suggest that plasma 24(S)-HC, along with the other cholesterol-derived markers examined in this study, can serve as biomarkers that will accelerate development of therapeutics for NPC1 disease. C1 [Tortelli, Brett; Fujiwara, Hideji; Zhang, Jessie; Sidhu, Rohini; Jiang, Xuntian; Schaffer, Jean E.; Ory, Daniel S.] Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, St Louis, MO 63110 USA. [Tortelli, Brett; Fujiwara, Hideji; Zhang, Jessie; Sidhu, Rohini; Jiang, Xuntian; Schaffer, Jean E.; Ory, Daniel S.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Bagel, Jessica H.; Vite, Charles H.] Univ Penn, Sch Vet Med, Dept Clin Studies, Philadelphia, PA 19104 USA. [Yanjanin, Nicole M.; Shankar, Roopa Kanakatti; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Hlth & Human Serv, Program Dev Endocrinol & Genet, Bethesda, MD USA. [Carillo-Carasco, Nuria; Heiss, John] NINDS, Dept Hlth & Human Serv, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Ottinger, Elizabeth] NCATS, Therapeut Rare & Neglected Dis TRND Program, Bethesda, MD USA. RP Ory, DS (reprint author), Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, Box 8086,660 S Euclid Ave, St Louis, MO 63110 USA. EM dory@wustl.edu RI Carrillo-Carrasco, Nuria/B-9034-2009; Sidhu, Rohini/G-3547-2012; OI Carrillo-Carrasco, Nuria/0000-0003-0374-0808; Heiss, John/0000-0002-3890-0165 FU Bench to Bedside Program, the Office of Rare Diseases Research; Therapies for Rare and Neglected Diseases (TRND) Program in the National Center for Advancing Translational Sciences of the National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH CTSA [UL1 TR000448]; Dana's Angels Research Trust; Ara Parseghian Medical Research Foundation; [R01 NS081985]; [R01 NS073661]; [NCRR02512]; [P40-02512] FX This work was supported by the Bench to Bedside Program, the Office of Rare Diseases Research and the Therapies for Rare and Neglected Diseases (TRND) Program in the National Center for Advancing Translational Sciences of the National Institutes of Health, and the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Additional support was provided by R01 NS081985 to D.S.O. and J.E.S., R01 NS073661 to C. H. V, NCRR02512 and P40-02512, NIH CTSA UL1 TR000448 to D.S.O and C. H. V, a grant from Dana's Angels Research Trust to D.S.O and C. H. V., and a grant from the Ara Parseghian Medical Research Foundation to F. D. P. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 56 TC 8 Z9 8 U1 0 U2 6 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 NOV 15 PY 2014 VL 23 IS 22 BP 6022 EP 6033 DI 10.1093/hmg/ddu331 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AT1CY UT WOS:000344671900015 PM 24964810 ER PT J AU Purrington, KS Slettedahl, S Bolla, MK Michailidou, K Czene, K Nevanlinna, H Bojesen, SE Andrulis, IL Cox, A Hall, P Carpenter, J Yannoukakos, D Haiman, CA Fasching, PA Mannermaa, A Winqvist, R Brenner, H Lindblom, A Chenevix-Trench, G Benitez, J Swerdlow, A Kristensen, V Guenel, P Meindl, A Darabi, H Eriksson, M Fagerholm, R Aittomaki, K Blomqvist, C Nordestgaard, BG Nielsen, SF Flyger, H Wang, XS Olswold, C Olson, JE Mulligan, AM Knight, JA Tchatchou, S Reed, MWR Cross, SS Liu, JJ Li, JM Humphreys, K Clarke, C Scott, R Fostira, F Fountzilas, G Konstantopoulou, I Henderson, BE Schumacher, F Le Marchand, L Ekici, AB Hartmann, A Beckmann, MW Hartikainen, JM Kosma, VM Kataja, V Jukkola-Vuorinen, A Pylkas, K Kauppila, S Dieffenbach, AK Stegmaier, C Arndt, V Margolin, S Balleine, R Perez, JIA Zamora, MP Menendez, P Ashworth, A Jones, M Orr, N Arveux, P Kerbrat, P Truong, T Bugert, P Toland, AE Ambrosone, CB Labreche, F Goldberg, MS Dumont, M Ziogas, A Lee, E Dite, GS Apicella, C Southey, MC Long, JR Shrubsole, M Deming-Halverson, S Ficarazzi, F Barile, M Peterlongo, P Durda, K Jaworska-Bieniek, K Tollenaar, RAEM Seynaeve, C Bruning, T Ko, YD Van Deurzen, CHM Martens, JWM Kriege, M Figueroa, JD Chanock, SJ Lissowska, J Tomlinson, I Kerin, MJ Miller, N Schneeweiss, A Tapper, WJ Gerty, SM Durcan, L Mclean, C Milne, RL Baglietto, L Silva, ID Fletcher, O Johnson, N Van'T Veer, LJ Cornelissen, S Forsti, A Torres, D Rudiger, T Rudolph, A Flesch-Janys, D Nickels, S Weltens, C Floris, G Moisse, M Dennis, J Wang, Q Dunning, AM Shah, M Brown, J Simard, J Anton-Culver, H Neuhausen, SL Hopper, JL Bogdanova, N Dork, T Zheng, W Radice, P Jakubowska, A Lubinski, J Devillee, P Brauch, H Hooning, M Garcia-Closas, M Sawyer, E Burwinkel, B Marmee, F Eccles, DM Giles, GG Peto, J Schmidt, M Broeks, A Hamann, U Chang-Claude, J Lambrechts, D Pharoah, PDP Easton, D Pankratz, VS Slager, S Vachon, CM Couch, FJ AF Purrington, Kristen S. Slettedahl, Seth Bolla, Manjeet K. Michailidou, Kyriaki Czene, Kamila Nevanlinna, Heli Bojesen, Stig E. Andrulis, Irene L. Cox, Angela Hall, Per Carpenter, Jane Yannoukakos, Drakoulis Haiman, Christopher A. Fasching, Peter A. Mannermaa, Arto Winqvist, Robert Brenner, Hermann Lindblom, Annika Chenevix-Trench, Georgia Benitez, Javier Swerdlow, Anthony Kristensen, Vessela Guenel, Pascal Meindl, Alfons Darabi, Hatef Eriksson, Mikael Fagerholm, Rainer Aittomaki, Kristiina Blomqvist, Carl Nordestgaard, Borge G. Nielsen, Sune F. Flyger, Henrik Wang, Xianshu Olswold, Curtis Olson, Janet E. Mulligan, Anna Marie Knight, Julia A. Tchatchou, Sandrine Reed, Malcolm W. R. Cross, Simon S. Liu, Jianjun Li, Jingmei Humphreys, Keith Clarke, Christine Scott, Rodney Fostira, Florentia Fountzilas, George Konstantopoulou, Irene Henderson, Brian E. Schumacher, Fredrick Le Marchand, Loic Ekici, Arif B. Hartmann, Arndt Beckmann, Matthias W. Hartikainen, Jaana M. Kosma, Veli-Matti Kataja, Vesa Jukkola-Vuorinen, Arja Pylkas, Katri Kauppila, Saila Dieffenbach, Aida Karina Stegmaier, Christa Arndt, Volker Margolin, Sara Balleine, Rosemary Arias Perez, Jose Ignacio Pilar Zamora, M. Menendez, Primitiva Ashworth, Alan Jones, Michael Orr, Nick Arveux, Patrick Kerbrat, Pierre Therese Truong Bugert, Peter Toland, Amanda E. Ambrosone, Christine B. Labreche, France Goldberg, Mark S. Dumont, Martine Ziogas, Argyrios Lee, Eunjung Dite, Gillian S. Apicella, Carmel Southey, Melissa C. Long, Jirong Shrubsole, Martha Deming-Halverson, Sandra Ficarazzi, Filomena Barile, Monica Peterlongo, Paolo Durda, Katarzyna Jaworska-Bieniek, Katarzyna Tollenaar, Robert A. E. M. Seynaeve, Caroline Bruening, Thomas Ko, Yon-Dschun Van Deurzen, Carolien H. M. Martens, John W. M. Kriege, Mieke Figueroa, Jonine D. Chanock, Stephen J. Lissowska, Jolanta Tomlinson, Ian Kerin, Michael J. Miller, Nicola Schneeweiss, Andreas Tapper, William J. Gerty, Susan M. Durcan, Lorraine Mclean, Catriona Milne, Roger L. Baglietto, Laura Silva, Isabel dos Santos Fletcher, Olivia Johnson, Nichola Van'T Veer, Laura J. Cornelissen, Sten Foersti, Asta Torres, Diana Ruediger, Thomas Rudolph, Anja Flesch-Janys, Dieter Nickels, Stefan Weltens, Caroline Floris, Giuseppe Moisse, Matthieu Dennis, Joe Wang, Qin Dunning, Alison M. Shah, Mitul Brown, Judith Simard, Jacques Anton-Culver, Hoda Neuhausen, Susan L. Hopper, John L. Bogdanova, Natalia Doerk, Thilo Zheng, Wei Radice, Paolo Jakubowska, Anna Lubinski, Jan Devillee, Peter Brauch, Hiltrud Hooning, Maartje Garcia-Closas, Montserrat Sawyer, Elinor Burwinkel, Barbara Marmee, Frederick Eccles, Diana M. Giles, Graham G. Peto, Julian Schmidt, Marjanka Broeks, Annegien Hamann, Ute Chang-Claude, Jenny Lambrechts, Diether Pharoah, Paul D. P. Easton, Douglas Pankratz, V. Shane Slager, Susan Vachon, Celine M. Couch, Fergus J. CA ABCTB Investigators Australian Ovarian Canc Study Grp kConFab Investigators GENICA Network TI Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CANCER SUSCEPTIBILITY LOCI; PROSTATE-CANCER; CELL-DIVISION; LUNG-CANCER; RISK LOCI; POLYMORPHISM; TACC2; AMPLIFICATION; PROGRESSION AB Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 x 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 x 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 x 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 x 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer. C1 [Purrington, Kristen S.; Slettedahl, Seth; Olswold, Curtis; Olson, Janet E.; Pankratz, V. 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[Sawyer, Elinor] Kings Coll London, Guys Hosp, Div Canc Studies, London WC2R 2LS, England. RP Couch, FJ (reprint author), Mayo Clin, Stabile 2-42,200 First St SW, Rochester, MN 55905 USA. EM couch.fergus@mayo.edu RI Brenner, Hermann/B-4627-2017; manoukian, siranoush/E-7132-2017; Peissel, Bernard/E-8187-2017; Jakubowska, Anna/O-8050-2014; Li, Jingmei/I-2904-2012; Knight, Julia/A-6843-2012; Andrulis, Irene/E-7267-2013; Hartikainen, Jaana/E-6256-2015; Garcia-Closas, Montserrat /F-3871-2015; Shrubsole, Martha/K-5052-2015; Dork, Thilo/J-8620-2012; Bowtell, David/H-1007-2016; Bruning, Thomas/G-8120-2015; OI Brenner, Hermann/0000-0002-6129-1572; manoukian, siranoush/0000-0002-6034-7562; Peissel, Bernard/0000-0001-9233-3571; Li, Jingmei/0000-0001-8587-7511; Garcia-Closas, Montserrat /0000-0003-1033-2650; Shrubsole, Martha/0000-0002-5591-7575; Bowtell, David/0000-0001-9089-7525; Bruning, Thomas/0000-0001-9560-5464; Nevanlinna, Heli/0000-0002-0916-2976; Czene, Kamila/0000-0002-3233-5695; Arias Perez, Jose Ignacio/0000-0003-4500-397X; Dunning, Alison Margaret/0000-0001-6651-7166; dos Santos Silva, Isabel/0000-0002-6596-8798; Cox, Angela/0000-0002-5138-1099; Moisse, Matthieu/0000-0001-8880-9311; Yannoukakos, Drakoulis/0000-0001-7509-3510 FU National Institutes of Health (NIH) [CA128978]; Specialized Program of Research Excellence (SPORE) in Breast Cancer to Mayo Clinic [P50 CA116201]; Breast Cancer Research Foundation; Department of Defence [W81XWH-10-1-0341]; European Community [223175, HEALTH-F2-2009-223175]; Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C490/A10124]; National Institutes of Health Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Canadian Institutes of Health Research (CIHR); Komen Foundation for the Cure; Ovarian Cancer Research Fund; National Cancer Institute, National Institutes of Health [RFA-CA-06-503]; Breast Cancer Family Registry (BCFR); Cancer Care Ontario [U01 CA69467]; Northern California Cancer Center [U01 CA69417]; University of Melbourne [U01 CA69638]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; Dutch Cancer Society [NKI 2007-3839, 2009 4363, RUL 1997-1505, DDHK 2004-3124, DDHK 2009-4318]; BBMRI-NL; Dutch government [NWO 184.021.007]; The Cancer Institute NSW; National Breast Cancer Foundation; ELAN-Fond of the University Hospital of Erlangen; Breakthrough Breast Cancer; NHS; National Cancer Research Network (NCRN); CR-UK [C1287/A10118, C1287/A12014]; European Union COST programme [BM0606]; NIHR Comprehensive Biomedical Research Centre, Guy's and St. Thomas' NHS Foundation Trust; King's College London, UK; Oxford Biomedical Research Centre; Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ); Fondation de France; Institut National du Cancer (INCa); Ligue Nationale contre le Cancer; Ligue contre le Cancer Grand Ouest; Agence Nationale de Securite Sanitaire (ANSES); Agence Nationale de la Recherche (ANR); Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Herlev Hospital; Genome Spain Foundation; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI11/00923, PI081120]; Instituto de Salud Carlos III; California Breast Cancer Act; California Breast Cancer Research Fund [97-10500]; National Institutes of Health [CA128978, R01 CA77398, CA63464, CA098758, CA132839, R01CA100374]; Lon V Smith Foundation [LVS39420]; European Union (European Social Fund-ESF); Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF)-Research Funding Program: Thales; Baden Wurttemberg Ministry of Science, Research and Arts; German Cancer Aid (Deutsche Krebshilfe); Deutsche Krebshilfe [107 352]; Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114, 01KH0402]; Robert Bosch Foundation, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum; Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany; Helsinki University Central Hospital Research Fund; Academy of Finland [132473]; Finnish Cancer Society; The Nordic Cancer Union; Sigrid Juselius Foundation; Friends of Hannover Medical School; Rudolf Bartling Foundation; Stockholm County Council; Karolinska Institutet; The Swedish Cancer Society; Stockholm Cancer Foundation; Bert von Kantzow's foundation; Kuopio University Hospital; Cancer Fund of North Savo; Finnish Cancer Organizations; University of Eastern Finland; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council of South Australia; Cancer Foundation of Western Australia; Stichting tegen Kanker [232-2008, 196-2010]; FWO; Deutsche Krebshilfe e.V. [70-2892-BR I]; Hamburg Cancer Society; German Cancer Research Center; Italian Association for Cancer Research (AIRC); Fondazione IRCCS Istituto Nazionale Tumori; National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; Komen Race for the Cure; VicHealth and Cancer Council Victoria; Australian NHMRC [209057, 251553, 504711]; The Canadian Breast Cancer Research Initiative; Quebec Breast Cancer Foundation; Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program [CRN-87521]; Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]; Norwegian Research council [155218/V40, 175240/S10]; FUGE-NFR [181600/V11]; Swizz Bridge Award; Finnish Cancer Foundation; University of Oulu; Oulu University Hospital; National Cancer Institute [UM1 CA164920]; Biobanking and Biomolecular Resources Research Infrastructure [BBMRI-NL CP16]; National Cancer Institute, Department of Health and Human Services, USA; Marit and Hans Rausings Initiative Against Breast Cancer; Agency for Science, Technology and Research of Singapore (A*STAR); US National Institute of Health; Susan G. Komen Breast Cancer Foundation; Yorkshire Cancer Research [S295, S299, S305PA]; UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; DKFZ; Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; Institute of Cancer Research (ICR); [KULPFV/10/016-SymBioSysII]; [P30 CA68485]; [PBZ_KBN_122/P05/2004] FX Part of this work was supported by the National Institutes of Health (NIH) grant (CA128978) and a Specialized Program of Research Excellence (SPORE) in Breast Cancer to Mayo Clinic (P50 CA116201), the Breast Cancer Research Foundation, the Department of Defence (W81XWH-10-1-0341) and the European Community's Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692), the National Institutes of Health Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112-the GAME-ON initiative), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure and the Ovarian Cancer Research Fund. The ABCFS, NC-BCFR and OFBCR work was supported by the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Northern California Cancer Center (U01 CA69417), University of Melbourne (U01 CA69638). Samples from the NC-BCFR were processed and distributed by the Coriell Institute for Medical Research. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Australia Fellow and a Victorian Breast Cancer Research Consortium Group Leader. M. C. S. is a NHMRC Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader. The ABCS study was supported by the Dutch Cancer Society (grants NKI 2007-3839; 2009 4363) and BBMRI-NL, which is a Research Infrastructure financed by the Dutch government (NWO 184.021.007) The Australian Breast Cancer Tissue Bank is generously supported by the National Health and Medical Research Council of Australia, The Cancer Institute NSW and the National Breast Cancer Foundation. The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The BCAC is funded by CR-UK (C1287/A10118 and C1287/A12014). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). D. F. E. is a Principal Research Fellow of CR-UK. E. S. is supported by NIHR Comprehensive Biomedical Research Centre, Guy's and St. Thomas' NHS Foundation Trust in partnership with King's College London, UK I. T. is supported by the Oxford Biomedical Research Centre.; The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ) The CECILE study was funded by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Ligue contre le Cancer Grand Ouest, Agence Nationale de Securite Sanitaire (ANSES), Agence Nationale de la Recherche (ANR) The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital The CNIO-BCS was supported by the Genome Spain Foundation, the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI11/00923 and PI081120). The Human Genotyping-CEGEN Unit (CNIO) is supported by the Instituto de Salud Carlos III. The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. HAC receives support from the Lon V Smith Foundation (LVS39420). The work of Demokritos has been co-financed by the European Union (European Social Fund-ESF) and Greek national funds through the Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF)-Research Funding Program: Thales. Investing in knowledge society through the European Social Fund. The ESTHER study was supported by a grant from the Baden Wurttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GC-HBOC was supported by Deutsche Krebshilfe (107 352) The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The HEBCS was financilly supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, The Swedish Cancer Society, the Stockholm Cancer Foundation, and Bert von Kantzow's foundation.; The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland and by the strategic funding of the University of Eastern Finland kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia and the Cancer Foundation of Western Australia. R. B. was a Cancer Institute NSW Fellow. LMBC is supported by the 'Stichting tegen Kanker' (232-2008 and 196-2010). D.L. is supported by the FWO and the KULPFV/10/016-SymBioSysII. The MARIE study was supported by the Deutsche Krebshilfe e.V. (70-2892-BR I), the Hamburg Cancer Society, the German Cancer Research Center and the genotype work in part by the Federal Ministry of Education and Research (BMBF) Germany (01KH0402). MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects '5 x 1000'). The MCBCS was supported by the National Institutes of Health grant (CA128978), an National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Breast Cancer Research Foundation and the Komen Race for the Cure and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. MCCS cohort recruitment in was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. The MEC was support by National Institutes of Health grants CA63464, CA54281, CA098758 and CA132839. The Canadian Breast Cancer Research Initiative supported the initial case-control study. This work was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program-grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade-grant # PSR-SIIRI-701. The NBCS was supported by grants from the Norwegian Research council, 155218/V40, 175240/S10 to ALBD, FUGE-NFR 181600/V11 to VNK and a Swizz Bridge Award to ALBD. The NBHS was supported by National Institutes of Health grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland, the University of Oulu and the Oulu University Hospital. This work for OFBCR was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the BCFR. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16).; The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The pKARMA study was supported by Marit and Hans Rausings Initiative Against Breast Cancer. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health and the Susan G. Komen Breast Cancer Foundation. The SBCS was supported by Yorkshire Cancer Research S295, S299, S305PA SEARCH is funded by a programme grant from Cancer Research UK (C490/A10124) and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. SKKDKFZS is supported by the DKFZ. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. The TNBCC was supported by a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), grants from the Komen Foundation for the Cure and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. The UKBGS is funded by Breakthrough Breast Cancer and the Institute of Cancer Research (ICR). ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. NR 41 TC 4 Z9 6 U1 2 U2 24 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 NOV 15 PY 2014 VL 23 IS 22 BP 6034 EP 6046 DI 10.1093/hmg/ddu300 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AT1CY UT WOS:000344671900016 PM 24927736 ER PT J AU Koster, R Mitra, N D'Andrea, K Vardhanabhuti, S Chung, CC Wang, ZM Erickson, RL Vaughn, DJ Litchfield, K Rahman, N Greene, MH McGlynn, KA Turnbull, C Chanock, SJ Nathanson, KL Kanetsky, PA AF Koster, Roelof Mitra, Nandita D'Andrea, Kurt Vardhanabhuti, Saran Chung, Charles C. Wang, Zhaoming Erickson, R. Loren Vaughn, David J. Litchfield, Kevin Rahman, Nazneen Greene, Mark H. McGlynn, Katherine A. Turnbull, Clare Chanock, Stephen J. Nathanson, Katherine L. Kanetsky, Peter A. TI Pathway-based analysis of GWAs data identifies association of sex determination genes with susceptibility to testicular germ cell tumors SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CARCINOMA IN-SITU; TRANSCRIPTION FACTOR GATA-4; TESTIS DIFFERENTIATION; EXPRESSION PROFILES; ENRICHMENT ANALYSIS; MAMMALIAN TESTIS; DMRT1; CANCER; VARIANTS AB Genome-wide association (GWA) studies of testicular germ cell tumor (TGCT) have identified 18 susceptibility loci, some containing genes encoding proteins important in male germ cell development. Deletions of one of these genes, DMRT1, lead to male-to-female sex reversal and are associated with development of gonadoblastoma. To further explore genetic association with TGCT, we undertook a pathway-based analysis of SNP marker associations in the Penn GWAs (349 TGCT cases and 919 controls). We analyzed a custom-built sex determination gene set consisting of 32 genes using three different methods of pathway-based analysis. The sex determination gene set ranked highly compared with canonical gene sets, and it was associated with TGCT (FDRG(5) = 2.28 x 10(-5), FDRM = 0.014 and FDRI = 0.008 for Gene Set Analysis-SNP (GSA-SNP), Meta-Analysis Gene Set Enrichment of Variant Associations (MAGENTA) and Improved Gene Set Enrichment Analysis for Genomewide Association Study (i-GSEA4GWAS) analysis, respectively). The association remained after removal of DMRT1 from the gene set (FDRG = 0.0002, FDRM = 0.055 and FDRI = 0.009). Using data from the NCI GWA scan (582 TGCT cases and 1056 controls) and UK scan (986 TGCT cases and 4946 controls), we replicated these findings (NCI: FDRG = 0.006, FDRM = 0.014, FDRI = 0.033, and UK: FDRG = 1.04 x 10(-6), FDRM = 0.016, FDRI = 0.025). After removal of DMRT1 from the gene set, the sex determination gene set remains associated ith TGCT in the NCI (FDRG = 0.039, FDRM = 0.050 and FDRI = 0.055) and UK scans (FDRG = 3.00 x 10(-5), FDRM = 0.056 and FDRI = 0.044). With the exception of DMRT1, genes in the sex determination gene set have not previously been identified as TGCT susceptibility loci in these GWA scans, demonstrating the complementary nature of a pathway-based approach for genome-wide analysis of TGCT. C1 [Koster, Roelof; D'Andrea, Kurt; Nathanson, Katherine L.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Mitra, Nandita; Vardhanabhuti, Saran; Kanetsky, Peter A.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Vaughn, David J.] Univ Penn, Perelman Sch Med, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Vaughn, David J.; Nathanson, Katherine L.; Kanetsky, Peter A.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Chung, Charles C.; Wang, Zhaoming; Greene, Mark H.; McGlynn, Katherine A.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Wang, Zhaoming] NCI, Canc Genome Res Lab, Div Canc Epidemiol & Genet, SAIC Frederick Inc, Frederick, MD 21701 USA. [Erickson, R. Loren] Walter Reed Army Inst Res, Silver Spring, MD USA. [Litchfield, Kevin; Rahman, Nazneen; Turnbull, Clare] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. RP Kanetsky, PA (reprint author), H Lee Moffitt Canc Ctr & Res Inst, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM peter.kanetsky@moffitt.org RI Koster, Roelof/E-2158-2016; Rahman, Nazneen/D-2802-2013 OI Koster, Roelof/0000-0003-1424-8579; Litchfield, Kevin/0000-0002-3725-0914; Rahman, Nazneen/0000-0003-4376-0440 FU Abramson Cancer Center at the University of Pennsylvania; US National Institutes of Health [R01CA114478]; NCI; Westat, Inc. [HHSN261200655004C]; Institute of Cancer Research, Cancer Research UK; Wellcome Trust FX The Penn GWAS (PENN) was supported by the Abramson Cancer Center at the University of Pennsylvania and US National Institutes of Health grant R01CA114478 to P. A. K. and K.L.N. The NCIGWAS work was supported by the Intramural Research Program of the NCI and by support services contract HHSN261200655004C with Westat, Inc. The UK testicular cancer study was supported by the Institute of Cancer Research, Cancer Research UK and the Wellcome Trust and made use of control data generated by the Wellcome Trust Case Control Consortium 2 (WTCCC2). NR 75 TC 13 Z9 14 U1 1 U2 11 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 NOV 15 PY 2014 VL 23 IS 22 BP 6061 EP 6068 DI 10.1093/hmg/ddu305 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AT1CY UT WOS:000344671900018 PM 24943593 ER PT J AU Milne, RL Burwinkel, B Michailidou, K Arias-Perez, JI Zamora, MP Menendez-Rodriguez, P Hardisson, D Mendiola, M Gonzalez-Neira, A Pita, G Alonso, MR Dennis, J Wang, Q Bolla, MK Swerdlow, A Ashworth, A Orr, N Schoemaker, M Ko, YD Brauch, H Hamann, U Andrulis, IL Knight, JA Glendon, G Tchatchou, S Matsuo, K Ito, H Iwata, H Tajima, K Li, JM Brand, JS Brenner, H Dieffenbach, AK Arndt, V Stegmaier, C Lambrechts, D Peuteman, G Christiaens, MR Smeets, A Jakubowska, A Lubinski, J Jaworska-Bieniek, K Durda, K Hartman, M Hui, M Lim, WY Chan, CW Marme, F Yang, RX Bugert, P Lindblom, A Margolin, S Garcia-Closas, M Chanock, SJ Lissowska, J Figueroa, JD Bojesen, SE Nordestgaard, BG Flyger, H Hooning, MJ Kriege, M van den Ouweland, AMW Koppert, LB Fletcher, O Johnson, N Dos-Santos-Silva, I Peto, J Zheng, W Deming-Halverson, S Shrubsole, MJ Long, JR Chang-Claude, J Rudolph, A Seibold, P Flesch-Janys, D Winqvist, R Pylkas, K Jukkola-Vuorinen, A Grip, M Cox, A Cross, SS Reed, MWR Schmidt, MK Broeks, A Cornelissen, S Braaf, L Kang, D Choi, JY Park, SK Noh, DY Simard, J Dumont, M Goldberg, MS Labreche, F Fasching, PA Hein, A Ekici, AB Beckmann, MW Radice, P Peterlongo, P Azzollini, J Barile, M Sawyer, E Tomlinson, I Kerin, M Miller, N Hopper, JL Schmidt, DF Makalic, E Southey, MC Teo, SH Yip, CH Sivanandan, K Tay, WT Shen, CY Hsiung, CN Yu, JC Hou, MF Guenel, P Truong, T Sanchez, M Mulot, C Blot, W Cai, QY Nevanlinna, H Muranen, TA Aittomaki, K Blomqvist, C Wu, AH Tseng, CC Van den Berg, D Stram, DO Bogdanova, N Dork, T Muir, K Lophatananon, A Stewart-Brown, S Siriwanarangsan, P Mannermaa, A Kataja, V Kosma, VM Hartikainen, JM Shu, XO Lu, W Gao, YT Zhang, B Couch, FJ Toland, AE Yannoukakos, D Sangrajrang, S McKay, J Wang, XS Olson, JE Vachon, C Purrington, K Severi, G Baglietto, L Haiman, CA Henderson, BE Schumacher, F Le Marchand, L Devilee, P Tollenaar, RAEM Seynaeve, C Czene, K Eriksson, M Humphreys, K Darabi, H Ahmed, S Shah, M Pharoah, PDP Hall, P Giles, GG Benitez, J Dunning, AM Chenevix-Trench, G Easton, DF AF Milne, Roger L. Burwinkel, Barbara Michailidou, Kyriaki Arias-Perez, Jose-Ignacio Pilar Zamora, M. Menendez-Rodriguez, Primitiva Hardisson, David Mendiola, Marta Gonzalez-Neira, Anna Pita, Guillermo Rosario Alonso, M. Dennis, Joe Wang, Qin Bolla, Manjeet K. Swerdlow, Anthony Ashworth, Alan Orr, Nick Schoemaker, Minouk Ko, Yon-Dschun Brauch, Hiltrud Hamann, Ute Andrulis, Irene L. Knight, Julia A. Glendon, Gord Tchatchou, Sandrine Matsuo, Keitaro Ito, Hidemi Iwata, Hiroji Tajima, Kazuo Li, Jingmei Brand, Judith S. Brenner, Hermann Dieffenbach, Aida Karina Arndt, Volker Stegmaier, Christa Lambrechts, Diether Peuteman, Gilian Christiaens, Marie-Rose Smeets, Ann Jakubowska, Anna Lubinski, Jan Jaworska-Bieniek, Katarzyna Durda, Katazyna Hartman, Mikael Hui, Miao Lim, Wei Yen Chan, Ching Wan Marme, Federick Yang, Rongxi Bugert, Peter Lindblom, Annika Margolin, Sara Garcia-Closas, Montserrat Chanock, Stephen J. Lissowska, Jolanta Figueroa, Jonine D. Bojesen, Stig E. Nordestgaard, Borge G. Flyger, Henrik Hooning, Maartje J. Kriege, Mieke van den Ouweland, Ans M. W. Koppert, Linetta B. Fletcher, Olivia Johnson, Nichola dos-Santos-Silva, Isabel Peto, Julian Zheng, Wei Deming-Halverson, Sandra Shrubsole, Martha J. Long, Jirong Chang-Claude, Jenny Rudolph, Anja Seibold, Petra Flesch-Janys, Dieter Winqvist, Robert Pylkas, Katri Jukkola-Vuorinen, Arja Grip, Mervi Cox, Angela Cross, Simon S. Reed, Malcolm W. R. Schmidt, Marjanka K. Broeks, Annegien Cornelissen, Sten Braaf, Linde Kang, Daehee Choi, Ji-Yeob Park, Sue K. Noh, Dong-Young Simard, Jacques Dumont, Martine Goldberg, Mark S. Labreche, France Fasching, Peter A. Hein, Alexander Ekici, Arif B. Beckmann, Matthias W. Radice, Paolo Peterlongo, Paolo Azzollini, Jacopo Barile, Monica Sawyer, Elinor Tomlinson, Ian Kerin, Michael Miller, Nicola Hopper, John L. Schmidt, Daniel F. Makalic, Enes Southey, Melissa C. Teo, Soo Hwang Yip, Cheng Har Sivanandan, Kavitta Tay, Wan-Ting Shen, Chen-Yang Hsiung, Chia-Ni Yu, Jyh-Cherng Hou, Ming-Feng Guenel, Pascal Therese Truong Sanchez, Marie Mulot, Claire Blot, William Cai, Qiuyin Nevanlinna, Heli Muranen, Taru A. Aittomaki, Kristiina Blomqvist, Carl Wu, Anna H. Tseng, Chiu-Chen Van den Berg, David Stram, Daniel O. Bogdanova, Natalia Doerk, Thilo Muir, Kenneth Lophatananon, Artitaya Stewart-Brown, Sarah Siriwanarangsan, Pornthep Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Shu, Xiao-Ou Lu, Wei Gao, Yu-Tang Zhang, Ben Couch, Fergus J. Toland, Amanda E. Yannoukakos, Drakoulis Sangrajrang, Suleeporn McKay, James Wang, Xianshu Olson, Janet E. Vachon, Celine Purrington, Kristen Severi, Gianluca Baglietto, Laura Haiman, Christopher A. Henderson, Brian E. Schumacher, Fredrick Le Marchand, Loic Devilee, Peter Tollenaar, Robert A. E. M. Seynaeve, Caroline Czene, Kamila Eriksson, Mikael Humphreys, Keith Darabi, Hatef Ahmed, Shahana Shah, Mitul Pharoah, Paul D. P. Hall, Per Giles, Graham G. Benitez, Javier Dunning, Alison M. Chenevix-Trench, Georgia Easton, Douglas F. CA GENICA Network kConFab Investigators Australian Ovarian Canc Study Grp TNBCC TI Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CONFER SUSCEPTIBILITY; IDENTIFIES 2; RISK; LOCI; VARIANTS; METAANALYSIS; ALLELES; 5P12 AB Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 x 10 26], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 x 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 x 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 x 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 x 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act. C1 [Milne, Roger L.; Severi, Gianluca; Baglietto, Laura; Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3004, Australia. [Milne, Roger L.; Hopper, John L.; Schmidt, Daniel F.; Makalic, Enes; Severi, Gianluca; Baglietto, Laura; Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Milne, Roger L.; Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Programme, Madrid, Spain. [Gonzalez-Neira, Anna; Pita, Guillermo; Rosario Alonso, M.; Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Genotyping CEGEN Unit, Madrid, Spain. [Burwinkel, Barbara; Marme, Federick; Yang, Rongxi] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Marme, Federick; Yang, Rongxi] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. 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[Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.] Seoul Natl Univ, Grad Sch, Dept Biomed Sci, Seoul, South Korea. [Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.] Seoul Natl Univ, Canc Res Inst, Seoul, South Korea. [Simard, Jacques; Dumont, Martine] Ctr Hosp Univ Quebec, Res Ctr, Genom Ctr, Charlesbourg, PQ, Canada. [Simard, Jacques; Dumont, Martine] Univ Laval, Quebec City, PQ G1K 7P4, Canada. [Goldberg, Mark S.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Goldberg, Mark S.] McGill Univ, Ctr Hlth, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ, Canada. [Labreche, France] Univ Montreal, Dept Sante Environm & Sante Travail, Dept Med Sociale & Prevent, Montreal, PQ, Canada. [Fasching, Peter A.; Hein, Alexander; Beckmann, Matthias W.] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Breast Ctr Franconia, Dept Gynecol & Obstet, D-91054 Erlangen, Germany. [Ekici, Arif B.] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Inst Human Genet, D-91054 Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Radice, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Unit Mol Bases Genet Risk & Genet Testing, Dept Prevent & Predict Med, Milan, Italy. [Azzollini, Jacopo] Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Dept Prevent & Predict Med, Milan, Italy. [Peterlongo, Paolo] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy. [Barile, Monica] IEO, Div Canc Prevent & Genet, Milan, Italy. [Sawyer, Elinor] Kings Coll London, Guys & St Thomas NHS Fdn Trust, Comprehens Biomed Res Ctr, Div Canc, London WC2R 2LS, England. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Tomlinson, Ian] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England. [Kerin, Michael; Miller, Nicola] Natl Univ Ireland, Sch Med, Clin Sci Inst, Galway, Ireland. [Teo, Soo Hwang; Sivanandan, Kavitta] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Malaysia. [Teo, Soo Hwang; Yip, Cheng Har] Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia. [Tay, Wan-Ting] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 117548, Singapore. [Shen, Chen-Yang; Hsiung, Chia-Ni] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Shen, Chen-Yang] China Med Univ, Coll Publ Hlth, Taichong, Taiwan. [Yu, Jyh-Cherng] Triserv Gen Hosp, Taipei, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Chung Ho Mem Hosp, Ctr Canc, Kaohsiung, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Chung Ho Mem Hosp, Dept Surg, Kaohsiung, Taiwan. [Guenel, Pascal; Therese Truong; Sanchez, Marie] INSERM, CESP Ctr Res Epidemiol & Populat Hlth, U1018, Villejuif, France. [Guenel, Pascal; Therese Truong; Sanchez, Marie] Univ Paris 11, UMRS 1018, Villejuif, France. [Mulot, Claire] INSERM, U775, Paris, France. [Mulot, Claire] Ctr Ressources Biol EPIGENETEC, Paris, France. [Blot, William; Cai, Qiuyin] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Nevanlinna, Heli; Muranen, Taru A.] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Nevanlinna, Heli; Muranen, Taru A.] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Blomqvist, Carl] Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland. [Wu, Anna H.; Tseng, Chiu-Chen; Van den Berg, David; Stram, Daniel O.; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Bogdanova, Natalia; Doerk, Thilo] Hannover Med Sch, Dept Obstet & Gynaecol, Hannover, Germany. [Bogdanova, Natalia] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah] Warwick Med Sch, Div Hlth Sci, Coventry, W Midlands, England. [Siriwanarangsan, Pornthep] Minist Publ Hlth, Nonthaburi, Thailand. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio, Finland. [Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Bioctr Kuopio, Kuopio, Finland. [Kataja, Vesa] Univ Eastern Finland, Sch Med, Inst Clin Med, Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Kuopio Univ Hosp, Dept Clin Pathol, SF-70210 Kuopio, Finland. [Kataja, Vesa] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland. [Lu, Wei] Shanghai Ctr Dis Control & Prevent, Shanghai, Peoples R China. [Gao, Yu-Tang] Shanghai Canc Inst, Shanghai, Peoples R China. [Couch, Fergus J.; Wang, Xianshu] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Couch, Fergus J.; Olson, Janet E.; Vachon, Celine; Purrington, Kristen] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [TNBCC] Mayo Clin, Rochester, MN USA. [Toland, Amanda E.] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Yannoukakos, Drakoulis] Natl Ctr Sci Res Demokritos, INRASTES, Mol Diagnost Lab, Athens, Greece. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok, Thailand. [McKay, James] Int Agcy Res Canc, Genet Susceptibil Grp, F-69372 Lyon, France. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Tollenaar, Robert A. E. M.] Leiden Univ, Med Ctr, Dept Surg Oncol, Leiden, Netherlands. RP Milne, RL (reprint author), Canc Council Victoria, Canc Epidemiol Ctr, 615 St Kilda Rd, Melbourne, Vic 3004, Australia. EM roger.milne@cancervic.org.au RI Hartikainen, Jaana/E-6256-2015; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Hein, Alexander/F-6999-2010; Jakubowska, Anna/O-8050-2014; Teo, Soo-hwang/H-2353-2014; Li, Jingmei/I-2904-2012; Knight, Julia/A-6843-2012; Andrulis, Irene/E-7267-2013; Gonzalez-Neira, Anna/C-5791-2015; Hartman, Mikael/B-4324-2011; Yip, Cheng-Har/B-1909-2010; Shrubsole, Martha/K-5052-2015; Szeszenia-Dabrowska, Neonila/F-7190-2010; Dork, Thilo/J-8620-2012; Hardisson, David/E-2832-2010; Bowtell, David/H-1007-2016; Bruning, Thomas/G-8120-2015; Brenner, Hermann/B-4627-2017; Azzollini, Jacopo/E-7134-2017; Peissel, Bernard/E-8187-2017; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Hein, Alexander/0000-0003-2601-3398; Li, Jingmei/0000-0001-8587-7511; Shrubsole, Martha/0000-0002-5591-7575; Hardisson, David/0000-0002-2183-3699; Bowtell, David/0000-0001-9089-7525; Bruning, Thomas/0000-0001-9560-5464; Brenner, Hermann/0000-0002-6129-1572; Azzollini, Jacopo/0000-0002-9364-9778; Peissel, Bernard/0000-0001-9233-3571; Schoemaker, Minouk/0000-0001-8403-2234; Nevanlinna, Heli/0000-0002-0916-2976; Czene, Kamila/0000-0002-3233-5695; Eeles, Rosalind/0000-0002-3698-6241; Arias Perez, Jose Ignacio/0000-0003-4500-397X; Dunning, Alison Margaret/0000-0001-6651-7166; dos Santos Silva, Isabel/0000-0002-6596-8798; Cox, Angela/0000-0002-5138-1099; Yannoukakos, Drakoulis/0000-0001-7509-3510; Giles, Graham/0000-0003-4946-9099; Muranen, Taru/0000-0002-5895-1808; Matsuo, Keitaro/0000-0003-1761-6314; Arndt, Volker/0000-0001-9320-8684 FU Cancer Research UK [C1287/A10118, C1287/A12014, C1287/A10710, C490/A10124]; European Community [223175, HEALTH-F2-2009-223175]; European Union COST programme [BM0606]; European Union [HEALTH-F2-2009-223175]; Canadian Institutes of Health Research; Ministry of Economic Development, Innovation and Export Trade of Quebec [PSR-SIIRI-701]; National Cancer Institute (USA) [UM1 CA164920]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; National Health and Medical Research Council (NHMRC); Dutch Cancer Society [NKI2007-3839, NKI2009-4363, RUL 1997-1505, DDHK 2004-3124, DDHK 2009-4318]; Breast Cancer Research Trust, UK; University Hospital of Erlangen; Cancer Research UK; Breakthrough Breast Cancer; NHS; National Cancer Research Network (NCRN); NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust; King's College London, UK; Wellcome Trust [090532/Z/09/Z]; Oxford Biomedical Research Centre; Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ); Fondation de France; French National Institute of Cancer (INCa); The National League against Cancer; National Agency for Environmental and Occupational Health and Food Safety (ANSES); National Agency for Research (ANR); Association for Research against Cancer (ARC); Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Herlev Hospital; Genome Spain Foundation; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI11/00923, PI081120]; Instituto de Salud Carlos III; Michael Manzella Foundation (MMF); California Breast Cancer Act; California Breast Cancer Research Fund [97-10500]; National Institutes of Health [R01 CA77398]; Lon V Smith Foundation [LVS39420]; Baden Wurttemberg Ministry of Science, Research and Arts; German Cancer Aid (Deutsche Krebshilfe); Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114, 01KH0402]; Robert Bosch Foundation, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance; Institute of the Ruhr University Bochum (IPA); Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus Bonn, Germany; Helsinki University Central Hospital Research Fund; Academy of Finland [132473]; Finnish Cancer Society; The Nordic Cancer Union; Sigrid Juselius Foundation; Ministry of Education, Science, Sports, Culture and Technology of Japan; Ministry Health, Labour and Welfare of Japan; Takeda Science Foundation; National Cancer Center Research and Development Fund; German Academic Exchange Program; Friends of Hannover Medical School; Stockholm County Council; Karolinska Institutet; Stockholm Cancer Foundation; Swedish Cancer Society; Kuopio University Hospital; Cancer Fund of North Savo; Finnish Cancer Organizations; University of Eastern Finland; National Breast Cancer Foundation; NHMRC; Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council of South Australia; Cancer Foundation of Western Australia; NHMRC [145684, 288704, 454508, 199600]; United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; California Breast Cancer Research Program [1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098]; California Department of Health; National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program [N01CN25403]; Stichting tegen Kanker [232-2008, 196-2010]; Deutsche Krebshilfe e.V. [70-2892-BR I]; Hamburg Cancer Society; Italian Association for Cancer Research (AIRC); Fondazione IRCCS Istituto Nazionale Tumori; NIH [CA122340, CA128978, CA63464, CA54281, CA098758, CA132839, R01CA100374, R01CA64277, R01CA148667, R37CA70867, R01 CA092447]; Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; Breast Cancer Research Foundation; VicHealth; Cancer Council Victoria; Australian NHMRC [209057, 251553, 504711]; Quebec Breast Cancer Foundation; Canadian Institutes of Health Research [CRN-87521]; Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]; Malaysian Ministry of Science, Technology and Innovation (MOSTI); Malaysian Ministry of Higher Education [UM.C/HlR/MOHE/06]; Cancer Research Initiatives Foundation (CARIF); Biomedical Research Council, Singapore [BMRC08/1/35/19]; National medical Research Council, Singapore [NMRC/CG/SERI/2010]; Norwegian Research council [155218/V40, 175240/S10, FUGE-NFR 181600/V11]; Norwegian Research council (Swizz Bridge Award); Finnish Cancer Foundation; University of Oulu; Oulu University Hospital; Biobanking and Biomolecular Resources Research Infrastructure [BBMRI-NL CP16]; National Cancer Institute, Department of Health and Human Services, USA; Marit and Hans Rausings Initiative Against Breast Cancer; Cancer Risk Prediction Center (CRisP); Linnaeus Centre - Swedish Research Council [70867902]; Agency for Science, Technology and Research of Singapore (A*STAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Swedish Cancer Society [5128-B07-01PAF]; Yorkshire Cancer Research [S305PA, S299, S295]; National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC); UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; BRL (Basic Research Laboratory) program through the National Research Foundation of Korea - Ministry of Education, Science and Technology [2012-0000347]; National Medical Research Council Start-up Grant; National Medical Research Council Centre Grant [NMRC/CG/NCIS /2010]; Biomedical Research Council [05/1/21/19/425]; DKFZ; Polish Foundation of Science; Komen Foundation for the Cure; Ohio State University Comprehensive Cancer Center; Stefanie Spielman Fund for Breast Cancer Research; European Union (European Social Fund - ESF); Greek National Funds through the Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF)-Research Funding Program of the General Secretariat for Research & Technology: ARISTEIA; Institute of Biomedical Sciences; Academia Sinica; National Science Council, Taiwan; Institute of Cancer Research (ICR); Wellcome Trust; [P30 CA68485]; [PBZ_KBN_122/P05/2004] FX BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program and the Ministry of Economic Development, Innovation and Export Trade of Quebec (PSR-SIIRI-701). Additional support for the iCOGS infrastructure was provided by the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112-the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The ABCFS and OFBCR work was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow and M. C. S. is a NHMRC Senior Research Fellow. The OFBCR work was also supported by the Canadian Institutes of Health Research 'CIHR Team in Familial Risks of Breast Cancer' program. The ABCS was funded by the Dutch Cancer Society Grant no. NKI2007-3839 and NKI2009-4363. The ACP study is funded by the Breast Cancer Research Trust, UK. The work of the BBCC was partly funded by ELAN-Programme of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). E. S. is supported by NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, UK. Core funding to the Wellcome Trust Centre for Human Genetics was provided by the Wellcome Trust (090532/Z/09/Z). I. T. is supported by the Oxford Biomedical Research Centre. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CECILE study was funded by the Fondation de France, the French National Institute of Cancer (INCa), The National League against Cancer, the National Agency for Environmental and Occupational Health and Food Safety (ANSES), the National Agency for Research (ANR), and the Association for Research against Cancer (ARC). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The CNIO-BCS was supported by the Genome Spain Foundation, the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI11/00923 and PI081120).; The Human Genotyping-CEGEN Unit, CNIO is supported by the Instituto de Salud Carlos III. D. A. was supported by a Fellowship from the Michael Manzella Foundation (MMF) and was a participant in the CNIO Summer Training Program. The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. HAC receives support from the Lon V Smith Foundation (LVS39420). The ESTHER study was supported by a grant from the Baden Wurttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus Bonn, Germany. The HEBCS was supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. The HERPACC was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from Ministry Health, Labour and Welfare of Japan, by a research grant from Takeda Science Foundation, by Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan and by National Cancer Center Research and Development Fund. The HMBCS was supported by short-term fellowships from the German Academic Exchange Program (to N.B), and the Friends of Hannover Medical School (to N.B.). Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Stockholm Cancer Foundation and the Swedish Cancer Society. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland and by the strategic funding of the University of Eastern Finland. kConFab is supported by grants from the National Breast Cancer Foundation, the NHMRC, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia and the Cancer Foundation of Western Australia. The kConFab Clinical Follow Up Study was funded by the NHMRC (145684, 288704, 454508). Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command (DAMD17-01-1-0729), the Cancer Council of Tasmania and Cancer Foundation of Western Australia and the NHMRC (199600). G. C. T. and P. W. are supported by the NHMRC.; LAABC is supported by grants (1RB-0287, 3PB-0102, 5PB-0018 and 10PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP) which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403. LMBC is supported by the 'Stichting tegen Kanker' (232-2008 and 196-2010). The MARIE study was supported by the Deutsche Krebshilfe e.V. (70-2892-BR I), the Federal Ministry of Education and Research (BMBF) Germany (01KH0402), the Hamburg Cancer Society and the German Cancer Research Center (DKFZ). MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated a 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects '5 x 1000'). The MCBCS was supported by the NIH grants (CA122340, CA128978) and a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. The MEC was supported by NIH grants CA63464, CA54281, CA098758 and CA132839. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research (grant CRN-87521) and the Ministry of Economic Development, Innovation and Export Trade (grant PSR-SIIRI-701). MYBRCA is funded by research grants from the Malaysian Ministry of Science, Technology and Innovation (MOSTI), Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation (CARIF). Additional controls were recruited by the Singapore Eye Research Institute, which was supported by a grant from the Biomedical Research Council (BMRC08/1/35/19= 10 pack-years of smoking who were free of clinical cardiovascular disease. RV volumes and mass were assessed using magnetic resonance imaging. COPD and COPD severity were defined according to standard spirometric criteria. The percentage of emphysema was defined as the percentage of lung regions <-950 Hounsfield units on full-lung computed tomography; emphysema subtypes were scored by radiologists. Results were adjusted for age, race/ethnicity, sex, height, weight, smoking status, pack-years, systemic hypertension, and sleep apnea. RESULTS Right ventricular end-diastolic volume (RVEDV) was reduced in COPD compared with control subjects (-7.8 ml; 95% confidence interval: -15.0 to -0.5 ml; p = 0.04). Increasing severity of COPD was associated with lower RVEDV (p = 0.004) and lower RV stroke volume (p < 0.001). RV mass and ejection fraction were similar between the groups. A greater percentage of emphysema also was associated with lower RVEDV (p = 0.005) and stroke volume (p < 0.001), as was the presence of centrilobular and paraseptal emphysema. CONCLUSIONS RV volumes are lower without significant alterations in RV mass and ejection fraction in contemporary COPD, and this reduction is related to the greater percentage of emphysema on computed tomography. (C) 2014 by the American College of Cardiology Foundation. C1 [Kawut, Steven M.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kawut, Steven M.] Univ Penn, Dept Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Poor, Hooman D.; Parikh, Megha A.; Smith, Benjamin M.; Barr, Graham] Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY 10032 USA. [Hueper, Katja; Vogel-Claussen, Jens] Hannover Med Sch, Dept Radiol, Hannover, Germany. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Prince, Martin R.; Austin, John H. M.] Columbia Univ, Dept Radiol, Coll Phys & Surg, New York, NY 10032 USA. [Hoffman, Eric A.] Univ Iowa, Dept Radiol, Iowa City, IA 52242 USA. [Barr, Graham] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. RP Barr, G (reprint author), Columbia Univ, Med Ctr, Presbyterian Hosp, 9 East 105,630 West 168th St, New York, NY 10032 USA. EM rgb9@columbia.edu RI Hueper, Katja/J-9566-2016; Prince, Martin/S-6850-2016; OI Hueper, Katja/0000-0002-3195-4400; Bluemke, David/0000-0002-8323-8086; Prince, Martin/0000-0002-9883-0584 FU National Institutes of Health [R01-HL093081, R01-HL077612, R01-HL075476]; [N01-HC95159-HC95169]; [UL1-RR024156]; [K24-HL103844]; [R01-HL086719] FX The MESA COPD study is supported by the National Institutes of Health R01-HL093081, R01-HL077612, and R01-HL075476. ME SA is supported by N01-HC95159-HC95169 and UL1-RR024156. Dr. Kawut is supported by K24-HL103844 and R01-HL086719. Dr. Hoffman is the founder of and a shareholder in Vida Diagnostics Inc. Dr. Prince has patent agreements with GE, Siemens, Philips, Toshiba, Hitachi, Bayer HealthCare, Bracco, Mallinkrodt, Medrad, and Lantheus. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 43 TC 13 Z9 14 U1 3 U2 5 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 NOV 11 PY 2014 VL 64 IS 19 BP 2000 EP 2009 DI 10.1016/j.jacc.2014.07.991 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AT0HI UT WOS:000344617200005 PM 25440095 ER PT J AU Frommelt, PC Gerstenberger, E Cnota, JF Cohen, MS Gorentz, J Hill, KD John, JB Levine, JC Lu, J Mahle, WT McCandless, RT Mertens, L Pearson, GD Spencer, C Thacker, D Williams, IA Wong, PC Newburger, JW AF Frommelt, Peter C. Gerstenberger, Eric Cnota, James F. Cohen, Meryl S. Gorentz, Jessica Hill, Kevin D. John, J. Blaine Levine, Jami C. Lu, Jimmy Mahle, William T. McCandless, Rachel T. Mertens, Luc Pearson, Gail D. Spencer, Carolyn Thacker, Deepika Williams, Ismee A. Wong, Pierre C. Newburger, Jane W. CA Pediat Heart Network Investigators TI Impact of Initial Shunt Type on Cardiac Size and Function in Children With Single Right Ventricle Anomalies Before the Fontan Procedure The Single Ventricle Reconstruction Extension Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE echocardiography; hypoplastic left heart syndrome; Norwood ID LEFT-HEART SYNDROME; PULMONARY-ARTERY CONDUIT; BLALOCK-TAUSSIG SHUNT; NORWOOD PROCEDURE; RISK-FACTORS; MORTALITY; TRANSPLANTATION; HEMODYNAMICS; PERFORMANCE; MULTICENTER AB BACKGROUND In children with single right ventricular (RV) anomalies, changes in RV size and function may be influenced by shunt type chosen at the time of the Norwood procedure. OBJECTIVES The study sought to identify shunt-related differences in echocardiographic findings at 14 months and <= 6 months pre-Fontan in survivors of the Norwood procedure. METHODS We compared 2-dimensional and Doppler echocardiographic indices of RV size and function, neo-aortic and tricuspid valve annulus dimensions and function, and aortic size and patency at 14.1 +/- 1.2 months and 33.6 +/- 9.6 months in subjects randomized to a Norwood procedure using either the modified Blalock-Taussig shunt (MBTS) or right ventricle to pulmonary artery shunt (RVPAS). RESULTS Acceptable echocardiograms were available at both time points in 240 subjects (114 MBTS, 126 RVPAS). At 14 months, all indices were similar between shunt groups. From the 14-month to pre-Fontan echocardiogram, the MBTS group had stable indexed RV volumes and ejection fraction, while the RVPAS group had increased RV end-systolic volume (p = 0.004) and decreased right ventricular ejection fraction (RVEF) (p = 0.004). From 14 months to pre-Fontan, the treatment groups were similar with respect to decline in indexed neo-aortic valve area, >mild neo-aortic valve regurgitation (<5% at each time), indexed tricuspid valve area, and >= moderate tricuspid valve regurgitation (<20% at each time). CONCLUSIONS Initial Norwood shunt type influences pre-Fontan RV remodeling during the second and third years of life in survivors with single RV anomalies, with greater RVEF deterioration after RVPAS. Encouragingly, other indices of RV function remain stable before Fontan regardless of shunt type. (Comparison of Two Types of Shunts in Infants with Single Ventricle Defect Undergoing Staged Reconstruction-Pediatric Heart Network; NCT00115934) (C) 2014 by the American College of Cardiology Foundation. C1 [Frommelt, Peter C.; Gorentz, Jessica] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Gerstenberger, Eric] New England Res Inst, Watertown, MA 02172 USA. [Cnota, James F.] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Cohen, Meryl S.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Hill, Kevin D.] Duke Univ, Durham, NC USA. [John, J. Blaine] Congenital Heart Inst Florida Pediatrix, Tampa, FL USA. [Levine, Jami C.; Newburger, Jane W.] Boston Childrens Hosp, Boston, MA USA. [Lu, Jimmy] Univ Michigan, Ann Arbor, MI 48109 USA. [Mahle, William T.] Emory Univ, Sch Med, Atlanta, GA USA. [McCandless, Rachel T.] Primary Childrens Med Ctr, Salt Lake City, UT USA. [Mertens, Luc] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Pearson, Gail D.] NHLBI, NIH, Bethesda, MD 20892 USA. [Spencer, Carolyn] Med Univ S Carolina, Charleston, SC 29425 USA. [Thacker, Deepika] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Williams, Ismee A.] Cornell Univ, Med Ctr, New York, NY 10021 USA. [Wong, Pierre C.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. RP Frommelt, PC (reprint author), Childrens Hosp Wisconsin, 9000 West Wisconsin Ave MS 713, Milwaukee, WI 53226 USA. EM pfrommelt@chw.org FU National Heart, Lung, and Blood Institute [HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057, HL109781, HL109737]; Gilead Scholars in Cardiology Program FX The study was supported by U01 grants from the National Heart, Lung, and Blood Institute (HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057, HL109781, HL109737). The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the National Heart, Lung, and Blood Institute. Dr. Hill has received grant support from the Gilead Scholars in Cardiology Program. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 21 TC 12 Z9 12 U1 0 U2 2 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 NOV 11 PY 2014 VL 64 IS 19 BP 2026 EP 2035 DI 10.1016/j.jacc.2014.08.033 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AT0HI UT WOS:000344617200009 PM 25440099 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI Horizontal transfer beyond genes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID PROKARYOTES; GENOMES; TREE; QUANTIFICATION; CLASSIFICATION; HYPOTHESIS; EVOLUTION C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov NR 14 TC 1 Z9 1 U1 2 U2 20 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 NOV 11 PY 2014 VL 111 IS 45 BP 15865 EP 15866 DI 10.1073/pnas.1418789111 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AS8WW UT WOS:000344526800020 PM 25359214 ER PT J AU Deville, P Linard, C Martin, S Gilbert, M Stevens, FR Gaughan, AE Blondel, VD Tatem, AJ AF Deville, Pierre Linard, Catherine Martin, Samuel Gilbert, Marius Stevens, Forrest R. Gaughan, Andrea E. Blondel, Vincent D. Tatem, Andrew J. TI Dynamic population mapping using mobile phone data SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE population distribution; phone calls; human mobility; census; remote sensing ID POSITIONING DATA; PREDICTABILITY; RISK; MODELS; PATTERNS; NETWORK; SCIENCE; MALARIA; AFRICA; HAITI AB During the past few decades, technologies such as remote sensing, geographical information systems, and global positioning systems have transformed the way the distribution of human population is studied and modeled in space and time. However, the mapping of populations remains constrained by the logistics of censuses and surveys. Consequently, spatially detailed changes across scales of days, weeks, or months, or even year to year, are difficult to assess and limit the application of human population maps in situations in which timely information is required, such as disasters, conflicts, or epidemics. Mobile phones (MPs) now have an extremely high penetration rate across the globe, and analyzing the spatiotemporal distribution of MP calls geolocated to the tower level may overcome many limitations of census-based approaches, provided that the use of MP data is properly assessed and calibrated. Using datasets of more than 1 billion MP call records from Portugal and France, we show how spatially and temporarily explicit estimations of population densities can be produced at national scales, and how these estimates compare with outputs produced using alternative human population mapping methods. We also demonstrate how maps of human population changes can be produced over multiple timescales while preserving the anonymity of MP users. With similar data being collected every day by MP network providers across the world, the prospect of being able to map contemporary and changing human population distributions over relatively short intervals exists, paving the way for new applications and a near real-time understanding of patterns and processes in human geography. C1 [Deville, Pierre; Blondel, Vincent D.] Catholic Univ Louvain, Dept Appl Math, B-1348 Louvain La Neuve, Belgium. [Deville, Pierre] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. [Deville, Pierre] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Deville, Pierre; Linard, Catherine; Gilbert, Marius] Fonds Natl Rech Sci, B-1000 Brussels, Belgium. [Linard, Catherine; Gilbert, Marius] Univ Libre Bruxelles, B-1050 Brussels, Belgium. [Martin, Samuel] Univ Lorraine, CNRS, Ctr Rech Automat Nancy, UMR 7039, F-54518 Vandoeuvre Les Nancy, France. [Stevens, Forrest R.; Gaughan, Andrea E.] Univ Louisville, Dept Geog & Geosci, Louisville, KY 40292 USA. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton SO17 1BJ, Hants, England. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Tatem, Andrew J.] Flowminder Fdn, S-17177 Stockholm, Sweden. RP Linard, C (reprint author), Fonds Natl Rech Sci, B-1000 Brussels, Belgium. EM linard.catherine@gmail.com OI Linard, Catherine/0000-0002-0819-7755; Gilbert, Marius/0000-0003-3708-3359; Stevens, Forrest/0000-0002-9328-3753 FU Fonds National de la Recherche Scientifique (FNRS) [PDR T.0073.13]; NIH/National Institute of Allergy and Infectious Diseases [U19AI089674]; Bill & Melinda Gates Foundation [OPP1106427, 1032350]; Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, and Fogarty International Center, NIH FX We thank three anonymous referees for their useful comments on an earlier version of this paper. P. D., C. L. and M. G. are supported by the Fonds National de la Recherche Scientifique (FNRS); part of this work was supported by the FNRS (PDR T.0073.13). A.J.T. is supported by funding from the NIH/National Institute of Allergy and Infectious Diseases (U19AI089674), the Bill & Melinda Gates Foundation (OPP1106427,1032350), and the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, and Fogarty International Center, NIH. This work forms part of the WorldPop Project (www.worldpop.org.uk) and Flowminder Foundation (www.flowminder.org). NR 72 TC 59 Z9 62 U1 6 U2 59 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 NOV 11 PY 2014 VL 111 IS 45 BP 15888 EP 15893 DI 10.1073/pnas.1408439111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AS8WW UT WOS:000344526800025 PM 25349388 ER PT J AU Tokunaga, K Saitoh, N Goldberg, IG Sakamoto, C Yasuda, Y Yoshida, Y Yamanaka, S Nakao, M AF Tokunaga, Kazuaki Saitoh, Noriko Goldberg, Ilya G. Sakamoto, Chiyomi Yasuda, Yoko Yoshida, Yoshinori Yamanaka, Shinya Nakao, Mitsuyoshi TI Computational image analysis of colony and nuclear morphology to evaluate human induced pluripotent stem cells SO SCIENTIFIC REPORTS LA English DT Article ID HUMAN FIBROBLASTS; DIFFERENTIATION; CHROMATIN; MOUSE; PML; REORGANIZATION; TRANSITIONS; GENERATION; INDUCTION; DYNAMICS AB Non-invasive evaluation of cell reprogramming by advanced image analysis is required to maintain the quality of cells intended for regenerative medicine. Here, we constructed living and unlabelled colony image libraries of various human induced pluripotent stem cell (iPSC) lines for supervised machine learning pattern recognition to accurately distinguish bona fide iPSCs from improperly reprogrammed cells. Furthermore, we found that image features for efficient discrimination reside in cellular components. In fact, extensive analysis of nuclear morphologies revealed dynamic and characteristic signatures, including the linear form of the promyelocytic leukaemia (PML)-defined structure in iPSCs, which was reversed to a regular sphere upon differentiation. Our data revealed that iPSCs have a markedly different overall nuclear architecture that may contribute to highly accurate discrimination based on the cell reprogramming status. C1 [Tokunaga, Kazuaki; Saitoh, Noriko; Sakamoto, Chiyomi; Yasuda, Yoko; Nakao, Mitsuyoshi] Kumamoto Univ, Inst Mol Embryol & Genet, Dept Med Cell Biol, Chuo Ku, Kumamoto 8600811, Japan. [Tokunaga, Kazuaki; Saitoh, Noriko; Nakao, Mitsuyoshi] Japan Sci & Technol Agcy, CREST, Tokyo, Japan. [Goldberg, Ilya G.] Natl Inst Aging, Image Informat & Computat Biol Unit, Genet Lab, NIH, Baltimore, MD 21224 USA. [Yoshida, Yoshinori; Yamanaka, Shinya] Kyoto Univ, Ctr iPS Cell Res & Applicat, Sakyo Ku, Kyoto 6068507, Japan. [Yamanaka, Shinya] Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA. RP Saitoh, N (reprint author), Kumamoto Univ, Inst Mol Embryol & Genet, Dept Med Cell Biol, Chuo Ku, 2-2-1 Honjo, Kumamoto 8600811, Japan. EM norikos@kumamoto-u.ac.jp; mnakao@gpo.kumamoto-u.ac.jp RI Goldberg, Ilya/H-5307-2011 OI Goldberg, Ilya/0000-0001-8514-6110 FU Ministry of Education, Culture, Sports, Science and Technology of Japan; Japan Science and Technology Agency (CREST) FX We thank Dr. Tamiyo Kobayashi (Olympus, Japan) for technical assistance. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Japan Science and Technology Agency (CREST) (M.N. and N.S.). NR 37 TC 5 Z9 5 U1 2 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 NOV 11 PY 2014 VL 4 AR 6996 DI 10.1038/srep06996 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT2JF UT WOS:000344760100011 PM 25385348 ER PT J AU Wollny, G Kellman, P AF Wollny, Gert Kellman, Peter TI Free breathing myocardial perfusion data sets for performance analysis of motion compensation algorithms SO GIGASCIENCE LA English DT Article DE Heart; Image registration; Motion compensation; Perfusion; Validation ID CARDIOVASCULAR MAGNETIC-RESONANCE; INDEPENDENT COMPONENT ANALYSIS; MR IMAGE SEQUENCES; BLOOD-FLOW; REGISTRATION; QUANTIFICATION; VALIDATION AB Background: Perfusion quantification by using first-pass gadolinium-enhanced myocardial perfusion magnetic resonance imaging (MRI) has proved to be a reliable tool for the diagnosis of coronary artery disease that leads to reduced blood flow to the myocardium. The image series resulting from such acquisition usually exhibits a breathing motion that needs to be compensated for if a further automatic analysis of the perfusion is to be executed. Various algorithms have been presented to facilitate such a motion compensation, but the lack of publicly available data sets hinders a proper, reproducible comparison of these algorithms. Material: Free breathing perfusion MRI series of ten patients considered clinically to have a stress perfusion defect were acquired; for each patient a rest and a stress study was executed. Manual segmentations of the left ventricle myocardium and the right-left ventricle insertion point are provided for all images in order to make a unified validation of the motion compensation algorithms and the perfusion analysis possible. In addition, all the scripts and the software required to run the experiments are provided alongside the data, and to enable interested parties to directly run the experiments themselves, the test bed is also provided as a virtual hard disk. Findings: To illustrate the utility of the data set two motion compensation algorithms with publicly available implementations were applied to the data and earlier reported results about the performance of these algorithms could be confirmed. Conclusion: The data repository alongside the evaluation test bed provides the option to reliably compare motion compensation algorithms for myocardial perfusion MRI. In addition, we encourage that researchers add their own annotations to the data set, either to provide inter-observer comparisons of segmentations, or to make other applications possible, for example, the validation of segmentation algorithms. C1 [Wollny, Gert] Univ Politecn Madrid, ETSI Telecomunicac, Biomed Imaging Technol, E-28040 Madrid, Spain. [Wollny, Gert] Ciber BBN, Zaragoza, Spain. [Kellman, Peter] NHLBI, Cardiac Energet Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Wollny, G (reprint author), Univ Politecn Madrid, ETSI Telecomunicac, Biomed Imaging Technol, Ave Complutense 30, E-28040 Madrid, Spain. EM gw.fossdev@gmail.com OI Wollny, Gert/0000-0002-3611-0100 FU Spain's Ministry of Science and Innovation through INNPACTO (PRECISION); Comunidad de Madrid (ARTEMIS) [S2009/DPI-1802]; European Regional Development Funds (FEDER); Intramural Research Program of the NIH, National Heart, Lung and Blood Institute FX This work was in part supported by Spain's Ministry of Science and Innovation through INNPACTO (PRECISION), by the Comunidad de Madrid (ARTEMIS S2009/DPI-1802), and the European Regional Development Funds (FEDER). The data was provided with the support of the Intramural Research Program of the NIH, National Heart, Lung and Blood Institute. The authors also wish to thank Maria-Jesus Ledesma-Carbayo and Andres Santos for their feedback and comments. Finally, we would like to thank the patients who provided informed consent that this data can be redistributed in anonymized and un-linked form. NR 31 TC 1 Z9 1 U1 0 U2 0 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 NOV 11 PY 2014 VL 3 AR 23 DI 10.1186/2047-217X-3-23 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CX4GO UT WOS:000365657400001 PM 25392734 ER PT J AU Du, XJ Gertz, EM Wojtowicz, D Zhabinskaya, D Levens, D Benham, CJ Schaffer, AA Przytycka, TM AF Du, Xiangjun Gertz, E. Michael Wojtowicz, Damian Zhabinskaya, Dina Levens, David Benham, Craig J. Schaeffer, Alejandro A. Przytycka, Teresa M. TI Potential non-B DNA regions in the human genome are associated with higher rates of nucleotide mutation and expression variation SO NUCLEIC ACIDS RESEARCH LA English DT Article ID G-QUADRUPLEX STRUCTURES; HUMAN INHERITED DISEASE; DOUBLE-HELICAL DNA; C-MYC GENE; FORMING SEQUENCES; H-DNA; ESCHERICHIA-COLI; MAMMALIAN-CELLS; G4 DNA; SACCHAROMYCES-CEREVISIAE AB While individual non-B DNA structures have been shown to impact gene expression, their broad regulatory role remains elusive. We utilized genomic variants and expression quantitative trait loci (eQTL) data to analyze genome-wide variation propensities of potential non-B DNA regions and their relation to gene expression. Independent of genomic location, these regions were enriched in nucleotide variants. Our results are consistent with previously observed mutagenic properties of these regions and counter a previous study concluding that G-quadruplex regions have a reduced frequency of variants. While such mutagenicity might undermine functionality of these elements, we identified in potential non-B DNA regions a signature of negative selection. Yet, we found a depletion of eQTL-associated variants in potential non-B DNA regions, opposite to what might be expected from their proposed regulatory role. However, we also observed that genes downstream of potential non-B DNA regions showed higher expression variation between individuals. This coupling between mutagenicity and tolerance for expression variability of downstream genes may be a result of evolutionary adaptation, which allows reconciling mutagenicity of non-B DNA structures with their location in functionally important regions and their potential regulatory role. C1 [Du, Xiangjun; Gertz, E. Michael; Wojtowicz, Damian; Schaeffer, Alejandro A.; Przytycka, Teresa M.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Zhabinskaya, Dina; Benham, Craig J.] Univ Calif Davis, Genome Ctr, Davis, CA 95616 USA. [Levens, David] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Schaffer, AA (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM schaffer@helix.nih.gov; przytyck@ncbi.nlm.nih.gov RI Levens, David/C-9216-2009 OI Levens, David/0000-0002-7616-922X FU Intramural Research Program of the US National Institutes of Health, National Library of Medicine; Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research; NSF [DBI 08-50214] FX Intramural Research Program of the US National Institutes of Health, National Library of Medicine (XD, DW, TMP); Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research (DL); NSF DBI 08-50214 (CB). NR 88 TC 3 Z9 3 U1 3 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD NOV 10 PY 2014 VL 42 IS 20 BP 12367 EP 12379 DI 10.1093/nar/gku921 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AY6RL UT WOS:000347693200010 PM 25336616 ER PT J AU Cole, HA Ocampo, J Iben, JR Chereji, RV Clark, DJ AF Cole, Hope A. Ocampo, Josefina Iben, James R. Chereji, Razvan V. Clark, David J. TI Heavy transcription of yeast genes correlates with differential loss of histone H2B relative to H4 and queued RNA polymerases SO NUCLEIC ACIDS RESEARCH LA English DT Article ID GENOME-WIDE; IN-VIVO; BUDDING YEAST; SACCHAROMYCES-CEREVISIAE; MASTER REGULATOR; H3 EXCHANGE; NUCLEOSOME; ELONGATION; CHROMATIN; REPLICATION AB Eukaryotic chromatin is composed of nucleosomes, which contain nearly two coils of DNA wrapped around a central histone octamer. The octamer contains an H3-H4 tetramer and two H2A-H2B dimers. Gene activation is associated with chromatin disruption: a wider nucleosome-depleted region (NDR) at the promoter and reduced nucleosome occupancy over the coding region. Here, we examine the nature of disrupted chromatin after induction, using MNase-seq to map nucleosomes and subnucleosomes, and a refined high-resolution ChIP-seq method to map H4, H2B and RNA polymerase II (Pol II) genomewide. Over coding regions, induced genes show a differential loss of H2B relative to H4, which correlates with Pol II density and the appearance of subnucleosomes. After induction, Pol II is surprisingly low at the promoter, but accumulates on the gene and downstream of the termination site, implying that dissociation is very slow. Thus, induction-dependent chromatin disruption reflects both eviction of H2A-H2B dimers and the presence of queued Pol II elongation complexes. We propose that slow Pol II dissociation after transcription is a major factor in chromatin disruption and that it may be of critical importance in gene regulation. C1 [Cole, Hope A.; Ocampo, Josefina; Iben, James R.; Chereji, Razvan V.; Clark, David J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Clark, DJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM clarkda@mail.nih.gov OI Chereji, Razvan/0000-0002-0572-6412 FU Intramural Research Program of the National Institutes of Health (NICHD) FX Intramural Research Program of the National Institutes of Health (NICHD). Funding for open access charge: Intramural Research program of the National Institutes of Health (NICHD). NR 53 TC 8 Z9 8 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD NOV 10 PY 2014 VL 42 IS 20 BP 12512 EP 12522 DI 10.1093/nar/gku1013 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AY6RL UT WOS:000347693200021 PM 25348398 ER PT J AU Hartog, CS Natanson, C Sun, JF Klein, HG Reinhart, K AF Hartog, Christiane S. Natanson, Charles Sun, Junfeng Klein, Harvey G. Reinhart, Konrad TI Concerns over use of hydroxyethyl starch solutions SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID RENAL-FUNCTION; SEVERE SEPSIS; VOLUME RESUSCITATION; FLUID RESUSCITATION; TRIALS; METAANALYSIS; MORTALITY; SURGERY; SAFETY C1 [Hartog, Christiane S.; Reinhart, Konrad] Jena Univ Hosp, Ctr Sepsis Care & Control, Dept Anaesthesiol & Intens Care Med, D-07747 Jena, Germany. [Natanson, Charles; Sun, Junfeng] NIH, Crit Care Med Dept, Bethesda, MD 20892 USA. [Klein, Harvey G.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RP Reinhart, K (reprint author), Jena Univ Hosp, Ctr Sepsis Care & Control, Dept Anaesthesiol & Intens Care Med, D-07747 Jena, Germany. EM konrad.reinhart@med.uni-jena.de NR 30 TC 15 Z9 15 U1 0 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 NOV 10 PY 2014 VL 349 AR g5981 DI 10.1136/bmj.g5981 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA AU2JP UT WOS:000345444800003 PM 25385352 ER PT J AU Waterfall, JJ Meltzer, PS AF Waterfall, Joshua J. Meltzer, Paul S. TI Building through Breaking: The Development of Cancer Neochromosomes SO CANCER CELL LA English DT Editorial Material ID SOFT-TISSUE TUMORS; RING CHROMOSOMES AB In this issue of Cancer Cell, Garsed and colleagues combine chromosome flow sorting and deep sequencing to characterize the structure of oncogene-containing neochromosomes in liposarcoma and provide evidence that they are generated by a combination of multiple dynamic and destructive processes. C1 [Waterfall, Joshua J.; Meltzer, Paul S.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Meltzer, PS (reprint author), NCI, Genet Branch, Ctr Canc Res, 37 Convent Dr, Bethesda, MD 20892 USA. EM pmeltzer@mail.nih.gov NR 10 TC 0 Z9 0 U1 2 U2 5 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 NOV 10 PY 2014 VL 26 IS 5 BP 593 EP 595 DI 10.1016/j.ccell.2014.10.013 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AT5KA UT WOS:000344980900002 PM 25517741 ER PT J AU Guo, G Wang, L Liu, HX Randall, T AF Guo, Guang Wang, Lin Liu, Hexuan Randall, Thomas TI Genomic Assortative Mating in Marriages in the United States SO PLOS ONE LA English DT Article ID BIOLOGICAL PATHWAYS; WIDE ASSOCIATION; HUMAN HEIGHT; 5 DECADES; LOCI; SCHIZOPHRENIA; DISORDERS; C6ORF217; VARIANTS; TRENDS AB Assortative mating in phenotype in human marriages has been widely observed. Using genome-wide genotype data from the Framingham Heart study (FHS; number of married couples = 989) and Health Retirement Survey (HRS; number of married couples = 3,474), this study investigates genomic assortative mating in human marriages. Two types of genomic marital correlations are calculated. The first is a correlation specific to a single married couple "averaged'' over all available autosomal single-nucleotide polymorphism (SNPs). In FHS, the average married-couple correlation is 0.0018 with p=3x10(-5); in HRS, it is 0.0017 with p=7.13x10(-13). The marital correlation among the positively assorting SNPs is 0.001 (p=.0043) in FHS and 0.015 (p=1.66x10(-24)) in HRS. The sizes of these estimates in FHS and HRS are consistent with what are suggested by the distribution of the allelic combination. The study also estimated SNP-specific correlation "averaged'' over all married couples. Suggestive evidence is reported. Future studies need to consider a more general form of genomic assortment, in which different allelic forms in homologous genes and non-homologous genes result in the same phenotype. C1 [Guo, Guang; Liu, Hexuan] Univ N Carolina, Dept Sociol, Chapel Hill, NC 27599 USA. [Guo, Guang; Liu, Hexuan] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. [Guo, Guang] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Wang, Lin] Duke Univ, Ctr Child & Family Policy, Durham, NC USA. [Randall, Thomas] NIEHS, Res Triangle Pk, NC 27709 USA. RP Guo, G (reprint author), Univ N Carolina, Dept Sociol, Chapel Hill, NC 27599 USA. EM guang_guo@unc.edu FU National Institutes of Health [RC1 DA029425-01] FX Funding provided by Challenge Grant RC1 DA029425-01, National Institutes of Health, 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 37 TC 4 Z9 4 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 NOV 10 PY 2014 VL 9 IS 11 AR e112322 DI 10.1371/journal.pone.0112322 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT3DP UT WOS:000344816700049 PM 25384046 ER PT J AU Zhang, JH Pandey, M Kahler, JF Loshakov, A Harris, B Dagur, PK Mo, YY Simonds, WF AF Zhang, Jian-Hua Pandey, Mritunjay Kahler, John F. Loshakov, Anna Harris, Benjamin Dagur, Pradeep K. Mo, Yin-Yuan Simonds, William F. TI Improving the specificity and efficacy of CRISPR/CAS9 and gRNA through target specific DNA reporter SO JOURNAL OF BIOTECHNOLOGY LA English DT Article DE CRISPR; CAS9; gRNA; EGFP reporter; Specificity ID GUIDED CAS9 NUCLEASE; HUMAN-CELLS; RNA; ENDONUCLEASE; MUTAGENESIS; GENERATION; DROSOPHILA; MULTIPLEX; SYSTEM; MICE AB Genomic engineering by the guide RNA (gRNA)-directed CRISPR/CAS9 is rapidly becoming a method of choice for various biological systems. However, pressing concerns remain regarding its off-target activities and wide variations in efficacies. While next generation sequencing (NGS) has been primarily used to evaluate the efficacies and off-target activities of gRNAs, it only detects the imperfectly repaired double strand DNA breaks (DSB) by the error-prone non-homologous end joining (NHEJ) mechanism and may not faithfully represent the DSB activities because the efficiency of NHEJ-mediated repair varies depending on the local chromatin environment. Here we describe a reporter system for unbiased detection and comparison of DSB activities that promises to improve the chance of success in genomic engineering and to facilitate large-scale screening of CAS9 activities and gRNA libraries. Additionally, we demonstrated that the tolerances to mismatches between a gRNA and the corresponding target DNA can occur at any position of the gRNA, and depend on both specific gRNA sequences and CAS9 constructs used. Published by Elsevier B.V. C1 [Zhang, Jian-Hua; Pandey, Mritunjay; Kahler, John F.; Loshakov, Anna; Harris, Benjamin; Simonds, William F.] NIDDK, Metab Dis Branch, Bethesda, MD 20892 USA. [Dagur, Pradeep K.] NHLBI, Flow Cytometry Core Fac, NIH, Bethesda, MD 20892 USA. [Mo, Yin-Yuan] Univ Mississippi, Med Ctr, Inst Canc, Dept Pharmacol & Toxicol, Jackson, MS 39216 USA. RP Zhang, JH (reprint author), NIH, Bldg 10,Room 8C 205,10 Ctr Dr MSC 1752, Bethesda, MD 20892 USA. EM jianhuaz@mail.nih.gov FU Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases; National Heart Lung and Blood Institute FX This research was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Heart Lung and Blood Institute. NR 19 TC 5 Z9 6 U1 3 U2 53 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1656 EI 1873-4863 J9 J BIOTECHNOL JI J. Biotechnol. PD NOV 10 PY 2014 VL 189 BP 1 EP 8 DI 10.1016/j.jbiotec.2014.08.033 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA AS3NL UT WOS:000344184900001 PM 25193712 ER PT J AU Tian, L Durazo-Arvizu, RA Myers, G Brooks, S Sarafin, K Sempos, CT AF Tian, Lu Durazo-Arvizu, Ramon A. Myers, Gary Brooks, Steve Sarafin, Kurtis Sempos, Christopher T. TI The estimation of calibration equations for variables with heteroscedastic measurement errors SO STATISTICS IN MEDICINE LA English DT Article DE calibration study; coefficient of variation (CV); heteroscedastic measurement error and estimating equations ID REGRESSION-ANALYSIS; STANDARDIZATION; PREDICTION AB In clinical chemistry and medical research, there is often a need to calibrate the values obtained from an old or discontinued laboratory procedure to the values obtained from a new or currently used laboratory method. The objective of the calibration study is to identify a transformation that can be used to convert the test values of one laboratory measurement procedure into the values that would be obtained using another measurement procedure. However, in the presence of heteroscedastic measurement error, there is no good statistical method available for estimating the transformation. In this paper, we propose a set of statistical methods for a calibration study when the magnitude of the measurement error is proportional to the underlying true level. The corresponding sample size estimation method for conducting a calibration study is discussed as well. The proposed new method is theoretically justified and evaluated for its finite sample properties via an extensive numerical study. Two examples based on real data are used to illustrate the procedure. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Tian, Lu] Stanford Univ, Dept Hlth Res & Policy, Palo Alto, CA 94304 USA. [Durazo-Arvizu, Ramon A.] Loyola Univ, Dept Publ Hlth, Chicago, IL 60611 USA. [Myers, Gary] Amer Assoc Clin Chem, Dept Programs & Policy, Washington, DC USA. [Brooks, Steve; Sarafin, Kurtis] Hlth Canada, Dept Bur Nutr, Ottawa, ON K1A 0L2, Canada. [Sempos, Christopher T.] NIH, Dept Off Dietary Supplements, Bethesda, MD 20892 USA. RP Durazo-Arvizu, RA (reprint author), Loyola Univ Chicago, Dept Publ Hlth Sci, Maywood, IL 60153 USA. EM rdurazo@luc.edu NR 25 TC 4 Z9 4 U1 0 U2 3 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 NOV 9 PY 2014 VL 33 IS 25 BP 4420 EP 4436 DI 10.1002/sim.6235 PG 17 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 AQ6DK UT WOS:000342898500007 PM 24935784 ER PT J AU Zhang, ZW Liu, CL Kim, S Liu, AY AF Zhang, Zhiwei Liu, Chunling Kim, Sungduk Liu, Aiyi TI Prevalence estimation subject to misclassification: the mis-substitution bias and some remedies SO STATISTICS IN MEDICINE LA English DT Article DE dilution effect; group testing; maximum likelihood; optimal design; pooled testing; sensitivity; specificity; test error ID HUMAN-IMMUNODEFICIENCY-VIRUS; GROUP-TESTING PROCEDURE; REGRESSION-ANALYSIS; INFECTION-RATES; VARIABLE SIZE; BLOOD-DONORS; RARE DISEASE; POOLED SERA; MODELS; HIV AB We consider the problem of estimating the prevalence of a disease under a group testing framework. Because assays are usually imperfect, misclassification of disease status is a major challenge in prevalence estimation. To account for possible misclassification, it is usually assumed that the sensitivity and specificity of the assay are known and independent of the group size. This assumption is often questionable, and substitution of incorrect values of an assay's sensitivity and specificity can result in a large bias in the prevalence estimate, which we refer to as the mis-substitution bias. In this article, we propose simple designs and methods for prevalence estimation that do not require known values of assay sensitivity and specificity. If a gold standard test is available, it can be applied to a validation subsample to yield information on the imperfect assay's sensitivity and specificity. When a gold standard is unavailable, it is possible to estimate assay sensitivity and specificity, either as unknown constants or as specified functions of the group size, from group testing data with varying group size. We develop methods for estimating parameters and for finding or approximating optimal designs, and perform extensive simulation experiments to evaluate and compare the different designs. An example concerning human immunodeficiency virus infection is used to illustrate the validation subsample design. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Zhang, Zhiwei] US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Liu, Chunling] Hong Kong Polytech Univ, Dept Appl Math, Hong Kong, Hong Kong, Peoples R China. [Kim, Sungduk; Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. RP Zhang, ZW (reprint author), US FDA, DBS, OSB, CDRH, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM zhiwei.zhang@fda.hhs.gov RI Liu, Chunling/A-4827-2015; OI Liu, Chunling/0000-0003-3410-445X; Liu, Aiyi/0000-0002-6618-5082 FU Hong Kong research grant [BQ25U]; National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We thank three anonymous reviewers for their insightful and constructive comments that have improved the manuscript greatly. Dr. Chunling Liu's research was partially supported by Hong Kong research grant BQ25U. The research of Drs. Aiyi Liu and Sung-Duk Kim was supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. The views expressed in this article do not represent the official position of the US Food and Drug Administration. NR 43 TC 3 Z9 3 U1 0 U2 2 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 NOV 9 PY 2014 VL 33 IS 25 BP 4482 EP 4500 DI 10.1002/sim.6268 PG 19 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 AQ6DK UT WOS:000342898500011 PM 25043925 ER PT J AU Kouyos, RD Metcalf, CJE Birger, R Klein, EY zur Wiesch, PA Ankomah, P Arinaminpathy, N Bogich, TL Bonhoeffer, S Brower, C Chi-Johnston, G Cohen, T Day, T Greenhouse, B Huijben, S Metlay, J Mideo, N Pollitt, LC Read, AF Smith, DL Standley, C Wale, N Grenfell, B AF Kouyos, Roger D. Metcalf, C. Jessica E. Birger, Ruthie Klein, Eili Y. zur Wiesch, Pia Abel Ankomah, Peter Arinaminpathy, Nimalan Bogich, Tiffany L. Bonhoeffer, Sebastian Brower, Charles Chi-Johnston, Geoffrey Cohen, Ted Day, Troy Greenhouse, Bryan Huijben, Silvie Metlay, Joshua Mideo, Nicole Pollitt, Laura C. Read, Andrew F. Smith, David L. Standley, Claire Wale, Nina Grenfell, Bryan TI The path of least resistance: aggressive or moderate treatment? SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE drug resistance; evolution; treatment strategies ID DRUG-RESISTANCE; ANTIBIOTIC-RESISTANCE; ANTIRETROVIRAL THERAPY; IN-VITRO; PLASMODIUM-FALCIPARUM; ESCHERICHIA-COLI; ANTIMICROBIAL RESISTANCE; TUBERCULOSIS TREATMENT; EVOLUTIONARY DYNAMICS; MALARIA PARASITES AB The evolution of resistance to antimicrobial chemotherapy is a major and growing cause of human mortality and morbidity. Comparatively little attention has been paid to how different patient treatment strategies shape the evolution of resistance. In particular, it is not clear whether treating individual patients aggressively with high drug dosages and long treatment durations, or moderately with low dosages and short durations can better prevent the evolution and spread of drug resistance. Here, we summarize the very limited available empirical evidence across different pathogens and provide a conceptual framework describing the information required to effectively manage drug pressure to minimize resistance evolution. C1 [Kouyos, Roger D.; Metcalf, C. Jessica E.; Birger, Ruthie; Klein, Eili Y.; Arinaminpathy, Nimalan; Bogich, Tiffany L.; Brower, Charles; Grenfell, Bryan] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Kouyos, Roger D.] Univ Zurich, Univ Hosp Zurich, Div Infect Dis & Hosp Epidemiol, Zurich, Switzerland. [Metcalf, C. Jessica E.; Smith, David L.] Univ Oxford, Dept Zool, Oxford, England. [zur Wiesch, Pia Abel; Cohen, Ted] Harvard Univ, Brigham & Womens Hosp, Sch Publ Hlth, Div Global Hlth Equ, Boston, MA 02115 USA. [zur Wiesch, Pia Abel; Cohen, Ted] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Ankomah, Peter] Emory Univ, Dept Biol, Atlanta, GA 30322 USA. [Bonhoeffer, Sebastian] Swiss Fed Inst Technol, Inst Integrat Biol, Zurich, Switzerland. [Chi-Johnston, Geoffrey] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Klein, Eili Y.] Johns Hopkins Univ, Dept Emergency Med, Ctr Adv Modeling, Baltimore, MD USA. [Day, Troy] Queens Univ, Dept Math, Kingston, ON, Canada. [Day, Troy] Queens Univ, Dept Biol, Kingston, ON K7L 3N6, Canada. [Greenhouse, Bryan] Univ Calif San Francisco, Dept Med, Div Infect Dis, San Francisco, CA USA. [Pollitt, Laura C.; Read, Andrew F.; Wale, Nina] Penn State Univ, Ctr Infect Dis Dynam, State Coll, PA USA. [Pollitt, Laura C.; Read, Andrew F.; Wale, Nina] Penn State Univ, Dept Biol, State Coll, PA USA. [Pollitt, Laura C.; Read, Andrew F.] Penn State Univ, Dept Entomol, State Coll, PA USA. [Metlay, Joshua] Massachusetts Gen Hosp, Gen Med Div, Boston, MA 02114 USA. [Mideo, Nicole] Univ Toronto, Dept Ecol & Evolutionary Biol, Toronto, ON, Canada. [Bogich, Tiffany L.; Read, Andrew F.; Grenfell, Bryan] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Arinaminpathy, Nimalan] Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis Epidemiol, London, England. [Standley, Claire] George Washington Univ, Dept Hlth Policy, Washington, DC USA. [Pollitt, Laura C.] Univ Edinburgh, Ctr Immunol Infect & Evolut, Edinburgh, Midlothian, Scotland. [Huijben, Silvie] Univ Barcelona, Hosp Clin, Barcelona Ctr Int Hlth Res, Barcelona, Spain. [Brower, Charles] Ctr Dis Dynam Econ & Policy, Washington, DC USA. RP Birger, R (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM rbirger@princeton.edu RI Birger, Ruthie/F-2416-2014; Bonhoeffer, Sebastian/A-2735-2008; Kouyos, Roger/G-6226-2014; Smith, David/L-8850-2013; OI Birger, Ruthie/0000-0002-2960-5084; Bonhoeffer, Sebastian/0000-0001-8052-3925; Kouyos, Roger/0000-0002-9220-8348; Bogich, Tiffany/0000-0002-8143-5289; Smith, David/0000-0003-4367-3849; Greenhouse, Bryan/0000-0003-0287-9111; Klein, Eili/0000-0002-1304-5289 FU RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Science and Technology Directorate, Department of Homeland Security [HSHQDC-12-C-00058] FX This work emerged from a meeting funded by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health; Science and Technology Directorate, Department of Homeland Security; contract HSHQDC-12-C-00058. We thank C. Ovenden for comments on an earlier draft. NR 63 TC 20 Z9 20 U1 3 U2 19 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 NOV 7 PY 2014 VL 281 IS 1794 AR 20140566 DI 10.1098/rspb.2014.0566 PG 8 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA CE0RL UT WOS:000351512500002 PM 25253451 ER PT J AU Meseda, CA Srinivasan, K Wise, J Catalano, J Yamada, KM Dhawan, S AF Meseda, Clement A. Srinivasan, Kumar Wise, Jasen Catalano, Jennifer Yamada, Kenneth M. Dhawan, Subhash TI Non-coding RNAs and heme oxygenase-1 in vaccinia virus infection SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Vaccinia; Non-coding RNAs; Heme oxygenase-1; Host defense; Gene expression ID INDUCTION; REPLICATION; MALARIA AB Small nuclear RNAs (snRNAs) are <200 nucleotide non-coding uridylate-rich RNAs. Although the functions of many snRNAs remain undetermined, a population of snRNAs is produced during the early phase of infection of cells by vaccinia virus. In the present study, we demonstrate a direct correlation between expression of the cytoprotective enzyme heme oxygenase-1 (HO-1), suppression of selective snRNA expression, and inhibition of vaccinia virus infection of macrophages. Hemin induced HO-1 expression, completely reversed virus-induced host snRNA expression, and suppressed vaccinia virus infection. This involvement of specific virus-induced snRNAs and associated gene clusters suggests a novel HO-1-dependent host-defense pathway in poxvirus infection. Published by Elsevier Inc. C1 [Srinivasan, Kumar; Dhawan, Subhash] US FDA, Ctr Biol Evaluat & Res, Div Transfus Transmitted Dis, Bethesda, MD 20014 USA. [Meseda, Clement A.] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD 20014 USA. [Wise, Jasen] Qiagen, Frederick, MD USA. [Catalano, Jennifer] US FDA, Ctr Tobacco Prod, Bethesda, MD 20014 USA. [Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Dhawan, S (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Transfus Transmitted Dis, Bethesda, MD 20014 USA. EM subhash.dhawan@fda.hhs.gov FU FDA; NIDCR Intramural Research Programs FX S.D., conceptualized, designed, performed, analyzed experiments and wrote the paper; C.A.M., K.S. and J.W., performed and analyzed experiments; J.C. and K.M.Y. analyzed experiments. We thank Dr. Jerry Weir for supporting this study. This paper is dedicated to the memory of Dr. Kumar Srinivasan. The findings and conclusions in this paper have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. This work was supported by FDA and NIDCR Intramural Research Programs. NR 15 TC 1 Z9 1 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 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD NOV 7 PY 2014 VL 454 IS 1 BP 84 EP 88 DI 10.1016/j.bbrc.2014.10.035 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AX1FN UT WOS:000346693500015 PM 25450361 ER PT J AU Taylor-Douglas, DC Basu, A Gardner, RM Aspelund, S Wen, X Yanovski, JA AF Taylor-Douglas, Dezmond C. Basu, Arunabha Gardner, Ryan M. Aspelund, Sender Wen, Xin Yanovski, Jack A. TI Evaluation of hypothalamic murine and human melanocortin 3 receptor transcript structure SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Melanocortin 3 receptor; RNA ligase mediated rapid amplification of cDNA ends; Untranslated regions ID UNTRANSLATED REGIONS; GENE-EXPRESSION; MESSENGER-RNAS; HUMAN OBESITY; MOUSE; IDENTIFICATION; LINKAGE; GENOME; MC3R; FAT AB The melanocortin 3 receptor (MC3R) is involved in regulation of energy homeostasis. However, its transcript structure is not well understood. We therefore studied initiation and termination sites for hypothalamic murine Mc3r and human MC3R transcripts. Rapid Amplification of cDNA Ends (RACE) was performed for the 5' and 3' ends of murine and human hypothalamic RNA. 5' RACE experiments using hypothalamic murine RNA indicated mouse hypothalamus expresses two major Mc3r transcription start sites: one with a 5' UTR approximately 368 bases in length and another previously unknown transcript with a 5' UTR approximately 440 bases in length. 5' RACE experiments using human hypothalamic RNA identified a 5' UTR beginning 533 bases upstream of the start codon with a 248 base splice. 3' RACE experiments using hypothalamic murine RNA indicated the 3' UTR terminates approximately 1286 bases after the translational stop codon, with a previously unknown 787 base splice between consensus splice donor and acceptor sites. 3' RACE experiments using human MC3R transcript indicated the 3' UTR terminates approximately 115-160 bases after the translational stop codon. These data provide insight into melanocortin 3 receptor transcript structure. Published by Elsevier Inc. C1 [Taylor-Douglas, Dezmond C.; Basu, Arunabha; Gardner, Ryan M.; Aspelund, Sender; Wen, Xin; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Taylor-Douglas, Dezmond C.] Howard Univ, Coll Med, Dept Physiol, Washington, DC 20059 USA. RP Yanovski, JA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,Hatfield Clin Res Ctr, 10 Ctr Dr,Bldg 10,Room 1-3330,MSC 1103, Bethesda, MD 20892 USA. EM jy15i@nih.gov OI Yanovski, Jack/0000-0001-8542-1637 FU NICHD Intramural Research Program [ZIA-HD-00641]; National Institute on Minority Health and Health Disparities, NIH; NICHD Scholar Program FX Research support: NICHD Intramural Research Program ZIA-HD-00641 (to JAY) with supplemental support from the National Institute on Minority Health and Health Disparities, NIH. DCTD was supported by the NICHD Scholar Program. J. Yanovski is a commissioned officer in the U.S. Public Health Service (PHS). NR 19 TC 1 Z9 1 U1 0 U2 1 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 NOV 7 PY 2014 VL 454 IS 1 BP 234 EP 238 DI 10.1016/j.bbrc.2014.10.072 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AX1FN UT WOS:000346693500040 PM 25450386 ER PT J AU Tian, Q Simonsick, EM Erickson, KI Aizenstein, HJ Glynn, NW Boudreau, RM Newman, AB Kritchevsky, SB Yaffe, K Harris, T Rosano, C AF Tian, Qu Simonsick, Eleanor M. Erickson, Kirk I. Aizenstein, Howard J. Glynn, Nancy W. Boudreau, Robert M. Newman, Anne B. Kritchevsky, Stephen B. Yaffe, Kristine Harris, Tamara Rosano, Caterina CA Hlth ABC Study TI Cardiorespiratory fitness and brain diffusion tensor imaging in adults over 80 years of age SO BRAIN RESEARCH LA English DT Article DE Cardiorespiratory fitness; Diffusion tensor imaging; Microstructural integrity; Very old adults; Neuroepidemiology ID WHITE-MATTER INTEGRITY; FUNCTIONING OLDER-ADULTS; DISTANCE CORRIDOR WALK; AEROBIC FITNESS; PHYSICAL-ACTIVITY; BODY-COMPOSITION; GAIT SPEED; SUBSEQUENT DISABILITY; PSYCHOMOTOR SPEED; HEALTHY SENIORS AB A positive association between cardiorespiratory fitness (CRF) and white matter integrity has been consistently reported in older adults. However, it is unknown whether this association exists in adults over 80 with a range of chronic disease conditions and low physical activity participation, which can influence both CRF and brain health. This study examined whether higher CRF was associated with greater microstructural integrity of gray and white matter in areas related to memory and information processing in adults over 80 and examined moderating effects of chronic diseases and physical activity. CRF was measured as time to walk 400 m as quickly as possible with concurrent 3 T diffusion tensor imaging in 164 participants (57.1% female, 40.3% black). Fractional anisotropy (FA) was computed for cingulum, uncinate and superior longitudinal fasciculi. Mean diffusivity (MD) was computed for dorsolateral prefrontal cortex, hippocampus, parahippocampus, and entorhinal cortex. Moderating effects were tested using hierarchical regression models. Higher CRF was associated with higher FA in cingulum and lower MD in hippocampus and entorhinal cortex (beta, sex-adjusted p: -0.182, 0.019; 0.165, 0.035; and 0.220, 0.006, respectively). Hypertension attenuated the association with MD in entorhinal cortex. Moderating effects of chronic diseases and physical activity in walking and climbing stairs on these associations were not significant. The association of higher CRF with greater microstructural integrity in selected subcortical areas appears robust, even among very old adults with a range of chronic diseases. Intervention studies should investigate whether increasing CRP can preserve memory and information processing by improving microstructure and potential effects of hypertension management. (C) 2014 Elsevier B.V. All rights reserved. C1 [Tian, Qu; Glynn, Nancy W.; Boudreau, Robert M.; Newman, Anne B.; Rosano, Caterina] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Simonsick, Eleanor M.] NIA, Intramural Res Program, Baltimore, MD 21225 USA. [Erickson, Kirk I.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Aizenstein, Howard J.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. [Aizenstein, Howard J.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15213 USA. [Aizenstein, Howard J.] Univ Pittsburgh, Dept Clin & Translat Sci, Pittsburgh, PA 15213 USA. [Kritchevsky, Stephen B.] Wake Forest Sch Med, Sticht Ctr Aging, Sect Gerontol & Geriatr, Winston Salem, NC USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94121 USA. [Harris, Tamara] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Tian, Q (reprint author), 251 Bayview Blvd,Suite 100,Room 04B316, Baltimore, MD 21224 USA. EM qu.tian@nih.gov RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010; Boudreau, Robert/0000-0003-0162-5187; Glynn, Nancy/0000-0003-2265-0162 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, K23-AG028966-01]; NIA [R01-AG028050, R01-AG029232, P30-AG024827]; NINR [R01-NR012459]; Intramural Research Program of the NIH, National Institute on Aging FX This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, K23-AG028966-01; NIA grants R01-AG028050, R01-AG029232, P30-AG024827, and NINR grant R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 57 TC 6 Z9 6 U1 4 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD NOV 7 PY 2014 VL 1588 BP 63 EP 72 DI 10.1016/j.brainres.2014.09.003 PG 10 WC Neurosciences SC Neurosciences & Neurology GA AU2SX UT WOS:000345468900007 PM 25204690 ER PT J AU Cheng, S Enserro, D Xanthakis, V Sullivan, LM Murabito, JM Benjamin, EJ Polak, JF O'Donnell, CJ Wolf, PA O'Connor, GT Keaney, JF Vasan, RS AF Cheng, Susan Enserro, Danielle Xanthakis, Vanessa Sullivan, Lisa M. Murabito, Joanne M. Benjamin, Emelia J. Polak, Joseph F. O'Donnell, Christopher J. Wolf, Philip A. O'Connor, George T. Keaney, John F. Vasan, Ramachandran S. TI Association of exhaled carbon monoxide with subclinical cardiovascular disease and their conjoint impact on the incidence of cardiovascular outcomes SO EUROPEAN HEART JOURNAL LA English DT Article DE Carbon monoxide; Subclinical vascular disease; Cardiovascular outcomes ID HEME OXYGENASE-1/CARBON MONOXIDE; SMOOTH-MUSCLE-CELLS; METABOLIC SYNDROME; RISK; ATHEROSCLEROSIS; HYPERTENSION; EXPRESSION; PROTECTION; APOPTOSIS; EXPOSURE AB Aims Whereas endogenous carbon monoxide (CO) is cytoprotective at physiologic levels, excess CO concentrations are associated with cardiometabo tic risk and may represent an important marker of progression from subclinical to clinical cardiovascular disease (CVD). Methods and results In 1926 participants of the Framingham Offspring Study (aged 57 +/- 10 years, 46% women), we investigated the relationship of exhaled CO, a surrogate of blood CO concentration, with both prevalent subdinical CVD and incident clinical CVD events. Presence of subdinical CVD was determined using a comprehensive panel of diagnostic tests used to assess cardiac and vascular structure and function. Individuals with the highest (>5 p.p.m.) compared with lowest (<= 4 p.p.m.) CO exposure were more Likely to have subclinical CVD [odds ratios (OR): 1.67, 95% CI: 1.32-2.12; P < 0.001]. During the follow-up period (mean 5 +/- 3 years), 193 individuals developed overt CVD. Individuals with both high CO levels and any baseline subdinical CVD developed overt CVD at an almost four-fold higher rate compared with those with low CO Levels and no subclinical disease (22.1 vs. 6.3%). Notably, elevated CO was associated with incident CVD in the presence [hazards ration (HR): 1.83, 95% CI: 1.08-3.11; P = 0.026] but not in the absence (HR: 0.80, 95% CI: 0.42-1.53; P = 0.51) of subclinical CVD (Pmteractton = 0.019). Similarly, subclinical CVD was associated with incident CVD in the presence of high but not low CO exposure. Conclusion Our findings in a community-based sample suggest that elevated CO is a marker of greater subctinical CVD burden and, furthermore, a potential key component in the progression from subdinical to clinical CVD. C1 [Cheng, Susan; Xanthakis, Vanessa; Murabito, Joanne M.; Benjamin, Emelia J.; O'Donnell, Christopher J.; Wolf, Philip A.; O'Connor, George T.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Cheng, Susan] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Enserro, Danielle; Xanthakis, Vanessa; Sullivan, Lisa M.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Xanthakis, Vanessa; Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Cardiol, Boston, MA 02118 USA. [Polak, Joseph F.] Tufts Univ New England Med Ctr, Dept Radiol, Boston, MA 02111 USA. [O'Donnell, Christopher J.] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Wolf, Philip A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [O'Connor, George T.] Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. [Keaney, John F.] Univ Massachusetts, Sch Med, Dept Med, Boston, MA 02125 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Epidemiol, Boston, MA 02118 USA. RP Cheng, S (reprint author), NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. EM scheng3@partners.org OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health; Boston University School of Medicine; National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; American College of Cardiology/Merck Research Fellowship in Cardiovascular Disease and Cardiometabolic Disorders; [R01-N5017950]; [K99HL107642] FX 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. This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195). This work was supported in part by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract no. N01-HC-25195) and grants R01-N5017950 and K99HL107642 and the American College of Cardiology/Merck Research Fellowship in Cardiovascular Disease and Cardiometabolic Disorders (S.C.). NR 38 TC 4 Z9 4 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD NOV 7 PY 2014 VL 35 IS 42 SI SI BP 2980 EP 2987 DI 10.1093/eurheartj/ehu052 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AU1FX UT WOS:000345367500014 PM 24574370 ER PT J AU Donninger, H Clark, JA Monaghan, MK Schmidt, ML Vos, M Clark, GJ AF Donninger, Howard Clark, Jennifer A. Monaghan, Megan K. Schmidt, M. Lee Vos, Michele Clark, Geoffrey J. TI Cell Cycle Restriction Is More Important Than Apoptosis Induction for RASSF1A Protein Tumor Suppression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ASSOCIATION DOMAIN FAMILY-1; DEATH INDUCER C19ORF5; BINDING-PROTEIN; EPIGENETIC INACTIVATION; MICROTUBULE DYNAMICS; MST2 PATHWAY; K-RAS; EFFECTOR; KINASE; METHYLATION AB The Ras association domain family protein 1A (RASSF1A) is arguably one of the most frequently inactivated tumor suppressors in human cancer. RASSF1A modulates apoptosis via the Hippo and Bax pathways but also modulates the cell cycle. In part, cell cycle regulation appears to be dependent upon the ability of RASSF1A to complex with microtubules and regulate their dynamics. Which property of RASSF1A, apoptosis induction or microtubule regulation, is responsible for its tumor suppressor function is not known. We have identified a short conserved motif that is essential for the binding of RASSF family proteins with microtubule-associated proteins. By making a single point mutation in the motif, we were able to generate a RASSF1A variant that retains wild-type apoptotic properties but completely loses the ability to bind microtubule-associated proteins and complex with microtubules. Comparison of this mutant to wild-type RASSF1A showed that, despite retaining its proapoptotic properties, the mutant was completely unable to induce cell cycle arrest or suppress the tumorigenic phenotype. Therefore, it appears that the cell cycle/microtubule effects of RASSF1A are key to its tumor suppressor function rather than its apoptotic effects. C1 [Donninger, Howard; Clark, Jennifer A.; Monaghan, Megan K.] Univ Louisville, Dept Med, James Graham Brown Canc Ctr, Mol Targets Program, Louisville, KY 40202 USA. [Schmidt, M. Lee] Univ Louisville, Dept Biochem & Mol Biol, James Graham Brown Canc Ctr, Mol Targets Program, Louisville, KY 40202 USA. [Clark, Geoffrey J.] Univ Louisville, Dept Pharmacol & Toxicol, James Graham Brown Canc Ctr, Mol Targets Program, Louisville, KY 40202 USA. [Vos, Michele] NCI, Cell & Canc Biol Branch, NIH, Rockville, MD 20850 USA. RP Clark, GJ (reprint author), Univ Louisville, Dept Pharmacol & Toxicol, James Graham Brown Canc Ctr, Mol Targets Program, 505 S Hancock St, Louisville, KY 40202 USA. EM gjclar01@louisville.edu FU National Institutes of Health [1P20 RR18733, R01 CA133171-01A2] FX This work was supported, in whole or in part, by National Institutes of Health Grants 1P20 RR18733 and R01 CA133171-01A2 (to G.J.C.). NR 41 TC 11 Z9 11 U1 1 U2 2 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 NOV 7 PY 2014 VL 289 IS 45 BP 31287 EP 31295 DI 10.1074/jbc.M114.609537 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AS9GA UT WOS:000344549900033 PM 25225292 ER PT J AU Rao, DK Liu, HY Ambudkar, SV Mayer, M AF Rao, Divya K. Liu, Haiyan Ambudkar, Suresh V. Mayer, Michael TI A Combination of Curcumin with Either Gramicidin or Ouabain Selectively Kills Cells That Express the Multidrug Resistance-linked ABCG2 Transporter SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BREAST-CANCER CELLS; P-GLYCOPROTEIN; ATPASE ACTIVITY; COLLATERAL SENSITIVITY; CARDIAC-GLYCOSIDES; DRUG-RESISTANCE; TUMOR-CELLS; K+-ATPASE; APOPTOSIS; PROTEIN AB This paper introduces a strategy to kill selectively multidrug-resistant cells that express the ABCG2 transporter (also called breast cancer resistance protein, or BCRP). The approach is based on specific stimulation of ATP hydrolysis by ABCG2 transporters with subtoxic doses of curcumin combined with stimulation of ATP hydrolysis by Na+, K+-ATPase with subtoxic doses of gramicidin A or ouabain. After 72 h of incubation with the drug combinations, the resulting over consumption of ATP by both pathways inhibits the efflux activity of ABCG2 transporters, leads to depletion of intracellular ATP levels below the viability threshold, and kills resistant cells selectively over cells that lack ABCG2 transporters. This strategy, which was also tested on a clinically relevant human breast adenocarcinoma cell line (MCF-7/FLV1), exploits the overexpression of ABCG2 transporters and induces caspase-dependent apoptotic cell death selectively in resistant cells. This work thus introduces a novel strategy to exploit collateral sensitivity (CS) with a combination of two clinically used compounds that individually do not exert CS. Collectively, this work expands the current knowledge on ABCG2-mediated CS and provides a potential strategy for discovery of CS drugs against drug-resistant cancer cells. C1 [Rao, Divya K.; Liu, Haiyan; Mayer, Michael] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA. [Mayer, Michael] Univ Michigan, Dept Chem Engn, Ann Arbor, MI 48109 USA. [Ambudkar, Suresh V.] NCI, Lab Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Mayer, M (reprint author), Univ Michigan, Dept Biomed Engn, 1101 Beal Ave, Ann Arbor, MI 48109 USA. EM mimayer@umich.edu RI Mayer, Michael/C-1299-2010 OI Mayer, Michael/0000-0002-6148-5756 FU National Institutes of Health [1R01GM081705]; Intramural Research Program of the NCI National Institutes of Health Center for Cancer Research FX This work was supported, in whole or in part, by National Institutes of Health Grant 1R01GM081705 (to M. M.) and by the Intramural Research Program of the NCI National Institutes of Health Center for Cancer Research (to S.V.A.). NR 58 TC 9 Z9 9 U1 0 U2 10 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 NOV 7 PY 2014 VL 289 IS 45 BP 31397 EP 31410 DI 10.1074/jbc.M114.576819 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AS9GA UT WOS:000344549900043 PM 25253691 ER PT J AU Beard, WA Shock, DD Batra, VK Prasad, R Wilson, SH AF Beard, William A. Shock, David D. Batra, Vinod K. Prasad, Raiendra Wilson, Samuel H. TI Substrate-induced DNA Polymerase beta Activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE EXCISION-REPAIR; ACTIVE-SITE; NUCLEOTIDE INCORPORATION; SUBDOMAIN MOTIONS; KINETIC ANALYSES; GASTRIC-CANCER; MINOR-GROOVE; INDUCED FIT; MECHANISM; FIDELITY AB DNA polymerases and substrates undergo conformational changes upon forming protein-ligand complexes. These conformational adjustments can hasten or deter DNA synthesis and influence substrate discrimination. From structural comparison of binary DNA and ternary DNA-dNTP complexes of DNA polymerase beta, several side chains have been implicated in facilitating formation of an active ternary complex poised for chemistry. Site-directed mutagenesis of these highly conserved residues (Asp-192, Arg-258, Phe-272, Glu-295, and Tyr-296) and kinetic characterization provides insight into the role these residues play during correct and incorrect insertion as well as their role in conformational activation. The catalytic efficiencies for correct nucleotide insertion for alanine mutants were wild type similar to R258A > F272A similar to Y296A > E295A > D192A. Because the efficiencies for incorrect insertion were affected to about the same extent for each mutant, the effects on fidelity were modest (< 5-fold). The R258A mutant exhibited an increase in the single- turnover rate of correct nucleotide insertion. This suggests that the wild-type Arg-258 side chain generates a population of non-productive ternary complexes. Structures of binary and ternary substrate complexes of the R258A mutant and a mutant associated with gastric carcinomas, E295K, provide molecular insight into intermediate structural conformations not appreciated previously. Although the R258A mutant crystal structures were similar to wild-type enzyme, the open ternary complex structure of E295K indicates that Arg-258 stabilizes a nonproductive conformation of the primer terminus that would decrease catalysis. Significantly, the open E295K ternary complex binds two metal ions indicating that metal binding cannot overcome the modified interactions that have interrupted the closure of the N-subdomain. C1 [Beard, William A.; Shock, David D.; Batra, Vinod K.; Prasad, Raiendra; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, 111 T W Alexander Dr,POB 12233,MD F1-12, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU National Institutes of Health [P41 GM-103311] FX We thank Drs. K. Bebenek and B. D. Freudenthal for critical reading of the manuscript and valuable discussions. Molecular graphics images were produced using the Chimera package from the Resource for Biocomputing; Visualization, and Informatics at the University of California, San Francisco (Supported by National Institutes of Health Grant P41 GM-103311). NR 58 TC 9 Z9 9 U1 5 U2 8 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 NOV 7 PY 2014 VL 289 IS 45 BP 31411 EP 31422 DI 10.1074/jbc.M114.607432 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AS9GA UT WOS:000344549900044 PM 25261471 ER PT J AU Knutsen, AK Magrath, E McEntee, JE Xing, FX Prince, JL Bayly, PV Butman, JA Pham, DL AF Knutsen, Andrew K. Magrath, Elizabeth McEntee, Julie E. Xing, Fangxu Prince, Jerry L. Bayly, Philip V. Butman, John A. Pham, Dzung L. TI Improved measurement of brain deformation during mild head acceleration using a novel tagged MRI sequence SO JOURNAL OF BIOMECHANICS LA English DT Article DE Magnetic resonance imaging (MRD); Acceleration; Deformation; Strain; Traumatic brain injury (TBI) ID MAGNETIC-RESONANCE ELASTOGRAPHY; SINGLE IMAGE PLANE; MOTION TRACKING; ALZHEIMERS-DISEASE; MYOCARDIAL MOTION; IN-VIVO; INJURY; TISSUE; TRAUMA; IMPACT AB In vivo measurements of human brain deformation during mild acceleration are needed to help validate computational models of traumatic brain injury and to understand the factors that govern the mechanical response of the brain. Tagged magnetic resonance imaging is a powerful, noninvasive technique to track tissue motion in vivo which has been used to quantify brain deformation in live human subjects. However, these prior studies required from 72 to 144 head rotations to generate deformation data for a single image slice, precluding its use to investigate the entire brain in a single subject. Here, a novel method is introduced that significantly reduces temporal variability in the acquisition and improves the accuracy of displacement estimates. Optimization of the acquisition parameters in a gelatin phantom and three human subjects leads to a reduction in the number of rotations from 72 to 144 to as few as 8 for a single image slice. The ability to estimate accurate, well-resolved, fields of displacement and strain in far fewer repetitions will enable comprehensive studies of acceleration-induced deformation throughout the human brain in vivo. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Knutsen, Andrew K.; Magrath, Elizabeth; McEntee, Julie E.; Butman, John A.; Pham, Dzung L.] Henry M Jackson Fdn, Ctr Neurosci & Regenerat Med, Bethesda, MD 20892 USA. [Xing, Fangxu; Prince, Jerry L.] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. [Prince, Jerry L.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. [Bayly, Philip V.] Dept Mech Engn & Mat Sci, St Louis, MO USA. [Bayly, Philip V.] Washington Univ, Dept Biomed Engn, St Louis, MO USA. [Butman, John A.] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. RP Knutsen, AK (reprint author), Henry M Jackson Fdn, Ctr Neurosci & Regenerat Med, 9000 Rockville Pike,Bldg 10-B1N264B, Bethesda, MD 20892 USA. EM andrew.knutsen@nih.gov RI Butman, John/J-2780-2013; OI Butman, John/0000-0002-1547-9195; Bayly, Philip/0000-0003-4303-0704 FU Department of Defense in the Center for Neuroscience and Regenerative Medicine; National Institutes of Health [R01-NS055951] FX We would like to thank the seven participants for their time and effort. We would also like to acknowledge Bruce Pritchard, Danny Trang, and George Do Id at the NINDS Machine Shop for their assistance. Support for this work included funding from Department of Defense in the Center for Neuroscience and Regenerative Medicine and from the National Institutes of Health (R01-NS055951). NR 34 TC 1 Z9 1 U1 1 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 EI 1873-2380 J9 J BIOMECH JI J. Biomech. PD NOV 7 PY 2014 VL 47 IS 14 BP 3475 EP 3481 DI 10.1016/j.jbiomech.2014.09.010 PG 7 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA AT8KZ UT WOS:000345183500007 PM 25287113 ER PT J AU Chen, L Choyke, PL Wang, NY Clarke, R Bhujwalla, ZM Hillman, EMC Wang, G Wang, Y AF Chen, Li Choyke, Peter L. Wang, Niya Clarke, Robert Bhujwalla, Zaver M. Hillman, Elizabeth M. C. Wang, Ge Wang, Yue TI Unsupervised Deconvolution of Dynamic Imaging Reveals Intratumor Vascular Heterogeneity and Repopulation Dynamics SO PLOS ONE LA English DT Article ID INFORMATION-THEORETIC CRITERIA; CONTRAST-ENHANCED MRI; TUMOR HETEROGENEITY; BREAST-CANCER; EVOLUTION; TOMOGRAPHY; KINETICS AB With the existence of biologically distinctive malignant cells originated within the same tumor, intratumor functional heterogeneity is present in many cancers and is often manifested by the intermingled vascular compartments with distinct pharmacokinetics. However, intratumor vascular heterogeneity cannot be resolved directly by most in vivo dynamic imaging. We developed multi-tissue compartment modeling (MTCM), a completely unsupervised method of deconvoluting dynamic imaging series from heterogeneous tumors that can improve vascular characterization in many biological contexts. Applying MTCM to dynamic contrast-enhanced magnetic resonance imaging of breast cancers revealed characteristic intratumor vascular heterogeneity and therapeutic responses that were otherwise undetectable. MTCM is readily applicable to other dynamic imaging modalities for studying intratumor functional and phenotypic heterogeneity, together with a variety of foreseeable applications in the clinic. C1 [Chen, Li] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Chen, Li; Wang, Niya; Wang, Yue] Virginia Polytech Inst & State Univ, Dept Elect & Comp Engn, Arlington, VA 22203 USA. [Clarke, Robert] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Bhujwalla, Zaver M.] Johns Hopkins Univ, Sch Med, Dept Radiol & Radiol Sci, Baltimore, MD 21205 USA. [Hillman, Elizabeth M. C.] Columbia Univ, Dept Biomed Engn, New York, NY 10027 USA. [Wang, Ge] Rensselaer Polytech Inst, Biomed Imaging Ctr, Dept Biomed Engn, Troy, NY 12180 USA. RP Wang, Y (reprint author), Virginia Polytech Inst & State Univ, Dept Elect & Comp Engn, Arlington, VA 22203 USA. EM yuewang@vt.edu RI Clarke, Robert/A-6485-2008; OI Clarke, Robert/0000-0002-9278-0854; Hillman, Elizabeth M. C./0000-0001-5511-1451 FU National Institutes of Health [EB000830, NS29525, CA149147] FX This work was funded by the National Institutes of Health under Grants EB000830, NS29525, and CA149147. The funder's URL is http://www.nih.gov/. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 1 Z9 1 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 NOV 7 PY 2014 VL 9 IS 11 AR e112143 DI 10.1371/journal.pone.0112143 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT3WF UT WOS:000344863100056 PM 25379705 ER PT J AU Benard, VB Thomas, CC King, J Massetti, GM Doria-Rose, VP Saraiya, M AF Benard, Vicki B. Thomas, Cheryll C. King, Jessica Massetti, Greta M. Doria-Rose, V. Paul Saraiya, Mona TI Vital Signs: Cervical Cancer Incidence, Mortality, and Screening - United States, 2007-2012 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID VACCINATION; PREVENTION; PREVALENCE; RATES; AGE AB Background: Cervical cancer screening is one of the greatest cancer prevention achievements, yet some women still develop or die from this disease. Objective: To assess recent trends in cervical cancer incidence and mortality, current screening percentages, and factors associated with higher incidence and death rates and inadequate screening. Methods: Percentages of women who had not been screened for cervical cancer in the past 5 years were estimated using data from the 2012 Behavioral Risk Factor Surveillance System survey. State-specific cervical cancer incidence data from the United States Cancer Statistics and mortality data from the National Vital Statistics System were used to calculate incidence and death rates for 2011 by state. Incidence and death rates and annual percentage changes from 2007 to 2011 were calculated by state and U. S. Census region. Results: In 2012, the percentage of women who had not been screened for cervical cancer in the past 5 years was estimated to be 11.4%; the percentage was larger for women without health insurance (23.1%) and for those without a regular health care provider (25.5%). From 2007 to 2011, the cervical cancer incidence rate decreased by 1.9% per year while the death rate remained stable. The South had the highest incidence rate (8.5 per 100,000), death rate (2.7 per 100,000), and percentage of women who had not been screened in the past 5 years (12.3%). Conclusions: Trends in cervical cancer incidence rates have decreased slightly while death rates have been stable over the last 5 years. The proportion of inadequately screened women is higher among older women, Asians/ Pacific Islanders, and American Indians/ Alaska Natives. Implications for Public Health Practice: There continue to be women who are not screened as recommended, and women who die from this preventable cancer. Evidence-based public health approaches are available to increase women's access to screening and timely follow-up of abnormal results. C1 [Benard, Vicki B.; Thomas, Cheryll C.; King, Jessica; Massetti, Greta M.; Saraiya, Mona] CDC, Div Canc Prevent & Control, Atlanta, GA 30333 USA. [Doria-Rose, V. Paul] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Benard, VB (reprint author), CDC, Div Canc Prevent & Control, Atlanta, GA 30333 USA. EM vbenard@cdc.gov NR 16 TC 26 Z9 26 U1 1 U2 8 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD NOV 7 PY 2014 VL 63 IS 44 BP 1004 EP 1009 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AT1ZM UT WOS:000344729700005 PM 25375072 ER PT J AU Costello, RB Lentino, CV Boyd, CC O'Connell, ML Crawford, CC Sprengel, ML Deuster, PA AF Costello, Rebecca B. Lentino, Cynthia V. Boyd, Courtney C. O'Connell, Meghan L. Crawford, Cindy C. Sprengel, Meredith L. Deuster, Patricia A. TI The effectiveness of melatonin for promoting healthy sleep: a rapid evidence assessment of the literature SO NUTRITION JOURNAL LA English DT Review DE Melatonin; Sleep; Systematic review; Rapid evidence assessment of the literature (REAL); Dietary supplements; Military health ID HUMAN CIRCADIAN-RHYTHMS; NIGHT-SHIFT WORK; TRAUMATIC BRAIN-INJURY; DOUBLE-BLIND TRIAL; JET-LAG; EXOGENOUS MELATONIN; PRIMARY INSOMNIA; DAYTIME SLEEP; BRIGHT LIGHT; DEPLOYMENT AB A systematic review was conducted using Samueli Institute's Rapid Evidence Assessment of the Literature (REAL(C)) process to determine the evidence base for melatonin as an agent to optimize sleep or improve sleep quality, and generalize the results to a military, civilian, or other healthy, active, adult population. Multiple databases were searched yielding 35 randomized controlled trials (RCTs) meeting the review's inclusion criteria, which were assessed for methodological quality as well as for melatonin effectiveness. The majority of included studies were high quality (83.0%). Overall, according to Grading Recommendations, Assessment Development and Evaluation (GRADE) methodology, weak recommendations were made for preventing phase shifts from jet lag, for improving insomnia in both healthy volunteers and individuals with a history of insomnia, and for initiating sleep and/or improving sleep efficacy. Based on the literature to date, no recommendations for use in shift workers or to improve hormonal phase shift changes in healthy people can be made at this time. Larger and longer-duration RCTs utilizing well characterized products are needed to warrant melatonin recommendations in young, healthy adults. C1 [Costello, Rebecca B.; Lentino, Cynthia V.; Deuster, Patricia A.] Uniformed Serv Univ Hlth Sci, Dept Mil & Emergency Med, Bethesda, MD 20814 USA. [Costello, Rebecca B.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Boyd, Courtney C.; O'Connell, Meghan L.; Crawford, Cindy C.; Sprengel, Meredith L.] Samueli Inst, Alexandria, VA 22314 USA. RP Deuster, PA (reprint author), Uniformed Serv Univ Hlth Sci, Dept Mil & Emergency Med, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM patricia.deuster@usuhs.edu RI Deuster, Patricia/G-3838-2015 OI Deuster, Patricia/0000-0002-7895-0888 FU Defense Health Program; USUHS, Consortium for Health and Military Performance, Human Performance Resource Center [G191FL] FX This work was supported by the Defense Health Program and USUHS, Consortium for Health and Military Performance, Human Performance Resource Center, G191FL. The opinions or assertions contained herein are the private ones of the author(s) and are not to be construed as official or reflecting the views of the Uniformed Services University, Department of the Army, Department of the Air Force, Department of the Navy or the United States Department of Defense and the National Institutes of Health, Department of Health and Human Services. NR 76 TC 10 Z9 10 U1 11 U2 37 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2891 J9 NUTR J JI Nutr. J. PD NOV 7 PY 2014 VL 13 AR 106 DI 10.1186/1475-2891-13-106 PG 17 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AT7FI UT WOS:000345101900001 PM 25380732 ER PT J AU Zhao, XL Chen, WJ Liu, ZH Guo, JL Zhou, ZY Crommen, J Moaddel, R Jiang, ZJ AF Zhao, XiangLong Chen, WeiJia Liu, ZhengHua Guo, JiaLiang Zhou, ZhengYin Crommen, Jacques Moaddel, Ruin Jiang, ZhengJin TI A novel mixed phospholipid functionalized monolithic column for early screening of drug induced phospholipidosis risk SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Drug-induced phospholipidosis; Immobilized artificial membrane; Mixed phospholipid; Monolithic columns ID HYDROPHILIC INTERACTION CHROMATOGRAPHY; IMMOBILIZED ARTIFICIAL MEMBRANE; CATIONIC AMPHIPHILIC DRUGS; CELL-BASED APPROACH; IN-VITRO MODEL; PREDICTING PHOSPHOLIPIDOSIS; COMPLEX-FORMATION; INDUCTION; ASSAY; LIPOPHILICITY AB Drug-induced phospholipidosis (PLD) is characterized by the excessive accumulation of phospholipids, resulting in multilamellar vesicle structure within lysosomes. In the present study, a novel mixed phospholipid functionalized monolithic column was developed for the first time through a facile one-step co-polymerization approach. The phospholipid composition of the monolith can be adjusted quantitatively and accurately to mimic the mixed phospholipid environment of different biomembranes on a solid matrix. The mixed phospholipid functionalized monolith as a promising immobilized artificial membrane technique was used to study drug-phospholipid interaction. Scanning electron microscopy, elemental analysis, FT-IR spectra, zeta-potential analysis and micro-HPLC were carried out to characterize the physicochemical properties and separation performance of the monolith. Mechanism studies revealed that both hydrophobic and electrostatic interactions play an important role in the retention of analytes. The ratio of their contributions to retention can be easily manipulated by adjusting the composition of the mixed phospholipids, in order to better mimic the interaction between drugs and cell membrane. The obtained mixed phospholipid functionalized monolithic columns were applied to the screening of drug-induced PLD potency. Data from 79 drugs on the market demonstrated that the chromatographic hydrophobicity index referring to the mixed phospholipid functionalized monolith at pH 7.4 (CHI IAM(7.4)) for the selected drugs were highly correlated with the drug-induced PLD potency data obtained from other in vivo or in vitro assays. Moreover, the effect of the acidic phospholipid phosphatidylserine proportion on prediction accuracy was also investigated. The monolith containing 20% phosphatidylserine and 80% phosphatidylcholine exhibited the best prediction ability for the drug-induced PLD potency of the tested compounds. This research has led to the successful development of a novel and facile approach to prepare a mixed phospholipids functionalized monolith, which offers a reliable, cost-effective and high-throughput screening tool for early prediction of the PLD potency of drug candidates. (C) 2014 Elsevier B.V. All rights reserved. C1 [Zhao, XiangLong; Chen, WeiJia; Liu, ZhengHua; Guo, JiaLiang; Zhou, ZhengYin; Crommen, Jacques; Moaddel, Ruin; Jiang, ZhengJin] Jinan Univ, Dept Pharm, Guangzhou 510632, Guangdong, Peoples R China. [Zhao, XiangLong; Chen, WeiJia; Liu, ZhengHua; Guo, JiaLiang; Zhou, ZhengYin; Crommen, Jacques; Moaddel, Ruin; Jiang, ZhengJin] Jinan Univ, Guangdong Prov Key Lab Pharmacodynam Constituents, Guangzhou 510632, Guangdong, Peoples R China. [Crommen, Jacques] Univ Liege, Dept Pharmaceut Sci, Lab Analyt Pharmaceut Chem, B-4000 Liege, Belgium. [Moaddel, Ruin] NIA, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. RP Jiang, ZJ (reprint author), Jinan Univ, Dept Pharm, Guangzhou 510632, Guangdong, Peoples R China. EM jzjjackson@hotmail.com RI JIANG, ZHENGJIN/A-8409-2015 OI JIANG, ZHENGJIN/0000-0002-5612-4331 FU National Natural Science Foundation of China [81273477]; 111 Project [B13038]; National Institute on Aging FX We gratefully appreciate the financial support by the program from the National Natural Science Foundation of China (Grant: 81273477) and the 111 Project (No. B13038). This work was also supported by the intramural research program at the National Institute on Aging (RM). NR 49 TC 5 Z9 5 U1 3 U2 28 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD NOV 7 PY 2014 VL 1367 BP 99 EP 108 DI 10.1016/j.chroma.2014.09.048 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AS3US UT WOS:000344204100011 PM 25294294 ER PT J AU Munro, JB Gorman, J Ma, XC Zhou, Z Arthos, J Burton, DR Koff, WC Courter, JR Smith, AB Kwong, PD Blanchard, SC Mothes, W AF Munro, James B. Gorman, Jason Ma, Xiaochu Zhou, Zhou Arthos, James Burton, Dennis R. Koff, Wayne C. Courter, Joel R. Smith, Amos B., III Kwong, Peter D. Blanchard, Scott C. Mothes, Walther TI Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions SO SCIENCE LA English DT Article ID NEUTRALIZING ANTIBODY PG9; RECEPTOR-BINDING; STRUCTURAL BASIS; CD4 RECEPTOR; GP120; GLYCOPROTEIN; RECOGNITION; VACCINE; FUSION; BROAD AB The HIV-1 envelope (Env) mediates viral entry into host cells. To enable the direct imaging of conformational dynamics within Env, we introduced fluorophores into variable regions of the glycoprotein gp120 subunit and measured single-molecule fluorescence resonance energy transfer within the context of native trimers on the surface of HIV-1 virions. Our observations revealed unliganded HIV-1 Env to be intrinsically dynamic, transitioning between three distinct prefusion conformations, whose relative occupancies were remodeled by receptor CD4 and antibody binding. The distinct properties of neutralization-sensitive and neutralization-resistant HIV-1 isolates support a dynamics-based mechanism of immune evasion and ligand recognition. C1 [Munro, James B.; Ma, Xiaochu; Mothes, Walther] Yale Univ, Sch Med, Dept Microbial Pathogenesis, New Haven, CT 06536 USA. [Gorman, Jason; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Zhou, Zhou; Blanchard, Scott C.] Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA. [Arthos, James] NIAID, Immunoregulat Lab, 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.] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02129 USA. [Koff, Wayne C.] IAVI, New York, NY 10004 USA. [Courter, Joel R.; Smith, Amos B., III] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. RP Mothes, W (reprint author), Yale Univ, Sch Med, Dept Microbial Pathogenesis, 333 Cedar St, New Haven, CT 06536 USA. EM james.munro@tufts.edu; scb2005@med.cornell.edu; walther.mothes@yale.edu RI Blanchard, Scott/A-5804-2009 FU NIH [R21 AI100696, P01 56550, R01 GM098859]; Cancer Research Institute; China Scholarship Council; International AIDS Vaccine Initiative's (IAVI) Neutralizing Antibody Consortium; NIH Intramural Research Program (Vaccine Research Center); Bill & Melinda Gates Foundation; U.S. Agency for International Development (USAID); American people through USAID FX We thank J. Jin, L. Agosto, T. Wang, R. B. Altman, and M. R. Wasserman for assistance; C. Walsh, J. Binely, A. Trkola, and M. Krystal for reagents; and members of the Structural Biology Section, Vaccine Research Center, for critically reading the manuscript. We thank I. Wilson and J. Sodroski for encouraging us to extend our approach to a R5-tropic Env. The data presented in this paper are tabulated in the main paper and in the supplementary materials. This work was supported by NIH grants R21 AI100696 to W. M. and S. C. B; P01 56550 to W. M., S. C. B., and A. B. S.; and R01 GM098859 to S. C. B.; by the Irvington Fellows Program of the Cancer Research Institute to J. B. M; by a fellowship from the China Scholarship Council-Yale World Scholars to X. M.; by grants from the International AIDS Vaccine Initiative's (IAVI) Neutralizing Antibody Consortium to D. R. B., W. C. K., and P. D. K.; and by funding from the NIH Intramural Research Program (Vaccine Research Center) to P. D. K. IAVI's work is made possible by generous support from many donors including: the Bill & Melinda Gates Foundation and the U.S. Agency for International Development (USAID). This study is made possible by the generous support of the American people through USAID. The contents are the responsibility of the authors and do not necessarily reflect the views of USAID or the U.S. government. Reagents from the NIH are subject to nonrestrictive material transfer agreements. Patent applications pertaining to this work are the U.S. and World Application US2009/006049 and WO/2010/053583, Synthesis of JRC-II-191 (A. B. S., J.R.C.), U.S. Patent Application 13/202,351, Methods and Compositions for Altering Photopysical Properties of Fluorophores via Proximal Quenching (S. C. B., Z.Z.); U. S. Patent Application 14/373,402 Dye Compositions, Methods of Preparation, Conjugates Thereof, and Methods of Use (S. C. B., Z.Z.); and International and US Patent Application PCT/US13/42249 Reagents and Methods for Identifying Anti-HIV Compounds (S. C. B., J.B.M., W. M.). S. C. B. is a co-founder of Lumidyne Corporation. NR 42 TC 89 Z9 89 U1 6 U2 41 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 NOV 7 PY 2014 VL 346 IS 6210 BP 759 EP 763 DI 10.1126/science.1254426 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT1JT UT WOS:000344690100044 PM 25298114 ER PT J AU Grace, PM Ramos, KM Rodgers, KM Wang, X Hutchinson, MR Lewis, MT Morgan, KN Kroll, JL Taylor, FR Strand, KA Zhang, Y Berkelhammer, D Huey, MG Greene, LI Cochran, TA Yin, H Barth, DS Johnson, KW Rice, KC Maier, SF Watkins, LR AF Grace, P. M. Ramos, K. M. Rodgers, K. M. Wang, X. Hutchinson, M. R. Lewis, M. T. Morgan, K. N. Kroll, J. L. Taylor, F. R. Strand, K. A. Zhang, Y. Berkelhammer, D. Huey, M. G. Greene, L. I. Cochran, T. A. Yin, H. Barth, D. S. Johnson, K. W. Rice, K. C. Maier, S. F. Watkins, L. R. TI ACTIVATION OF ADULT RAT CNS ENDOTHELIAL CELLS BY OPIOID-INDUCED TOLL-LIKE RECEPTOR 4 (TLR4) SIGNALING INDUCES PROINFLAMMATORY, BIOCHEMICAL, MORPHOLOGICAL, AND BEHAVIORAL SEQUELAE SO NEUROSCIENCE LA English DT Article DE endothelial cell; CTAP; nalmefene; M3G; morphine; TLR4 ID NF-KAPPA-B; UNDERLYING NEUROPATHIC PAIN; HIV-1 ENVELOPE GLYCOPROTEIN; MORPHINE-TOLERANCE; NITRIC-OXIDE; MECHANICAL ALLODYNIA; SPINAL MICROGLIA; TACTILE ALLODYNIA; GENE-EXPRESSION; P-GLYCOPROTEIN AB CNS immune signaling contributes to deleterious opioid effects including hyperalgesia, tolerance, reward, and dependence/withdrawal. Such effects are mediated by opioid signaling at toll-like receptor 4 (TLR4), presumptively of glial origin. Whether CNS endothelial cells express TLR4 is controversial. If so, they would be well positioned for activation by blood-borne opioids, contributing to opioid-induced pro-inflammatory responses. These studies examined adult primary rat CNS endothelial cell responses to (-)-morphine or its mu opioid receptor (MOR)-inactive metabolite morphine-3-glucuronide (M3G), both known TLR4 agonists. We demonstrate that adult rat CNS endothelial cells express functional TLR4. M3G activated nuclear factor kappaB (NF-kappa B), increased tumor necrosis factor-alpha (TNF alpha) and cyclooxygenase-2 (COX2) mRNAs, and released prostaglandin E-2 (PGE(2)) from these cells. (-)-Morphine-induced upregulation of TNF alpha mRNA and PGE2 release were unmasked by pre-treatment with nalmefene, a MOR antagonist without TLR4 activity (unlike CTAP, shown to have both MOR- and TLR4-activity), suggestive of an interplay between MOR and TLR4 co-activation by (-)-morphine. In support, MOR-dependent Protein Kinase A (PKA) opposed TLR4 signaling, as PKA inhibition (H-89) also unmasked (-)-morphine-induced TNF alpha and COX2 mRNA upregulation. Intrathecal injection of CNS endothelial cells, stimulated in vitro with M3G, produced TLR4-dependent tactile allodynia. Further, cortical suffusion with M3G in vivo induced TLR4-dependent vasodilation. Finally, endothelial cell TLR4 activation by lipopolysaccharide and/or M3G was blocked by the glial inhibitors AV1013 and propentofylline, demonstrating endothelial cells as a new target of such drugs. These data indicate that (-)-morphine and M3G can activate CNS endothelial cells via TLR4, inducing proinflammatory, biochemical, morphological, and behavioral sequelae. CNS endothelial cells may have previously unanticipated roles in opioid-induced effects, in phenomena blocked by presumptive glial inhibitors, as well as TLR4-mediated phenomena more broadly. (C) 2014 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Grace, P. M.; Ramos, K. M.; Rodgers, K. M.; Wang, X.; Lewis, M. T.; Morgan, K. N.; Kroll, J. L.; Taylor, F. R.; Strand, K. A.; Zhang, Y.; Berkelhammer, D.; Huey, M. G.; Greene, L. I.; Cochran, T. A.; Barth, D. S.; Maier, S. F.; Watkins, L. R.] Univ Colorado, Dept Psychol, Boulder, CO 80309 USA. [Grace, P. M.; Ramos, K. M.; Rodgers, K. M.; Wang, X.; Lewis, M. T.; Morgan, K. N.; Kroll, J. L.; Taylor, F. R.; Strand, K. A.; Zhang, Y.; Berkelhammer, D.; Huey, M. G.; Greene, L. I.; Cochran, T. A.; Barth, D. S.; Maier, S. F.; Watkins, L. R.] Univ Colorado, Ctr Neurosci, Boulder, CO 80309 USA. [Wang, X.; Yin, H.] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. [Wang, X.; Yin, H.] Univ Colorado, BioFrontiers Inst, Boulder, CO 80309 USA. [Hutchinson, M. R.] Univ Adelaide, Discipline Physiol, Sch Med Sci, Adelaide, SA 5005, Australia. [Johnson, K. W.] MediciNova Inc, San Diego, CA USA. [Rice, K. C.] NIDA, Chem Biol Res Branch, Rockville, MD USA. [Rice, K. C.] NIAAA, Rockville, MD 20852 USA. RP Grace, PM (reprint author), Univ Colorado, Dept Psychol & Neurosci, Campus Box 345, Boulder, CO 80309 USA. EM peter.grace@colorado.edu RI Wang, Xiaohui/B-8126-2011; OI Wang, Xiaohui/0000-0002-3415-5612; Grace, Peter/0000-0002-8999-1220; Hutchinson, Mark/0000-0003-2154-5950; YIN, HANG/0000-0002-9762-4818 FU American Pain Society Future Leaders in Pain Research Small Grants Program; NINDS [F32NS066665]; NIH [DA024044, DE017782, DA023132]; American Australian Association Merck Company Foundation; Sir Keith Murdoch Fellowship; National Health and Medical Research Council [ID 465423, ID 1054091]; Australian Research Council [DP110100297]; NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA); National Institute of Alcohol Abuse and Alcoholism (NIAAA); [GM103843]; [GM101279] FX This work was supported by the American Pain Society Future Leaders in Pain Research Small Grants Program (KMR 2009-2011); F32NS066665 from NINDS (KMR 2010-2013); NIH grants DA024044, DE017782, and DA023132 (LRW); American Australian Association Merck Company Foundation (MRH) and Sir Keith Murdoch (PMG) Fellowships; a National Health and Medical Research Council CJ Martin Fellowship (ID 465423, MRH 2007-2010; ID 1054091, PMG 2013-); an Australian Research Council Research Fellowship (DP110100297, MRH 2011-); and GM103843 and GM101279 (HY). The work of the Drug Design and Synthesis Section, CBRB, NIDA, and NIAAA was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA) and the National Institute of Alcohol Abuse and Alcoholism (NIAAA). NR 95 TC 18 Z9 18 U1 2 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD NOV 7 PY 2014 VL 280 BP 299 EP 317 DI 10.1016/j.neuroscience.2014.09.020 PG 19 WC Neurosciences SC Neurosciences & Neurology GA AR5OG UT WOS:000343633100027 PM 25241065 ER PT J AU Kennedy, BK Berger, SL Brunet, A Campisi, J Cuervo, AM Epel, ES Franceschi, C Lithgow, GJ Morimoto, RI Pessin, JE Rando, TA Richardson, A Schadt, EE Wyss-Coray, T Sierra, F AF Kennedy, Brian K. Berger, Shelley L. Brunet, Anne Campisi, Judith Cuervo, Ana Maria Epel, Elissa S. Franceschi, Claudio Lithgow, Gordon J. Morimoto, Richard I. Pessin, Jeffrey E. Rando, Thomas A. Richardson, Arlan Schadt, Eric E. Wyss-Coray, Tony Sierra, Felipe TI Geroscience: Linking Aging to Chronic Disease SO CELL LA English DT Editorial Material ID LIFE-SPAN; LONGEVITY; CELLS AB Mammalian aging can be delayed with genetic, dietary, and pharmacologic approaches. Given that the elderly population is dramatically increasing and that aging is the greatest risk factor for a majority of chronic diseases driving both morbidity and mortality, it is critical to expand geroscience research directed at extending human healthspan. C1 [Kennedy, Brian K.; Campisi, Judith; Lithgow, Gordon J.] Buck Inst Res Aging, Novato, CA USA. [Berger, Shelley L.] Univ Penn, Perelman Sch Med, Penn Epigenet Program, Philadelphia, PA 19104 USA. [Berger, Shelley L.] Univ Penn, Perelman Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. [Berger, Shelley L.] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Berger, Shelley L.] Univ Penn, Perelman Sch Med, Dept Biol, Philadelphia, PA 19104 USA. [Brunet, Anne] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Brunet, Anne; Rando, Thomas A.] Stanford Univ, Glenn Ctr Biol Aging, Stanford, CA 94305 USA. [Campisi, Judith] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA. [Cuervo, Ana Maria] Albert Einstein Coll Med, Dept Dev & Mol Biol, Bronx, NY 10461 USA. [Cuervo, Ana Maria] Albert Einstein Coll Med, Inst Aging Studies, Bronx, NY 10461 USA. [Epel, Elissa S.] Univ Calif San Francisco, Sch Med, Dept Psychiat, San Francisco, CA 94143 USA. [Franceschi, Claudio] Bellaria Hosp, IRCCS Inst Neurol Sci Bologna, Bologna, Italy. [Franceschi, Claudio] Univ Bologna, CIG, Interdept Ctr L Galvani Integrated Studies Bioinf, Bologna 3, Italy. [Franceschi, Claudio] Univ Bologna, Dept Expt Diagnost & Specialty Med, DIMES, Bologna 3, Italy. [Morimoto, Richard I.] Northwestern Univ, Rice Inst Biomed Res, Dept Biochem Mol Biol & Cell Biol, Evanston, IL 60208 USA. [Pessin, Jeffrey E.] Albert Einstein Coll Med, Dept Med & Mol Pharmacol, Bronx, NY 10461 USA. [Rando, Thomas A.; Wyss-Coray, Tony] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [Rando, Thomas A.; Wyss-Coray, Tony] Vet Adm Palo Alto Hlth Care Syst, Ctr Tissue Regenerat Repair & Restorat, Palo Alto, CA 94304 USA. [Richardson, Arlan] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK 73104 USA. [Richardson, Arlan] Oklahoma City VA Med Ctr, Oklahoma City, OK 73104 USA. [Schadt, Eric E.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Schadt, Eric E.] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Sierra, Felipe] NIA, Div Aging Biol, Bethesda, MD 20892 USA. RP Kennedy, BK (reprint author), Buck Inst Res Aging, Novato, CA USA. EM bkennedy@buckinstitute.org FU NIA NIH HHS [P01 AG031782, P01 AG036695, R01 AG024287, R01 AG033373, R01 AG043080] NR 14 TC 97 Z9 98 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 NOV 6 PY 2014 VL 159 IS 4 BP 708 EP 712 DI 10.1016/j.cell.2014.10.039 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AS8TY UT WOS:000344522000002 PM 25417146 ER PT J AU Yutin, N Faure, G Koonin, EV Mushegian, AR AF Yutin, Natalya Faure, Guilhem Koonin, Eugene V. Mushegian, Arcady R. TI Chordopoxvirus protein F12 implicated in enveloped virion morphogenesis is an inactivated DNA polymerase SO BIOLOGY DIRECT LA English DT Article DE DNA polymerase; Exaptation; Poxviruses; Evolution of viruses ID MOLLUSCUM CONTAGIOSUM VIRUS; MULTIPLE SEQUENCE ALIGNMENT; EVOLUTION; SUPERFAMILY; PREDICTION; VIRULENCE; POXVIRUS; ORIGIN; FAMILY AB Through the course of their evolution, viruses with large genomes have acquired numerous host genes, most of which perform function in virus reproduction in a manner that is related to their original activities in the cells, but some are exapted for new roles. Here we report the unexpected finding that protein F12, which is conserved among the chordopoxviruses and is implicated in the morphogenesis of enveloped intracellular virions, is a derived DNA polymerase, possibly of bacteriophage origin, in which the polymerase domain and probably the exonuclease domain have been inactivated. Thus, F12 appears to present a rare example of a drastic, exaptive functional change in virus evolution. Reviewers: This article was reviewed by Frank Eisenhaber and Juergen Brosius. For complete reviews, go the Reviewers' Reports section. C1 [Yutin, Natalya; Faure, Guilhem; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Mushegian, Arcady R.] Natl Sci Fdn, Mol & Cellular Biosci Div, Arlington, VA 22230 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov OI Mushegian, Arcady/0000-0002-6809-9225 FU intramural funds of the US Department of Health and Human Services; Independent Research/Development program at the National Science Foundation FX NY, GF and EVK are supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). ARM was supported by the Independent Research/Development program at the National Science Foundation while working on this project. NR 28 TC 3 Z9 3 U1 1 U2 2 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 NOV 6 PY 2014 VL 9 AR 22 DI 10.1186/1745-6150-9-22 PG 6 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AT9KH UT WOS:000345245900001 PM 25374149 ER PT J AU Caballero, IS Yen, JY Hensley, LE Honko, AN Goff, AJ Connor, JH AF Caballero, Ignacio S. Yen, Judy Y. Hensley, Lisa E. Honko, Anna N. Goff, Arthur J. Connor, John H. TI Lassa and Marburg viruses elicit distinct host transcriptional responses early after infection SO BMC GENOMICS LA English DT Article DE Transcriptomics; Transcriptional response; Lassa virus; Marburg virus; Interferon-stimulated genes; Biomarker; Gene expression profile; Early stage diagnostics ID DIFFERENTIAL EXPRESSION ANALYSIS; HEMORRHAGIC-FEVER; CYNOMOLGUS MACAQUES; IMMUNE-RESPONSE; WEST-AFRICA; IN-VITRO; RNA-SEQ; EBOLA; APOPTOSIS; DISEASE AB Background: Lassa virus and Marburg virus are two causative agents of viral hemorrhagic fever. Their diagnosis is difficult because patients infected with either pathogen present similar nonspecific symptoms early after infection. Current diagnostic tests are based on detecting viral proteins or nucleic acids in the blood, but these cannot be found during the early stages of disease, before the virus starts replicating in the blood. Using the transcriptional response of the host during infection can lead to earlier diagnoses compared to those of traditional methods. Results: In this study, we use RNA sequencing to obtain a high-resolution view of the in vivo transcriptional dynamics of peripheral blood mononuclear cells (PBMCs) throughout both types of infection. We report a subset of host mRNAs, including heat-shock proteins like HSPA1B, immunoglobulins like IGJ, and cell adhesion molecules like SIGLEC1, whose differences in expression are strong enough to distinguish Lassa infection from Marburg infection in non-human primates. We have validated these infection-specific expression differences by using microarrays on a larger set of samples, and by quantifying the expression of individual genes using RT-PCR. Conclusions: These results suggest that host transcriptional signatures are correlated with specific viral infections, and that they can be used to identify highly pathogenic viruses during the early stages of disease, before standard detection methods become effective. C1 [Caballero, Ignacio S.] Boston Univ, Bioinformat Grad Program, Boston, MA 02215 USA. [Yen, Judy Y.; Connor, John H.] Boston Univ, Dept Microbiol, Sch Med, Boston, MA 02118 USA. [Hensley, Lisa E.; Honko, Anna N.; Goff, Arthur J.] US Army, Div Virol, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. [Hensley, Lisa E.; Honko, Anna N.] NIAID, Integrated Res Facil Ft Detrick, NIH, Ft Detrick, MD 21702 USA. RP Caballero, IS (reprint author), Boston Univ, Bioinformat Grad Program, 24 Cummington St, Boston, MA 02215 USA. EM nacho@bu.edu OI Connor, John/0000-0002-8867-7256; Honko, Anna/0000-0001-9165-148X FU National Institutes of Health [R01 AI1096159]; United States Army [W81XWH 100-02-0008, 11-02-0130]; Fulbright Commission Spain; Regional Government of Andalusia FX This work was supported by the National Institutes of Health grant R01 AI1096159, and the United States Army contracts W81XWH 100-02-0008 and 11-02-0130. ISC was supported by the Fulbright Commission Spain and the Regional Government of Andalusia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 6 Z9 6 U1 0 U2 7 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 NOV 6 PY 2014 VL 15 AR 960 DI 10.1186/1471-2164-15-960 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AT9MH UT WOS:000345250900001 PM 25377889 ER PT J AU Khera, AV Mehta, NN AF Khera, Amit V. Mehta, Nehal N. TI Single-cell transcriptomics: an emerging tool in the study of cardiometabolic disease SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Editorial Material DE Transcriptomics; Single-cell; Next generation sequencing; Cardiometabolic diseases ID PREIMPLANTATION GENETIC DIAGNOSIS; EXPRESSION C1 [Khera, Amit V.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Mehta, Nehal N.] NHLBI, Sect Inflammat & Cardiometab Dis, Bethesda, MD 20892 USA. RP Mehta, NN (reprint author), NHLBI, Sect Inflammat & Cardiometab Dis, Bldg 10, Bethesda, MD 20892 USA. EM nehal.mehta@nih.gov NR 17 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 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD NOV 6 PY 2014 VL 12 AR 312 DI 10.1186/s12967-014-0312-0 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AT8TK UT WOS:000345204600001 PM 25377125 ER PT J AU Guha, M Srinivasan, S Ruthel, G KKashina, A Carstens, RP Mendoza, A Khanna, C Van Winkle, T Avadhani, NG AF Guha, M. Srinivasan, S. Ruthel, G. Kashina, A. K. Carstens, R. P. Mendoza, A. Khanna, C. Van Winkle, T. Avadhani, N. G. TI Mitochondrial retrograde signaling induces epithelial-mesenchymal transition and generates breast cancer stem cells SO ONCOGENE LA English DT Article DE mitochondrial DNA; mitochondrial retrograde signaling; epithelial-mesenchymal transition; breast cancer; ESRP1; cancer stem cells ID DNA DEPLETION; RESPIRATORY STRESS; GENOME INSTABILITY; MTDNA DEPLETION; COPY NUMBER; IN-VIVO; MUTATIONS; ACTIVATION; RESISTANCE; APOPTOSIS AB Metastatic breast tumors undergo epithelial-to-mesenchymal transition (EMT), which renders them resistant to therapies targeted to the primary cancers. The mechanistic link between mtDNA (mitochondrial DNA) reduction, often seen in breast cancer patients, and EMT is unknown. We demonstrate that reducing mtDNA content in human mammary epithelial cells (hMECs) activates Calcineurin (Cn)-dependent mitochondrial retrograde signaling pathway, which induces EMT-like reprogramming to fibroblastic morphology, loss of cell polarity, contact inhibition and acquired migratory and invasive phenotype. Notably, mtDNA reduction generates breast cancer stem cells. In addition to retrograde signaling markers, there is an induction of mesenchymal genes but loss of epithelial markers in these cells. The changes are reversed by either restoring the mtDNA content or knockdown of CnA alpha mRNA, indicating the causal role of retrograde signaling in EMT. Our results point to a new therapeutic strategy for metastatic breast cancers targeted to the mitochondrial retrograde signaling pathway for abrogating EMT and attenuating cancer stem cells, which evade conventional therapies. We report a novel regulatory mechanism by which low mtDNA content generates EMT and cancer stem cells in hMECs. C1 [Guha, M.; Srinivasan, S.; Kashina, A. K.; Avadhani, N. G.] Univ Penn, Sch Vet Med, Dept Anim Biol, Philadelphia, PA 19104 USA. [Guha, M.; Srinivasan, S.; Kashina, A. K.; Avadhani, N. G.] Univ Penn, Sch Vet Med, Marie Lowe Ctr Comparat Oncol, Philadelphia, PA 19104 USA. [Ruthel, G.] Univ Penn, Sch Vet Med, Penn Vet Imaging Core, Philadelphia, PA 19104 USA. [Carstens, R. P.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Mendoza, A.; Khanna, C.] NCI, Tumor & Metastasis Biol Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Van Winkle, T.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. RP Avadhani, NG (reprint author), Univ Penn, Sch Vet Med, Dept Anim Biol, 3800 Spruce St, Philadelphia, PA 19104 USA. EM narayan@vet.upenn.edu FU NIH grant [CA-22762]; Harriet Ellison Woodward Trust FX This research was supported by NIH grant CA-22762 and an Endowment from the Harriet Ellison Woodward Trust to NGA. We thank Benjamin Cieply (Carstens laboratory) for providing reagents for the ESRP1 experiments; Drs Brett Kaufman and Jill Kolesar (Kaufman lab) for providing TFAM shRNA constructs; Dr Joseph Baur for the GFP shRNA plasmid; Dr Mauricio Reginato and members of his laboratory for sharing protocols and reagents for immunostaining of the MCF10A 3D spheres; and Drs Christopher Lengner and Qihong Huang for valuable comments on the manuscript. We thank Dr Leslie King for critical comments and editorial help. NR 54 TC 12 Z9 13 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD NOV 6 PY 2014 VL 33 IS 45 BP 5238 EP 5250 DI 10.1038/onc.2013.467 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AT7MD UT WOS:000345120400002 PM 24186204 ER PT J AU Yeung, MSY Zdunek, S Bergmann, O Bernard, S Salehpour, M Alkass, K Perl, S Tisdale, J Possnert, G Brundin, L Druid, H Frisen, J AF Yeung, Maggie S. Y. Zdunek, Sofia Bergmann, Olaf Bernard, Samuel Salehpour, Mehran Alkass, Kanar Perl, Shira Tisdale, John Possnert, Goran Brundin, Lou Druid, Henrik Frisen, Jonas TI Dynamics of Oligodendrocyte Generation and Myelination in the Human Brain SO CELL LA English DT Article ID WHITE-MATTER MICROSTRUCTURE; CENTRAL-NERVOUS-SYSTEM; ELECTRICAL-ACTIVITY; CELLS; NEUROGENESIS; PROTEINS; AGE; DIFFERENTIATION; PROLIFERATION; DEPENDS AB The myelination of axons by oligodendrocytes has been suggested to be modulated by experience, which could mediate neural plasticity by optimizing the performance of the circuitry. We have assessed the dynamics of oligodendrocyte generation and myelination in the human brain. The number of oligodendrocytes in the corpus callosum is established in childhood and remains stable after that. Analysis of the integration of nuclear bomb test-derived C-14 revealed that myelin is exchanged at a high rate, whereas the oligodendrocyte population in white matter is remarkably stable in humans, with an annual exchange of 1/300 oligodendrocytes. We conclude that oligodendrocyte turnover contributes minimally to myelin modulation in human white matter and that this instead may be carried out by mature oligodendrocytes, which may facilitate rapid neural plasticity. C1 [Yeung, Maggie S. Y.; Zdunek, Sofia; Bergmann, Olaf; Alkass, Kanar; Frisen, Jonas] Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden. [Bernard, Samuel] Univ Lyon, CNRS, UMR 5208, Inst Camille Jordan, F-69622 Villeurbanne, France. [Salehpour, Mehran; Possnert, Goran] Uppsala Univ, Dept Phys & Astron, S-75120 Uppsala, Sweden. [Alkass, Kanar; Druid, Henrik] Karolinska Inst, Dept Forens Med, S-17177 Stockholm, Sweden. [Perl, Shira; Tisdale, John] NHLBI, NIH, Bethesda, MD 20892 USA. [Brundin, Lou] Karolinska Univ Hosp, Karolinska Inst, Dept Neurol & Neurosurg, Dept Clin Neurosci, S-17177 Stockholm, Sweden. RP Frisen, J (reprint author), Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden. EM jonas.frisen@ki.se RI Bergmann, Olaf/A-5706-2009; Bernard, Samuel/A-5623-2009; OI Bergmann, Olaf/0000-0003-1065-4107; Bernard, Samuel/0000-0002-8442-9968; Brundin, Lou/0000-0003-4408-7817; Druid, Henrik/0000-0002-9198-023X FU Swedish Research Council; Swedish Cancer Society; Karolinska Institute; Tobias Stiftelsen; AFA Forsakringar; Strategic Research Programme in Stem Cells and Regenerative Medicine at Karolinska Institute (StratRegen); Swedish Foundation for Strategic Research; ERC; Torsten Soderbergs Stiftelse; Knut och Alice Wallenbergs Stiftelse FX We thank M. Carlen for discussions, L. Slomianka for advice on stereology, C. Lebel for providing imaging data, M. Toro and S. Giatrellis for help with flow cytometry, K. Hakansson for AMS sample preparation, and the National Institute of Child, Health, and Human Development (NICHD) Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD for providing tissue. This study was supported by grants from the Swedish Research Council, the Swedish Cancer Society, the Karolinska Institute, Tobias Stiftelsen, AFA Forsakringar, the Strategic Research Programme in Stem Cells and Regenerative Medicine at Karolinska Institute (StratRegen), Swedish Foundation for Strategic Research, the ERC, Torsten Soderbergs Stiftelse, and Knut och Alice Wallenbergs Stiftelse. NR 40 TC 54 Z9 54 U1 4 U2 16 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 NOV 6 PY 2014 VL 159 IS 4 BP 766 EP 774 DI 10.1016/j.cell.2014.10.011 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AS8TY UT WOS:000344522000010 PM 25417154 ER PT J AU Hackett, CS Quigley, DA Wong, RA Chen, J Cheng, C Song, YK Wei, JS Pawlikowska, L Bao, Y Goldenberg, DD Nguyen, K Gustafson, WC Rallapalli, SK Cho, YJ Cook, JM Kozlov, S Mao, JH Van Dyke, T Kwok, PY Khan, J Balmain, A Fan, QW Weiss, WA AF Hackett, Christopher S. Quigley, David A. Wong, Robyn A. Chen, Justin Cheng, Christine Song, Young K. Wei, Jun S. Pawlikowska, Ludmila Bao, Yun Goldenberg, David D. Kim Nguyen Gustafson, W. Clay Rallapalli, Sundari K. Cho, Yoon-Jae Cook, James M. Kozlov, Serguei Mao, Jian-Hua Van Dyke, Terry Kwok, Pui-Yan Khan, Javed Balmain, Allan Fan, QiWen Weiss, William A. TI Expression Quantitative Trait Loci and Receptor Pharmacology Implicate Arg1 and the GABA-A Receptor as Therapeutic Targets in Neuroblastoma SO CELL REPORTS LA English DT Article ID BREAST-CANCER SURVIVAL; TUMOR-SUSCEPTIBILITY; NITRIC-OXIDE; GUANIDINO COMPOUNDS; CELL-PROLIFERATION; ARGINASE-I; N-MYC; C-MYC; GENE; MOUSE AB The development of targeted therapeutics for neuroblastoma, the third most common tumor in children, has been limited by a poor understanding of growth signaling mechanisms unique to the peripheral nerve precursors from which tumors arise. In this study, we combined genetics with gene-expression analysis in the peripheral sympathetic nervous system to implicate arginase 1 and GABA signaling in tumor formation in vivo. In human neuroblastoma cells, either blockade of ARG1 or benzodiazepine-mediated activation of GABA-A receptors induced apoptosis and inhibited mitogenic signaling through AKT and MAPK. These results suggest that ARG1 and GABA influence both neural development and neuroblastoma and that benzodiazepines in clinical use may have potential applications for neuroblastoma therapy. C1 [Hackett, Christopher S.; Chen, Justin] Univ Calif San Francisco, Biomed Sci Grad Program, San Francisco, CA 94143 USA. [Hackett, Christopher S.; Wong, Robyn A.; Chen, Justin; Cheng, Christine; Bao, Yun; Goldenberg, David D.; Kim Nguyen; Fan, QiWen; Weiss, William A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Quigley, David A.; Balmain, Allan] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Song, Young K.; Wei, Jun S.; Khan, Javed] NCI, Oncogen Sect, Pediat Oncol Branch, Gaithersburg, MD 20877 USA. [Pawlikowska, Ludmila] Univ Calif San Francisco, Dept Anesthesia, San Francisco, CA 94143 USA. [Pawlikowska, Ludmila; Kwok, Pui-Yan] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Gustafson, W. Clay; Weiss, William A.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Rallapalli, Sundari K.; Cook, James M.] Univ Wisconsin, Dept Chem, Milwaukee, WI 53211 USA. [Rallapalli, Sundari K.; Cook, James M.] Univ Wisconsin, Dept Biochem, Milwaukee, WI 53211 USA. [Cho, Yoon-Jae] Stanford Univ, Dept Neurol, Sch Med, Stanford, CA 94305 USA. [Kozlov, Serguei; Van Dyke, Terry] NCI, Mouse Canc Genet Program, Ctr Adv Preclin Res, Frederick, MD 21702 USA. [Mao, Jian-Hua] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Kwok, Pui-Yan] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [Kwok, Pui-Yan] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Weiss, William A.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. RP Fan, QW (reprint author), Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. EM qiwen.fan@ucsf.edu; waweiss@gmail.com RI Khan, Javed/P-9157-2014; OI Khan, Javed/0000-0002-5858-0488; Weiss, William/0000-0003-2230-9132 FU March of Dimes; Concern Foundation; UCSF Academic Senate; NIH [R01CA102321, R01NS055750, P30CA82103, U01CA176287, R01MH046851, MH096463, NS076517]; ARRA [R01NS055750] FX The authors are grateful to the Marshfield Clinic and CIDR for genotyping, and to Fernando Pardo Manuel de Villena, Gary Churchill, Saunak Sen, Denise Lind, and Roger Nicoll for experimental advice and comments on the manuscript. This work was supported by the March of Dimes; the Concern Foundation; the UCSF Academic Senate; NIH R01CA102321, R01NS055750, P30CA82103, U01CA176287, and an ARRA supplement for R01NS055750 (to W.A.W.); and NIH R01MH046851, MH096463, and NS076517 (to J.M.C.). NR 55 TC 2 Z9 2 U1 0 U2 4 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 NOV 6 PY 2014 VL 9 IS 3 BP 1034 EP 1046 DI 10.1016/j.celrep.2014.09.046 PG 13 WC Cell Biology SC Cell Biology GA AS7ZI UT WOS:000344470000025 PM 25437558 ER PT J AU Huang, JH Kang, BH Pancera, M Lee, JH Tong, T Feng, Y Imamichi, H Georgiev, IS Chuang, GY Druz, A Doria-Rose, NA Laub, L Sliepen, K van Gils, MJ de la Pena, AT Derking, R Klasse, PJ Migueles, SA Bailer, RT Alam, M Pugach, P Haynes, BF Wyatt, RT Sanders, RW Binley, JM Ward, AB Mascola, JR Kwong, PD Connors, M AF Huang, Jinghe Kang, Byong H. Pancera, Marie Lee, Jeong Hyun Tong, Tommy Feng, Yu Imamichi, Hiromi Georgiev, Ivelin S. Chuang, Gwo-Yu Druz, Aliaksandr Doria-Rose, Nicole A. Laub, Leo Sliepen, Kwinten van Gils, Marit J. de la Pena, Alba Torrents Derking, Ronald Klasse, Per-Johan Migueles, Stephen A. Bailer, Robert T. Alam, Munir Pugach, Pavel Haynes, Barton F. Wyatt, Richard T. Sanders, Rogier W. Binley, James M. Ward, Andrew B. Mascola, John R. Kwong, Peter D. Connors, Mark TI Broad and potent HIV-1 neutralization by a human antibody that binds the gp41-gp120 interface SO NATURE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODIES; B-CELLS; DEPENDENT EPITOPE; ENV TRIMERS; CLEAVAGE; GP120; SERA; SPECIFICITIES; VULNERABILITY AB The isolation of human monoclonal antibodies is providing important insights into the specificities that underlie broad neutralization of HIV-1 (reviewed in ref. 1). Here we report a broad and extremely potent HIV-specific monoclonal antibody, termed 35O22, which binds a novel HIV-1 envelope glycoprotein (Env) epitope. 35O22 neutralized 62% of 181 pseudoviruses with a half-maximum inhibitory concentration (IC50)<50 mu gml(-1). The median IC50 of neutralized viruses was 0.033 mu gml(-1), among themost potent thus far described. 35O22 did not bind monomeric forms of Env tested, but did bind the trimeric BG505 SOSIP. 664. Mutagenesis and a reconstruction by negative-stain electron microscopy of the Fab in complex with trimer revealed that it bound to a conserved epitope, which stretched across gp120 and gp41. The specificity of 35O22 represents a novel site of vulnerability on HIV Env, which serum analysis indicates to be commonly elicited by natural infection. Binding to this new site of vulnerability may thus be an important complement to current monoclonal-antibody-based approaches to immunotherapies, prophylaxis and vaccine design. C1 [Huang, Jinghe; Kang, Byong H.; Imamichi, Hiromi; Laub, Leo; Migueles, Stephen A.; Connors, Mark] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Pancera, Marie; Georgiev, Ivelin S.; Chuang, Gwo-Yu; Druz, Aliaksandr; Doria-Rose, Nicole A.; Bailer, Robert T.; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Lee, Jeong Hyun; Wyatt, Richard T.; Ward, Andrew B.] Scripps Res Inst, Scripps Ctr HIV AIDS Vaccine Immunol & Immunogen, La Jolla, CA 92037 USA. [Lee, Jeong Hyun; Feng, Yu; Wyatt, Richard T.; Ward, Andrew B.] Scripps Res Inst, Int AIDS Vaccine Initiat IAVI Neutralizing Antibo, La Jolla, CA 92037 USA. [Tong, Tommy; Binley, James M.] San Diego Biomed Res Inst, San Diego, CA 92121 USA. [Sliepen, Kwinten; van Gils, Marit J.; de la Pena, Alba Torrents; Derking, Ronald; Sanders, Rogier W.] Univ Amsterdam, Acad Med Ctr, Dept Med Microbiol, NL-1100 DD Amsterdam, Netherlands. [Klasse, Per-Johan; Pugach, Pavel; Sanders, Rogier W.] Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10065 USA. [Alam, Munir; Haynes, Barton F.] Duke Univ, Duke Human Vaccine Inst, Durham, NC 27710 USA. RP Connors, M (reprint author), NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. EM mconnors@nih.gov RI Ward, Andrew/F-9203-2014; Huang, Jinghe/O-1986-2015; Koyuncu, ayfer/M-3872-2015 OI Ward, Andrew/0000-0001-7153-3769; FU Intramural Research Programs of NIAID, National Institutes of Health; NIH HIVRAD grant [P01 AI082362]; Aids Fonds Netherlands [2011032, 2012041]; Netherlands Organization for Scientific Research (NWO); European Research Council [ERC-StG-2011-280829-SHEV]; International AIDS Vaccine Initiative; NIH [AI93278, AI84714]; US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX We thank J. P. Moore for experiments using the BG505 SOSIP trimer, discussions of experimental data, and review of this manuscript. We thank K. Lloyd. R. Parks, J. Eudailey and J. Blinn for performing autoantibody assays. We also thank S. Moir for providing patient samples. This project has been funded in part with federal funds from the Intramural Research Programs of NIAID, National Institutes of Health. This work was also supported by the NIH HIVRAD grant P01 AI082362, and by the Aids Fonds Netherlands, grants 2011032 and 2012041. R. W. S. is a recipient of a Vidi grant from the Netherlands Organization for Scientific Research (NWO) and a Starting Investigator Grant from the European Research Council (ERC-StG-2011-280829-SHEV). J. H. L., Y.F., R. T. W. and A. W. are supported through the International AIDS Vaccine Initiative. J. M. B. is supported by NIH grants AI93278 and AI84714. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38. 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 47 TC 139 Z9 141 U1 8 U2 48 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 NOV 6 PY 2014 VL 515 IS 7525 BP 138 EP + DI 10.1038/nature13601 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AS3OE UT WOS:000344187500045 PM 25186731 ER PT J AU Szyniszewska, AM Tatem, AJ AF Szyniszewska, Anna M. Tatem, Andrew J. TI Global Assessment of Seasonal Potential Distribution of Mediterranean Fruit Fly, Ceratitis capitata (Diptera: Tephritidae) SO PLOS ONE LA English DT Article ID ANASTREPHA-FRATERCULUS DIPTERA; DOMINANT ANOPHELES VECTORS; FLIES DIPTERA; NORTHERN GREECE; SPP. DIPTERA; HOST PLANTS; SPATIOTEMPORAL DISTRIBUTION; GEOGRAPHICAL-DISTRIBUTION; POPULATION FLUCTUATIONS; NORTHWESTERN ARGENTINA AB The Mediterranean fruit fly (Medfly) is one of the world's most economically damaging pests. It displays highly seasonal population dynamics, and the environmental conditions suitable for its abundance are not constant throughout the year in most places. An extensive literature search was performed to obtain the most comprehensive data on the historical and contemporary spatio-temporal occurrence of the pest globally. The database constructed contained 2328 unique geolocated entries on Medfly detection sites from 43 countries and nearly 500 unique localities, as well as information on hosts, life stages and capture method. Of these, 125 localities had information on the month when Medfly was recorded and these data were complemented by additional material found in comprehensive databases available online. Records from 1980 until present were used for medfly environmental niche modeling. Maximum Entropy Algorithm (MaxEnt) and a set of seasonally varying environmental covariates were used to predict the fundamental niche of the Medfly on a global scale. Three seasonal maps were also produced: January-April, May-August and September-December. Models performed significantly better than random achieving high accuracy scores, indicating a good discrimination of suitable versus unsuitable areas for the presence of the species. C1 [Szyniszewska, Anna M.] Univ Florida, Dept Geog, Gainesville, FL 32611 USA. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Highland Hts, KY USA. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Szyniszewska, AM (reprint author), Univ Florida, Dept Geog, Gainesville, FL 32611 USA. EM aniasz@gmail.com FU USDA-APHIS-PPQ-CPHST Cooperative Agreement [12-8130-0158-CA]; NIH/NIAID [U19A1089674]; Bill & Melinda Gates Foundation [OPP110642749446, 1032350]; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX The study was financed by the USDA-APHIS-PPQ-CPHST Cooperative Agreement No. 12-8130-0158-CA titled "Construction of Multi-Disciplinary Tools to Assess Seasonal Risk of Mediterranean Fruit Fly Ceratitis Capitata (Medfly) importation to Florida and California.' AJT is supported by funding from NIH/NIAID (U19A1089674), the Bill & Melinda Gates Foundation (OPP110642749446, 1032350), and the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and 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 181 TC 8 Z9 9 U1 1 U2 38 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 NOV 6 PY 2014 VL 9 IS 11 AR e111582 DI 10.1371/journal.pone.0111582 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AS6XM UT WOS:000344402600049 PM 25375649 ER PT J AU Zanusso, G Bongianni, M Caughey, B AF Zanusso, Gianluigi Bongianni, Matilde Caughey, Byron TI A Test for Creutzfeldt-Jakob Disease Using Nasal Brushings REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID QUAKING-INDUCED CONVERSION; CEREBROSPINAL-FLUID C1 [Zanusso, Gianluigi; Bongianni, Matilde] Univ Verona, I-37100 Verona, Italy. [Caughey, Byron] NIAID, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Zanusso, G (reprint author), Univ Verona, I-37100 Verona, Italy. EM bcaughey@nih.gov OI ZANUSSO, Gianluigi/0000-0001-5199-6264 NR 2 TC 4 Z9 4 U1 0 U2 4 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 NOV 6 PY 2014 VL 371 IS 19 BP 1842 EP 1843 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AS3IH UT WOS:000344170300018 PM 25372096 ER PT J AU Wang, CL Chowdhury, S Driscoll, M Parent, CA Gupta, SK Losert, W AF Wang, Chenlu Chowdhury, Sagar Driscoll, Meghan Parent, Carole A. Gupta, S. K. Losert, Wolfgang TI The interplay of cell-cell and cell-substrate adhesion in collective cell migration SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE cell migration; cell-substrate adhesion; cell-cell adhesion; cell-shape dynamics; actin polymerization; Dictyostelium discoideum ID DICTYOSTELIUM-AMEBAS; FORCE; MECHANOTRANSDUCTION; MORPHOGENESIS; CHEMOTAXIS; GUIDANCE; CANCER AB Collective cell migration often involves notable cell-cell and cell-substrate adhesions and highly coordinated motion of touching cells. We focus on the interplay between cell-substrate adhesion and cell-cell adhesion. We show that the loss of cell-surface contact does not significantly alter the dynamic pattern of protrusions and retractions of fast migrating amoeboid cells (Dictyostelium discoideum), but significantly changes their ability to adhere to other cells. Analysis of the dynamics of cell shapes reveals that cells that are adherent to a surface may coordinate their motion with neighbouring cells through protrusion waves that travel across cell-cell contacts. However, while shape waves exist if cells are detached from surfaces, they do not couple cell to cell. In addition, our investigation of actin polymerization indicates that loss of cell-surface adhesion changes actin polymerization at cell-cell contacts. To further investigate cell-cell/cell-substrate interactions, we used optical micromanipulation to form cell-substrate contact at controlled locations. We find that both cell-shape dynamics and cytoskeletal activity respond rapidly to the formation of cell-substrate contact. C1 [Wang, Chenlu] Univ Maryland, Biophys Grad Program, College Pk, MD 20742 USA. [Chowdhury, Sagar; Gupta, S. K.] Univ Maryland, Dept Mech Engn, College Pk, MD 20742 USA. [Chowdhury, Sagar; Gupta, S. K.] Univ Maryland, Syst Res Inst, College Pk, MD 20742 USA. [Driscoll, Meghan; Losert, Wolfgang] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [Parent, Carole A.; Losert, Wolfgang] Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. [Wang, Chenlu; Parent, Carole A.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Wang, CL (reprint author), Univ Maryland, Biophys Grad Program, College Pk, MD 20742 USA. EM clwang@umd.edu FU Center for Cancer Research, NCI, NIH; NSF [CPS0931508, PHY1205965] FX This work was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH as well as by the NSF grant nos. CPS0931508 and PHY1205965. NR 36 TC 4 Z9 4 U1 2 U2 38 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 EI 1742-5662 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD NOV 6 PY 2014 VL 11 IS 100 AR UNSP 20140684 DI 10.1098/rsif.2014.0684 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO5KF UT WOS:000341383000012 PM 25165597 ER PT J AU Liu, AM Tanaka, N Sun, L Guo, B Kim, JH Krausz, KW Fang, ZZ Jiang, CT Yang, JL Gonzalez, FJ AF Liu, Aiming Tanaka, Naoki Sun, Lu Guo, Bin Kim, Jung-Hwan Krausz, Kristopher W. Fang, Zhongze Jiang, Changtao Yang, Julin Gonzalez, Frank J. TI Saikosaponin d protects against acetaminophen-induced hepatotoxicity by inhibiting NF-kappa B and STAT3 signaling SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE Saikosaponin d; Acetaminophen; Hepatotoxicity; NF-kappa B; STAT3 ID INDUCED LIVER-INJURY; HEPATIC-INJURY; TOXICITY; MICE; INDUCTION; CELLS; ACETYLCYSTEINE; INTERLEUKIN-6; REGENERATION; INVOLVEMENT AB Overdose of acetaminophen (APAP) can cause acute liver injury that is sometimes fatal, requiring efficient pharmacological intervention. The traditional Chinese herb Bupleurum falcatum has been widely used for the treatment of several liver diseases in eastern Asian countries, and saikosaponin d (SSd) is one of its major pharmacologically-active components. However, the efficacy of Bupleurum falcatum or SSd on APAP toxicity remains unclear. C57/BL6 mice were administered SSd intraperitoneally once daily for 5 days, followed by APAP challenge. Biochemical and pathological analysis revealed that mice treated with SSd were protected against APAP-induced hepatotoxicity. SSd markedly suppressed phosphorylation of nuclear factor kappa B (NF-kappa B) and signal transducer and activator of transcription 3 (STAT3) and reversed the APAP-induced increases in the target genes of NF-kappa B, such as pro-inflammatory cytokine Il6 and Ccl2, and those of STAT3, such as Socs3, Fga, Fgb and Fgg. SSd also enhanced the expression of the anti-inflammatory cytokine Il10 mRNA. Collectively, these results demonstrate that SSd protects mice from APAP-induced hepatotoxicity mainly through down-regulating NF-kappa B- and STAT3-mediated inflammatory signaling. This study unveils one of the possible mechanisms of hepatoprotection caused by Bupleurum fakatum and/or SSd. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Liu, Aiming] Ningbo Univ, Sch Med, Ningbo 315211, Zhejiang, Peoples R China. [Liu, Aiming; Tanaka, Naoki; Sun, Lu; Kim, Jung-Hwan; Krausz, Kristopher W.; Fang, Zhongze; Jiang, Changtao; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Guo, Bin] Hunan Normal Univ, Changsha 410081, Hunan, Peoples R China. [Yang, Julin] Ningbo Coll Hlth Sci, Ningbo 315100, Zhejiang, Peoples R China. RP Liu, AM (reprint author), Ningbo Univ, Sch Med, Ningbo 315211, Zhejiang, Peoples R China. EM liuaiming@nbu.edu.cn FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; National Natural Science Foundation of China [81273582, 81302848]; K.C. Wong Magna Fund in Ningbo University FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. Financial support was also provided in part by National Natural Science Foundation of China [Grant 81273582 and 81302848], and the K.C. Wong Magna Fund in Ningbo University. NR 32 TC 11 Z9 11 U1 4 U2 15 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 EI 1872-7786 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD NOV 5 PY 2014 VL 223 BP 80 EP 86 DI 10.1016/j.cbi.2014.09.012 PG 7 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA AW6RZ UT WOS:000346397400010 PM 25265579 ER PT J AU Harper, NS Scott, BH Semple, MN McAlpine, D AF Harper, Nicol S. Scott, Brian H. Semple, Malcolm N. McAlpine, David TI The Neural Code for Auditory Space Depends on Sound Frequency and Head Size in an Optimal Manner SO PLOS ONE LA English DT Article ID INTERAURAL TIME DIFFERENCE; CENTRAL SPECTRUM THEORY; INFERIOR COLLICULUS; BINAURAL INTERACTION; GUINEA-PIG; UNANESTHETIZED RABBIT; LATERAL LEMNISCUS; DELAY SENSITIVITY; DORSAL NUCLEUS; SPATIAL CUE AB A major cue to the location of a sound source is the interaural time difference (ITD)-the difference in sound arrival time at the two ears. The neural representation of this auditory cue is unresolved. The classic model of ITD coding, dominant for a half-century, posits that the distribution of best ITDs (the ITD evoking a neuron's maximal response) is unimodal and largely within the range of ITDs permitted by head-size. This is often interpreted as a place code for source location. An alternative model, based on neurophysiology in small mammals, posits a bimodal distribution of best ITDs with exquisite sensitivity to ITDs generated by means of relative firing rates between the distributions. Recently, an optimal-coding model was proposed, unifying the disparate features of these two models under the framework of efficient coding by neural populations. The optimal-coding model predicts that distributions of best ITDs depend on head size and sound frequency: for high frequencies and large heads it resembles the classic model, for low frequencies and small head sizes it resembles the bimodal model. The optimal-coding model makes key, yet unobserved, predictions: for many species, including humans, both forms of neural representation are employed, depending on sound frequency. Furthermore, novel representations are predicted for intermediate frequencies. Here, we examine these predictions in neurophysiological data from five mammalian species: macaque, guinea pig, cat, gerbil and kangaroo rat. We present the first evidence supporting these untested predictions, and demonstrate that different representations appear to be employed at different sound frequencies in the same species. C1 [Harper, Nicol S.; McAlpine, David] UCL, Ear Inst, London, England. [Harper, Nicol S.] Univ Calif Berkeley, Redwood Ctr Theoret Neurosci, Berkeley, CA 94720 USA. [Scott, Brian H.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Scott, Brian H.; Semple, Malcolm N.] NYU, Ctr Neural Sci, New York, NY 10003 USA. RP Harper, NS (reprint author), Univ Oxford, Dept Physiol Anat & Genet, Sherrington Bldg, Oxford, England. EM nicol.harper@eng.ox.ac.uk FU Wellcome Trust [040044, WT076508AIA]; Sir Henry Wellcome Postdoctoral Fellowship; Department of Physiology, Anatomy and Genetics, University of Oxford; Action on Hearing Loss [PA07]; National Institute on Deafness and Other Communication Disorders [DC-05287-01]; New York University; W. M. Keck Foundation; MRC Programme [G0300417] FX Nicol S. Harper was supported by the Wellcome Trust (040044), (WT076508AIA), including a Sir Henry Wellcome Postdoctoral Fellowship, by the Department of Physiology, Anatomy and Genetics, University of Oxford and by Action on Hearing Loss (PA07). Brian H. Scott was supported by the National Institute on Deafness and Other Communication Disorders (DC-05287-01) and by a James Arthur Fellowship from New York University. Malcolm N. Semple was supported by the W. M. Keck Foundation. David McAlpine was supported by an MRC Programme Grant (G0300417). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 8 Z9 8 U1 1 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 NOV 5 PY 2014 VL 9 IS 11 AR e108154 DI 10.1371/journal.pone.0108154 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AS9IQ UT WOS:000344556900002 PM 25372405 ER PT J AU Lippincott-Schwartz, J AF Lippincott-Schwartz, Jennifer TI Quantitative cell biology: transforming the conceptual, theoretical, instrumental, and methodological approaches to cell biology SO MOLECULAR BIOLOGY OF THE CELL LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM jlippin@helix.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 3 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD NOV 5 PY 2014 VL 25 IS 22 SI SI BP 3437 EP 3437 DI 10.1091/mbc.E14-08-1297 PG 1 WC Cell Biology SC Cell Biology GA AS4IE UT WOS:000344236800001 PM 25368415 ER PT J AU Grove, J Metcalf, DJ Knight, AE Wavre-Shapton, ST Sun, T Protonotarios, ED Griffin, LD Lippincott-Schwartz, J Marsh, M AF Grove, Joe Metcalf, Daniel J. Knight, Alex E. Wavre-Shapton, Silene T. Sun, Tony Protonotarios, Emmanouil D. Griffin, Lewis D. Lippincott-Schwartz, Jennifer Marsh, Mark TI Flat clathrin lattices: stable features of the plasma membrane SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID PROTEIN-COUPLED RECEPTORS; COATED VESICLE FORMATION; TRANS-GOLGI-NETWORK; MEDIATED ENDOCYTOSIS; ELECTRON-MICROSCOPY; BETA-ARRESTINS; FLUORESCENT-PROBES; UNCOATING ATPASE; LIVING CELLS; PIT DYNAMICS AB Clathrin-mediated endocytosis (CME) is a fundamental property of eukaryotic cells. Classical CME proceeds via the formation of clathrin-coated pits (CCPs) at the plasma membrane, which invaginate to form clathrin-coated vesicles, a process that is well understood. However, clathrin also assembles into flat clathrin lattices (FCLs); these structures remain poorly described, and their contribution to cell biology is unclear. We used quantitative imaging to provide the first comprehensive description of FCLs and explore their influence on plasma membrane organization. Ultrastructural analysis by electron and superresolution microscopy revealed two discrete populations of clathrin structures. CCPs were typified by their sphericity, small size, and homogeneity. FCLs were planar, large, and heterogeneous and present on both the dorsal and ventral surfaces of cells. Live microscopy demonstrated that CCPs are short lived and culminate in a peak of dynamin recruitment, consistent with classical CME. In contrast, FCLs were long lived, with sustained association with dynamin. We investigated the biological relevance of FCLs using the chemokine receptor CCR5 as a model system. Agonist activation leads to sustained recruitment of CCR5 to FCLs. Quantitative molecular imaging indicated that FCLs partitioned receptors at the cell surface. Our observations suggest that FCLs provide stable platforms for the recruitment of endocytic cargo. C1 [Grove, Joe; Wavre-Shapton, Silene T.; Sun, Tony; Marsh, Mark] UCL, MRC, Mol Cell Biol Lab, London WC1E 6BT, England. [Protonotarios, Emmanouil D.; Griffin, Lewis D.] UCL, CoMPLEX, London WC1E 6BT, England. [Grove, Joe] UCL, Inst Immun & Transplantat, London NW3 2PF, England. [Metcalf, Daniel J.; Knight, Alex E.] Natl Phys Lab, Teddington TW11 0LW, Middx, England. [Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Grove, J (reprint author), UCL, MRC, Mol Cell Biol Lab, Mortimer St, London WC1E 6BT, England. EM j.grove@ucl.ac.uk; m.marsh@ucl.ac.uk RI Knight, Alex/C-6041-2008; Marsh, Mark/B-4105-2009; OI Knight, Alex/0000-0001-7302-1636; Marsh, Mark/0000-0002-0213-3259; Grove, Joseph/0000-0001-5390-7579 FU UK Medical Research Council [MC_U122665002]; European Molecular Biology Organization; Royal Free Charity FX We thank colleagues in the MRC, Laboratory for Molecular Cell Biology and National Physical Laboratory for ongoing discussions during the development of this work and Frances Brodsky, Annegret Pelchen-Matthews, Ricardo Henriques, and Chris Stefan for critically reading the manuscript. We also acknowledge Janos Kriston-Vizi and Schuyler Van Engelenburg for technical assistance. This work was funded by UK Medical Research Council core funding to the MRC-University College London Laboratory for Molecular Cell Biology University Unit (Grant MC_U122665002), a short-term fellowship to J.G. from the European Molecular Biology Organization, and the Royal Free Charity. NR 89 TC 13 Z9 13 U1 2 U2 12 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD NOV 5 PY 2014 VL 25 IS 22 SI SI BP 3581 EP 3594 DI 10.1091/mbc.E14-06-1154 PG 14 WC Cell Biology SC Cell Biology GA AS4IE UT WOS:000344236800022 PM 25165141 ER PT J AU Ranganathan, R AF Ranganathan, Rajesh TI NINDS Translational Programs: Priming the Pump of Neurotherapeutics Discovery and Development SO NEURON LA English DT Editorial Material ID CHALLENGE; CALL AB The National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH) recently issued a new suite of funding opportunities for neurotherapeutics development. The goals are to build a contiguous bridge from basic science, accelerate the advancement of promising projects to clinical testing with the contributions of multidisciplinary teams, and enhance hand-off to subsequent funders. C1 [Ranganathan, Rajesh] Natl Inst Neurol Disorders & Stroke, Off Translat Res, Off Director, NIH,US Dept HHS, Bethesda, MD 20892 USA. [Ranganathan, Rajesh] NINDS, Off Translat Res, Bethesda, MD 20892 USA. RP Ranganathan, R (reprint author), Natl Inst Neurol Disorders & Stroke, Off Translat Res, Off Director, NIH,US Dept HHS, Bethesda, MD 20892 USA. EM rajesh.ranganathan@nih.gov NR 18 TC 1 Z9 1 U1 0 U2 2 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 NOV 5 PY 2014 VL 84 IS 3 BP 515 EP 520 DI 10.1016/j.neuron.2014.10.026 PG 6 WC Neurosciences SC Neurosciences & Neurology GA AS3HK UT WOS:000344168100002 PM 25442927 ER PT J AU Jensen, FE Amara, SG AF Jensen, Frances E. Amara, Susan G. TI Found in Translation: Training the Next Generation of Translational Neuroscientists SO NEURON LA English DT Editorial Material ID SCIENCE AB Integrated, multidisciplinary programs for training physicians and scientists in translational science have become essential in efforts to meet the demand for more effective translation of basic science discoveries into new clinical applications. C1 [Jensen, Frances E.] Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Amara, Susan G.] NIMH, NIH, Bethesda, MD 20892 USA. RP Jensen, FE (reprint author), Univ Penn, Dept Neurol, Perelman Sch Med, 3400 Spruce St,3rd Floor Dulles Bldg, Philadelphia, PA 19104 USA. EM frances.jensen@uphs.upenn.edu; susan.amara@nih.gov NR 8 TC 1 Z9 1 U1 0 U2 3 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 NOV 5 PY 2014 VL 84 IS 3 BP 542 EP 545 DI 10.1016/j.neuron.2014.10.043 PG 4 WC Neurosciences SC Neurosciences & Neurology GA AS3HK UT WOS:000344168100007 PM 25442932 ER PT J AU Choi, DW Armitage, R Brady, LS Coetzee, T Fisher, W Hyman, S Pande, A Paul, S Potter, W Roin, B Sherer, T AF Choi, Dennis W. Armitage, Robert Brady, Linda S. Coetzee, Timothy Fisher, William Hyman, Steven Pande, Atul Paul, Steven Potter, William Roin, Benjamin Sherer, Todd TI Medicines for the Mind: Policy-Based "Pull'' Incentives for Creating Breakthrough CNS Drugs SO NEURON LA English DT Review ID RESEARCH-AND-DEVELOPMENT; ACCELERATED APPROVAL; BRAND-NAME; TRENDS; COST; PRODUCTIVITY; COMPETITION; INNOVATION; DISORDERS; DISEASES AB Several large pharmaceutical companies have selectively downsized their neuroscience research divisions, reflecting a growing view that developing drugs to treat brain diseases is more difficult and often more time-consuming and expensive than developing drugs for other therapeutic areas, and thus represents a weak area for investment. These withdrawals reduce global neuroscience translational capabilities and pose a serious challenge to society's interests in ameliorating the impact of nervous system diseases. While the path forward ultimately lies in improving understandings of disease mechanisms, many promising therapeutic approaches have already been identified, and rebalancing the underlying risk/reward calculus could help keep companies engaged in making CNS drugs. One way to do this that would not require upfront funding is to change the policies that regulate market returns for the most-needed breakthrough drugs. The broader neuroscience community including clinicians and patients should convene to develop and advocate for such policy changes. C1 [Choi, Dennis W.] SUNY Stony Brook, Dept Neurol, Stony Brook, NY 11794 USA. [Choi, Dennis W.] SUNY Stony Brook, Inst Neurosci, Stony Brook, NY 11794 USA. [Choi, Dennis W.] Korea Inst Sci & Technol, Brain Sci Inst, Seoul 136791, South Korea. [Armitage, Robert] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Brady, Linda S.; Potter, William] NIMH, NIH, Bethesda, MD 20892 USA. [Coetzee, Timothy] Natl Multiple Sclerosis Soc, Washington, DC 20005 USA. [Fisher, William] Harvard Univ, Sch Law, Cambridge, MA 02138 USA. [Hyman, Steven] Broad Inst MIT & Harvard Univ, Cambridge, MA 02142 USA. [Pande, Atul] Ver BioConsulting, Durham, NC 27707 USA. [Paul, Steven] Voyager Therapeut, Cambridge, MA 02139 USA. [Roin, Benjamin] MIT, Alfred P Sloan Sch Management, Cambridge, MA 02142 USA. [Sherer, Todd] Michael J Fox Fdn Parkinsons Res, New York, NY 10163 USA. RP Choi, DW (reprint author), SUNY Stony Brook, Dept Neurol, Stony Brook, NY 11794 USA. EM dennis.choi@stonybrookmedicine.edu NR 50 TC 5 Z9 5 U1 3 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 NOV 5 PY 2014 VL 84 IS 3 BP 554 EP 563 DI 10.1016/j.neuron.2014.10.027 PG 10 WC Neurosciences SC Neurosciences & Neurology GA AS3HK UT WOS:000344168100009 PM 25442934 ER PT J AU Smith, JG Luk, K Schulz, CA Engert, JC Do, R Hindy, G Rukh, G Dufresne, L Almgren, P Owens, DS Harris, TB Peloso, GM Kerr, KF Wong, Q Smith, AV Budoff, MJ Rotter, JI Cupples, LA Rich, S Kathiresan, S Orho-Melander, M Gudnason, V O'Donnell, CJ Post, WS Thanassoulis, G AF Smith, J. Gustav Luk, Kevin Schulz, Christina-Alexandra Engert, James C. Do, Ron Hindy, George Rukh, Gull Dufresne, Line Almgren, Peter Owens, David S. Harris, Tamara B. Peloso, Gina M. Kerr, Kathleen F. Wong, Quenna Smith, Albert V. Budoff, Matthew J. Rotter, Jerome I. Cupples, L. Adrienne Rich, Stephen Kathiresan, Sekar Orho-Melander, Marju Gudnason, Vilmundur O'Donnell, Christopher J. Post, Wendy S. Thanassoulis, George CA CHARGE Extracoronary TI Association of Low-Density Lipoprotein Cholesterol-Related Genetic Variants With Aortic Valve Calcium and Incident Aortic Stenosis SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID MENDELIAN RANDOMIZATION; HEART-DISEASE; EARLY LESION; RISK; PROGRESSION; CALCIFICATION; ATHEROSCLEROSIS; STATINS; DESIGN; TRIAL AB IMPORTANCE Plasma low-density lipoprotein cholesterol (LDL-C) has been associated with aortic stenosis in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression. OBJECTIVE To evaluate whether genetic data are consistent with an association between LDL-C, high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG) and aortic valve disease. DESIGN, SETTING, AND PARTICIPANTS Using a Mendelian randomization study design, we evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, constructed using single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids, were associated with aortic valve disease. We included community-based cohorts participating in the CHARGE consortium (n = 6942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n = 1295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n = 2527), Age Gene/Environment Study-Reykjavik (2000-2012; n = 3120), and the Malmo Diet and Cancer Study (MDCS, 1991-2010; n = 28 461). MAIN OUTCOMES AND MEASURES Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS. RESULTS The prevalence of aortic valve calcium across the 3 CHARGE cohorts was 32% (n = 2245). In the MDCS, over a median follow-up time of 16.1 years, aortic stenosis developed in 17 per 1000 participants (n = 473) and aortic valve replacement for aortic stenosis occurred in 7 per 1000 (n = 205). Plasma LDL-C, but not HDL-C or TG, was significantly associated with incident aortic stenosis (hazard ratio [HR] per mmol/L, 1.28; 95% CI, 1.04-1.57; P = .02; aortic stenosis incidence: 1.3% and 2.4% in lowest and highest LDL-C quartiles, respectively). The LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; P = .007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; P = .02; aortic stenosis incidence: 1.9% and 2.6% in lowest and highest GRS quartiles, respectively). In sensitivity analyses excluding variants weakly associated with HDL-C or TG, the LDL-C GRS remained associated with aortic valve calcium (P = .03) and aortic stenosis (P = .009). In instrumental variable analysis, LDL-C was associated with an increase in the risk of incident aortic stenosis (HR per mmol/L, 1.51; 95% CI, 1.07-2.14; P = .02). CONCLUSIONS AND RELEVANCE Genetic predisposition to elevated LDL-C was associated with presence of aortic valve calcium and incidence of aortic stenosis, providing evidence supportive of a causal association between LDL-C and aortic valve disease. Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation. Copyright 2014 American Medical Association. All rights reserved. C1 [Smith, J. Gustav] Lund Univ, Dept Cardiol, Lund, Sweden. [Smith, J. Gustav] Skane Univ Hosp, Dept Heart Failure & Valvular Dis, Lund, Sweden. [Smith, J. Gustav; Schulz, Christina-Alexandra; Hindy, George; Rukh, Gull; Almgren, Peter; Orho-Melander, Marju] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Smith, J. Gustav; Peloso, Gina M.; Kathiresan, Sekar] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Luk, Kevin; Engert, James C.; Dufresne, Line; Thanassoulis, George] McGill Univ, Ctr Hlth, Montreal, PQ H3A 1A1, Canada. [Engert, James C.; Thanassoulis, George] Res Inst, Dept Med, Montreal, PQ H3A 1A1, Canada. [Smith, J. Gustav; Do, Ron; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Smith, J. Gustav; Do, Ron; Kathiresan, Sekar] Harvard Univ, Sch Med, Boston, MA USA. [Owens, David S.] Univ Washington, Dept Med, Seattle, WA USA. [Harris, Tamara B.] NIA, Bethesda, MD 20892 USA. [Kerr, Kathleen F.; Wong, Quenna] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Budoff, Matthew J.; Rotter, Jerome I.] Harbor UCLA, Los Angeles Biomed Res Inst, Los Angeles, CA USA. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Cupples, L. Adrienne; O'Donnell, Christopher J.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Rich, Stephen] Univ Virginia, Charlottesville, VA USA. [Kathiresan, Sekar; O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [O'Donnell, Christopher J.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Bethesda, MD 20892 USA. [Post, Wendy S.] Johns Hopkins Univ, Dept Internal Med, Div Cardiol, Baltimore, MD USA. RP Thanassoulis, G (reprint author), McGill Univ, Ctr Hlth, 687 Pine Ave W H4-55, Montreal, PQ H3A 1A1, Canada. EM george.thanassoulis@mcgill.ca RI Gudnason, Vilmundur/K-6885-2015; Smith, Albert/K-5150-2015; Kerr, Kathleen/A-2893-2013; Hindy, George/H-1864-2016; OI Gudnason, Vilmundur/0000-0001-5696-0084; Smith, Albert/0000-0003-1942-5845; Hindy, George/0000-0002-7257-9299; Owens, David/0000-0002-7293-9688 FU Swedish Cancer Society; Swedish Medical Research Council; Swedish Dairy Association; Albert Pahlsson Foundation; Gunnar Nilsson Foundation; Malmo city council; Swedish Heart-Lung Foundation; Swedish National Health Service; Crafoord Foundation; Skane University Hospital; Thorsten Westerstrom Foundation; National Institute on Aging [N01-AG-12100]; National Eye Institute; National Institute on Deafness and Other Communication Disorders; National Heart, Lung, and Blood Institute (NHLBI); National Institute on Aging Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (Icelandic parliament); NHLBI [N02-HL-64278, UL1 RR024156, R01-HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259, N01-HC-25195]; American College of Cardiology Foundation/Merck Adult Cardiology Research Fellowship Award; GlaxoSmithKline Research and Education Foundation for Cardiovascular Disease Young Investigator Award; Clinician-Scientist Salary Award from the Fonds de la Recherche du Quebec-Sante; RI-MUHC/Merck Research Competition; Canadian Institutes of Health Research [MOP-119380, MOP-126033]; [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]; [N01-HC-65226]; [R01 HL071739] FX The Malmo Diet and Cancer study was supported by the Swedish Cancer Society, the Swedish Medical Research Council, the Swedish Dairy Association, the Albert Pahlsson and Gunnar Nilsson Foundations, and the Malmo city council. Dr J. G. Smith was supported by the Swedish Heart-Lung Foundation, governmental funding of clinical research within the Swedish National Health Service, the Crafoord Foundation, Skane University Hospital, and the Thorsten Westerstrom Foundation. The Age, Gene/Environment Susceptibility-Reykjavik Study was supported by a grant from the National Institute on Aging (N01-AG-12100) and by the National Eye Institute, the National Institute on Deafness and Other Communication Disorders, the National Heart, Lung, and Blood Institute (NHLBI), the National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (Icelandic parliament). The MESA, MESA CARe, and the MESA SHARe project were supported by contracts N01-HC-95159 through 95169, N01-HC-65226, and N02-HL-64278 and grants from the NHLBI (UL1 RR024156, R01-HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259). Computed tomographic measures in MESA were supported by a grant to Dr Budoff (R01 HL071739). The Framingham Heart Study was supported by contracts from the NHLBI (N01-HC-25195, N02-HL-64278) with Affymetrix for genotyping services. Dr Kathiresan was supported by the American College of Cardiology Foundation/Merck Adult Cardiology Research Fellowship Award and the GlaxoSmithKline Research and Education Foundation for Cardiovascular Disease Young Investigator Award. Dr Thanassoulis was supported by a Clinician-Scientist Salary Award from the Fonds de la Recherche du Quebec-Sante and operating grants from the RI-MUHC/Merck Research Competition and the Canadian Institutes of Health Research (MOP-119380 and MOP-126033). NR 30 TC 35 Z9 38 U1 2 U2 14 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 NOV 5 PY 2014 VL 312 IS 17 BP 1764 EP 1771 DI 10.1001/jama.2014.13959 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AS3QX UT WOS:000344194500014 PM 25344734 ER PT J AU Fonger, GC Hakkinen, P Jordan, S Publicker, S AF Fonger, George Charles Hakkinen, Pertti Jordan, Shannon Publicker, Stephanie TI The National Library of Medicine's (NLM) Hazardous Substances Data Bank (HSDB): Background, recent enhancements and future plans SO TOXICOLOGY LA English DT Article DE Information; Databases; Online; National Library of Medicine AB The National Library of Medicine's (NLM) Division of Specialized Information Services (SIS) Toxicology and Environmental Health Information Program is responsible for the management of the online Hazardous Substances Data Bank (HSDB). HSDB, a part of NLM's Toxicology Data Network (TOXNET (R)), is a file of chemical/substance information with one record for each specific chemical or substance, or for a category of chemicals or substances. Like the rest of TOXNET's databases and other resources, HSDB is available online at no cost to global users. HSDB has approximately 5600 chemicals and substances, with a focus on toxicology information and also on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, and related areas of likely interest to HSDB users. All data are from a core set of books, government documents, technical reports, selected primary journal literature, and other online sources of information, with a goal of linking the HSDB content to as much publicly available information as possible. HSDB's content is peer-reviewed by the Scientific Review Panel, a group of experts in the areas covering the scope of HSDB content. Recent enhancements include the addition of chemical structures to HSDB records, the addition of new subfields such as age groups for human data, more occupational exposure standards, and the addition of information on numerous nanomaterials. Examples of future plans include providing more exposure-related information, e.g., uses of a chemical or substance in consumer products; the addition of information summaries aimed towards consumers and other members of the public wanting to learn about a chemical or substance; more visual content such as diagrams (images) of the pathways of metabolism of a substance; and enhanced search features and navigation. Published by Elsevier Ireland Ltd. C1 [Fonger, George Charles; Hakkinen, Pertti; Jordan, Shannon; Publicker, Stephanie] Natl Lib Med, Div Specialized Informat Serv, Bethesda, MD 20894 USA. RP Fonger, GC (reprint author), Natl Inst Hlth, Natl Lib Med, Specialized Informat Serv Div, 6707 Democracy Blvd,Suite 510, Bethesda, MD 20894 USA. EM fongerg@mail.nlm.nih.gov RI Hakkinen, Pertti/G-4803-2016 OI Hakkinen, Pertti/0000-0002-8295-9738 FU Intramural NIH HHS [Z99 LM999999] NR 3 TC 8 Z9 8 U1 2 U2 17 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD NOV 5 PY 2014 VL 325 BP 209 EP 216 DI 10.1016/j.tox.2014.09.003 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA AR7UO UT WOS:000343785400021 PM 25223694 ER PT J AU Svitin, A Malov, S Cherkasov, N Geerts, P Rotkevich, M Dobrynin, P Shevchenko, A Guan, L Troyer, J Hendrickson, S Dilks, HH Oleksyk, TK Donfield, S Gomperts, E Jabs, DA Sezgin, E Van Natta, M Harrigan, PR Brumme, ZL O'Brien, SJ AF Svitin, Anton Malov, Sergey Cherkasov, Nikolay Geerts, Paul Rotkevich, Mikhail Dobrynin, Pavel Shevchenko, Andrey Guan, Li Troyer, Jennifer Hendrickson, Sher Dilks, Holli Hutcheson Oleksyk, Taras K. Donfield, Sharyne Gomperts, Edward Jabs, Douglas A. Sezgin, Efe Van Natta, Mark Harrigan, P. Richard Brumme, Zabrina L. O'Brien, Stephen J. TI GWATCH: a web platform for automated gene association discovery analysis SO GIGASCIENCE LA English DT Article DE AIDS; HIV; Complex diseases; Genome-wide association studies (GWAS); Whole genome sequencing (WGS) ID GENOME-WIDE ASSOCIATION; AIDS RESTRICTION; HIV-1 INFECTION; VARIANTS; DISEASE; TRAITS; GWAS; PROGRESSION; ERA AB Background: As genome-wide sequence analyses for complex human disease determinants are expanding, it is increasingly necessary to develop strategies to promote discovery and validation of potential disease-gene associations. Findings: Here we present a dynamic web-based platform - GWATCH - that automates and facilitates four steps in genetic epidemiological discovery: 1) Rapid gene association search and discovery analysis of large genome-wide datasets; 2) Expanded visual display of gene associations for genome-wide variants (SNPs, indels, CNVs), including Manhattan plots, 2D and 3D snapshots of any gene region, and a dynamic genome browser illustrating gene association chromosomal regions; 3) Real-time validation/replication of candidate or putative genes suggested from other sources, limiting Bonferroni genome-wide association study (GWAS) penalties; 4) Open data release and sharing by eliminating privacy constraints (The National Human Genome Research Institute (NHGRI) Institutional Review Board (IRB), informed consent, The Health Insurance Portability and Accountability Act (HIPAA) of 1996 etc.) on unabridged results, which allows for open access comparative and meta-analysis. Conclusions: GWATCH is suitable for both GWAS and whole genome sequence association datasets. We illustrate the utility of GWATCH with three large genome-wide association studies for HIV-AIDS resistance genes screened in large multicenter cohorts; however, association datasets from any study can be uploaded and analyzed by GWATCH. C1 [Svitin, Anton; Malov, Sergey; Cherkasov, Nikolay; Rotkevich, Mikhail; Dobrynin, Pavel; Shevchenko, Andrey; Guan, Li; O'Brien, Stephen J.] St Petersburg State Univ, Theodosius Dobzhansky Ctr Genome Bioinformat, St Petersburg 199004, Russia. [Malov, Sergey] St Petersburg Electrotech Univ, Dept Math, St Petersburg 197376, Russia. [Geerts, Paul] Sci Data Visualizat Consultant, Turner, ACT 2612, Australia. [Troyer, Jennifer] NCI, Genet & Genom Grp, Adv Technol Program, SAIC Frederick, Frederick, MD 21702 USA. [Hendrickson, Sher] Shepherd Univ, Dept Biol, Shepherdstown, WV 25443 USA. [Dilks, Holli Hutcheson] Vanderbilt Univ, Med Ctr, Res Off, Vanderbilt Technol Adv Genom, Nashville, TN 37204 USA. [Oleksyk, Taras K.] Univ Puerto Rico, Dept Biol, Mayaguez, PR 00680 USA. [Donfield, Sharyne] Rho Inc, Dept Biostat, Chapel Hill, NC 27517 USA. [Gomperts, Edward] Childrens Hosp, Div Hematol Oncol, Los Angeles, CA 90027 USA. [Jabs, Douglas A.] Icahn Sch Med Mt Sinai, Dept Ophthalmol, New York, NY 10029 USA. [Jabs, Douglas A.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [Sezgin, Efe; Van Natta, Mark] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Harrigan, P. Richard] British Columbia Ctr Excellence HIV AIDS, Vancouver, BC V6Z 1Y6, Canada. [Harrigan, P. Richard] Univ British Columbia, Fac Med, Div AIDS, Vancouver, BC V6T 1Z3, Canada. [Brumme, Zabrina L.] Simon Fraser Univ, Fac Hlth Sci, Burnaby, BC V5A 1S6, Canada. [O'Brien, Stephen J.] Nova SE Univ, Oceanog Ctr, Ft Lauderdale, FL 33004 USA. RP Svitin, A (reprint author), St Petersburg State Univ, Theodosius Dobzhansky Ctr Genome Bioinformat, St Petersburg 199004, Russia. EM anton.svitin@gmail.com; lgdchief@gmail.com RI Rotkevich, Mikhail/N-2647-2015; Sezgin, Efe/B-8418-2012 OI Rotkevich, Mikhail/0000-0002-1650-7688; Sezgin, Efe/0000-0002-8000-7485 FU Russian Ministry of Science Mega [11.G34.31.0068]; National Institutes of Health, National Institute of Child Health and Human Development [R01-HD-41224]; National Eye Institute, National Institutes of Health [U10EY008052, U10EY008057, U10EY008067]; Canadian Institutes for Health Research; Michael Smith Foundation for Health Research FX We gratefully acknowledge the prior collaborative contribution of the patients, health care givers and investigators of HIV-AIDS cohorts who developed and catalogued the demographic information used in this illustration. This work was supported in part by Russian Ministry of Science Mega-grant No. 11.G34.31.0068; Stephen J. O'Brien, Principal Investigator. The Hemophilia Growth and Development Study is funded by the National Institutes of Health, National Institute of Child Health and Human Development, R01-HD-41224. This work was supported by the National Eye Institute, National Institutes of Health (grants U10EY008052, U10EY008057, and U10EY008067). ZLB is supported by a New Investigator Award from the Canadian Institutes for Health Research and a Scholar Award from the Michael Smith Foundation for Health Research. NR 37 TC 0 Z9 0 U1 1 U2 5 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 NOV 5 PY 2014 VL 3 AR 18 DI 10.1186/2047-217X-3-18 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CX4GE UT WOS:000365656300001 PM 25374661 ER PT J AU Golosova, O Henderson, R Vaskin, Y Gabrielian, A Grekhov, G Nagarajan, V Oler, AJ Nones, MQ Hurt, D Fursov, M Huyen, Y AF Golosova, Olga Henderson, Ross Vaskin, Yuriy Gabrielian, Andrei Grekhov, German Nagarajan, Vijayaraj Oler, Andrew J. Nones, Mariam Qui Hurt, Darrell Fursov, Mikhail Huyen, Yentram TI Unipro UGENE NGS pipelines and components for variant calling, RNA-seq and ChIP-seq data analyses SO PEERJ LA English DT Article DE Bioinformatics; Next-generation sequencing; Data analysis; ChIP-seq; Variant calling; RNA-seq ID READ ALIGNMENT; WORKFLOWS; TOPHAT; GENE AB The advent of Next Generation Sequencing (NGS) technologies has opened new possibilities for researchers. However, the more biology becomes a data-intensive field, the more biologists have to learn how to process and analyze NGS data with complex computational tools. Even with the availability of common pipeline specifications, it is often a time-consuming and cumbersome task for a bench scientist to install and configure the pipeline tools. We believe that a unified, desktop and biologist-friendly front end to NGS data analysis tools will substantially improve productivity in this field. Here we present NGS pipelines "Variant Calling with SAMtools", "Tuxedo Pipeline for RNA-seq Data Analysis" and "Cistrome Pipeline for ChIP-seq Data Analysis" integrated into the Unipro UGENE desktop toolkit. We describe the available UGENE infrastructure that helps researchers run these pipelines on different datasets, store and investigate the results and re-run the pipelines with the same parameters. These pipeline tools are included in the UGENE NGS package. Individual blocks of these pipelines are also available for expert users to create their own advanced workflows. C1 [Golosova, Olga; Vaskin, Yuriy; Grekhov, German; Fursov, Mikhail] Unipro Ctr Informat Technol, Novosibirsk, Russia. [Henderson, Ross; Gabrielian, Andrei; Nagarajan, Vijayaraj; Oler, Andrew J.; Nones, Mariam Qui; Hurt, Darrell; Huyen, Yentram] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. RP Nagarajan, V (reprint author), NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM nagarajanv@mail.nih.gov FU Office of Science Management and Operations (OSMO) of the NIAID FX This project was supported by the Office of Science Management and Operations (OSMO) of the NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 18 TC 5 Z9 5 U1 0 U2 3 PU PEERJ INC PI LONDON PA 341-345 OLD ST, THIRD FLR, LONDON, EC1V 9LL, ENGLAND SN 2167-8359 J9 PEERJ JI PeerJ PD NOV 4 PY 2014 VL 2 AR e644 DI 10.7717/peerj.644 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AY5PU UT WOS:000347625200007 PM 25392756 ER PT J AU Pinsky, PF Gierada, DS Hocking, W Patz, EF Kramer, BS AF Pinsky, Paul F. Gierada, David S. Hocking, William Patz, Edward F., Jr. Kramer, Barnett S. TI National Lung Screening Trial Findings by Age: Medicare-Eligible Versus Under-65 Population SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID SERVICES TASK-FORCE; CANCER RESECTION; WEDGE RESECTION; LOBECTOMY; MORTALITY; RADIOTHERAPY; SURVIVAL; DATABASE; OUTCOMES; SURGERY AB Background: The NLST (National Lung Screening Trial) showed reduced lung cancer mortality in high-risk participants (smoking history of >= 30 pack-years) aged 55 to 74 years who were randomly assigned to screening with low-dose computed tomography (LDCT) versus those assigned to chest radiography. An advisory panel recently expressed reservations about Medicare coverage of LDCT screening because of concerns about performance in the Medicare-aged population, which accounted for only 25% of the NLST participants. Objective: To examine the results of the NLST LDCT group by age (Medicare-eligible vs. <65 years). Design: Secondary analysis of a group from a randomized trial (NCT00047385). Setting: 33 U.S. screening centers. Patients: 19 612 participants aged 55 to 64 years (under-65 cohort) and 7110 participants aged 65 to 74 years (65+ cohort) at randomization. Intervention: 3 annual rounds of LDCT screening. Measurements: Demographics, smoking and medical history, screening examination adherence and results, diagnostic follow-up procedures and complications, lung cancer diagnoses, treatment, survival, and mortality. Results: The aggregate false-positive rate was higher in the 65+ cohort than in the under-65 cohort (27.7% vs. 22.0%; P < 0.001). Invasive diagnostic procedures after false-positive screening results were modestly more frequent in the older cohort (3.3% vs. 2.7%; P = 0.039). Complications from invasive procedures were low in both groups (9.8% in the under-65 cohort vs. 8.5% in the 65+ cohort). Prevalence and positive predictive value (PPV) were higher in the 65+ cohort (PPV, 4.9% vs. 3.0%). Resection rates for screen-detected cancer were similar (75.6% in the under-65 cohort vs. 73.2% in the 65+ cohort). Five-year all-cause survival was lower in the 65+ cohort (55.1% vs. 64.1%; P = 0.018). Limitation: The oldest screened patient was aged 76 years. Conclusion: NLST participants aged 65 years or older had a higher rate of false-positive screening results than those younger than 65 years but a higher cancer prevalence and PPV. Screen-detected cancer was treated similarly in the groups. C1 [Pinsky, Paul F.; Kramer, Barnett S.] NCI, Bethesda, MD 20892 USA. [Gierada, David S.] Washington Univ, Sch Med, St Louis, MO 63110 USA. Marshfield Clin Fdn Med Res & Educ, Marshfield, WI USA. [Patz, Edward F., Jr.] Duke Univ, Sch Med, Durham, NC 27710 USA. RP Pinsky, PF (reprint author), NCI, 9609 Med Ctr Dr,Room 5E108, Bethesda, MD 20892 USA. EM pp4f@nih.gov FU National Institutes of Health FX National Institutes of Health. NR 21 TC 23 Z9 23 U1 1 U2 6 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 NOV 4 PY 2014 VL 161 IS 9 BP 627 EP U120 DI 10.7326/M14-1484 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AX9TE UT WOS:000347244100003 PM 25199624 ER PT J AU Osinusi, A Kohli, A Marti, MM Nelson, A Zhang, XZ Meissner, EG Silk, R Townsend, K Pang, PS Subramanian, GM McHutchison, JG Fauci, AS Masur, H Kottilil, S AF Osinusi, Anu Kohli, Anita Marti, Miriam M. Nelson, Amy Zhang, Xiaozhen Meissner, Eric G. Silk, Rachel Townsend, Kerry Pang, Phillip S. Subramanian, G. Mani McHutchison, John G. Fauci, Anthony S. Masur, Henry Kottilil, Shyam TI Re-treatment of Chronic Hepatitis C Virus Genotype 1 Infection After Relapse An Open-Label Pilot Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID SOFOSBUVIR PLUS RIBAVIRIN; TREATMENT-NAIVE; IN-VITRO; NS5A INHIBITOR; UNITED-STATES; HCV; RESISTANCE; LEDIPASVIR; POLYMERASE; SYSTEM AB Background: The interferon (IFN)-free regimen of sofosbuvir and ribavirin for 24 weeks was recently approved to treat chronic hepatitis C virus (HCV) genotype 1 (GT-1) infection for patients ineligible for IFN. However, sofosbuvir plus ribavirin therapy is associated with relapse in 15% to 30% of patients with HCV GT-1. Neither the mechanism of relapse nor the optimal re-treatment strategy for these patients is defined. Objective: To assess the safety and efficacy of sofosbuvir plus ledipasvir in patients with chronic HCV GT-1 that relapsed after sofosbuvir plus ribavirin therapy. Design: Phase 2a, open-label study. (ClinicalTrials.gov: NCT01805882) Setting: Single U.S site. Patients: 14 patients with HCV GT-1 that relapsed after treatment with sofosbuvir plus ribavirin for 24 weeks were re-treated with sofosbuvir plus ledipasvir for 12 weeks. Measurements: HCV RNA concentration and population sequencing to detect NS5B S282T mutations. Results: All 14 patients treated with sofosbuvir plus ledipasvir for 12 weeks achieved a sustained virologic response, including 7 with advanced liver disease (Knodell Histology Activity Index score of 3 or 4) and 1 with a detectable NS5B S282T mutation after sofosbuvir plus ribavirin therapy. Sofosbuvir plus ledipasvir was well-tolerated with few adverse events. Four grade 3 events (elevated serum creatinine in a patient with baseline renal insufficiency, hypercholesterolemia, and hypophosphatemia) occurred. There were no grade 4 events or treatment discontinuations. Limitation: Small sample size. Conclusion: The fixed-dose combination of sofosbuvir plus ledipasvir was efficacious in a small cohort of patients with HCV GT-1 that relapsed after sofosbuvir plus ribavirin therapy, even in the setting of advanced liver disease. Larger studies are needed to confirm these preliminary efficacy results. C1 Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. NIAID, Immunoregulat Lab, NIH, Ctr Clin, Bethesda, MD 20892 USA. Leidos Biomed Res, Frederick, MD USA. Frederick Natl Lab Canc Res, Frederick, MD USA. [Osinusi, Anu; Pang, Phillip S.; Subramanian, G. Mani; McHutchison, John G.] Gilead Sci Inc, Foster City, CA 94404 USA. RP Kottilil, S (reprint author), NIH, 10-11N204,9000 Rockville Pike, Bethesda, MD 20892 USA. EM skottilil@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; National Institutes of Health; National Cancer Institute; Gilead Sciences FX National Institute of Allergy and Infectious Diseases, National Institutes of Health, National Cancer Institute, and Gilead Sciences. NR 23 TC 29 Z9 29 U1 0 U2 4 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 NOV 4 PY 2014 VL 161 IS 9 BP 634 EP U126 DI 10.7326/M14-1211 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA AX9TE UT WOS:000347244100004 PM 25364884 ER PT J AU Scheibye-Knudsen, M Mitchell, SJ Fang, EF Iyama, T Ward, T Wang, J Dunn, CA Singh, N Veith, S Hasan-Olive, MM Mangerich, A Wilson, MA Mattson, MP Bergersen, LH Cogger, VC Warren, A Le Couteur, DG Moaddel, R Wilson, DM Croteau, DL de Cabo, R Bohr, VA AF Scheibye-Knudsen, Morten Mitchell, Sarah J. Fang, Evandro F. Iyama, Teruaki Ward, Theresa Wang, James Dunn, Christopher A. Singh, Nagendra Veith, Sebastian Hasan-Olive, Md Mahdi Mangerich, Aswin Wilson, Mark A. Mattson, Mark P. Bergersen, Linda H. Cogger, Victoria C. Warren, Alessandra Le Couteur, David G. Moaddel, Ruin Wilson, David M., III Croteau, Deborah L. de Cabo, Rafael Bohr, Vilhelm A. TI A High-Fat Diet and NAD(+) Activate Sirt1 to Rescue Premature Aging in Cockayne Syndrome SO CELL METABOLISM LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; GROUP-B PROTEIN; KETOGENIC DIET; POLY(ADP-RIBOSE) POLYMERASE-1; OXIDATIVE STRESS; DNA LESIONS; TRANSCRIPTION; INHIBITOR; DISEASES; PATHWAY AB Cockayne syndrome (CS) is an accelerated aging disorder characterized by progressive neurodegeneration caused by mutations in genes encoding the DNA repair proteins CS group A or B (CSA or CSB). Since dietary interventions can alter neurodegenerative processes, Csb(m/m) mice were given a high-fat, caloric-restricted, or resveratrol-supplemented diet. High-fat feeding rescued the metabolic, transcriptomic, and behavioral phenotypes of Csb(m/m) mice. Furthermore, premature aging in CS mice, nematodes, and human cells results from aberrant PARP activation due to deficient DNA repair leading to decreased SIRT1 activity and mitochondrial dysfunction. Notably, beta-hydroxybutyrate levels are increased by the high-fat diet, and beta-hydroxybutyrate, PARP inhibition, or NAD(+) supplementation can activate SIRT1 and rescue CS-associated phenotypes. Mechanistically, CSB can displace activated PARP1 from damaged DNA to limit its activity. This study connects two emerging longevity metabolites, beta-hydroxybutyrate and NAD(+), through the deacetylase SIRT1 and suggests possible interventions for CS. C1 [Scheibye-Knudsen, Morten; Fang, Evandro F.; Iyama, Teruaki; Wang, James; Dunn, Christopher A.; Wilson, David M., III; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Mitchell, Sarah J.; Ward, Theresa; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Singh, Nagendra; Moaddel, Ruin] NIA, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. [Hasan-Olive, Md Mahdi; Wilson, Mark A.; Mattson, Mark P.] NIA, Lab Neurosci, NIH, Baltimore, MD 21224 USA. [Mitchell, Sarah J.; Cogger, Victoria C.; Le Couteur, David G.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Veith, Sebastian; Mangerich, Aswin] Univ Konstanz, Dept Biol, Mol Toxicol Grp, D-78457 Constance, Germany. [Bergersen, Linda H.] Univ Oslo, Inst Basic Med Sci, Dept Anat, Brain & Muscle Energy Grp,Synapt Neurochem Lab, N-0317 Oslo, Norway. [Cogger, Victoria C.; Warren, Alessandra; Le Couteur, David G.] Concord Hosp, Ctr Educ & Res Ageing, Sydney, NSW 2139, Australia. [Cogger, Victoria C.; Warren, Alessandra; Le Couteur, David G.] Concord Hosp, ANZAC Res Inst, Sydney, NSW 2139, Australia. [Cogger, Victoria C.; Warren, Alessandra; Le Couteur, David G.] Univ Sydney, Sydney, NSW 2139, Australia. [Bergersen, Linda H.; Bohr, Vilhelm A.] Univ Copenhagen, ICMM, Danish Ctr Hlth Aging, Copenhagen, Denmark. RP de Cabo, R (reprint author), NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. EM decabora@grc.nia.nih.gov; vbohr@nih.gov RI Singh, Nagendra/K-8966-2015; de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Scheibye-Knudsen, Morten/0000-0002-6637-1280; , rafael/0000-0003-2830-5693 FU National Medical Health and Research Council of Australia CJ Martin Early Career Fellowship (RGMS) [ID 2010-01671]; DFG [1331]; Zukunftskolleg Konstanz; NIA/NIH FX We are grateful to Dawn Nines, Dawn Phillips, and Justine Lucas for their excellent animal care. We thank Dr. Alexander Burkle for discussion and critical reading of the manuscript. We thank Elisa Ferrando-May (University of Konstanz) for the kind gift of HeLa PARP1-/- cells. S.J.M. was supported by a National Medical Health and Research Council of Australia CJ Martin Early Career Fellowship (RGMS ID 2010-01671). S. V. was supported by a fellowship of the DFG-funded Research Training Group 1331. A.M. was supported by the Zukunftskolleg Konstanz. Funding was provided by the Intramural Research Program of the NIA/NIH. NR 29 TC 40 Z9 41 U1 3 U2 24 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD NOV 4 PY 2014 VL 20 IS 5 BP 840 EP 855 DI 10.1016/j.cmet.2014.10.005 PG 16 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA AT4YF UT WOS:000344947800019 PM 25440059 ER PT J AU Day, CP Carter, J Ohler, ZW Bonomi, C El Meskini, R Martin, P Graff-Cherry, C Feigenbaum, L Tuting, T Van Dyke, T Hollingshead, M Merlino, G AF Day, Chi-Ping Carter, John Ohler, Zoe Weaver Bonomi, Carrie El Meskini, Rajaa Martin, Philip Graff-Cherry, Cari Feigenbaum, Lionel Tueting, Thomas Van Dyke, Terry Hollingshead, Melinda Merlino, Glenn TI "Glowing Head'' Mice: A Genetic Tool Enabling Reliable Preclinical Image-Based Evaluation of Cancers in Immunocompetent Allografts SO PLOS ONE LA English DT Article ID IN-VIVO; TRANSGENE EXPRESSION; IMMUNE-RESPONSES; TUMOR-SUPPRESSOR; DRUG DEVELOPMENT; PITUITARY-GLAND; LUNG METASTASIS; BONE-MARROW; CELLS; MOUSE AB Preclinical therapeutic assessment currently relies on the growth response of established human cell lines xenografted into immunocompromised mice, a strategy that is generally not predictive of clinical outcomes. Immunocompetent genetically engineered mouse (GEM)-derived tumor allograft models offer highly tractable preclinical alternatives and facilitate analysis of clinically promising immunomodulatory agents. Imageable reporters are essential for accurately tracking tumor growth and response, particularly for metastases. Unfortunately, reporters such as luciferase and GFP are foreign antigens in immunocompetent mice, potentially hindering tumor growth and confounding therapeutic responses. Here we assessed the value of reporter-tolerized GEMs as allograft recipients by targeting minimal expression of a luciferase-GFP fusion reporter to the anterior pituitary gland (dubbed the "Glowing Head'' or GH mouse). The luciferase-GFP reporter expressed in tumor cells induced adverse immune responses in wildtype mouse, but not in GH mouse, as transplantation hosts. The antigenicity of optical reporters resulted in a decrease in both the growth and metastatic potential of the labeled tumor in wildtype mice as compared to the GH mice. Moreover, reporter expression can also alter the tumor response to chemotherapy or targeted therapy in a context-dependent manner. Thus the GH mice and experimental approaches vetted herein provide concept validation and a strategy for effective, reproducible preclinical evaluation of growth and response kinetics for traceable tumors. C1 [Day, Chi-Ping; Merlino, Glenn] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Carter, John; Bonomi, Carrie] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, In Vivo Evaluat, Frederick, MD USA. [Van Dyke, Terry] NCI, Ctr Adv Preclin Res, Ctr Canc Res, Frederick, MD 21701 USA. [Ohler, Zoe Weaver; El Meskini, Rajaa; Martin, Philip] Leidos Biomed Res Inc, Ctr Adv Preclin Res, Natl Lab Canc Res, Frederick, MD USA. [Graff-Cherry, Cari; Feigenbaum, Lionel] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Lab Anim Sci Program, Frederick, MD USA. [Tueting, Thomas] Univ Hosp Bonn, Dept Dermatol & Allergy, Bonn, Germany. [Hollingshead, Melinda] NCI, Biol Testing Branch, Dev Therapeut Program, Frederick, MD 21701 USA. RP Merlino, G (reprint author), NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. EM gmerlino@helix.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis; Center for Cancer Research, NCI, NIH; Leidos Biomedical Research Inc. 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 work was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis and Intramural Research Program of the Center for Cancer Research, NCI, NIH. Leidos Biomedical Research Inc. provided support in the form of salaries for authors John Carter, Zoe Weaver-Ohler, Carrie Bonomi, Rajaa El Meskini, Philip Martin, Cari Graff-Cherry, and Lionel Feigenbaum, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. NR 38 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 NOV 4 PY 2014 VL 9 IS 11 AR e109956 DI 10.1371/journal.pone.0109956 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AS6XG UT WOS:000344402000013 PM 25369133 ER PT J AU Geiger, TR Ha, NH Faraji, F Michael, HT Rodriguez, L Walker, RC Green, JE Simpson, RM Hunter, KW AF Geiger, Thomas R. Ngoc-Han Ha Faraji, Farhoud Michael, Helen T. Rodriguez, Loren Walker, Renard C. Green, Jeffery E. Simpson, R. Mark Hunter, Kent W. TI Functional Analysis of Prognostic Gene Expression Network Genes in Metastatic Breast Cancer Models SO PLOS ONE LA English DT Article ID KINASE AURORA-A; TPX2 GENE; CARCINOMA; TUMORS; SUSCEPTIBILITY; COMPLEX; PROTEIN; SYSTEM; TARGET; CELLS AB Identification of conserved co-expression networks is a useful tool for clustering groups of genes enriched for common molecular or cellular functions [1]. The relative importance of genes within networks can frequently be inferred by the degree of connectivity, with those displaying high connectivity being significantly more likely to be associated with specific molecular functions [2]. Previously we utilized cross-species network analysis to identify two network modules that were significantly associated with distant metastasis free survival in breast cancer. Here, we validate one of the highly connected genes as a metastasis associated gene. Tpx2, the most highly connected gene within a proliferation network specifically prognostic for estrogen receptor positive (ER+) breast cancers, enhances metastatic disease, but in a tumor autonomous, proliferation-independent manner. Histologic analysis suggests instead that variation of TPX2 levels within disseminated tumor cells may influence the transition between dormant to actively proliferating cells in the secondary site. These results support the co-expression network approach for identification of new metastasis-associated genes to provide new information regarding the etiology of breast cancer progression and metastatic disease. C1 [Geiger, Thomas R.; Ngoc-Han Ha; Faraji, Farhoud; Michael, Helen T.; Rodriguez, Loren; Walker, Renard C.; Green, Jeffery E.; Simpson, R. Mark; Hunter, Kent W.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hunter, KW (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov OI Faraji, Farhoud/0000-0001-5078-813X FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the 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 31 TC 4 Z9 4 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 NOV 4 PY 2014 VL 9 IS 11 AR e111813 DI 10.1371/journal.pone.0111813 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AS6XG UT WOS:000344402000106 PM 25368990 ER PT J AU Harden, JL Lewis, SM Pierson, KC Suarez-Farinas, M Lentini, T Ortenzio, FS Zaba, LC Goldbach-Mansky, R Bowcock, AM Lowes, MA AF Harden, Jamie L. Lewis, Steven M. Pierson, Katherine C. Suarez-Farinas, Mayte Lentini, Tim Ortenzio, Francesca S. Zaba, Lisa C. Goldbach-Mansky, Raphaela Bowcock, Anne M. Lowes, Michelle A. TI CARD14 Expression in Dermal Endothelial Cells in Psoriasis SO PLOS ONE LA English DT Article ID NF-KAPPA-B; INNATE IMMUNITY; INFLAMMATION; PATHOGENESIS; SIGNALOSOME; ACTIVATION; MICROARRAY; MUTATIONS; PATHWAYS; THERAPY AB Mutations in the caspase recruitment domain, family member 14 (CARD14) gene have recently been described in psoriasis patients, and explain the psoriasis susceptibility locus 2 (PSORS2). CARD14 is a scaffolding protein that regulates NF-kappa B activation, and psoriasis-associated CARD14 mutations lead to enhanced NF-kappa B signaling. CARD14 is expressed mainly in epidermal keratinocytes, but also in unidentified dermal cells. In this manuscript, the identity of the dermal cell types expressing CARD14, as well the potential functional consequence of overactive CARD14 in these dermal cell types, was determined. Using two-color immunofluorescence, dermal CARD14 did not co-localize with T-cells, dendritic cells, or macrophages. However, dermal CARD14 did highly co-localize with CD31(+) endothelial cells (ECs). CARD14 was also expressed non-dermal endothelial cells, such as aortic endothelial cells, which may indicate a role of CARD14(+) ECs in the systemic inflammation and cardiovascular comorbidities associated with psoriasis. Additionally, phosphorylated NF-kappa B was found in psoriatic CARD14(+) CD31(+) ECs, demonstrating this pathway is active in dermal ECs in psoriasis. Transfection of dermal ECs with psoriasis-associated CARD14 mutations resulted in increased expression of several chemokines, including CXCL10, IL-8, and CCL2. These results provide preliminary evidence that CARD14 expression in ECs may contribute to psoriasis through increased expression of chemokines and facilitating recruitment of immune cells into skin. C1 [Harden, Jamie L.; Lewis, Steven M.; Pierson, Katherine C.; Suarez-Farinas, Mayte; Lentini, Tim; Ortenzio, Francesca S.; Zaba, Lisa C.; Lowes, Michelle A.] Rockefeller Univ, Invest Dermatol Lab, New York, NY 10021 USA. [Suarez-Farinas, Mayte] Rockefeller Univ, Ctr Clin & Translat Sci, New York, NY 10021 USA. [Goldbach-Mansky, Raphaela] NIAMS, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD USA. [Bowcock, Anne M.] Univ London Imperial Coll Sci Technol & Med, London, England. RP Lowes, MA (reprint author), Rockefeller Univ, Invest Dermatol Lab, 1230 York Ave, New York, NY 10021 USA. EM lowesm@rockefeller.edu OI Bowcock, Anne/0000-0001-8691-9090; Lowes, Michelle A/0000-0003-4256-478X FU National Center for Research Resources [8 UL1 TR000043]; National Center for Advancing Translational Sciences (NCATS); National Institutes of Health [AR050266]; National Psoriasis Foundation; NIH [1R01AR060222]; National Institutes of Health Medical Scientist Training Program (MSTP) [GM07739]; Rockefeller University Center for Clinical and Translational Science (RUCCTS) Pilot Project award FX This study was supported in part by grant # 8 UL1 TR000043 from the National Center for Research Resources and the National Center for Advancing Translational Sciences (NCATS), and AR050266 (AMB) from the National Institutes of Health. The CARD14 research project was supported by a National Psoriasis Foundation Discovery grant to MAL. NIH 1R01AR060222 fully or partially supported MAL, JLH, and MSF. At the time of the research, LCZ was supported by National Institutes of Health Medical Scientist Training Program (MSTP) grant GM07739, and the study of aortic specimens was supported by a 2009 Rockefeller University Center for Clinical and Translational Science (RUCCTS) Pilot Project award. FSO is an RUCCTS-supported medical student. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 13 Z9 13 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 NOV 4 PY 2014 VL 9 IS 11 AR e111255 DI 10.1371/journal.pone.0111255 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AS6XG UT WOS:000344402000046 PM 25369198 ER PT J AU Guo, DY Dexheimer, TS Pommier, Y Nash, HA AF Guo, DongYu Dexheimer, Thomas S. Pommier, Yves Nash, Howard A. TI Neuroprotection and repair of 3 '-blocking DNA ends by glaikit (gkt) encoding Drosophila tyrosyl-DNA phosphodiesterase 1 (TDP1) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE aging; neuroscience; DNA repair; topoisomerase; fly ID STRAND BREAK REPAIR; TOPOISOMERASE-I COMPLEXES; SPINOCEREBELLAR ATAXIA; LIFE-SPAN; COVALENT COMPLEXES; CLEAVAGE COMPLEXES; AXONAL NEUROPATHY; NERVOUS-SYSTEM; HUMAN-CELLS; DAMAGE AB Tyrosyl-DNA phosphodiesterase (TDP1) is a phylogenetically conserved enzyme critical for the removal of blocking lesions at the 3' ends of DNA or RNA. This study analyzes the Drosophila TDP1 gene ortholog glaikit (gkt) and its possible role(s) in the repair of endogenous DNA lesions and neuroprotection. To do so, we studied a homozygous PiggyBac insertion (c03958) that disrupts the 5' UTR of gkt. Protein extracts of c03958 flies were defective in hydrolyzing 3'-DNA-tyrosyl residues, demonstrating that gkt is the Drosophila TDP1. Although the mutant is generally healthy and fertile, females exhibit reduced lifespan and diminished climbing ability. This phenotype was rescued by neuronal expression of TDP1. In addition, when c03958 larvae were exposed to bleomycin, an agent that produces oxidative DNA damage, or topoisomerase I-targeted drugs (camptothecin and a noncamptothecin indenoisoquinoline derivative, LMP-776), survivors displayed rough eye patches, which were rescued by neuronal expression of TDP1. Our study establishes that gkt is the Drosophila TDP1 gene, and that it is critical for neuroprotection, normal longevity, and repair of damaged DNA. C1 [Guo, DongYu; Nash, Howard A.] NIMH, Sect Mol Genet, Mol Biol Lab, Bethesda, MD 20892 USA. [Dexheimer, Thomas S.; Pommier, Yves] NCI, Lab Mol Pharmacol, Dev Therapeut Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Guo, DY (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM dongyu.guo@fda.hhs.gov; pommier@nih.gov FU NIH Intramural Program, National Institute of Diabetes and Digestive and Kidney Diseases; Center for Cancer Research of the National Cancer Institute [Z01 BC 006161] FX The authors thank Dr. Alena Naumova and Dr. Christophe Marchand (Laboratory of Molecular Pharmacology, Developmental Therapeutics Branch) for help in running the TDP1 activity experiments. They also thank Dr. Shar-yin N. Huang (Laboratory of Molecular Pharmacology, Developmental Therapeutics Branch) and Benjamin H. White (Neural Function Section, National Institute of Mental Health) for critical reading and editing of the manuscript and for constructive suggestions. This work was supported by the NIH Intramural Program, National Institute of Diabetes and Digestive and Kidney Diseases, and the Center for Cancer Research of the National Cancer Institute (Z01 BC 006161). NR 56 TC 6 Z9 6 U1 1 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 NOV 4 PY 2014 VL 111 IS 44 BP 15816 EP 15820 DI 10.1073/pnas.1415011111 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AS2CY UT WOS:000344088100053 PM 25331878 ER PT J AU Stoddard, JL Niemela, JE Fleisher, TA Rosenzweig, SD AF Stoddard, Jennifer L. Niemela, Julie E. Fleisher, Thomas A. Rosenzweig, Sergio D. TI Targeted NGS: a cost-effective approach to molecular diagnosis of PIDs SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE primary immunodeficiency; mutation analysis; Sanger sequencing; next-generation sequencing; genotype-phenotype correlation; SNV; INDEL ID PRIMARY IMMUNODEFICIENCIES AB Background: Primary immunodeficiencies (PIDs) are a diverse group of disorders caused by multiple genetic defects. Obtaining a molecular diagnosis for PID patients using a phenotype-based approach is often complex, expensive, and not always successful. Next-generation sequencing (NGS) methods offer an unbiased genotype-based approach, which can facilitate molecular diagnostics. Objective: To develop an efficient NGS method to identify variants in PID-related genes. Methods: We performed HaloPlex custom target enrichment and NGS using the IonTorrent PGM to screen 173 genes in 11 healthy controls, 13 PID patients previously evaluated with either an identified mutation or SNP and 120 patients with undiagnosed PIDs. Sensitivity and specificity were determined by comparing NGS and Sanger sequencing results for 33 patients. Run metrics and coverage analyses were done to identify systematic deficiencies. Results: A molecular diagnosis was identified for 18 of 120 patients who previously lacked a genetic diagnosis, including 9 who had atypical presentations and extensive previous genetic and functional studies. Our NGS method detected variants with 98.1% sensitivity and >99.9% specificity. Uniformity was variable (72-89%), and we were not able to reliably sequence 45 regions (45/2455 or 1.8% of total regions) due to low (<20) average read depth or <90% region coverage; thus, we optimized probe hybridization conditions to improve read-depth and coverage for future analyses, and established criteria to help identify true positives. Conclusion: While NGS methods are not as sensitive as Sanger sequencing for individual genes, targeted NGS is a cost-effective, first-line genetic test for the evaluation of patients with PIDs. This approach decreases time to diagnosis, increases diagnostic rate, and provides insight into the genotype phenotype correlation of PIDs in a cost-effective way. C1 [Stoddard, Jennifer L.; Niemela, Julie E.; Fleisher, Thomas A.; Rosenzweig, Sergio D.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Niemela, JE (reprint author), 10 Ctr Dr,Bldg 10 2C306, Bethesda, MD 20892 USA. EM jniemela@cc.nih.gov; srosenzweig@cc.nih.gov OI Niemela, Julie/0000-0003-4197-3792 FU Intramural Research Program of the NIH, Clinical Center FX This research was supported by the Intramural Research Program of the NIH, Clinical Center. NR 12 TC 19 Z9 19 U1 0 U2 4 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD NOV 3 PY 2014 VL 5 BP 1 EP 7 AR 531 DI 10.3389/fimmu.2014.00531 PG 7 WC Immunology SC Immunology GA CI1QG UT WOS:000354518600001 PM 25404929 ER PT J AU Zhang, Q Lai, SJ Zheng, CJ Zhang, HL Zhou, S Hu, WB Clements, ACA Zhou, XN Yang, WZ Hay, SI Yu, HJ Li, ZJ AF Zhang, Qian Lai, Shengjie Zheng, Canjun Zhang, Honglong Zhou, Sheng Hu, Wenbiao Clements, Archie C. A. Zhou, Xiao-Nong Yang, Weizhong Hay, Simon I. Yu, Hongjie Li, Zhongjie TI The epidemiology of Plasmodium vivax and Plasmodium falciparum malaria in China, 2004-2012: from intensified control to elimination SO MALARIA JOURNAL LA English DT Article DE Malaria; Epidemiology; Control; Elimination; China ID REPUBLIC-OF-CHINA; PROVINCE; SITUATION; PROGRESS; DISEASE AB Background: In China, the national malaria elimination programme has been operating since 2010. This study aimed to explore the epidemiological changes in patterns of malaria in China from intensified control to elimination stages. Methods: Data on nationwide malaria cases from 2004 to 2012 were extracted from the Chinese national malaria surveillance system. The secular trend, gender and age features, seasonality, and spatial distribution by Plasmodium species were analysed. Results: In total, 238,443 malaria cases were reported, and the proportion of Plasmodium falciparum increased drastically from <10% before 2010 to 55.2% in 2012. From 2004 to 2006, malaria showed a significantly increasing trend and with the highest incidence peak in 2006 (4.6/100,000), while from 2007 onwards, malaria decreased sharply to only 0.18/100,000 in 2012. Males and young age groups became the predominantly affected population. The areas affected by Plasmodium vivax malaria shrunk, while areas affected by P. falciparum malaria expanded from 294 counties in 2004 to 600 counties in 2012. Conclusions: This study demonstrated that malaria has decreased dramatically in the last five years, especially since the Chinese government launched a malaria elimination programme in 2010, and areas with reported falciparum malaria cases have expanded over recent years. These findings suggest that elimination efforts should be improved to meet these changes, so as to achieve the nationwide malaria elimination goal in China in 2020. C1 [Zhang, Qian; Lai, Shengjie; Zheng, Canjun; Zhang, Honglong; Zhou, Sheng; Yang, Weizhong; Yu, Hongjie; Li, Zhongjie] Chinese Ctr Dis Control & Prevent, Div Infect Dis, Key Lab Surveillance & Early Warning Infect Dis, Beijing 102206, Peoples R China. [Hu, Wenbiao] Queensland Univ Technol, Sch Publ Hlth & Social Work, Brisbane, Qld 4001, Australia. [Clements, Archie C. A.] Australian Natl Univ, Coll Med Biol & Environm, Res Sch Populat Hlth, Canberra, ACT, Australia. [Zhou, Xiao-Nong] Chinese Ctr Dis Control & Prevent, Natl Inst Parasit Dis, Shanghai, Peoples R China. [Hay, Simon I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. [Hay, Simon I.] NCI, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Zhou, Xiao-Nong] WHO Collaborating, Minist Hlth, Key Lab Biol Parasite & Vector, Shanghai, Peoples R China. RP Yu, HJ (reprint author), Chinese Ctr Dis Control & Prevent, Div Infect Dis, Key Lab Surveillance & Early Warning Infect Dis, 155 Changbai Rd, Beijing 102206, Peoples R China. EM yuhj@chinacdc.cn; lizj@chinacdc.cn RI Hay, Simon/F-8967-2015 OI Hay, Simon/0000-0002-0611-7272 FU Ministry of Science and Technology of China [2012ZX10004-201, 2012ZX10004-220]; Ministry of Health of China [201202006]; China UK Global Health [GHSP-CS-OP1]; Wellcome Trust [095066]; RAPIDD programme of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This study was supported by grants from the Ministry of Science and Technology of China (2012ZX10004-201, 2012ZX10004-220) and the Ministry of Health of China (No. 201202006), and China UK Global Health Support Programme (grant no. GHSP-CS-OP1). S.I.H. is funded by a Senior Research Fellowship from the Wellcome Trust (#095066). S.I.H. also acknowledges funding support from the RAPIDD programme of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. The funding bodies had no role in study design, data collection and analysis, preparation of the manuscript, or the decision to publish. NR 32 TC 5 Z9 11 U1 2 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 NOV 3 PY 2014 VL 13 AR 419 DI 10.1186/1475-2875-13-419 PG 9 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AU6LJ UT WOS:000345714300001 PM 25363492 ER PT J AU Mandal, A Mandal, S Park, MH AF Mandal, Ajeet Mandal, Swati Park, Myung Hee TI Genome-Wide Analyses and Functional Classification of Proline Repeat-Rich Proteins: Potential Role of eIF5A in Eukaryotic Evolution SO PLOS ONE LA English DT Article ID ELONGATION-FACTOR-P; FACTOR EF-P; SYNTHESIS INITIATION-FACTORS; AMINO-ACID; TRANSLATION ELONGATION; POSTTRANSLATIONAL SYNTHESIS; DEOXYHYPUSINE HYDROXYLASE; SACCHAROMYCES-CEREVISIAE; HYPUSINE MODIFICATION; PROMOTES TRANSLATION AB The eukaryotic translation factor, eIF5A has been recently reported as a sequence-specific elongation factor that facilitates peptide bond formation at consecutive prolines in Saccharomyces cerevisiae, as its ortholog elongation factor P (EF-P) does in bacteria. We have searched the genome databases of 35 representative organisms from six kingdoms of life for PPP (Pro-Pro- Pro) and/or PPG (Pro-Pro-Gly)-encoding genes whose expression is expected to depend on eIF5A. We have made detailed analyses of proteome data of 5 selected species, Escherichia coli, Saccharomyces cerevisiae, Drosophila melanogaster, Mus musculus and Homo sapiens. The PPP and PPG motifs are low in the prokaryotic proteomes. However, their frequencies markedly increase with the biological complexity of eukaryotic organisms, and are higher in newly derived proteins than in those orthologous proteins commonly shared in all species. Ontology classifications of S. cerevisiae and human genes encoding the highest level of polyprolines reveal their strong association with several specific biological processes, including actin/cytoskeletal associated functions, RNA splicing/turnover, DNA binding/transcription and cell signaling. Previously reported phenotypic defects in actin polarity and mRNA decay of eIF5A mutant strains are consistent with the proposed role for eIF5A in the translation of the polyproline-containing proteins. Of all the amino acid tandem repeats (>= 3 amino acids), only the proline repeat frequency correlates with functional complexity of the five organisms examined. Taken together, these findings suggest the importance of proline repeat-rich proteins and a potential role for eIF5A and its hypusine modification pathway in the course of eukaryotic evolution. C1 [Mandal, Ajeet; Mandal, Swati; Park, Myung Hee] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Park, MH (reprint author), NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM mhpark@nih.gov FU intramural program of the National Institute of Dental and Craniofacial Research; National Institutes of Health FX The research was supported by the intramural program of the National Institute of Dental and Craniofacial Research, 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 57 TC 18 Z9 19 U1 0 U2 10 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 NOV 3 PY 2014 VL 9 IS 11 AR UNSP e111800 DI 10.1371/journal.pone.0111800 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU4DB UT WOS:000345558100123 PM 25364902 ER PT J AU Nevo, I Woolard, K Cam, M Li, A Webster, JD Kotliarov, Y Kim, HS Ahn, S Walling, J Kotliarova, S Belova, G Song, H Bailey, R Zhang, W Fine, HA AF Nevo, Ido Woolard, Kevin Cam, Maggie Li, Aiguo Webster, Joshua D. Kotliarov, Yuri Kim, Hong Sug Ahn, Susie Walling, Jennifer Kotliarova, Svetlana Belova, Galina Song, Hua Bailey, Rolanda Zhang, Wei Fine, Howard A. TI Identification of Molecular Pathways Facilitating Glioma Cell Invasion In Situ SO PLOS ONE LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; NEURAL STEM-CELLS; GROWTH-FACTOR; GLIOBLASTOMA-MULTIFORME; EXPRESSION; ADHESION; PROGRESSION; MIGRATION; TUMORIGENICITY; PROLIFERATION AB Gliomas are mostly incurable secondary to their diffuse infiltrative nature. Thus, specific therapeutic targeting of invasive glioma cells is an attractive concept. As cells exit the tumor mass and infiltrate brain parenchyma, they closely interact with a changing micro-environmental landscape that sustains tumor cell invasion. In this study, we used a unique microarray profiling approach on a human glioma stem cell (GSC) xenograft model to explore gene expression changes in situ in Invading Glioma Cells (IGCs) compared to tumor core, as well as changes in host cells residing within the infiltrated microenvironment relative to the unaffected cortex. IGCs were found to have reduced expression of genes within the extracellular matrix compartment, and genes involved in cell adhesion, cell polarity and epithelial to mesenchymal transition (EMT) processes. The infiltrated microenvironment showed activation of wound repair and tissue remodeling networks. We confirmed by protein analysis the downregulation of EMT and polarity related genes such as CD44 and PARD3 in IGCs, and EFNB3, a tissue-remodeling agent enriched at the infiltrated microenvironment. OLIG2, a proliferation regulator and glioma progenitor cell marker upregulated in IGCs was found to function in enhancing migration and stemness of GSCs. Overall, our results unveiled a more comprehensive picture of the complex and dynamic cell autonomous and tumor-host interactive pathways of glioma invasion than has been previously demonstrated. This suggests targeting of multiple pathways at the junction of invading tumor and microenvironment as a viable option for glioma therapy. C1 [Nevo, Ido; Woolard, Kevin; Cam, Maggie; Li, Aiguo; Kotliarov, Yuri; Kim, Hong Sug; Ahn, Susie; Walling, Jennifer; Kotliarova, Svetlana; Belova, Galina; Song, Hua; Bailey, Rolanda; Zhang, Wei; Fine, Howard A.] NINDS, Neurooncol Branch, NCI, NIH, Bethesda, MD 20892 USA. [Webster, Joshua D.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Fine, HA (reprint author), NINDS, Neurooncol Branch, NCI, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM Howard.Fine@nyumc.org RI Kotliarov, Yuri/B-6938-2017 FU NIH Intramural Program (IRP) FX This work has been supported by the NIH Intramural Program (IRP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 8 Z9 8 U1 1 U2 10 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 NOV 3 PY 2014 VL 9 IS 11 AR e111783 DI 10.1371/journal.pone.0111783 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU4DB UT WOS:000345558100120 PM 25365423 ER PT J AU Schwarzenbach, H Eichelser, C Steinbach, B Tadewaldt, J Pantel, K Lobanenkov, V Loukinov, D AF Schwarzenbach, Heidi Eichelser, Corinna Steinbach, Bettina Tadewaldt, Josefine Pantel, Klaus Lobanenkov, Victor Loukinov, Dmitri TI Differential regulation of MAGE-A1 promoter activity by BORIS and Sp1, both interacting with the TATA binding protein SO BMC CANCER LA English DT Article DE DNA methylation; Histone modifications; Promoter activation; Protein protein interaction ID CANCER-TESTIS GENE; DNA METHYLATION; LUNG-CANCER; TRANSCRIPTIONAL ACTIVATION; EPIGENETIC REGULATION; HISTONE METHYLATION; EXPRESSION; CELLS; DEMETHYLATION; CTCF AB Background: As cancer-testis MAGE-A antigens are targets for tumor immunotherapy, it is important to study the regulation of their expression in cancers. This regulation appears to be rather complex and at the moment controversial. Although it is generally accepted that MAGE-A expression is controlled by epigenetics, the exact mechanisms of that control remain poorly understood. Methods: We analyzed the interplay of another cancer-testis gene, BORIS, and the transcription factors Ets-1 and Sp1 in the regulation of MAGE-A1 gene expression performing luciferase assays, quantitative real-time PCR, sodium bisulfite sequencing, chromatin immunoprecipitation assays and pull down experiments. Results: We detected that ectopically expressed BORIS could activate and demethylate both endogenous and methylated reporter MAGE-A1 promoter in MCF-7 and micrometastatic BCM1 cancer cell lines. Overexpression of Ets-1 could not further upregulate the promoter activity mediated by BORIS. Surprisingly, in co-transfection experiments we observed that Sp1 partly repressed the BORIS-mediated stimulation, while addition of Ets-1 expression plasmid abrogated the Sp1 mediated repression of MAGE-A1 promoter. Both BORIS and Sp1 interacted with the TATA binding protein (hTBP) suggesting the possibility of a competitive mechanism of action between BORIS and Sp1. Conclusions: Our findings show that BORIS and Sp1 have opposite effects on the regulation of MAGE-A1 gene expression. This differential regulation may be explained by direct protein-protein interaction of both factors or by interaction of MAGE-A1 promoter with BORIS alternatively spliced isoforms with different sequence specificity. We also show here that ectopic expression of BORIS can activate transcription from its own locus, inducing all its splice variants. C1 [Schwarzenbach, Heidi; Eichelser, Corinna; Steinbach, Bettina; Tadewaldt, Josefine; Pantel, Klaus] Univ Med Ctr Hamburg Eppendorf, Dept Tumor Biol, D-20246 Hamburg, Germany. [Lobanenkov, Victor; Loukinov, Dmitri] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Schwarzenbach, H (reprint author), Univ Med Ctr Hamburg Eppendorf, Dept Tumor Biol, Martinistr 52, D-20246 Hamburg, Germany. EM hschwarz@uke.uni-hamburg.de OI Lobanenkov, Victor/0000-0001-6665-3635 FU Stiftung fur Pathochemie and Molekulare Diagnostik, Bonn, Germany; Wilhelm Sanders Stiftung, Munchen, Germany FX The study was supported by the Stiftung fur Pathochemie and Molekulare Diagnostik, Bonn, Germany, and the Wilhelm Sanders Stiftung, Munchen, Germany. The funders had no role in study design data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 3 Z9 3 U1 1 U2 5 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 NOV 3 PY 2014 VL 14 AR 796 DI 10.1186/1471-2407-14-796 PG 15 WC Oncology SC Oncology GA AS8NF UT WOS:000344504700001 PM 25363021 ER PT J AU An, JH Jang, SM Kim, JW Kim, CH Song, PI Choi, KH AF An, Joo-Hee Jang, Sang-Min Kim, Jung-Woong Kim, Chul-Hong Song, Peter I. Choi, Kyung-Hee TI The expression of p21 is upregulated by forkhead box A1/2 in p53-null H1299 cells SO FEBS LETTERS LA English DT Article DE Transcription factor FOXA1/2; p21; Trichostatin A; Target gene; p53-Independent pathway ID HISTONE DEACETYLASE INHIBITORS; HEPATOCYTE NUCLEAR FACTOR-3-BETA; WAF1/CIP1 GENE PROMOTER; LUNG-CANCER; TUMOR-SUPPRESSOR; SP1 SITES; P21(WAF1/CIP1) EXPRESSION; TRANSCRIPTION FACTORS; EPITHELIAL-CELLS; DRUG-RESISTANCE AB The expression of the cell cycle inhibitor p21 is increased in response to various stimuli and stress signals through p53-dependent and independent pathways. We demonstrate in this study that forkhead box A1/2 (FOXA1/2) is a crucial transcription factor in the activation of p21 transcription via direct binding to the p21 promoter in p53-null H1299 lung carcinoma cells. In addition, histone deacetylase inhibitor trichostatin A (TSA)-mediated upregulation of p21 expression was repressed by knockdown of FOXA1/2 in H1299 cells. Consequently, these results suggest that FOXA1/2 is required for p53-independent p21 expression. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 [An, Joo-Hee; Jang, Sang-Min; Kim, Jung-Woong; Kim, Chul-Hong; Choi, Kyung-Hee] Chung Ang Univ, Dept Life Sci, Coll Nat Sci, Seoul 156756, South Korea. [Kim, Jung-Woong] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Song, Peter I.] Univ Colorado Denver, Dept Dermatol, Aurora, CO 80045 USA. RP Song, PI (reprint author), Univ Colorado Denver, Dept Dermatol, Anschutz Med Campus, Aurora, CO 80045 USA. EM PETER.SONG@ucdenver.edu; khchoi@cau.ac.kr FU National Research Foundation of Korea (NRF) grant - Korea government (MSIP) [2012008662]; Chung-Ang University research grant FX This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) [Grant No. 2012008662], and this research was supported by the Chung-Ang University research grant in 2011. NR 39 TC 4 Z9 4 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 EI 1873-3468 J9 FEBS LETT JI FEBS Lett. PD NOV 3 PY 2014 VL 588 IS 21 BP 4065 EP 4070 DI 10.1016/j.febslet.2014.09.033 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AS1YE UT WOS:000344075400040 PM 25281925 ER PT J AU Ianni, GR Cardillo, ER McQuire, M Chatterjee, A AF Ianni, Geena R. Cardillo, Eileen R. McQuire, Marguerite Chatterjee, Anjan TI Flying under the radar: figurative language impairments in focal lesion patients SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE metaphor; aphasia; focal lesion patients; figurative language; case study; sentence comprehension ID BRAIN-DAMAGED PATIENTS; RIGHT-HEMISPHERE; METAPHOR COMPREHENSION; NEURAL MECHANISMS; WORD MEANINGS; FMRI; SENTENCES; KNOWLEDGE; CONTEXT; CORTEX AB Despite the prevalent and natural use of metaphor in everyday language, the neural basis of this powerful communication device remains poorly understood. Early studies of brain-injured patients suggested the right hemisphere plays a critical role in metaphor comprehension, but more recent patient and neuroimaging studies do not consistently support this hypothesis. One explanation for this discrepancy is the challenge in designing optimal tasks for brain-injured populations. As traditional aphasia assessments do not assess figurative language comprehension, we designed a new metaphor comprehension task to consider whether impaired metaphor processing is missed by standard clinical assessments. Stimuli consisted of 60 pairs of moderately familiar metaphors and closely matched literal sentences. Sentences were presented visually in a randomized order, followed by four adjective-noun answer choices (target + three foil types). Participants were instructed to select the phrase that best matched the meaning of the sentence. We report the performance of three focal lesion patients and a group of 12 healthy, older controls. Controls performed near ceiling in both conditions, with slightly more accurate performance on literal than metaphoric sentences. While the Western Aphasia Battery (Kortesz, 1982) and the objects and actions naming battery (Druks and Masterson, 2000) indicated minimal to no language difficulty, our metaphor comprehension task indicated three different profiles of metaphor comprehension impairment in the patients' performance. Single case statistics revealed comparable impairment on metaphoric and literal sentences, disproportionately greater impairment on metaphors than literal sentences, and selective impairment on metaphors. We conclude our task reveals that patients can have selective metaphor comprehension deficits. These deficits are not captured by traditional neuropsychological language assessments, suggesting overlooked communication difficulties. C1 [Ianni, Geena R.] NIMH, Sect Neurocircuitry, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Cardillo, Eileen R.; McQuire, Marguerite; Chatterjee, Anjan] Univ Penn, Ctr Cognit Neurosci, Dept Neurol, Philadelphia, PA 19104 USA. RP Cardillo, ER (reprint author), Univ Penn, Ctr Cognit Neurosci, Dept Neurol, 3720 Walnut St B-51, Philadelphia, PA 19104 USA. EM eica@mail.med.upenn.edu FU National Institute of Health [R01-DC012511, T32AG000255-16]; University of Pennsylvania College Alumni Society FX This research was supported by a National Institute of Health grant (R01-DC012511) awarded to Anjan Chatterjee, a National Institute of Health training grant (T32AG000255-16), and a University of Pennsylvania College Alumni Society Research Grant awarded to Geena R. Ianni. The authors are particularly grateful to 444DX, 384BX, and 642KM for their participation. We would also like to thank Christine Watson for help with stimuli norming and selection using SOS, and Jonathan Yu, Casey Gorman, and Sam Cason for their assistance with stimuli norming and data collection. NR 63 TC 2 Z9 2 U1 5 U2 15 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD NOV 3 PY 2014 VL 8 AR UNSP 871 DI 10.3389/fnhum.2014.00871 PG 11 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AS0UL UT WOS:000343993900001 PM 25404906 ER PT J AU Sturrock, HJW Cohen, JM Keil, P Tatem, AJ Le Menach, A Ntshalintshali, NE Hsiang, MS Gosling, RD AF Sturrock, Hugh J. W. Cohen, Justin M. Keil, Petr Tatem, Andrew J. Le Menach, Arnaud Ntshalintshali, Nyasatu E. Hsiang, Michelle S. Gosling, Roland D. TI Fine-scale malaria risk mapping from routine aggregated case data SO MALARIA JOURNAL LA English DT Article AB Background: Mapping malaria risk is an integral component of efficient resource allocation. Routine health facility data are convenient to collect, but without information on the locations at which transmission occurred, their utility for predicting variation in risk at a sub-catchment level is presently unclear. Methods: Using routinely collected health facility level case data in Swaziland between 2011-2013, and fine scale environmental and ecological variables, this study explores the use of a hierarchical Bayesian modelling framework for downscaling risk maps from health facility catchment level to a fine scale (1 km x 1 km). Fine scale predictions were validated using known household locations of cases and a random sample of points to act as pseudo-controls. Results: Results show that fine-scale predictions were able to discriminate between cases and pseudo-controls with an AUC value of 0.84. When scaled up to catchment level, predicted numbers of cases per health facility showed broad correspondence with observed numbers of cases with little bias, with 84 of the 101 health facilities with zero cases correctly predicted as having zero cases. Conclusions: This method holds promise for helping countries in pre-elimination and elimination stages use health facility level data to produce accurate risk maps at finer scales. Further validation in other transmission settings and an evaluation of the operational value of the approach is necessary. C1 [Sturrock, Hugh J. W.; Hsiang, Michelle S.; Gosling, Roland D.] Univ Calif San Francisco, Global Hlth Grp, San Francisco, CA 94143 USA. [Cohen, Justin M.; Le Menach, Arnaud; Ntshalintshali, Nyasatu E.] Clinton Hlth Access Initiat, Boston, MA USA. [Keil, Petr] Yale Univ, Dept Ecol & Evolutionary Biol, New Haven, CT USA. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Tatem, Andrew J.] Flowminder Fdn, Stockholm, Sweden. [Hsiang, Michelle S.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. RP Sturrock, HJW (reprint author), Univ Calif San Francisco, Global Hlth Grp, San Francisco, CA 94143 USA. EM hugh.sturrock@ucsf.edu RI Keil, Petr/A-9875-2014; OI Cohen, Justin/0000-0003-4481-6784 FU Bill and Melinda Gates Foundation [1013170, 1034348, 1106900, 1032350, 1106427]; National Institutes of Health/National Institute of Allergy and Infectious Diseases K23 grant; Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene Fellowship Award; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; NIH/NIAID [U19AI089674]; EU [302868] FX We would like to thank Simon Kunene and Zulisile Zulu from the Swaziland National Malaria Control Programme for leading the collection of the surveillance data used in the study. Funding support was provided through a grant from the Bill and Melinda Gates Foundation (##1013170) to the UCSF Global Heath Group (HJWS, MSH, RG and NEN). JMC and ALM also acknowledge funding from the Bill and Melinda Gates Foundation (#1034348, and #1106900). MSH is additionally funded by a National Institutes of Health/National Institute of Allergy and Infectious Diseases K23 grant and a Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene Fellowship Award. AJT acknowledges funding support from the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, and is also supported by grants from NIH/NIAID (U19AI089674) and the Bill and Melinda Gates Foundation (#1032350 and #1106427). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. PK acknowledges funding from People Programme (Marie Curie Actions) of the EU's 7th Framework Programme (FP7/2007-2013) under REA grant agreement no. 302868. NR 37 TC 6 Z9 6 U1 1 U2 1 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 NOV 3 PY 2014 VL 13 AR 421 DI 10.1186/1475-2875-13-421 PG 9 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA V42AO UT WOS:000209586900001 PM 25366929 ER PT J AU Chatjuthamard-Kitsabunnarat, P Jiraporn, P Tong, SH AF Chatjuthamard-Kitsabunnarat, Pattanaporn Jiraporn, Pornsit Tong, Shenghui TI Does religious piety inspire corporate social responsibility (CSR)? Evidence from historical religious identification SO APPLIED ECONOMICS LETTERS LA English DT Article DE religion; CSR; corporate social responsibility; religious piety; instrumental variable; M14; G30; Z12 ID MATTER AB We explore the effect of religious piety on corporate social responsibility (CSR). Prior research links religion to honesty and risk aversion. Accordingly, religion induces managers to be more honest and likely view as opportunistic and unethical an exploitation of other stakeholders. Risk aversion also implies that managers are unlikely to take advantage of other stakeholders as stakeholders can take retaliatory actions against them. Religion therefore motivates managers to treat other stakeholders and the society at large more favourably, resulting in stronger CSR. Our evidence, based on over 17 000 observations across 16 years, shows that religious piety leads to stronger CSR. However, this is the case only when religious piety is sufficiently strong, that is, when it is beyond a certain threshold. To draw a causal inference, we use as our instruments religious piety in the distant past, that is from 1971 to 1952. Religious piety from decades ago is unlikely correlated with current CSR, except through its impact on contemporaneous piety. Our instrumental-variable analysis shows that the effect of religion on CSR is likely causal. C1 [Chatjuthamard-Kitsabunnarat, Pattanaporn] Chulalongkorn Univ, Sasin Grad Inst Business Adm, Bangkok, Thailand. [Jiraporn, Pornsit] Penn State Univ, Great Valley Sch Grad Profess Studies, Malvern, PA 19355 USA. [Jiraporn, Pornsit] NIDA, Bangkok, Thailand. [Tong, Shenghui] Cent Univ Finance & Econ, Beijing, Peoples R China. RP Chatjuthamard-Kitsabunnarat, P (reprint author), Chulalongkorn Univ, Sasin Grad Inst Business Adm, Bangkok, Thailand. EM pattanaporn.chatjuthamard@sasin.edu NR 14 TC 1 Z9 1 U1 3 U2 21 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1350-4851 EI 1466-4291 J9 APPL ECON LETT JI Appl. Econ. Lett. PD NOV 2 PY 2014 VL 21 IS 16 BP 1128 EP 1133 DI 10.1080/13504851.2014.912032 PG 6 WC Economics SC Business & Economics GA AS8XC UT WOS:000344527400005 ER PT J AU Eichelberger, L AF Eichelberger, Laura TI Spoiling and Sustainability: Technology, Water Insecurity, and Visibility in Arctic Alaska SO MEDICAL ANTHROPOLOGY LA English DT Article DE water insecurity; sanitation; vulnerability; technology; Inupiat ID POLITICAL ECOLOGY; NORTHWEST ALASKA; NATIVE VILLAGES; COMMUNITIES; SETTLEMENT; DISTRESS; VIOLENCE AB One third of households in Alaska Native villages lack running water and sewer services. Historically, this public health need drove policies to improve access to treated water and sanitation. However, despite public health being a stated priority of water infrastructure development, current policies require demonstrated economic sustainability in ways that render suffering from water insecurity invisible. In this article, I situate the introduction of water treatment technologies within the history of domination coproduced with vulnerability. These processes are reflected in local narratives describing the relationships between technology, tradition, and suffering. By drawing attention to the role of the state in creating vulnerability, village leaders are trying to historicize and insert their health concerns into the sustainability conversation using narratives that both fit within and challenge the ideology of sustainability. These narratives are thus central to Inupiat struggles for visibility. C1 [Eichelberger, Laura] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Eichelberger, L (reprint author), Univ Texas San Antonio, Dept Anthropol, One UTSA Circle, San Antonio, TX 78249 USA. EM laura.eichelberger@nih.gov NR 76 TC 0 Z9 0 U1 5 U2 22 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0145-9740 EI 1545-5882 J9 MED ANTHROPOL JI Med. Anthropol. PD NOV 2 PY 2014 VL 33 IS 6 BP 478 EP 496 DI 10.1080/01459740.2014.917374 PG 19 WC Anthropology; Reproductive Biology; Social Sciences, Biomedical SC Anthropology; Reproductive Biology; Biomedical Social Sciences GA AQ0YJ UT WOS:000342508300002 PM 24810479 ER PT J AU Osokina, IV Ignatev, P Platonov, FA Goldfarb, L Osakovskiy, V AF Osokina, I. V. Ignatev, P. Platonov, F. A. Goldfarb, L. Osakovskiy, V. TI MARKERS OF GENETIC SUSCEPTIBILITY TO TYPE 2 DIABETES MELLITUS IN YAKUTIAN POPULATION SO DIABETES RESEARCH AND CLINICAL PRACTICE LA English DT Meeting Abstract ID RISK C1 [Osokina, I. V.; Platonov, F. A.] State Res Inst Med Studies North, Endocrinol, Krasnoyarsk, Russia. [Ignatev, P.] Natl Med Res Ctr, Inst Hlth, Endocrinol, Yakutsk, Russia. [Platonov, F. A.] Natl Med Res Ctr, Inst Hlth, Yakutsk, Russia. [Goldfarb, L.] NINDS, Genet, NIH, Clin Neurogenet Unit, Bethesda, MD 20892 USA. [Osakovskiy, V.] Natl Med Res Ctr, Inst Hlth, Genet, Yakutsk, Russia. NR 4 TC 0 Z9 0 U1 2 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-8227 EI 1872-8227 J9 DIABETES RES CLIN PR JI Diabetes Res. Clin. Pract. PD NOV PY 2014 VL 106 SU 1 MA PO085 BP S88 EP S88 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CR1ZO UT WOS:000361124300175 ER PT J AU Khotskaya, YB Goverdhan, A Shen, J Sarvice, MP Chang, SS Hsu, MC Wei, YK Xia, WY Steeg, P Yu, DH Hung, MC AF Khotskaya, Yekaterina B. Goverdhan, Aarthi Shen, Jia Sarvice, Mariano Ponz Chang, Shih-Shin Hsu, Ming-Chuan Wei, Yongkun Xia, Weiya Steeg, Patricia Yu, Dihua Hung, Mien-Chie TI S6K1 promotes invasiveness of breast cancer cells in a novel model of triple-negative breast cancer metastasis SO MOLECULAR CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Translational Impact of Model Organisms in Cancer CY NOV 05-08, 2013 CL San Diego, CA SP Amer Assoc Canc Res C1 [Khotskaya, Yekaterina B.; Goverdhan, Aarthi; Shen, Jia; Sarvice, Mariano Ponz; Chang, Shih-Shin; Hsu, Ming-Chuan; Wei, Yongkun; Xia, Weiya; Yu, Dihua; Hung, Mien-Chie] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Steeg, Patricia] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD NOV PY 2014 VL 12 SU 11 MA A49 DI 10.1158/1557-3125.MODORG-A49 PG 1 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CQ9IW UT WOS:000360928600035 ER PT J AU Merlino, GT Day, CP Mishra, P Guo, T Zaida, R Davis, S Meltzer, P Noonan, F De Fabo, E Ohler-Weaver, Z Van Dyke, T AF Merlino, Glenn T. Day, Chi-Ping Mishra, Pravin Guo, Theresa Zaida, Raza Davis, Sean Meltzer, Paul Noonan, Frances De Fabo, Edward Ohler-Weaver, Zoe Van Dyke, Terry TI Modeling recurrent metastatic melanoma in the mouse SO MOLECULAR CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Translational Impact of Model Organisms in Cancer CY NOV 05-08, 2013 CL San Diego, CA SP Amer Assoc Canc Res C1 [Merlino, Glenn T.; Day, Chi-Ping; Mishra, Pravin; Guo, Theresa; Zaida, Raza; Davis, Sean; Meltzer, Paul] NCI, Bethesda, MD 20892 USA. [Mishra, Pravin; Noonan, Frances; De Fabo, Edward] George Washington Univ, Med Ctr, Washington, DC 20037 USA. [Ohler-Weaver, Zoe; Van Dyke, Terry] NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD NOV PY 2014 VL 12 SU 11 MA IA22 DI 10.1158/1557-3125.MODORG-IA22 PG 1 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CQ9IW UT WOS:000360928600085 ER PT J AU Ostrander, EA AF Ostrander, Elaine A. TI Canine cancer genetics: What dogs can tell us about ourselves SO MOLECULAR CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Translational Impact of Model Organisms in Cancer CY NOV 05-08, 2013 CL San Diego, CA SP Amer Assoc Canc Res C1 [Ostrander, Elaine A.] NHGRI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD NOV PY 2014 VL 12 SU 11 MA IA19 DI 10.1158/1557-3125.MODORG-IA19 PG 1 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CQ9IW UT WOS:000360928600083 ER PT J AU Thomas, R Simpson, M Mochizuki, H Williams, C Poorman, K Kennedy, K Mazcko, C Modiano, JF Breen, M AF Thomas, Rachael Simpson, Mark Mochizuki, Hiro Williams, Christina Poorman, Kelsey Kennedy, Katie Mazcko, Christina Modiano, Jaime F. Breen, Matthew TI Quality control and quality assurance of canine biological specimens available through the Pfizer-CCOGC, Inc. National Biorepository for Comparative Oncology Studies SO MOLECULAR CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Translational Impact of Model Organisms in Cancer CY NOV 05-08, 2013 CL San Diego, CA SP Amer Assoc Canc Res C1 [Thomas, Rachael; Mochizuki, Hiro; Williams, Christina; Poorman, Kelsey; Kennedy, Katie; Breen, Matthew] N Carolina State Univ, Raleigh, NC 27695 USA. [Simpson, Mark; Mazcko, Christina] NCI, NIH, Bethesda, MD 20892 USA. [Modiano, Jaime F.] Univ Minnesota, Minneapolis, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD NOV PY 2014 VL 12 SU 11 MA A51 DI 10.1158/1557-3125.MODORG-A51 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CQ9IW UT WOS:000360928600036 ER PT J AU Ambs, S AF Ambs, Stefan TI Distinct immune and metabolic signatures in prostate and breast tumors of African American patients SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract ID CANCER; RADIATION C1 [Ambs, Stefan] NCI, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 SU S MA PL01-01 DI 10.1158/1538-7755.DISP13-PL01-01 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CP4JA UT WOS:000359846600221 ER PT J AU Antwi, S Steck, SE Su, LJ Blackard, B Arp-Adams, S Hebert, JR Fontham, ETH Bensen, J Mohler, JL Arab, L AF Antwi, Samuel Steck, Susan E. Su, L. Joseph Blackard, Bonny Arp-Adams, Swann Hebert, James R. Fontham, Elizabeth T. H. Bensen, Jeannette Mohler, James L. Arab, Lenore TI Occupational and recreational physical activity in relation to prostate cancer aggressiveness: The North Carolina-Louisiana Prostate Cancer Project (PCaP) SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract C1 [Antwi, Samuel; Steck, Susan E.; Arp-Adams, Swann; Hebert, James R.] Univ S Carolina, Epidemiol & Biostat, Columbia, SC 29208 USA. [Antwi, Samuel; Steck, Susan E.; Arp-Adams, Swann; Hebert, James R.] Univ S Carolina, Canc Prevent & Control Program, Columbia, SC 29208 USA. [Su, L. Joseph] NCI, NIH, Rockville, MD USA. [Blackard, Bonny; Bensen, Jeannette] Univ N Carolina, Chapel Hill, NC USA. [Fontham, Elizabeth T. H.] Louisiana State Univ, Sch Publ Hlth, Hlth Sci Ctr, New Orleans, LA USA. [Mohler, James L.] Roswell Pk Canc Inst, Dept Urol, Buffalo, NY 14263 USA. [Arab, Lenore] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 SU S MA B08 DI 10.1158/1538-7755.DISP13-B08 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CP4JA UT WOS:000359846600078 ER PT J AU Arora, NK Hesse, BW Glasgow, R AF Arora, Neeraj K. Hesse, Bradford W. Glasgow, Russell TI Facilitating the patient-centeredness of care for individuals with multiple chronic illnesses: why does it matter? SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract C1 [Arora, Neeraj K.; Hesse, Bradford W.] NCI, Bethesda, MD 20892 USA. [Glasgow, Russell] Univ Colorado, Denver, CO 80202 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 SU S MA CN01-02 DI 10.1158/1538-7755-DISP13-CN01-02 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CP4JA UT WOS:000359846600207 ER PT J AU Banegas, MP Tao, L Altekruse, S Anderson, WF John, EM Clarke, CA Gomez, SL AF Banegas, Matthew P. Tao, Li Altekruse, Sean Anderson, William F. John, Esther M. Clarke, Christina A. Gomez, Scarlett L. TI Breast cancer subtype distribution and survival among Hispanic women in California SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract C1 [Banegas, Matthew P.; Altekruse, Sean; Anderson, William F.] NCI, Bethesda, MD 20892 USA. [Tao, Li; John, Esther M.; Clarke, Christina A.; Gomez, Scarlett L.] Canc Prevent Inst Calif, Fremont, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 SU S MA A73 DI 10.1158/1538-7755.DISP13-A73 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CP4JA UT WOS:000359846600055 ER PT J AU Chou, WYS AF Chou, Wen-ying Sylvia TI Using communication science to reduce cancer health disparities: Inequities in access and opportunities for narrowing the digital divide SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract C1 [Chou, Wen-ying Sylvia] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 SU S MA ED03-01 DI 10.1158/1538-7755.DISP13-ED03-01 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CP4JA UT WOS:000359846600213 ER PT J AU Dobi, A Rosen, P Farrell, J Degon, M Young, D Srivastava, S Kagan, J Petrovics, G Cullen, J McLeod, DG Sesterhenn, IA Srivastava, S AF Dobi, Albert Rosen, Philip Farrell, James Degon, Michael Young, Denise Srivastava, Sudhir Kagan, Jacob Petrovics, Gyorgy Cullen, Jennifer McLeod, David G. Sesterhenn, Isabel A. Srivastava, Shiv TI ERG-focused evaluations of prostate cancer of African American men and its potential impact on utility in biomarker development and in enhanced personalized medicine SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract C1 [Dobi, Albert; Young, Denise; Petrovics, Gyorgy; Cullen, Jennifer; Srivastava, Shiv] USUHS, CPDR, Dept Surg, Rockville, MD USA. [Rosen, Philip; Farrell, James; Degon, Michael; McLeod, David G.] USUHS, CPDR, Dept Surg, Bethesda, MD USA. [Rosen, Philip; Farrell, James; Degon, Michael; McLeod, David G.] WRNMMC, Urol Serv, Bethesda, MD USA. [Srivastava, Sudhir; Kagan, Jacob] NCI, Canc Biomarkers Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. [Sesterhenn, Isabel A.] Joint Pathol Ctr, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 SU S MA C18 DI 10.1158/1538-7755.DISP13-C18 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CP4JA UT WOS:000359846600152 ER PT J AU Figueroa, JD Edusei, L Adjei, E Titiloye, N Ylaya, K Addai, B Clegg-Lamptey, JN Awuah, B Nyarko, K Ansong, D Wlafe, S Brinton, LA Hewitt, S AF Figueroa, Jonine D. Edusei, Lawrence Adjei, Ernest Titiloye, Nicholas Ylaya, Kris Addai, Beatrice Clegg-Lamptey, Joe Nat Awuah, Baffour Nyarko, Kofi Ansong, Daniel Wlafe, Seth Brinton, Louise A. Hewitt, Stephen TI Impact of pathologic specimen quality on classifying molecular subtypes of breast cancer: A pilot study from three hospitals in Ghana, Africa SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract C1 [Figueroa, Jonine D.; Ylaya, Kris; Brinton, Louise A.; Hewitt, Stephen] NCI, Bethesda, MD 20892 USA. [Edusei, Lawrence; Clegg-Lamptey, Joe Nat] Korle Bu Teaching Hosp, Accra, Ghana. [Adjei, Ernest; Titiloye, Nicholas; Awuah, Baffour; Ansong, Daniel] Komfo Anokye Teaching Hosp, Kumasi, Ghana. [Addai, Beatrice; Wlafe, Seth] Peace & Love Hosp, Kumasi, Ghana. [Nyarko, Kofi] Univ Ghana, Accra, Ghana. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 SU S MA C11 DI 10.1158/1538-7755.DISP13-C11 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CP4JA UT WOS:000359846600148 ER PT J AU Horne, HN Devi, CRB Tang, TS Hewiti, SM Anderson, WF Yang, XR AF Horne, Hisani N. Devi, C. R. Beena Tang, Tieng-Swee Hewiti, Stephen M. Anderson, William F. Yang, Xiaohong R. TI Differences in breast cancer incidence and survival patterns by tumor subtype and ethnicity in Sarawak, Malaysia SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract C1 [Horne, Hisani N.; Hewiti, Stephen M.; Anderson, William F.; Yang, Xiaohong R.] NCI, Rockville, MD USA. [Devi, C. R. Beena; Tang, Tieng-Swee] Sarawak Gen Hosp, Kuching, Sarawak, Malaysia. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 SU S MA C81 DI 10.1158/1538-7755.DISP13-C81 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CP4JA UT WOS:000359846600194 ER PT J AU McMahon, DM Steck, SE Su, LJ Zhang, HM Hebert, JR Bensen, JT Fontham, ETH Mohler, JL Arab, L AF McMahon, Daria M. Steck, Susan E. Su, L. Joseph Zhang, Hongmei Hebert, James R. Bensen, Jeannette T. Fontham, Elizabeth T. H. Mohler, James L. Arab, Lenore TI Multivitamin supplement use and prostate cancer aggressiveness by race in the North Carolina-Louisiana Prostate Cancer Project (PCaP) SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract C1 [McMahon, Daria M.; Steck, Susan E.; Hebert, James R.] Univ S Carolina, Columbia, SC 29208 USA. [Su, L. Joseph] NCI, Rockville, MD USA. [Zhang, Hongmei] Univ Memphis, Memphis, TN 38152 USA. [Bensen, Jeannette T.] Univ N Carolina, Chapel Hill, NC USA. [Fontham, Elizabeth T. H.] Louisiana State Univ, New Orleans, LA USA. [Mohler, James L.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Arab, Lenore] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 SU S MA B05 DI 10.1158/1538-7755.DISP13-B05 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CP4JA UT WOS:000359846600076 ER PT J AU Nguyen, AB Breen, N Clark, TT Moser, R AF Nguyen, Anh B. Breen, Nancy Clark, Trenette T. Moser, Richard TI Health status and chronic conditions of biracial Asians in California 2001-2009 SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract C1 [Nguyen, Anh B.; Breen, Nancy; Moser, Richard] NCI, Rockville, MD USA. [Clark, Trenette T.] Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 SU S MA C83 DI 10.1158/1538-7755.DISP13-C83 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CP4JA UT WOS:000359846600196 ER PT J AU Palmer, N Weaver, K Hauser, S Talton, J Case, LD Lawrence, J Dezern, K Geiger, A AF Palmer, Nynikka Weaver, Kathryn Hauser, Sally Talton, Jennifer Case, L. Douglas Lawrence, Julia Dezern, Kimberly Geiger, Ann TI Racial disparities in barriers to follow-up care among breast cancer survivors SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract C1 [Palmer, Nynikka; Weaver, Kathryn; Hauser, Sally; Talton, Jennifer; Case, L. Douglas; Lawrence, Julia; Dezern, Kimberly] Wake Forest Sch Med, Winston Salem, NC USA. [Geiger, Ann] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 SU S MA C35 DI 10.1158/1538-7755.DISP13-C35 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CP4JA UT WOS:000359846600162 ER PT J AU Percy-Laurry, A Tatalovich, Z AF Percy-Laurry, Antoinette Tatalovich, Zaria TI Utilizing state cancer profiles for communicating lung cancer disparities SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract C1 [Percy-Laurry, Antoinette; Tatalovich, Zaria] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 SU S MA C07 DI 10.1158/1538-7755.DISP13-C07 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CP4JA UT WOS:000359846600144 ER PT J AU Yee, MK Wong, R Heron, DE AF Yee, Melissa K. Wong, Rosemary Heron, Dwight E. TI Models of patient navigation programs: Experience from the Cancer Disparities Research Partnership (CDRP) grantees SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract C1 [Yee, Melissa K.; Heron, Dwight E.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Wong, Rosemary] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 SU S MA A72 DI 10.1158/1538-7755.DISP13-A72 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CP4JA UT WOS:000359846600054 ER PT J AU Zheng, YL Huo, DZ Ogundiran, TO Falusi, AG Ojengbede, O Adebamowo, C Blot, WJ Zheng, W Cai, QY Signorello, LB Nathanson, KL Domchek, SM Rebbeck, TR Simon, MS Bennie, AJM Nemesure, B Wu, SY Leske, MC Ambs, S Odetunde, A Anetor, I Akinleye, S Niu, Q Zhang, J Pluzhnikov, A Konkashbaev, A Chen, L Gamazon, ER Lee, Y Cox, NJ Olopade, OO AF Zheng, Yonglan Huo, Dezheng Ogundiran, Temidayo O. Falusi, Adeyinka G. Ojengbede, Oladosu Adebamowo, Clement Blot, William J. Zheng, Wei Cai, Qiuyin Signorello, Lisa B. Nathanson, Katherine L. Domchek, Susan M. Rebbeck, Timothy R. Simon, Michael S. Bennie, Anselm J. M. Nemesure, Barbara Wu, Suh-Yuh Leske, Maria Cristina Ambs, Stefan Odetunde, Abayomi Anetor, Imaria Akinleye, Stella Niu, Qun Zhang, Jing Pluzhnikov, Anna Konkashbaev, Anuar Chen, Lin Gamazon, Eric R. Lee, Younghee Cox, Nancy J. Olopade, Olufunmilayo O. TI Replication of previously identified breast cancer susceptibility loci in a breast cancer case-control study on women of African ancestry SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract C1 [Zheng, Yonglan; Huo, Dezheng; Niu, Qun; Zhang, Jing; Pluzhnikov, Anna; Konkashbaev, Anuar; Chen, Lin; Gamazon, Eric R.; Lee, Younghee; Cox, Nancy J.; Olopade, Olufunmilayo O.] Univ Chicago, Chicago, IL 60637 USA. [Ogundiran, Temidayo O.; Falusi, Adeyinka G.; Ojengbede, Oladosu; Odetunde, Abayomi] Univ Ibadan, Ibadan, Nigeria. [Adebamowo, Clement] Univ Maryland, Baltimore, MD 21201 USA. [Blot, William J.; Zheng, Wei; Cai, Qiuyin] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Signorello, Lisa B.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.] Univ Penn, Philadelphia, PA 19104 USA. [Simon, Michael S.] Wayne State Univ, Detroit, MI USA. [Bennie, Anselm J. M.] Univ W Indies, Bridgetown, Barbados. [Nemesure, Barbara; Wu, Suh-Yuh; Leske, Maria Cristina] SUNY Stony Brook, Med Ctr, Stony Brook, NY 11794 USA. [Ambs, Stefan] NCI, Bethesda, MD 20892 USA. [Anetor, Imaria; Akinleye, Stella] Hlth Life All Fdn, Ibadan, Nigeria. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 SU S MA B11 DI 10.1158/1538-7755.DISP13-B11 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CP4JA UT WOS:000359846600080 ER PT J AU Bhattacharjee, S Mason, RP AF Bhattacharjee, Suchandra Mason, Ronald P. TI Site-Specific Radical Formation in DNA Induced by the Potent Oxidizing Agent HOCL, Using ESR, Immuno-Spin Trapping, LC-MS and MS/MS SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Bhattacharjee, Suchandra; Mason, Ronald P.] NIEHS, NIH, Morrisville, NC USA. NR 0 TC 0 Z9 0 U1 1 U2 2 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 NOV PY 2014 VL 76 SU 1 MA 332 BP S138 EP S138 DI 10.1016/j.freeradbiomed.2014.10.107 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CO9WA UT WOS:000359525800351 ER PT J AU Cheng, R Basudhar, D Bharadwaj, G Ridnour, L Wink, D Miranda, K AF Cheng, Robert Basudhar, Debashree Bharadwaj, Gaurav Ridnour, Lisa Wink, David Miranda, Katrina TI Chemotherapeutic Potential of Diazeniumdiolate-Based Aspirin Prodrugs in Breast Cancer SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Cheng, Robert; Ridnour, Lisa; Wink, David] NCI, Bethesda, MD 20892 USA. [Basudhar, Debashree; Bharadwaj, Gaurav; Miranda, Katrina] Univ Arizona, Tucson, AZ 85721 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2014 VL 76 SU 1 MA 286 BP S122 EP S122 DI 10.1016/j.freeradbiomed.2014.10.183 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CO9WA UT WOS:000359525800306 ER PT J AU Esworthy, S Cota, U Shen, BH Gao, Q Doroshow, JH Chu, FF AF Esworthy, Steven Cota, Ursula Shen, Binghui Gao, Qiang Doroshow, James H. Chu, Fong-Fong TI Nox1 Exacerbates Colitis Induced by Salmonella Typhimurium Infection in Mice SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Esworthy, Steven; Cota, Ursula; Shen, Binghui; Chu, Fong-Fong] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA USA. [Gao, Qiang] Henan Univ Sci & Tech, Affiliated Hosp 1, Luoyang, Henan, Peoples R China. [Doroshow, James H.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 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 NOV PY 2014 VL 76 SU 1 MA 123 BP S60 EP S60 DI 10.1016/j.freeradbiomed.2014.10.366 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CO9WA UT WOS:000359525800143 ER PT J AU Gladwell, W Yost, O Nelson, S McCaw, Z Gilmour, I Ciencewicki, J Kleeberger, S AF Gladwell, Wesley, II Yost, Oriana Nelson, Spencer McCaw, Zachary Gilmour, Ian Ciencewicki, Jonathan Kleeberger, Steven TI Differential Susceptibility to Diesel Exhaust Extract in Human Lymphoblastoid Cell Lines SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Gladwell, Wesley, II; Yost, Oriana; Nelson, Spencer; McCaw, Zachary; Ciencewicki, Jonathan; Kleeberger, Steven] NIEHS, Res Triangle Pk, NC USA. [Gilmour, Ian] US EPA, Washington, DC USA. NR 0 TC 0 Z9 0 U1 1 U2 2 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 NOV PY 2014 VL 76 SU 1 MA 125 BP S61 EP S61 DI 10.1016/j.freeradbiomed.2014.10.368 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CO9WA UT WOS:000359525800145 ER PT J AU Kumar, A Leinisch, F Kadiiska, MB Corbett, J Mason, RP AF Kumar, Ashutosh Leinisch, Fabian Kadiiska, Maria B. Corbett, Jean Mason, Ronald P. TI Immuno-Spin Trapping of Alpha-Synuclein Radical Formed in Maneb- and Paraquat-Induced Models of Parkinson's Disease SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Kumar, Ashutosh; Leinisch, Fabian; Kadiiska, Maria B.; Corbett, Jean; Mason, Ronald P.] NIEHS, NIH, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 NOV PY 2014 VL 76 SU 1 MA 30 BP S24 EP S25 DI 10.1016/j.freeradbiomed.2014.10.478 PG 2 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CO9WA UT WOS:000359525800050 ER PT J AU Mukhopadhyay, P Holovac, E Erdelyi, K Cinar, R Kunos, G van der Stelt, M Pacher, P AF Mukhopadhyay, Partha Holovac, Eileen Erdelyi, Katalin Cinar, Resat Kunos, George van der Stelt, Mario Pacher, Pal TI Peripherally Restricted, Selective Cannabinoid CB2 Receptor Agonist LEI-101 Prevents Cisplatin-Induced Nephrotoxicity by Attenuating Oxidative/Nitrative Stress and Inflammation SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Mukhopadhyay, Partha; Holovac, Eileen; Erdelyi, Katalin; Cinar, Resat; Kunos, George; Pacher, Pal] NIH, Bethesda, MD 20892 USA. [van der Stelt, Mario] Leiden Univ, NL-2300 RA Leiden, Netherlands. NR 0 TC 0 Z9 0 U1 1 U2 2 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 NOV PY 2014 VL 76 SU 1 MA 200 BP S87 EP S88 DI 10.1016/j.freeradbiomed.2014.10.306 PG 2 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CO9WA UT WOS:000359525800220 ER PT J AU Patel, VS Sampat, V Sharma, L Wu, WJ Sitapara, R Wang, HC Espey, M Mantell, LL AF Patel, Vivek Sudhir Sampat, Vaishali Sharma, Lokesh Wu, Wenjun Sitapara, Ravikumar Wang, Haichao Espey, Michael Mantell, Lin L. TI Ascorbic Acid Improves Hyperoxia-Compromised Host Defense against Pseudomonas Aeruginosa Infection SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Patel, Vivek Sudhir; Sampat, Vaishali; Sharma, Lokesh; Wu, Wenjun; Sitapara, Ravikumar; Mantell, Lin L.] St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Queens, NY USA. [Wang, Haichao; Mantell, Lin L.] Feinstein Inst Med Res, North Shore LIJ Hlth Sci, Ctr Inflammat & Immunol, Manhasset, NY USA. [Espey, Michael] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2014 VL 76 SU 1 MA 134 BP S63 EP S64 DI 10.1016/j.freeradbiomed.2014.10.377 PG 2 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CO9WA UT WOS:000359525800154 ER PT J AU Piknova, B Park, JW Swanson, KM Schechter, AN AF Piknova, Barbora Park, Ji Won Swanson, Kathryn M. Schechter, Alan N. TI Skeletal Muscle as an Endogenous Nitrate Reservoir SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Piknova, Barbora; Park, Ji Won; Swanson, Kathryn M.; Schechter, Alan N.] NIH, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2014 VL 76 SU 1 MA 13 BP S17 EP S18 DI 10.1016/j.freeradbiomed.2014.10.499 PG 2 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CO9WA UT WOS:000359525800033 ER PT J AU van't Erve, TJ Lih, F Eling, T Kadiiska, M Deterding, L Mason, R AF van't Erve, Thomas Joost Lih, Fred Eling, Thomas Kadiiska, Maria Deterding, Leesa Mason, Ronald TI The Ratio of 8-Iso-Prostaglandin F-2 alpha to Prostaglandin F-2 alpha distinguishes Enzymatic from Nonenzymatic Isoprostane Formation SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [van't Erve, Thomas Joost; Lih, Fred; Eling, Thomas; Kadiiska, Maria; Deterding, Leesa; Mason, Ronald] NIEHS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 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 NOV PY 2014 VL 76 SU 1 MA 348 BP S143 EP S143 DI 10.1016/j.freeradbiomed.2014.10.123 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CO9WA UT WOS:000359525800367 ER PT J AU Verhein, KC Nichols, JL Panduri, V Gladwell, W Marzec, J McCaw, Z Reeves, N Malphurs, J Solomon, G Wiltshire, T Burkholder, A Fargo, D Bell, D Van Houten, B Kleeberger, SR AF Verhein, Kirsten C. Nichols, Jennifer L. Panduri, Vijayalakshmi Gladwell, Wesley Marzec, Jacqui McCaw, Zachary Reeves, Nicole Malphurs, Jason Solomon, Greg Wiltshire, Tim Burkholder, Adam Fargo, David Bell, Douglas Van Houten, Bennett Kleeberger, Steven R. TI Genetic Determinants of Oxidant-Induced Nuclear and Mitochondrial DNA Lesions in a Neonatal Inbred Mouse Model of Acute Lung Injury SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Verhein, Kirsten C.; Panduri, Vijayalakshmi; Gladwell, Wesley; Marzec, Jacqui; McCaw, Zachary; Reeves, Nicole; Malphurs, Jason; Solomon, Greg; Burkholder, Adam; Fargo, David; Bell, Douglas; Kleeberger, Steven R.] NIEHS, Res Triangle Pk, NC USA. [Nichols, Jennifer L.] US EPA, Washington, DC USA. [Wiltshire, Tim] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Van Houten, Bennett] Univ Pittsburgh, Pittsburgh, PA 15260 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 NOV PY 2014 VL 76 SU 1 MA 409 BP S167 EP S168 DI 10.1016/j.freeradbiomed.2014.10.058 PG 2 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CO9WA UT WOS:000359525800428 ER PT J AU Wang, YP Mukhopadhyay, P Cao, ZX Wang, H Feng, DC Mechoulam, R Gao, B Pacher, P AF Wang, Yuping Mukhopadhyay, Partha Cao, Zongxian Wang, Hua Feng, Dechun Mechoulam, Rafael Gao, Bin Pacher, Pal TI Cannabidiol Protects against Chronic Plus Binge Alcohol Induced Liver Injury by Modulating Neutrophil Infiltration, E Selectin, Inflammation and Oxidative/Nitrative Stress SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Wang, Yuping; Mukhopadhyay, Partha; Cao, Zongxian; Wang, Hua; Feng, Dechun; Gao, Bin; Pacher, Pal] NIH, Bethesda, MD USA. [Mechoulam, Rafael] Hebrew Univ Jerusalem, IL-91905 Jerusalem, Israel. NR 0 TC 0 Z9 0 U1 1 U2 2 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 NOV PY 2014 VL 76 SU 1 MA 201 BP S88 EP S88 DI 10.1016/j.freeradbiomed.2014.10.307 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CO9WA UT WOS:000359525800221 ER PT J AU Vermund, S Qian, HZ Ruan, YH Shao, YM Liu, Y Milam, D Spiegel, H Li, DL Yin, L AF Vermund, Sten Qian, Han-zhu Ruan, Yuhua Shao, Yiming Liu, Yu Milam, Douglas Spiegel, Hans Li, Dongliang Yin, Lu TI New Evidence that Circumcision Might Protect MSM from HIV SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Vermund, Sten; Qian, Han-zhu; Liu, Yu; Milam, Douglas; Yin, Lu] Vanderbilt Univ, Nashville, TN USA. [Ruan, Yuhua; Shao, Yiming] Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China. [Spiegel, Hans] NIAID, Div Aids, NIH, Bethesda, MD USA. [Li, Dongliang] Chaoyang Dist Ctr Dis Control & Prevent, Beijing, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA A-101 BP 37 EP 37 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800002 ER PT J AU Kottilil, S AF Kottilil, Shyam TI The past, present and future of Hepatitis C Therapy SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Kottilil, Shyam] NIAID, NIH, LIR, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA A-105 BP 39 EP 39 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800006 ER PT J AU Pavlakis, G Valentin, A Li, JY Jalah, R Patel, V Rosati, M Kulkarni, V Alicea, C Vargas-Inchaustegui, D Guan, YJ Venzon, D Sardesai, N Fouts, T Pinter, A Robert-Guroff, M Montefiori, D Shen, SN Tomaras, G Felber, B AF Pavlakis, George Valentin, Antonio Li, Jinyao Jalah, Rashmi Patel, Vainav Rosati, Margherita Kulkarni, Viraj Alicea, Candido Vargas-Inchaustegui, Diego Guan, Yongjun Venzon, David Sardesai, Niranjan Fouts, Timothy Pinter, Abraham Robert-Guroff, Marjorie Montefiori, David Shen, Shaunna Tomaras, Georgia Felber, Barbara TI DNA and Protein Co-immunization Improves the Magnitude, Longevity, and mucosal dissemination of Immune Responses SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Pavlakis, George; Valentin, Antonio; Li, Jinyao; Jalah, Rashmi; Patel, Vainav; Rosati, Margherita; Kulkarni, Viraj; Alicea, Candido; Vargas-Inchaustegui, Diego; Venzon, David; Robert-Guroff, Marjorie; Felber, Barbara] NCI, Frederick, MD 21701 USA. [Guan, Yongjun] Inst Human Virol, Baltimore, MD USA. [Sardesai, Niranjan] Inovio Pharmaceut Inc, Plymouth Meeting, PA USA. [Fouts, Timothy] Profectus BioSci Inc, Baltimore, MD USA. [Pinter, Abraham] Univ Med & Dent New Jersey, Publ Hlth Res Inst, Newark, NJ 07103 USA. [Montefiori, David; Shen, Shaunna; Tomaras, Georgia] Duke Univ, Med Ctr, Durham, NC 27706 USA. RI Tomaras, Georgia/J-5041-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA A-112 BP 42 EP 42 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800013 ER PT J AU Berger, E AF Berger, Edward TI Targeted Cell Killing to Achieve a (Functional) Cure: Different Strategies for Acute Versus Chronic Infection SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Berger, Edward] NIAID, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA B-104 BP 45 EP 45 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800018 ER PT J AU Maldarelli, F Wu, XL Hughes, S Simonetti, F Kearney, M Coffin, J AF Maldarelli, Frank Wu, Xiaolin Hughes, Stephen Simonetti, Francesco Kearney, Mary Coffin, John TI HIV Persistence During Combination Antiretroviral Therapy SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Maldarelli, Frank] NIH, Intramural Res Program, Bethesda, MD USA. [Wu, Xiaolin] Leidos Inc, La Jolla, CA USA. [Hughes, Stephen; Simonetti, Francesco; Kearney, Mary; Coffin, John] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA B-109 BP 47 EP 47 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800023 ER EF