FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Soubias, O Kimura, T Teague, WE Hines, KG Yeliseev, AA Gawrisch, K AF Soubias, Olivier Kimura, Tomohiro Teague, Walter E., Jr. Hines, Kirk G. Yeliseev, Alexei A. Gawrisch, Klaus TI Lipid interaction with G protein-coupled membrane receptors studied by NMR SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 247th National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 16-20, 2014 CL Dallas, TX SP Amer Chem Soc C1 [Soubias, Olivier; Kimura, Tomohiro; Teague, Walter E., Jr.; Hines, Kirk G.; Yeliseev, Alexei A.; Gawrisch, Klaus] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. EM gawrisch@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 16 PY 2014 VL 247 MA 568-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA AZ8HD UT WOS:000348455204310 ER PT J AU Tarasova, OA Urusova, AF Zakharov, AV Filimonov, DA Poroikov, VV AF Tarasova, Olga A. Urusova, Alexandra F. Zakharov, Alexey V. Filimonov, Dmitry A. Poroikov, Vladimir V. TI Combining QSAR-analysis and fragment-based drug design in search for new anti-HIV agents SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 247th National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 16-20, 2014 CL Dallas, TX SP Amer Chem Soc C1 [Tarasova, Olga A.; Urusova, Alexandra F.; Filimonov, Dmitry A.; Poroikov, Vladimir V.] Russian Acad Med Sci, Orekhovich Inst Biomed Chem, Dept Bioinformat, Moscow, Russia. [Zakharov, Alexey V.] NCI, Ctr Canc Res, NIH, Frederick, MD 21701 USA. EM olga.a.tarasova@gmail.com; vladimir.poroikov@ibmc.msk.ru RI Tarasova, Olga/E-4318-2014 OI Tarasova, Olga/0000-0002-4230-3849 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 16 PY 2014 VL 247 MA 35-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA AZ8HD UT WOS:000348455204606 ER PT J AU Thiessen, P Yu, B Fu, G Bolton, E AF Thiessen, Paul Yu, Bo Fu, Gang Bolton, Evan TI PubChem in the cloud SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 247th National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 16-20, 2014 CL Dallas, TX SP Amer Chem Soc C1 [Thiessen, Paul; Yu, Bo; Fu, Gang; Bolton, Evan] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM bolton@ncbi.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 16 PY 2014 VL 247 MA 62-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA AZ8HD UT WOS:000348455203653 ER PT J AU Zakharov, AV Nicklaus, MC AF Zakharov, Alexey V. Nicklaus, Marc C. TI QSAR modelling of rodent acute toxicity SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 247th National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 16-20, 2014 CL Dallas, TX SP Amer Chem Soc C1 [Zakharov, Alexey V.; Nicklaus, Marc C.] NCI, US Dept HHS, NIH, Frederick, MD 21702 USA. EM alexey.zakharov@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 16 PY 2014 VL 247 MA 304-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA AZ8HD UT WOS:000348455204846 ER PT J AU Liu, ZH Vong, QP Liu, CY Zheng, YX AF Liu, Zhonghua Vong, Queenie P. Liu, Chengyu Zheng, Yixian TI Borg5 is required for angiogenesis by regulating persistent directional migration of the cardiac microvascular endothelial cells SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MOLECULAR-MECHANISMS; FIBROBLAST MIGRATION; MYOSIN-II; IN-VITRO; SEPTIN; CDC42; CYTOSKELETON; PROTEINS; FAMILY; MORPHOGENESIS AB The microvasculature is important for vertebrate organ development and homeostasis. However, the molecular mechanism of microvascular angiogenesis remains incompletely understood. Through studying Borg5 (Binder of the Rho GTPase 5), which belongs to a family of poorly understood effector proteins of the Cdc42 GTPase, we uncover a role for Borg5 in microvascular angiogenesis. Deletion of Borg5 in mice results in defects in retinal and cardiac microvasculature as well as heart development. Borg5 promotes angiogenesis by regulating persistent directional migration of the endothelial cells (ECs). In primary mouse cardiac ECs (MCECs), Borg5 associates with septins in the perinuclear region and colocalizes with actomyosin fibers. Both Borg5 deletion and septin 7 knockdown lead to a disruption of the perinuclear actomyosin and persistent directional migration. Our findings suggest that Borg5 and septin cytoskeleton spatially control actomyosin activity to ensure persistent directional migration of MCECs and efficient microvascular angiogenesis. Our studies reported here should offer a new avenue to further investigate the functions of Borg5, septin, and actomyosin in the microvasculature in the context of development and disease. C1 [Liu, Zhonghua; Vong, Queenie P.; Zheng, Yixian] Carnegie Inst Sci, Dept Embryol, Baltimore, MD 21218 USA. [Liu, Chengyu] NHLBI, iPSC, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, Genome Engn Core, NIH, Bethesda, MD 20892 USA. RP Zheng, YX (reprint author), Carnegie Inst Sci, Dept Embryol, Baltimore, MD 21218 USA. EM zheng@ciwemb.edu FU National Heart, Lung, and Blood Institute [R01 GM056312]; Howard Hughes Medical Institute FX We thank Ona Martin, Rong Chen, and Xiaohong Ma for technical support; Youngjo Kim for designing the Borg5 knockout screening primers; Elias T. Spiliotis for advice on septin antibodies; and Chen-Ming Fan and members of the Zheng lab for helpful comments. The research was supported by National Heart, Lung, and Blood Institute intramural research (C.L.), R01 GM056312, and the Howard Hughes Medical Institute (Q.P.V., Z.L., and Y.Z.). NR 38 TC 4 Z9 4 U1 0 U2 2 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 MAR 15 PY 2014 VL 25 IS 6 BP 841 EP 851 DI 10.1091/mbc.E13-09-0543 PG 11 WC Cell Biology SC Cell Biology GA AM1SX UT WOS:000339629700017 PM 24451259 ER PT J AU Sakai, H Fujigaki, H Mazur, SJ Appella, E AF Sakai, Hiroyasu Fujigaki, Hidetsugu Mazur, Sharlyn J. Appella, Ettore TI Wild-type p53-induced phosphatase 1 (Wip1) forestalls cellular premature senescence at physiological oxygen levels by regulating DNA damage response signaling during DNA replication SO CELL CYCLE LA English DT Article DE Wip1; p53; cellular senescence; DNA damage response; ATM; camptothecin ID DOUBLE-STRAND BREAKS; P53 TUMOR-SUPPRESSOR; OXIDATIVE STRESS; IN-VIVO; DOWN-REGULATION; PROTEIN PHOSPHATASE; IONIZING-RADIATION; GENOME MAINTENANCE; HUMAN FIBROBLASTS; ATM ACTIVATION AB Wip1 (protein phosphatase Mg2+/Mn2+-dependent 1D, Ppm1d) is a nuclear serine/threonine protein phosphatase that is induced by p53 following the activation of DNA damage response (DDR) signaling. Ppm1d(-/-) mouse embryonic fibroblasts (MEFs) exhibit premature senescence under conventional culture conditions; however, little is known regarding the role of Wip1 in regulating cellular senescence. In this study, we found that even at a representative physiological concentration of 3% O-2, Ppm1d(-/-) MEFs underwent premature cellular senescence that depended on the functional activation of p53. Interestingly, Ppm1d(-/-) MEFs showed increased H2AX phosphorylation levels without increased levels of reactive oxygen species (ROS) or DNA base damage compared with wild-type (Wt) MEFs, suggesting a decreased threshold for DDR activation or sustained DDR activation during recovery. Notably, the increased H2AX phosphorylation levels observed in Ppm1d(-/-) MEFs were primarily associated with S-phase cells and predominantly dependent on the activation of ATM. Moreover, these same phenotypes were observed when Wt and Ppm1d(-/-) MEFs were either transiently or chronically exposed to low levels of agents that induce replication-mediated double-stranded breaks. These findings suggest that Wip1 prevents the induction of cellular senescence at physiological oxygen levels by attenuating DDR signaling in response to endogenous double-stranded breaks that form during DNA replication. C1 [Sakai, Hiroyasu; Fujigaki, Hidetsugu; Mazur, Sharlyn J.; Appella, Ettore] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Appella, E (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM appellae@pop.nci.nih.gov FU Center for Canter Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the Center for Canter Research, National Cancer Institute, National Institutes of Health. NR 91 TC 6 Z9 7 U1 1 U2 10 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 MAR 15 PY 2014 VL 13 IS 6 BP 1015 EP 1029 DI 10.4161/cc.27920 PG 15 WC Cell Biology SC Cell Biology GA AI2AT UT WOS:000336659200022 PM 24552809 ER PT J AU Maciejewski, M Barlow, PN Tjandra, N AF Maciejewski, Mateusz Barlow, Paul N. Tjandra, Nico TI Decoding the Components of Dynamics in Three-Domain Proteins SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE protein dynamics; interdomain dynamics; protein function; nuclear magnetic resonance; protein structure ID MODEL-FREE APPROACH; NUCLEAR-MAGNETIC-RESONANCE; BODY STOCHASTIC APPROACH; NMR RELAXATION; MULTIDOMAIN PROTEINS; INTERDOMAIN MOBILITY; ROTATIONAL MOTIONS; BROWNIAN DYNAMICS; SPIN RELAXATION; DOMAIN MOTIONS AB In this study, we examine the feasibility and limitations of describing the motional behavior of three-domain proteins in which the domains are linearly connected. In addition to attempting the determination of the internal and overall reorientational correlation times, we investigate the existence of correlations in the motions between the three domains. Since in linearly arranged three-domain proteins, there are typically no experimental data that can directly report on motional correlation between the first and the third domain, we address this question by dynamics simulations. Two limiting cases occur: (1) for weak repulsive potentials and (2) when strong repulsive potentials are applied between sequential domains. The motions of the terminal domains become correlated in the case of strong interdomain repulsive potentials when these potentials do not allow the angle between the sequential domains to be smaller than about 60 degrees. Using the model-free (MF) and extended MF formalisms of Lipari and Szabo, we find that the motional behavior can be separated into two components; the first component represents the concerted overall motion of the three domains, and the second describes the independent component of the motion of each individual domain. We find that this division of the motional behavior of the protein is maintained only when their timescales are distinct and can be made when the angles between sequential domains remain between 60 degrees and 160 degrees. In this work, we identify and quantify interdomain motional correlations. (c) 2013 Wiley Periodicals, Inc. C1 [Maciejewski, Mateusz] Novartis Inst Biomed Res, Ctr Prote Chem, Cambridge, MA 02139 USA. [Barlow, Paul N.] Univ Edinburgh, Sch Chem, Edinburgh EH9 3JJ, Midlothian, Scotland. [Tjandra, Nico] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Maciejewski, M (reprint author), Novartis Inst Biomed Res, Ctr Prote Chem, 250 Massachusetts Ave, Cambridge, MA 02139 USA. EM paul.barlow@ed.ac.uk; tjandran@nhlbi.nih.gov FU Intramural Research Program of the NIH, NHLBI; Wellcome Trust/NIH PhD Studentship FX Contract grant sponsor: Intramural Research Program of the NIH, NHLBI (to N.T.); Contract grant sponsor: Wellcome Trust/NIH PhD Studentship(to M. M.) NR 38 TC 2 Z9 2 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0192-8651 EI 1096-987X J9 J COMPUT CHEM JI J. Comput. Chem. PD MAR 15 PY 2014 VL 35 IS 7 BP 518 EP 525 DI 10.1002/jcc.23510 PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA AE9ME UT WOS:000334331100002 PM 24323885 ER PT J AU Leeman-Neill, RJ Kelly, LM Liu, PY Brenner, AV Little, MP Bogdanova, TI Evdokimova, VN Hatch, M Zurnadzy, LY Nikiforova, MN Yue, NJ Zhang, M Mabuchi, K Tronko, MD Nikiforov, YE AF Leeman-Neill, Rebecca J. Kelly, Lindsey M. Liu, Pengyuan Brenner, Alina V. Little, Mark P. Bogdanova, Tetiana I. Evdokimova, Viktoria N. Hatch, Maureen Zurnadzy, Liudmyla Y. Nikiforova, Marina N. Yue, Ning J. Zhang, Miao Mabuchi, Kiyohiko Tronko, Mykola D. Nikiforov, Yuri E. TI ETV6-NTRK3 Is a Common Chromosomal Rearrangement in Radiation-Associated Thyroid Cancer SO CANCER LA English DT Article DE thyroid cancer; radiation; chromosomal rearrangements; NTRK3; Chernobyl ID ATOMIC-BOMB SURVIVORS; POST-CHERNOBYL; GENE FUSION; EXTERNAL RADIATION; ACCIDENT; UKRAINE; CHILDREN; LEUKEMIA; DISEASES; COHORT AB BACKGROUNDIn their previous analysis of papillary thyroid carcinomas (PTCs) from an Ukrainian-American cohort that was exposed to iodine-131 (I-131) from the Chernobyl accident, the authors identified RET/PTC rearrangements and other driver mutations in 60% of tumors. METHODSIn this study, the remaining mutation-negative tumors from that cohort were analyzed using RNA sequencing (RNA-Seq) and reverse transcriptase-polymerase chain reaction to identify novel chromosomal rearrangements and to characterize their relation with radiation dose. RESULTSThe ETS variant gene 6 (ETV6)-neurotrophin receptor 3 (NTRK3) rearrangement (ETV6-NTRK3) was identified by RNA-Seq in a tumor from a patient who received a high I-131 dose. Overall, the rearrangement was detected in 9 of 62 (14.5%) post-Chernobyl PTCs and in 3 of 151 (2%) sporadic PTCs (P=.019). The most common fusion type was between exon 4 of ETV6 and exon 14 of NTRK3. The prevalence of ETV6-NTRK3 rearrangement in post-Chernobyl PTCs was associated with increasing I-131 dose, albeit at borderline significance (P=.126). The group of rearrangement-positive PTCs (ETV6-NTRK3, RET/PTC, PAX8-PPAR) was associated with significantly higher dose response compared with the group of PTCs with point mutations (BRAF, RAS; P<.001). In vitro exposure of human thyroid cells to 1 gray of I-131 and -radiation resulted in the formation of ETV6-NTRK3 rearrangement at a rate of 7.9x10(-6) cells and 3.0x10(-6) cells, respectively. CONCLUSIONSThe authors report the occurrence of ETV6-NTRK3 rearrangements in thyroid cancer and demonstrate that this rearrangement is significantly more common in tumors associated with exposure to I-131 and has a borderline significant dose response. Moreover, ETV6-NTRK3 rearrangement can be directly induced in thyroid cells by ionizing radiation in vitro and, thus, may represent a novel mechanism of radiation-induced carcinogenesis. Cancer 2014;120:799-807. (c) 2013 American Cancer Society. The occurrence of ETV6-NTRK3 rearrangements in thyroid cancer is analyzed, and the results indicate that these rearrangements are significantly more common in tumors associated with exposure to iodine-131. Moreover, the findings demonstrate that ETV6-NTRK3 rearrangements can be induced in thyroid cells by ionizing radiation in vitro, and this is likely to serve as a novel mechanism of radiation-induced carcinogenesis. C1 [Leeman-Neill, Rebecca J.; Kelly, Lindsey M.; Evdokimova, Viktoria N.; Nikiforova, Marina N.; Nikiforov, Yuri E.] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA. [Liu, Pengyuan] Med Coll Wisconsin, Dept Physiol, Milwaukee, WI 53226 USA. [Liu, Pengyuan] Med Coll Wisconsin, Ctr Canc, Milwaukee, WI 53226 USA. [Brenner, Alina V.; Little, Mark P.; Hatch, Maureen; Mabuchi, Kiyohiko] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Bogdanova, Tetiana I.; Zurnadzy, Liudmyla Y.; Tronko, Mykola D.] Ukraine Acad Med Sci, State Inst P Komisarenko Inst Endocrinol & Metab, Kiev, Ukraine. [Yue, Ning J.; Zhang, Miao] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Radiat Oncol, Canc Inst New Jersey, New Brunswick, NJ USA. RP Nikiforov, YE (reprint author), Univ Pittsburgh, Dept Pathol, Clinical Lab Bldg,Room 8031,3477 Euler Way, Pittsburgh, PA 15213 USA. EM nikiforovye@upmc.edu OI Little, Mark/0000-0003-0980-7567 FU National Institutes of Health (NIH) [R01 CA88041]; Intramural Research Program of the NIH, National Cancer Institute FX This work was supported by National Institutes of Health (NIH) grant R01 CA88041 and in part by the Intramural Research Program of the NIH, National Cancer Institute. NR 42 TC 42 Z9 46 U1 0 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 MAR 15 PY 2014 VL 120 IS 6 BP 799 EP 807 DI 10.1002/cncr.28484 PG 9 WC Oncology SC Oncology GA AB9UB UT WOS:000332140100007 PM 24327398 ER PT J AU Langford, AT Resnicow, K Dimond, EP Denicoff, AM St Germain, D McCaskill-Stevens, W Enos, RA Carrigan, A Wilkinson, K Go, RS AF Langford, Aisha T. Resnicow, Ken Dimond, Eileen P. Denicoff, Andrea M. St. Germain, Diane McCaskill-Stevens, Worta Enos, Rebecca A. Carrigan, Angela Wilkinson, Kathy Go, Ronald S. TI Racial/Ethnic Differences in Clinical Trial Enrollment, Refusal Rates, Ineligibility, and Reasons for Decline Among Patients at Sites in the National Cancer Institute's Community Cancer Centers Program SO CANCER LA English DT Article DE racial; ethnic; African Americans; Hispanic; minorities; clinical trials; medical research; cancer ID PARTICIPATION; DISPARITIES; BARRIERS; AGE AB BACKGROUNDThis study examined racial/ethnic differences among patients in clinical trial (CT) enrollment, refusal rates, ineligibility, and desire to participate in research within the National Cancer Institute's Community Cancer Centers Program (NCCCP) Clinical Trial Screening and Accrual Log. METHODSData from 4509 log entries were evaluated in this study. Four logistic regression models were run using physical/medical conditions, enrollment into a CT, patient eligible but declined a CT, and no desire to participate in research as dependent variables. RESULTSAge65 years (OR=1.51, 95% CI=1.28-1.79), males (OR=2.28, 95% CI=1.92-2.71), and non-Hispanic black race (OR=1.53, 95% CI=1.2-1.96) were significantly associated with more physical/medical conditions. Age65 years was significantly associated with lower CT enrollment (OR=0.83, 95% CI=0.7-0.98). Males (OR=0.78, 95% CI=0.65-0.94) and a higher grade level score for consent form readability (OR=0.9, 95% CI=0.83-0.97) were significantly associated with lower refusal rates. Consent page length20 was significantly associated with lower odds of no desire to participate in research among CT decliners (OR=0.75, 95% CI=0.58-0.98). CONCLUSIONSThere were no racial/ethnic differences in CT enrollment, refusal rates, or no desire to participate in research as the reason given for CT refusal. Higher odds of physical/medical conditions were associated with older age, males, and non-Hispanic blacks. Better management of physical/medical conditions before and during treatment may increase the pool of eligible patients for CTs. Future work should examine the role of comorbidities, sex, age, and consent form characteristics on CT participation. Cancer 2014;120:877-884. (c) 2013 American Cancer Society. There were no racial/ethnic differences in clinical trial (CT) enrollment, refusal rates, or no desire to participate in research as the reason given for CT refusal; however, higher odds of physical/medical conditions were associated with older age, males, and non-Hispanic blacks. Better management of physical/medical conditions before and during treatment may increase the pool of eligible patients for CTs. C1 [Langford, Aisha T.; Resnicow, Ken] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Dimond, Eileen P.; St. Germain, Diane; McCaskill-Stevens, Worta] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Denicoff, Andrea M.] NCI, Canc Therapy Evaluat Program, Bethesda, MD USA. [Enos, Rebecca A.] EMMES Corp, Rockville, MD USA. [Carrigan, Angela] SAIC Frederick Inc, Clin Res Directorate CMRP, Frederick Natl Lab Canc Res, Frederick, MD USA. [Wilkinson, Kathy] Billings Clin Canc Ctr, Billings, MT USA. [Go, Ronald S.] Gundersen Hlth Syst, La Crosse, WI USA. RP Langford, AT (reprint author), Univ Michigan, Sch Publ Hlth, 1415 Washington Hts, Ann Arbor, MI 48109 USA. EM alangfor@umich.edu OI Langford, Aisha/0000-0003-1758-691X FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] 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. The content of this publication does not necessarily reflect the views of 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 27 TC 18 Z9 18 U1 2 U2 4 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 MAR 15 PY 2014 VL 120 IS 6 BP 877 EP 884 DI 10.1002/cncr.28483 PG 8 WC Oncology SC Oncology GA AB9UB UT WOS:000332140100016 PM 24327389 ER PT J AU Bates, SE AF Bates, Susan E. TI It's All About the Test: The Complexity of Companion Diagnostic Co-development in Personalized Medicine SO CLINICAL CANCER RESEARCH LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 3 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 MAR 15 PY 2014 VL 20 IS 6 BP 1418 EP 1418 DI 10.1158/1078-0432.CCR-14-0223 PG 1 WC Oncology SC Oncology GA AE2ON UT WOS:000333812700004 PM 24634464 ER PT J AU Rubin, EH Allen, JD Nowak, JA Bates, SE AF Rubin, Eric H. Allen, Jeffrey D. Nowak, Jan A. Bates, Susan E. TI Developing Precision Medicine in a Global World SO CLINICAL CANCER RESEARCH LA English DT Article ID L265P SOMATIC MUTATION; CELL LUNG-CANCER; MYD88 L265P; COMPANION DIAGNOSTICS; WALDENSTROM MACROGLOBULINEMIA; BREAST-CANCER; CLINICAL-ONCOLOGY; AMERICAN-SOCIETY; EUROPEAN-UNION; PRIME-TIME AB Advances in understanding the biology of cancer, as well as advances in diagnostic technologies, such as the advent of affordable high-resolution DNA sequencing, have had a major impact on the approach to identification of specific alterations in a given patient's cancer that could be used as a basis for treatment selection, and hence the development of companion diagnostics. Although there are now several examples of successful development of companion diagnostics that allow identification of patients who will achieve the greatest benefit from a new therapeutic, the path to coapproval of a diagnostic test along with a new therapeutic is complex and often inefficient. This review and the accompanying articles examine the current state of companion diagnostic development in the United States and Europe from academic, industry, regulatory, and economic perspectives. See all articles in this CCR Focus section, "The Precision Medicine Conundrum: Approaches to Companion Diagnostic Co-development." (C)2014 AACR. C1 [Rubin, Eric H.] Merck Res Labs, N Wales, PA 19454 USA. [Allen, Jeffrey D.] Friends Canc Res, Arlington, VA USA. [Nowak, Jan A.] NorthShore Univ Hlth Syst Pathol & Lab Med, Evanston, IL USA. [Bates, Susan E.] NCI, Dev Therapeut Branch, Bethesda, MD 20892 USA. RP Rubin, EH (reprint author), Merck Res Labs, 351 North Sumneytown Pike, N Wales, PA 19454 USA. EM eric_rubin@merck.com NR 32 TC 19 Z9 20 U1 1 U2 17 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 MAR 15 PY 2014 VL 20 IS 6 BP 1419 EP 1427 DI 10.1158/1078-0432.CCR-14-0091 PG 9 WC Oncology SC Oncology GA AE2ON UT WOS:000333812700005 PM 24634465 ER PT J AU Parkinson, DR McCormack, RT Keating, SM Gutman, SI Hamilton, SR Mansfield, EA Piper, MA DeVerka, P Frueh, FW Jessup, JM McShane, LM Tunis, SR Sigman, CC Kelloff, GJ AF Parkinson, David R. McCormack, Robert T. Keating, Susan M. Gutman, Steven I. Hamilton, Stanley R. Mansfield, Elizabeth A. Piper, Margaret A. DeVerka, Patricia Frueh, Felix W. Jessup, J. Milburn McShane, Lisa M. Tunis, Sean R. Sigman, Caroline C. Kelloff, Gary J. TI Evidence of Clinical Utility: An Unmet Need in Molecular Diagnostics for Patients with Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; PATHOLOGISTS GUIDELINE RECOMMENDATIONS; OMICS-BASED PREDICTORS; BREAST-CANCER; COLORECTAL-CANCER; AMERICAN-SOCIETY; DRUG DEVELOPMENT; TRIAL DESIGNS; TUMOR-MARKERS; BIOMARKERS AB This article defines and describes best practices for the academic and business community to generate evidence of clinical utility for cancer molecular diagnostic assays. Beyond analytical and clinical validation, successful demonstration of clinical utility involves developing sufficient evidence to demonstrate that a diagnostic test results in an improvement in patient outcomes. This discussionis complementary to theoretical frameworks described in previously published guidance and literature reports by the U. S. Food and Drug Administration, Centers for Disease Control and Prevention, Institute of Medicine, and Center for Medical Technology Policy, among others. These reports are comprehensive and specifically clarify appropriate clinical use, adoption, and payer reimbursement for assay manufacturers, as well as Clinical Laboratory Improvement Amendments-certified laboratories, including those that develop assays (laboratory developed tests). Practical criteria and steps for establishing clinical utility are crucial to subsequent decisions for reimbursement without which high-performing molecular diagnostics will have limited availability to patients with cancer and fail to translate scientific advances into high-quality and cost-effective cancer care. See all articles in this CCR Focus section, "The Precision Medicine Conundrum: Approaches to Companion Diagnostic Co-development." (C)2014 AACR. C1 [Parkinson, David R.] New Enterprise Associates Inc, Menlo Pk, CA USA. [Keating, Susan M.; Sigman, Caroline C.] CCS Associates, Mountain View, CA USA. [Gutman, Steven I.] Myraqa, Redwood Shores, CA USA. [McCormack, Robert T.] Johnson & Johnson Veridex LLC, Raritan, NJ USA. [Hamilton, Stanley R.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Mansfield, Elizabeth A.] Off In Vitro Diagnost, Personalized Med Program, Ctr Diagnost & Radiol Hlth, Silver Spring, MD USA. [DeVerka, Patricia; Tunis, Sean R.] Ctr Med Technol Policy, Baltimore, MD USA. [Frueh, Felix W.] Opus Three LLC, Rockville, MD USA. [Jessup, J. Milburn; McShane, Lisa M.; Kelloff, Gary J.] NCI, Div Canc Treatment & Diag, Rockville, MD USA. [Piper, Margaret A.] Kaiser Permanente Ctr Hlth Res, Kaiser Permanente Res, Evidence Based Practice Ctr, Portland, OR USA. RP Parkinson, DR (reprint author), New Enterprise Associates, Menlo Pk, CA 94025 USA. EM dparkinson@nea.com FU National Institutes of Health Biomarkers Consortium FX The authors wish to gratefully acknowledge the support of the Foundation for the National Institutes of Health Biomarkers Consortium in providing a venue for carrying out this project. NR 97 TC 31 Z9 31 U1 0 U2 14 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 MAR 15 PY 2014 VL 20 IS 6 BP 1428 EP 1444 DI 10.1158/1078-0432.CCR-13-2961 PG 17 WC Oncology SC Oncology GA AE2ON UT WOS:000333812700006 PM 24634466 ER PT J AU Knowles, MR Ostrowski, LE Leigh, MW Sears, PR Davis, SD Wolf, WE Hazucha, MJ Carson, JL Olivier, KN Sagel, SD Rosenfeld, M Ferkol, TW Dell, SD Milla, CE Randell, SH Yin, WN Sannuti, A Metjian, HM Noone, PG Noone, PJ Olson, CA Patrone, MV Dang, H Lee, HS Hurd, TW Gee, HY Otto, EA Halbritter, J Kohl, S Kircher, M Krischer, J Bamshad, MJ Nickerson, DA Hildebrandt, F Shendure, J Zariwala, MA AF Knowles, Michael R. Ostrowski, Lawrence E. Leigh, Margaret W. Sears, Patrick R. Davis, Stephanie D. Wolf, Whitney E. Hazucha, Milan J. Carson, Johnny L. Olivier, Kenneth N. Sagel, Scott D. Rosenfeld, Margaret Ferkol, Thomas W. Dell, Sharon D. Milla, Carlos E. Randell, Scott H. Yin, Weining Sannuti, Aruna Metjian, Hilda M. Noone, Peadar G. Noone, Peter J. Olson, Christina A. Patrone, Michael V. Dang, Hong Lee, Hye-Seung Hurd, Toby W. Gee, Heon Yung Otto, Edgar A. Halbritter, Jan Kohl, Stefan Kircher, Martin Krischer, Jeffrey Bamshad, Michael J. Nickerson, Deborah A. Hildebrandt, Friedhelm Shendure, Jay Zariwala, Maimoona A. TI Mutations in RSPH1 Cause Primary Ciliary Dyskinesia with a Unique Clinical and Ciliary Phenotype SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE cilia; Kartagener syndrome; ciliopathy; exome sequencing; RSPH1 ID OF-FUNCTION MUTATIONS; INNER DYNEIN ARMS; REGULATORY COMPLEX; BODY ASYMMETRY; OUTER; DEFECTS; RANDOMIZATION; HUMANS; MOTILITY; ZMYND10 AB Rationale: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia, but the genetic cause is not defined for all patients with PCD. Objectives: To identify disease-causing mutations in novel genes, we performed exome sequencing, follow-up characterization, mutation scanning, and genotype-phenotype studies in patients with PCD. Methods: Whole-exome sequencing was performed using NimbleGen capture and Illumina HiSeq sequencing. Sanger-based sequencing was used for mutation scanning, validation, and segregation analysis. Measurements and Main Results: We performed exome sequencing on an affected sib-pair with normal ultrastructure in more than 85% of cilia. A homozygous splice-site mutation was detected in RSPH1 in both siblings; parents were carriers. Screening RSPH1 in 413 unrelated probands, including 325 with PCD and 88 with idiopathic bronchiectasis, revealed biallelic loss-of-function mutations in nine additional probands. Five affected siblings of probands in RSPH1 families harbored the familial mutations. The 16 individuals with RSPH1 mutations had some features of PCD; however, nasal nitric oxide levels were higher than in patients with PCD with other gene mutations (98.3 vs. 20.7 nl/min; P < 0.0003). Additionally, individuals with RSPH1 mutations had a lower prevalence (8 of 16) of neonatal respiratory distress, and later onset of daily wet cough than typical for PCD, and better lung function (FEU, compared with 75 age- and sex-matched PCD cases (73.0 vs 61.8, FEV1% predicted; P = 0.043). Cilia from individuals with RSPH1 mutations had normal beat frequency (6.1 +/- Hz at 25 degrees C), but an abnormal, circular beat pattern. Conclusions: The milder clinical disease and higher nasal nitric oxide in individuals with biallelic imitations in RSPH1 provides evidence of a unique genotype-phenotype relationship in PCD, and suggests that mutations in RSPH1 may be associated with residual ciliary function. C1 [Knowles, Michael R.; Ostrowski, Lawrence E.; Sears, Patrick R.; Wolf, Whitney E.; Hazucha, Milan J.; Yin, Weining; Sannuti, Aruna; Metjian, Hilda M.; Noone, Peadar G.; Noone, Peter J.; Olson, Christina A.; Patrone, Michael V.; Dang, Hong] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. [Leigh, Margaret W.; Davis, Stephanie D.; Carson, Johnny L.] Univ N Carolina, Sch Med, Dept Pediat, Chapel Hill, NC USA. [Randell, Scott H.] Univ N Carolina, Sch Med, Dept Cell Biol & Physiol, Chapel Hill, NC USA. [Zariwala, Maimoona A.] Univ N Carolina, Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC USA. [Olivier, Kenneth N.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Sagel, Scott D.] Univ Colorado, Dept Pediat, Sch Med, Aurora, CO USA. [Rosenfeld, Margaret] Univ Washington, Sch Med, Seattle Childrens Hosp, Seattle, WA USA. [Rosenfeld, Margaret; Bamshad, Michael J.] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. [Kircher, Martin; Bamshad, Michael J.; Nickerson, Deborah A.; Shendure, Jay] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA USA. [Ferkol, Thomas W.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Dell, Sharon D.] Univ Toronto, Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada. [Milla, Carlos E.] Stanford Univ, Dept Pediat, Palo Alto, CA 94304 USA. [Metjian, Hilda M.] Raleigh Pulm & Allergy, Raleigh, NC USA. [Lee, Hye-Seung; Krischer, Jeffrey] Univ S Florida, Dept Pediat, Tampa, FL 33620 USA. [Hurd, Toby W.; Gee, Heon Yung; Otto, Edgar A.; Halbritter, Jan; Kohl, Stefan; Hildebrandt, Friedhelm] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Hildebrandt, Friedhelm] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Knowles, MR (reprint author), Cyst Fibrosis Ctr, 7019 Thurston Bowles Bldg,CB7248, Chapel Hill, NC 27599 USA. EM knowles@med.unc.edu; zariwala@med.unc.edu OI Otto, Edgar/0000-0002-2387-9973; Kircher, Martin/0000-0001-9278-5471 FU NIH-ORDR-NHLBI [U54HL096458-06]; NIH-NHLBI [5R01HL071798, 1R01HL117836, HHSN268201100037C.]; NIH-NHGRI [U54HG006493]; NIH-R01 [DK068306]; Intramural Research Program of the NIH-NIAID; NIH-NCATS [UL1TR000083]; Chapel Hill [UL1TR000154]; Cystic Fibrosis Foundation [CFF R026-CRO7, R026-CR11]; NIH-NIDDK [P30-DK065988] FX Supported by NIH-ORDR-NHLBI grant 5 U54HL096458-06 (M.R.K., M.W.L., J.L.C., M.J.H., S. D. Davis, S. D. Dell, T.W.F., S.D.S., K.N.O., M.R., C.E.M., and M.A.Z), by NIH-NHLBI grants 5R01HL071798 and 1R01HL117836 (M.R.K., L.E.O., and M.A.Z.), by NIH-NHGRI grant 1 U54HG006493 (M.J.B., DAN., and J.S.), and by NIH-R01 DK068306 (F.H.). K.N.O. is supported by the Intramural Research Program of the NIH-NIAID. Resequencing was provided through RS&G by NIH-NHLBI contract # HHSN268201100037C. The work was supported by NIH-NCATS grants UL1TR000083 to University of North Carolina, Chapel Hill, UL1TR000154 to University of Colorado CTSI, Cystic Fibrosis Foundation grants CFF R026-CRO7 and R026-CR11, and NIH-NIDDK grant P30-DK065988. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. NR 51 TC 35 Z9 36 U1 1 U2 13 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAR 15 PY 2014 VL 189 IS 6 BP 707 EP 717 DI 10.1164/rccm.201311-20470C PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA AD6OQ UT WOS:000333381100015 PM 24568568 ER PT J AU Mahmood, SS Levy, D Vasan, RS Wang, TJ AF Mahmood, Syed S. Levy, Daniel Vasan, Ramachandran S. Wang, Thomas J. TI The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective SO LANCET LA English DT Review ID ISOLATED SYSTOLIC HYPERTENSION; POPULATION-BASED COHORT; ATRIAL-FIBRILLATION; RISK-FACTORS; FOLLOW-UP; MYOCARDIAL-INFARCTION; DIABETES-MELLITUS; NATURAL-HISTORY; BLOOD PRESSURE; FAILURE AB On Sept 29, 2013, the Framingham Heart Study will celebrate 65 years since the examination of the first volunteer in 1948. During this period, the study has provided substantial insight into the epidemiology and risk factors of cardiovascular disease. The origins of the study are closely linked to the cardiovascular health of President Franklin D Roosevelt and his premature death from hypertensive heart disease and stroke in 1945. In this Review we describe the events leading to the foundation of the Framingham Heart Study, and provide a brief historical overview of selected contributions from the study. C1 [Mahmood, Syed S.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. [Levy, Daniel; Vasan, Ramachandran S.; Wang, Thomas J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Levy, Daniel] NHLBI, Populat Res Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Wang, Thomas J.] Vanderbilt Univ, Div Cardiovasc Med, Nashville, TN 37235 USA. RP Wang, TJ (reprint author), Vanderbilt Univ Sch Med, Div Cardiovasc Med, Nashville, TN 37232 USA. EM thomas.j.wang@vanderbilt.edu OI Mahmood, Syed Saad/0000-0001-6938-1321; Ramachandran, Vasan/0000-0001-7357-5970 FU NIH [N01-HC-25195] FX We thank Paul Sorlie (National Heart, Lung, and Blood Institute, Bethesda, MD, USA) for his assistance in granting access to the Framingham Archives. We thank Gerald Oppenheimer (Department of Sociomedical Sciences, Columbia University, New York, NY, USA) for comments on the history of the Framingham Heart Study. This work was supported by NIH contract N01-HC-25195. NR 81 TC 79 Z9 86 U1 8 U2 36 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD MAR 15 PY 2014 VL 383 IS 9921 BP 999 EP 1008 DI 10.1016/S0140-6736(13)61752-3 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AD8MR UT WOS:000333520700030 PM 24084292 ER PT J AU Vogel, SS van der Meer, BW Blank, PS AF Vogel, Steven S. van der Meer, B. Wieb Blank, Paul S. TI Estimating the distance separating fluorescent protein FRET pairs SO METHODS LA English DT Article DE GFP; Kappa squared ID ENERGY-TRANSFER; LIVING CELLS; MOLECULAR-SPECTROSCOPY; GREEN; DYNAMICS; MATURATION; MICROSCOPY; ACCEPTORS; VENUS AB Forster resonance energy transfer (FRET) describes a physical phenomenon widely applied in biomedical research to estimate separations between biological molecules. Routinely, genetic engineering is used to incorporate spectral variants of the green fluorescent protein (GFPs), into cellular expressed proteins. The transfer efficiency or rate of energy transfer between donor and acceptor FPs is then assayed. As appreciable FRET occurs only when donors and acceptors are in close proximity (1-10 nm), the presence of FRET may indicate that the engineered proteins associate as interacting species. For a homogeneous population of FRET pairs the separations between FRET donors and acceptors can be estimated from a measured FRET efficiency if it is assumed that donors and acceptors are randomly oriented and rotate extensively during their excited state (dynamic regime). Unlike typical organic fluorophores, the rotational correlation-times of FPs are typically much longer than their fluorescence lifetime; accordingly FPs are virtually static during their excited state. Thus, estimating separations between FP FRET pairs is problematic. To overcome this obstacle, we present here a simple method for estimating separations between FPs using the experimentally measured average FRET efficiency. This approach assumes that donor and acceptor fluorophores are randomly oriented, but do not rotate during their excited state (static regime). This approach utilizes a Monte-Carlo simulation generated look-up table that allows one to estimate the separation, normalized to the Forster distance, from the average FRET efficiency. Assuming a dynamic regime overestimates the separation significantly (by 10% near 0.5 and 30% near 0.75 efficiencies) compared to assuming a static regime, which is more appropriate for estimates of separations between FPs. (C) 2013 Published by Elsevier Inc. C1 [Vogel, Steven S.] NIAAA, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. [van der Meer, B. Wieb] Western Kentucky Univ, Dept Phys & Astron, Bowling Green, KY 42101 USA. [Blank, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Vogel, SS (reprint author), NIAAA, Lab Mol Physiol, NIH, 5625 Fishers Lane,Room TS-06F MSC 9411, Bethesda, MD 20892 USA. EM stevevog@mail.nih.gov OI Vogel, Steven/0000-0002-3005-2667 FU intramural programs of the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism; Eunice Kennedy Shriver National Institute of Child Health and Human Development Bethesda, MD, USA FX This work was funded by intramural programs of the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development Bethesda, MD 20892, USA. NR 34 TC 14 Z9 14 U1 3 U2 29 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD MAR 15 PY 2014 VL 66 IS 2 BP 131 EP 138 DI 10.1016/j.ymeth.2013.06.021 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AE1ZM UT WOS:000333773100003 PM 23811334 ER PT J AU Gahl, RF Tekle, E Tjandra, N AF Gahl, Robert F. Tekle, Ephrem Tjandra, Nico TI Single color FRET based measurements of conformational changes of proteins resulting from translocation inside cells SO METHODS LA English DT Article DE FRET; Live-cell imaging; Microinjection; Translocation; Apoptosis; Conformational changes ID APOPTOSIS; BAX; MITOCHONDRIA; CYTOSOL AB Translocation of proteins to different parts of the cell is necessary for many cellular mechanisms as a means for regulation and a variety of other functions. Identifying how these proteins undergo conformational changes or interact with various partners during these events is critical to understanding how these mechanisms are executed. A protocol is presented that identifies conformational changes in a protein that occur during translocation while overcoming challenges in extracting distance information in very different environments of a living cell. Only two samples are required to be prepared and are observed with one optical setup. Live-cell FRET imaging has been applied to identify conformational changes between two native cysteines in Bax, a member of the Bcl-2 family of proteins that regulates apoptosis. Bax exists in the cytosol and translocates to the mitochondria outer membrane upon apoptosis induction. The distance, r, between the two native cysteines in the cytosolic structure of Bax necessitates the use of a FRET donor accepter pair with R-0 similar to r as the most sensitive probe for identifying structural changes at these positions. Alexa Fluor 546 and Dabcyl, a dark acceptor, were used as FRET pairs resulting in single color intensity variations of Alexa-546 as a measure of FRET efficiency. An internal reference, conjugated to Bax, was employed to normalize changes in fluorescence intensity of Alexa Fluor 546 due to inherent inhomogeneities in the living cell. This correction allowed the true FRET effects to be measured with increased precision during translocation. Normalization of intensities to the internal reference identified a FRET efficiency of 0.45 +/- 0.14 in the cytosol and 0.11 +/- 0.20 in the mitochondria. The procedure for the conjugation of the internal reference and FRET probes as well as the data analysis is presented. Published by Elsevier Inc. C1 [Gahl, Robert F.; Tjandra, Nico] NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Tekle, Ephrem] NHLBI, Biochem Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM tjandran@nhlbi.nih.gov FU Intramural Research Programs of National Heart, Lung, and Blood Institute of the NIH FX This work was supported by the Intramural Research Programs of National Heart, Lung, and Blood Institute of the NIH. NR 18 TC 4 Z9 4 U1 1 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD MAR 15 PY 2014 VL 66 IS 2 BP 180 EP 187 DI 10.1016/j.ymeth.2013.07.011 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AE1ZM UT WOS:000333773100008 PM 23872323 ER PT J AU Rahim, NAA Pelet, S Mofrad, MRK So, PTC Kamm, RD AF Rahim, Nur Aida Abdul Pelet, Serge Mofrad, Mohammad R. K. So, Peter T. C. Kamm, Roger D. TI Quantifying intracellular protein binding thermodynamics during mechanotransduction based on FRET spectroscopy SO METHODS LA English DT Article DE FRET; FLIM; FCS; Mechanotransduction; Paxillin; Focal adhesion kinase ID CROSS-CORRELATION SPECTROSCOPY; FOCAL ADHESION KINASE; FLUORESCENCE CORRELATION SPECTROSCOPY; ISOTHERMAL TITRATION CALORIMETRY; LIVING CELLS; IMAGING MICROSCOPY; IN-VIVO; TYROSINE PHOSPHORYLATION; 2-PHOTON EXCITATION; ENDOTHELIAL-CELLS AB Mechanical force modulates myriad cellular functions including migration, alignment, proliferation, and gene transcription. Mechanotransduction, the transmission of mechanical forces and its translation into biochemical signals, may be mediated by force induced protein conformation changes, subsequently modulating protein signaling. For the paxillin and focal adhesion kinase interaction, we demonstrate that force-induced changes in protein complex conformation, dissociation constant, and binding Gibbs free energy can be quantified by lifetime-resolved fluorescence energy transfer microscopy combined with intensity imaging calibrated by fluorescence correlation spectroscopy. Comparison with in vitro data shows that this interaction is allosteric in vivo. Further, spatially resolved imaging and inhibitor assays show that this protein interaction and its mechano-sensitivity are equal in the cytosol and in the focal adhesions complexes indicating that the mechano-sensitivity of this interaction must be mediated by soluble factors but not based on protein tyrosine phosphorylation. (C) 2013 Published by Elsevier Inc. C1 [Rahim, Nur Aida Abdul; So, Peter T. C.; Kamm, Roger D.] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Pelet, Serge; So, Peter T. C.; Kamm, Roger D.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Pelet, Serge] Univ Lausanne, Dept Fundamental Microbiol, CH-1015 Lausanne, Switzerland. [Mofrad, Mohammad R. K.] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA. [So, Peter T. C.] MIT, Laser Biomed Res Ctr, A NIH NIBIB Res Resource, Cambridge, MA 02139 USA. RP So, PTC (reprint author), MIT, Dept Mech & Biol Engn, NE47-279,77 Mass Ave, Cambridge, MA 02139 USA. EM ptso@mit.edu OI Pelet, Serge/0000-0002-0245-049X; /0000-0002-7232-304X FU NIH [9P41EB015871-26A1, R01-EX017656, 5 R01 NS051320, 4R44EB012415-02]; NSF [CBET-0939511]; National Research Foundation Singapore through the Singapore MIT Alliance for Research and Technology's BioSym research programme; Singapore-MIT Alliance 2; MIT SkolTech initiative; MIT-Dana Fabre Cancer Center Bridge Funding; McGovern Institute Neurotechnology (MINT) program; Hamamatsu Corporation FX PTCSO acknowledges supports from: NIH 9P41EB015871-26A1, R01-EX017656, 5 R01 NS051320, 4R44EB012415-02, NSF CBET-0939511, the National Research Foundation Singapore through the Singapore MIT Alliance for Research and Technology's BioSym research programme, the Singapore-MIT Alliance 2, the MIT SkolTech initiative, the MIT-Dana Fabre Cancer Center Bridge Funding, The McGovern Institute Neurotechnology (MINT) program, and the Hamamatsu Corporation. The authors would also like to thank Prof. Keith Berland of Emory University for his invaluable suggestion in combining intensity imaging with FCS calibration to quantify the concentration of green and red diffusing species in the cells. NR 71 TC 3 Z9 3 U1 0 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD MAR 15 PY 2014 VL 66 IS 2 BP 208 EP 221 DI 10.1016/j.ymeth.2013.10.007 PG 14 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AE1ZM UT WOS:000333773100011 ER PT J AU Vidarsdottir, H Fang, F Chang, M Aspelund, T Fall, K Jonsdottir, MK Jonsson, PV Cotch, MF Harris, TB Launer, LJ Gudnason, V Valdimarsdottir, U AF Vidarsdottir, Halldora Fang, Fang Chang, Milan Aspelund, Thor Fall, Katja Jonsdottir, Maria K. Jonsson, Palmi V. Cotch, Mary Frances Harris, Tamara B. Launer, Lenore J. Gudnason, Vilmundur Valdimarsdottir, Unnur TI Spousal Loss and Cognitive Function in Later Life: A 25-year Follow-up in the AGES-Reykjavik Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE dementia; executive function; marital status; memory; psychological stress ID WHITE-MATTER LESIONS; ALZHEIMERS-DISEASE; MARITAL-STATUS; OLDER-ADULTS; MYOCARDIAL-INFARCTION; MEMORY PERFORMANCE; SOCIAL NETWORK; STRESS; DEMENTIA; RISK AB The aim of this study was to investigate the associations between loss of a life partner and the development of dementia and decline in cognitive function in later life. We used an Icelandic cohort of 4,370 participants in the Age, Gene/Environment Susceptibility-Reykjavik Study who were living as married in 1978 (born in 1907-1935) and were either still married (unexposed cohort) or widowed (exposed cohort) at follow-up (in 2002-2006). We ascertained history of marital status and spouse's death by record linkage to the Registry of the Total Population, Statistics Iceland. The outcome measures were as follows: 1) dementia and mild cognitive impairment; and 2) memory, speed of processing, and executive function. During the observation period, 3,007 individuals remained married and 1,363 lost a spouse through death. We did not find any significant associations between loss of a spouse and our outcome variables, except that widowed women had poorer executive function (mean = -0.08) during the first 2 years after their husbands' deaths compared with still-married women (mean = 0.09). Our findings do not support the notion that the risk of dementia is increased following the loss of a spouse, yet women demonstrate a seemingly temporary decline in executive function following the death of a partner. C1 [Vidarsdottir, Halldora; Aspelund, Thor; Valdimarsdottir, Unnur] Univ Iceland, Ctr Publ Hlth Sci, IS-101 Reykjavik, Iceland. [Fang, Fang] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Chang, Milan; Jonsdottir, Maria K.; Jonsson, Palmi V.] Natl Univ Hosp Reykjavik, Geriatr Res Ctr, Reykjavik, Iceland. [Chang, Milan] Reykjavik Univ, Sch Sci & Engn, Dept Sports Sci, Reykjavik, Iceland. [Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Fall, Katja] Orebro Univ Hosp, Dept Clin Epidemiol & Biostat, Orebro, Sweden. [Jonsdottir, Maria K.] Univ Iceland, Fac Psychol, IS-101 Reykjavik, Iceland. [Jonsson, Palmi V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Jonsson, Palmi V.] Natl Univ Hosp Reykjavik, Dept Geriatr, Reykjavik, Iceland. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Valdimarsdottir, Unnur] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Vidarsdottir, H (reprint author), Univ Iceland, Ctr Publ Hlth Sci, Stapi v-Hringbraut, IS-101 Reykjavik, Iceland. EM halldvi@hi.is RI Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015; OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084; Cotch, Mary Frances/0000-0002-2046-4350; Fang, Fang/0000-0002-3310-6456; Fall, Katja/0000-0002-3649-2639 FU University of Iceland Research Fund for Graduate Students; Icelandic Research Fund for Graduate Students (Rannis); Memorial Fund of Helga Jonsdottir and Sigurlidi Kristjansson; Research Fund of Oldrunarrad Islands; Icelandic Gerontological Society Research Fund; Fund of Gudmundur Andresson; Swedish Society for Medical Research; National Institute on Aging [N01-AG-1-2100]; National Institute on Aging; Icelandic Parliament; Icelandic Heart Association FX H.V. was supported by the University of Iceland Research Fund for Graduate Students, the Icelandic Research Fund for Graduate Students (Rannis), the Memorial Fund of Helga Jonsdottir and Sigurlidi Kristjansson, the Research Fund of Oldrunarrad Islands, the Icelandic Gerontological Society Research Fund, and the Fund of Gudmundur Andresson. F. F. was supported by a postdoctoral fellowship from the Swedish Society for Medical Research. This study was also funded in part by the National Institute on Aging (contract N01-AG-1-2100), the intramural research program of the National Institute on Aging, the Icelandic Heart Association, and the Icelandic Parliament. NR 47 TC 3 Z9 3 U1 1 U2 13 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 MAR 15 PY 2014 VL 179 IS 6 BP 674 EP 683 DI 10.1093/aje/kwt321 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AD4UP UT WOS:000333246800004 PM 24444551 ER PT J AU Nogueira, L Freedman, ND Engels, EA Warren, JL Castro, F Koshiol, J AF Nogueira, Leticia Freedman, Neal D. Engels, Eric A. Warren, Joan L. Castro, Felipe Koshiol, Jill TI Gallstones, Cholecystectomy, and Risk of Digestive System Cancers SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cancer; cholecystectomy; digestive system; gallstones; gastric cancer; liver; pancreas ID POPULATION-BASED COHORT; LARGE-BOWEL-CANCER; COLORECTAL-CANCER; PANCREATIC-CANCER; BILE-ACIDS; COLON-CANCER; DIABETES-MELLITUS; EXTRAHEPATIC CHOLANGIOCARCINOMA; UNITED-STATES; BILIARY-TRACT AB Gallstones and cholecystectomy may be related to digestive system cancer through inflammation, altered bile flux, and changes in metabolic hormone levels. Although gallstones are recognized causes of gallbladder cancer, associations with other cancers of the digestive system are poorly established. We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database (1992-2005), which includes 17 cancer registries that cover approximately 26% of the US population, to identify first primary cancers (n = 236,850) occurring in persons aged = 66 years and 100,000 cancer-free population-based controls frequency-matched by calendar year, age, and gender. Odds ratios and 95% confidence intervals were calculated using logistic regression analysis, adjusting for the matching factors. Gallstones and cholecystectomy were associated with increased risk of noncardia gastric cancer (odds ratio (OR) = 1.21 (95% confidence interval (CI): 1.11, 1.32) and OR = 1.26 (95% CI: 1.13, 1.40), respectively), small-intestine carcinoid (OR = 1.27 (95% CI: 1.01, 1.60) and OR = 1.78 (95% CI: 1.41, 2.25)), liver cancer (OR = 2.35 (95% CI: 2.18, 2.54) and OR = 1.26 (95% CI: 1.12, 1.41)), and pancreatic cancer (OR = 1.24 (95% CI: 1.16, 1.31) and OR = 1.23 (95% CI: 1.15, 1.33)). Colorectal cancer risk associated with gallstones and cholecystectomy decreased with increasing distance from the common bile duct (P-trend < 0.001). Hence, gallstones and cholecystectomy are associated with the risk of cancers occurring throughout the digestive tract. C1 [Nogueira, Leticia; Engels, Eric A.; Castro, Felipe; Koshiol, Jill] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol, Bethesda, MD 20892 USA. [Freedman, Neal D.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Warren, Joan L.] NCI, Hlth Serv & Econ Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Nogueira, L (reprint author), NCI, 9609 Med Ctr Dr,MSC 7248, Bethesda, MD 20892 USA. EM leticia.nogueira@nih.gov RI Freedman, Neal/B-9741-2015 OI Freedman, Neal/0000-0003-0074-1098 NR 92 TC 14 Z9 16 U1 2 U2 11 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 MAR 15 PY 2014 VL 179 IS 6 BP 731 EP 739 DI 10.1093/aje/kwt322 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AD4UP UT WOS:000333246800010 PM 24470530 ER PT J AU Yang, PY Patrick, E Tan, SX Fazakerley, DJ Burchfield, J Gribben, C Prior, MJ James, DE Yang, YH AF Yang, Pengyi Patrick, Ellis Tan, Shi-Xiong Fazakerley, Daniel J. Burchfield, James Gribben, Christopher Prior, Matthew J. James, David E. Yang, Yee Hwa TI Direction pathway analysis of large-scale proteomics data reveals novel features of the insulin action pathway SO BIOINFORMATICS LA English DT Article ID SET ENRICHMENT ANALYSIS; GENE-EXPRESSION DATA; GOODNESS-OF-FIT; GLUT4 TRAFFICKING; 3T3-L1 ADIPOCYTES; PLASMA-MEMBRANE; METAANALYSIS; PLATFORMS; KNOWLEDGE; TOOLS AB Motivation: With the advancement of high-throughput techniques, large-scale profiling of biological systems with multiple experimental perturbations is becoming more prevalent. Pathway analysis incorporates prior biological knowledge to analyze genes/proteins in groups in a biological context. However, the hypotheses under investigation are often confined to a 1D space (i.e. up, down, either or mixed regulation). Here, we develop direction pathway analysis (DPA), which can be applied to test hypothesis in a high-dimensional space for identifying pathways that display distinct responses acrossmultiple perturbations. Results: Our DPA approach allows for the identification of pathways that display distinct responses across multiple perturbations. To demonstrate the utility and effectiveness, we evaluated DPA under various simulated scenarios and applied it to study insulin action in adipocytes. A major action of insulin in adipocytes is to regulate the movement of proteins from the interior to the cell surface membrane. Quantitative mass spectrometry-based proteomics was used to study this process on a large-scale. The combined dataset comprises four separate treatments. By applying DPA, we identified that several insulin responsive pathways in the plasma membrane trafficking are only partially dependent on the insulin-regulated kinase Akt. We subsequently validated our findings through targeted analysis of key proteins from these pathways using immunoblotting and live cell microscopy. Our results demonstrate that DPA can be applied to dissect pathway networks testing diverse hypotheses and integrating multiple experimental perturbations. C1 [Yang, Pengyi] NIEHS, Syst Biol Grp, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Yang, Pengyi; Patrick, Ellis; Yang, Yee Hwa] Univ Sydney, Sch Math & Stat, Sydney, NSW 2006, Australia. [Yang, Pengyi; Tan, Shi-Xiong; Fazakerley, Daniel J.; Burchfield, James; Gribben, Christopher; Prior, Matthew J.; James, David E.] Garvan Inst Med Res, Diabet & Obes Program, Sydney, NSW 2006, Australia. [Tan, Shi-Xiong] ASTAR, Inst Mol & Cellular Biol, Metab Human Dis Unit, Proteos 138673, Singapore. RP Yang, YH (reprint author), Univ Sydney, Sch Math & Stat, Sydney, NSW 2006, Australia. EM jean.yang@sydney.edu.au RI Yang, Pengyi/B-1002-2010; Yang, Jean /D-2920-2015; OI Yang, Pengyi/0000-0003-1098-3138; Yang, Jean /0000-0002-5271-2603; Patrick, Ellis/0000-0002-5253-4747 FU Australian Research Council (ARC) [FT0991918, DP0984267]; National Health and Medical Research Council (NHMRC); NHMRC Senior Principal Research FX Australian Research Council (ARC) grants (FT0991918 and DP0984267 to Y.Y.) and by an National Health and Medical Research Council (NHMRC) program grant (to D.E.J.). D.E.J. is also recipient of an NHMRC Senior Principal Research. D.F. is a Sir Henry Wellcome Post-Doctoral Fellow of the Wellcome Trust. NR 34 TC 5 Z9 5 U1 0 U2 12 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 MAR 15 PY 2014 VL 30 IS 6 BP 808 EP 814 DI 10.1093/bioinformatics/btt616 PG 7 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 AD4VR UT WOS:000333249900010 PM 24167158 ER PT J AU Xu, SW Liu, ZP Liu, PQ AF Xu, Suowen Liu, Zhiping Liu, Peiqing TI Targeting hydrogen sulfide as a promising therapeutic strategy for atherosclerosis SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Review DE Atherosclerosis; Cystathionine gamma-lyase; Gasotransmitter; Hydrogen sulfide ID CYSTATHIONINE GAMMA-LYASE; E KNOCKOUT MICE; LOW-DENSITY-LIPOPROTEIN; SMOOTH-MUSCLE-CELLS; ACCELERATES ATHEROSCLEROSIS; SIGNALING PATHWAYS; DIALLYL DISULFIDE; DEFICIENT MICE; NITRIC-OXIDE; OXIDIZED LDL AB Physiological concentrations of nitric oxide (NO) and carbon monoxide (CO) have multiple protective effects in the cardiovascular system. Recent studies have implicated hydrogen sulfide (H2S) as a new member of vasculoprotective gasotransmitter family, behaving similarly to NO and CO. H2S has been demonstrated to inhibit multiple key aspects of atherosclerosis, including atherogenic modification of LDL, monocytes adhesion to the endothelial cells, macrophage-derived foam cell formation and inflammation, smooth muscle cell proliferation, neointimal hyperplasia, vascular calcification, and thrombogenesis. H2S also decreases plasma homocysteine levels in experimental animal models. In the human body, H2S production is predominantly catalyzed by cystathionine-beta-synthase (CBS) and cystathionine.-lyase (CSE). CSE is the primary H2S-producing enzyme in the vasculature. Growing evidence suggests that atherosclerosis is associated with vascular CSE/H2S deficiency and that H2S supplementation by exogenous H2S donors (such as NaHS and GYY4137) attenuates, and H2S synthesis suppression by inhibitors (such as D, L-propargylglycine) aggravates the development of atherosclerotic plaques. However, it remains elusive whether CSE deficiency plays a causative role in atherosclerosis. A recent study (Circulation. 2013; 127: 2523-2534) demonstrates that decreased endogenous H2S production by CSE genetic deletion accelerates atherosclerosis in athero-prone ApoE(-/-) mice, pinpointing that endogenously produced H2S by CSE activation may be of benefit in the prevention and treatment of atherosclerosis. This study will facilitate the development of H2S-based pharmaceuticals with therapeutic applications in atherosclerosis-related cardiovascular diseases. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Xu, Suowen; Liu, Zhiping; Liu, Peiqing] Sun Yat Sen Univ, Sch Pharmaceut Sci, Dept Pharmacol & Toxicol, Guangzhou 510006, Guangdong, Peoples R China. [Xu, Suowen] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Xu, SW (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM suowen.xu@gmail.com; liupq@mail.sysu.edu.cn FU National Natural Science Foundation of China [81072641, 81273499]; National Science and Technology Major Project of China "Key New Drug Creation and Manufacturing Program" [2011ZX09401-307]; Team Item of the Natural Science Foundation of Guangdong Province [S2011030003190]; Major Project of Guangdong Province [2008A030201013, 2012A080201007]; Major Project of Department of Education of Guangdong Province [CXZD1006]; Ministry of Education of China FX The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (No. 81072641 and No. 81273499), the National Science and Technology Major Project of China "Key New Drug Creation and Manufacturing Program" (No. 2011ZX09401-307), Team Item of the Natural Science Foundation of Guangdong Province (No. S2011030003190), Major Project of Guangdong Province (No. 2008A030201013 and No. 2012A080201007), and Major Project of Department of Education of Guangdong Province (No. CXZD1006). S.X. is a recipient of "New Investigator Award" from the Ministry of Education of China. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. NR 50 TC 20 Z9 27 U1 1 U2 27 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD MAR 15 PY 2014 VL 172 IS 2 BP 313 EP 317 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AC5AC UT WOS:000332531800055 PM 24491853 ER PT J AU Liu, CY Bluemke, DA Gerstenblith, G Zimmerman, SL Li, J Zhu, H Lai, SH Lai, H AF Liu, Chia-Ying Bluemke, David A. Gerstenblith, Gary Zimmerman, Stefan L. Li, Ji Zhu, Hong Lai, Shenghan Lai, Hong TI Myocardial steatosis and its association with obesity and regional ventricular dysfunction: Evaluated by magnetic resonance tagging and H-1 spectroscopy in healthy African Americans SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Cardiac steatosis; African Americans; MR tagging; MR spectroscopy; LV regional function ID HEART-DISEASE; DIABETES-MELLITUS; HARP MRI; HUMANS; LEPTIN; REPRODUCIBILITY; TRIGLYCERIDE; MECHANISMS AB Background: Cardiac steatosis is common in patients with diabetes or obesity, and cardiac steatosis may result in cardiomyopathy. However, factors associated with cardiac steatosis have not been reported in healthy individuals without diabetes and hypertension. The objectives of this study were to explore factors associated with myocardial triglyceride levels, and to examine the association between myocardial triglyceride and regional left ventricular (LV) function in healthy African Americans (AAs). Methods: Between November 2010 and June 2012, 92 healthy AAs aged 21 years or older, without clinical evidence of cardiac dysfunction, coronary artery disease, diabetes, or hypertension from Baltimore, Maryland, were enrolled in an observational proton magnetic resonance spectroscopy and imaging study investigating factors associated with cardiac steatosis, and the relationships between cardiac steatosis and LV volumes and LV function. Results: Among the participants, all had a low Framingham risk; 31 had a normal BMI, 23 were overweight and 38 were obese. The median myocardial triglyceride content was 0.5% (IQR: 0.3-1.0%). Among the factors investigated, BMI (R-2= 0.43, p= < 0.0001) was independently associated with myocardial triglyceride. Overall, myocardial triglyceride was not associated with LV EF/structure, but may be associated with regional LV function. Conclusions: In healthy AA adults, obesity is associated with cardiac steatosis. In contrast to studies in patients with diabetes suggesting a link between cardiac steatosis and LV dysfunction, this study found no relationship between cardiac steatosis and left ventricular volumes or EF, though there is some evidence suggesting that cardiac steatosis may be associated with LV regional function in healthy AA women. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Liu, Chia-Ying; Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Gerstenblith, Gary; Lai, Shenghan] Johns Hopkins Sch Med, Dept Med, Baltimore, MD 21287 USA. [Zimmerman, Stefan L.; Lai, Shenghan; Lai, Hong] Johns Hopkins Sch Med, Dept Radiol, Baltimore, MD 21287 USA. [Li, Ji; Zhu, Hong; Lai, Shenghan] Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD 21287 USA. [Zhu, Hong] Tianjin Med Univ, Dept Epidemiol & Biostat, Tianjin, Peoples R China. RP Lai, SH (reprint author), Johns Hopkins Sch Med, 600 N Wolfe St, Baltimore, MD 21287 USA. EM slai@jhmi.edu OI Bluemke, David/0000-0002-8323-8086 FU National Institute on Drug Abuse; National Institutes of Health (NIH) [R01-DA 12777, DA25524, DA15020] FX We thank the study participants for their contributions. The study was supported by grants from the National Institute on Drug Abuse, National Institutes of Health (NIH R01-DA 12777, DA25524 and DA15020). NR 23 TC 7 Z9 7 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD MAR 15 PY 2014 VL 172 IS 2 BP 381 EP 387 DI 10.1016/j.ijcard.2014.01.074 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AC5AC UT WOS:000332531800065 PM 24507737 ER PT J AU Olivieri, L Krieger, A Chen, MY Kim, P Kanter, JP AF Olivieri, Laura Krieger, Axel Chen, Marcus Y. Kim, Peter Kanter, Joshua P. TI 3D heart model guides complex stent angioplasty of pulmonary venous baffle obstruction in a Mustard repair of D-TGA SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Letter DE Congenital heart disease; Cardiac interventions; Transposition of the great arteries; Computed tomography; 3D printing C1 [Olivieri, Laura; Kanter, Joshua P.] Childrens Natl Med Ctr, Div Cardiol, Washington, DC 20010 USA. [Olivieri, Laura; Krieger, Axel; Kim, Peter; Kanter, Joshua P.] Childrens Natl Med Ctr, Sheik Zayed Inst Pediat Surg Innovat, Washington, DC 20010 USA. [Chen, Marcus Y.] NHLBI, NIH, Adv Cardiovasc Imaging Lab, Bethesda, MD 20892 USA. RP Olivieri, L (reprint author), Childrens Natl Med Ctr, Div Cardiol, 111 Michigan Ave NW Suite W3-200, Washington, DC 20010 USA. EM lolivier@childrensnational.org NR 6 TC 22 Z9 28 U1 0 U2 16 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD MAR 15 PY 2014 VL 172 IS 2 BP E297 EP E298 DI 10.1016/j.ijcard.2013.12.192 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AC5AC UT WOS:000332531800015 PM 24447757 ER PT J AU Han, S Lin, YC Wu, TX Salgado, AD Mexhitaj, I Wuest, SC Romm, E Ohayon, J Goldbach-Mansky, R Vanderver, A Marques, A Toro, C Williamson, P Cortese, I Bielekova, B AF Han, Sungpil Lin, Yen Chih Wu, Tianxia Salgado, Alan D. Mexhitaj, Ina Wuest, Simone C. Romm, Elena Ohayon, Joan Goldbach-Mansky, Raphaela Vanderver, Adeline Marques, Adriana Toro, Camilo Williamson, Peter Cortese, Irene Bielekova, Bibiana TI Comprehensive Immunophenotyping of Cerebrospinal Fluid Cells in Patients with Neuroimmunological Diseases SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROGRESSIVE MULTIPLE-SCLEROSIS; CENTRAL-NERVOUS-SYSTEM; PLASMACYTOID DENDRITIC CELLS; AICARDI-GOUTIERES SYNDROME; HERPES-SIMPLEX-VIRUS; T-CELLS; B-CELLS; MENINGEAL INFLAMMATION; CNS REMYELINATION; IMMUNE-RESPONSES AB We performed unbiased, comprehensive immunophenotyping of cerebrospinal fluid (CSF) and blood leukocytes in 221 subjects referred for the diagnostic work-up of neuroimmunological disorders to obtain insight about disease-specific phenotypes of intrathecal immune responses. Quantification of 14 different immune cell subsets, coupled with the assessment of their activation status, revealed physiological differences between intrathecal and systemic immunity, irrespective of final diagnosis. Our data are consistent with a model where the CNS shapes intrathecal immune responses to provide effective protection against persistent viral infections, especially by memory T cells, plasmacytoid dendritic cells, and CD56(bright) NK cells. Our data also argue that CSF immune cells do not simply reflect cells recruited from the periphery. Instead, they represent a mixture of cells that are recruited from the blood, have been activated intrathecally and leave the CNS after performing effector functions. Diagnosis-specific differences provide mechanistic insight into the disease process in the defined subtypes of multiple sclerosis (MS), neonatal onset multisystem inflammatory disease, and Aicardi-Goutieres syndrome. This analysis also determined that secondary-progressive MS patients are immunologically closer to relapsing-remitting patients as compared with patients with primary-progressive MS. Because CSF immunophenotyping captures the biology of the intrathecal inflammatory processes, it has the potential to guide optimal selection of immunomodulatory therapies in individual patients and monitor their efficacy. Our study adds to the increasing number of publications that demonstrate poor correlation between systemic and intrathecal inflammatory biomarkers in patients with neuroimmunological diseases and stresses the importance of studying immune responses directly in the intrathecal compartment. C1 [Han, Sungpil; Lin, Yen Chih; Salgado, Alan D.; Mexhitaj, Ina; Wuest, Simone C.; Romm, Elena; Ohayon, Joan; Cortese, Irene; Bielekova, Bibiana] NINDS, Neuroimmunol Dis Unit, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Han, Sungpil] Pusan Natl Univ, Sch Med, Yangsan 626870, South Korea. [Wu, Tianxia] NINDS, Clin Neurosci Program, NIH, Bethesda, MD 20892 USA. [Goldbach-Mansky, Raphaela] NIAMSD, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD 20892 USA. [Vanderver, Adeline] George Washington Univ, Childrens Natl Med Ctr, Dept Integrat Syst Biol, Washington, DC 20010 USA. [Marques, Adriana] NIAID, Lab Clin Infect Dis, Clin Studies Unit, NIH, Bethesda, MD 20892 USA. [Toro, Camilo] NHGRI, NIH, Undiagnosed Dis Program, Bethesda, MD 20892 USA. [Williamson, Peter] NINDS, Translat Mycol Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Bielekova, Bibiana] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA. RP Bielekova, B (reprint author), NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. EM Bibi.Bielekova@nih.gov OI Han, Sungpil/0000-0002-4674-7682 FU National Institute of Neurological Disorders and Stroke/National Institutes of Health FX This work was supported by the intramural research program of the National Institute of Neurological Disorders and Stroke/National Institutes of Health. NR 57 TC 20 Z9 20 U1 1 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 MAR 15 PY 2014 VL 192 IS 6 BP 2551 EP 2563 DI 10.4049/jimmunol.1302884 PG 13 WC Immunology SC Immunology GA AC7IX UT WOS:000332702700004 PM 24510966 ER PT J AU Kim, PS Jochems, C Grenga, I Donahue, RN Tsang, KY Gulley, JL Schlom, J Farsaci, B AF Kim, Peter S. Jochems, Caroline Grenga, Italia Donahue, Renee N. Tsang, Kwong Y. Gulley, James L. Schlom, Jeffrey Farsaci, Benedetto TI Pan-Bcl-2 Inhibitor, GX15-070 (Obatoclax), Decreases Human T Regulatory Lymphocytes while Preserving Effector T Lymphocytes: A Rationale for Its Use in Combination Immunotherapy SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; CELL LUNG-CANCER; SYNERGISTIC ANTILEUKEMIA ACTIVITY; DOMAIN-3 MIMETIC GX15-070; MCL-1 DOWN-REGULATION; PHASE-I; FAMILY ANTAGONIST; BH3-MIMETIC GX15-070; ABT-737 RESISTANCE; MESYLATE GX15-070 AB Bcl-2 inhibitors are currently being evaluated in clinical studies for treatment of patients with solid tumors and hematopoietic malignancies. In this study we explored the potential for combining the pan-Bcl-2 inhibitor GX15-070 (GX15; obatoclax) with immunotherapeutic modalities. We evaluated the in vitro effects of GX15 on human T cell subsets obtained from PBMCs in terms of activation, memory, and suppressive function. Our results indicated that in healthy-donor PBMCs, mature-activated T cells were more resistant to GX15 than early-activated T cells, and that GX15 preserved memory but not non-memory T cell populations. Furthermore, GX15 increased the apoptosis of regulatory T cells (Tregs), profoundly downregulated FOXP3 and CTLA-4 in a dose-dependent manner, and decreased their suppressive function. Treating PBMCs obtained from ovarian cancer patients with GX15 also resulted in increased CD8(+):Treg and CD4(+):Treg ratios. These results support preclinical studies in which mice vaccinated before treatment with GX15 showed the greatest reduction in metastatic lung tumors as a result of increased apoptotic resistance of mature CD8(+) T cells and decreased Treg function brought about by GX15. Taken together, these findings suggest that when a Bcl-2 inhibitor is combined with active immunotherapy in humans, such as the use of a vaccine or immune checkpoint inhibitor, immunotherapy should precede administration of the Bcl-2 inhibitor to allow T cells to become mature, and thus resistant to the cytotoxic effects of the Bcl-2 inhibitor. C1 [Kim, Peter S.; Jochems, Caroline; Grenga, Italia; Donahue, Renee N.; Tsang, Kwong Y.; Gulley, James L.; Schlom, Jeffrey; Farsaci, Benedetto] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Farsaci, Benedetto/L-9837-2014; OI Farsaci, Benedetto/0000-0001-8275-2561; Kim, Peter/0000-0003-4108-299X FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 39 TC 11 Z9 11 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2014 VL 192 IS 6 BP 2622 EP 2633 DI 10.4049/jimmunol.1301369 PG 12 WC Immunology SC Immunology GA AC7IX UT WOS:000332702700011 PM 24516200 ER PT J AU Robertson, SJ Lubick, KJ Freedman, BA Carmody, AB Best, SM AF Robertson, Shelly J. Lubick, Kirk J. Freedman, Brett A. Carmody, Aaron B. Best, Sonja M. TI Tick-Borne Flaviviruses Antagonize Both IRF-1 and Type I IFN Signaling To Inhibit Dendritic Cell Function SO JOURNAL OF IMMUNOLOGY LA English DT Article ID WEST-NILE-VIRUS; JAPANESE ENCEPHALITIS-VIRUS; NF-KAPPA-B; INTERFERON REGULATORY FACTOR-1; MOUSE EMBRYO FIBROBLASTS; IL-12 PRODUCTION; GENE-EXPRESSION; DENGUE VIRUS; TRANSCRIPTION FACTORS; ADAPTIVE IMMUNITY AB Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, is a leading cause of viral encephalitis in Europe and Asia. Dendritic cells (DCs), as early cellular targets of infection, provide an opportunity for flaviviruses to inhibit innate and adaptive immune responses. Flaviviruses modulate DC function, but the mechanisms underpinning this are not defined. We examined the maturation phenotype and function of murine bone marrow-derived DCs infected with Langat virus (LGTV), a naturally attenuated member of the TBEV serogroup. LGTV infection failed to induce DC maturation or a cytokine response. Treatment with LPS or LPS/IFN-gamma, strong inducers of inflammatory cytokines, resulted in enhanced TNF-alpha and IL-6 production, but suppressed IL-12 production in infected DCs compared with uninfected "bystander" cells or mock-infected controls. LGTV-mediated antagonism of type I IFN (IFN-I) signaling contributed to inhibition of IL-12p40 mRNA expression at late time points after stimulation. However, early suppression was still observed in DCs lacking the IFN-I receptor (Ifnar(-/-)), suggesting that additional mechanisms of antagonism exist. The early IFN-independent inhibition of IL-12p40 was nearly abolished in DCs deficient in IFN regulatory factor-1 (IRF-1), a key transcription factor required for IL-12 production. LGTV infection did not affect Irf-1 mRNA expression, but rather diminished IRF-1 protein levels and nuclear localization. The effect on IRF-1 was also observed in DCs infected with the highly virulent Sofjin strain of TBEV. Thus, antagonism of IRF-1 is a novel mechanism that synergizes with the noted ability of flaviviruses to suppress IFN-alpha/beta receptor-dependent signaling, resulting in the orchestrated evasion of host innate immunity. C1 [Robertson, Shelly J.; Lubick, Kirk J.; Freedman, Brett A.; Best, Sonja M.] NIAID, Innate Immun & Pathogenesis Unit, Virol Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Carmody, Aaron B.] NIAID, Res Technol Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Best, SM (reprint author), NIAID, Virol Lab, Rocky Mt Labs, NIH, 903 South 4th St, Hamilton, MT 59840 USA. EM sbest@niaid.nih.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 58 TC 9 Z9 9 U1 1 U2 16 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 MAR 15 PY 2014 VL 192 IS 6 BP 2744 EP 2755 DI 10.4049/jimmunol.1302110 PG 12 WC Immunology SC Immunology GA AC7IX UT WOS:000332702700023 PM 24532583 ER PT J AU O'Connor, GM Vivian, JP Widjaja, JM Bridgeman, JS Gostick, E Lafont, BAP Anderson, SK Price, DA Brooks, AG Rossjohn, J McVicar, DW AF O'Connor, Geraldine M. Vivian, Julian P. Widjaja, Jacqueline M. Bridgeman, John S. Gostick, Emma Lafont, Bernard A. P. Anderson, Stephen K. Price, David A. Brooks, Andrew G. Rossjohn, Jamie McVicar, Daniel W. TI Mutational and Structural Analysis of KIR3DL1 Reveals a Lineage-Defining Allotypic Dimorphism That Impacts Both HLA and Peptide Sensitivity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MHC CLASS-I; NATURAL-KILLER-CELLS; INHIBITORY RECEPTORS; NK-CELLS; POLYMORPHISM; RECOGNITION; ALLELES; REACTIVITY; BINDING; CLONES AB Killer Ig-like receptors (KIRs) control the activation of human NK cells via interactions with peptide-laden HLAs. KIR3DL1 is a highly polymorphic inhibitory receptor that recognizes a diverse array of HLA molecules expressing the Bw4 epitope, a group with multiple polymorphisms incorporating variants within the Bw4 motif. Genetic studies suggest that KIR3DL1 variation has functional significance in several disease states, including HIV infection. However, owing to differences across KIR3DL1 allotypes, HLA-Bw4, and associated peptides, the mechanistic link with biological outcome remains unclear. In this study, we elucidated the impact of KIR3DL1 polymorphism on peptide-laden HLA recognition. Mutational analysis revealed that KIR residues involved in water-mediated contacts with the HLA-presented peptide influence peptide binding specificity. In particular, residue 282 (glutamate) in the D2 domain underpins the lack of tolerance of negatively charged C-terminal peptide residues. Allotypic KIR3DL1 variants, defined by neighboring residue 283, displayed differential sensitivities to HLA-bound peptide, including the variable HLA-B*57:01-restricted HIV-1 Gag-derived epitope TW10. Residue 283, which has undergone positive selection during the evolution of human KIRs, also played a central role in Bw4 subtype recognition by KIR3DL1. Collectively, our findings uncover a common molecular regulator that controls HLA and peptide discrimination without participating directly in peptide-laden HLA interactions. Furthermore, they provide insight into the mechanics of interaction and generate simple, easily assessed criteria for the definition of KIR3DL1 functional groupings that will be relevant in many clinical applications, including bone marrow transplantation. C1 [O'Connor, Geraldine M.; McVicar, Daniel W.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Vivian, Julian P.; Rossjohn, Jamie] Monash Univ, Sch Biomed Sci, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. [Widjaja, Jacqueline M.; Brooks, Andrew G.] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3010, Australia. [Bridgeman, John S.; Gostick, Emma; Price, David A.; Rossjohn, Jamie] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [Lafont, Bernard A. P.] NIAID, Nonhuman Primate Immunogenet & Cellular Immunol U, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Anderson, Stephen K.] Leidos Biomedical Res Inc, Basic Sci Program, Expt Immunol Lab, Frederick Natl Lab, Frederick, MD 21702 USA. [Price, David A.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP McVicar, DW (reprint author), NCI, Bldg 560,Room 31-50, Frederick, MD 21702 USA. EM mcvicard@mail.nih.gov RI Price, David/C-7876-2013; McVicar, Daniel/G-1970-2015; OI Price, David/0000-0001-9416-2737; Brooks, Andrew/0000-0002-4085-9683; Rossjohn, Jamie/0000-0002-2020-7522 FU Intramural AIDS Targeted Antiviral Program of the National Institutes of Health; National Health and Medical Research Council of Australia; Association for International Cancer Research; Intramural Research Program of the National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN26120080001E] FX This work was supported by the Intramural AIDS Targeted Antiviral Program of the National Institutes of Health, the National Health and Medical Research Council of Australia, the Association for International Cancer Research (to A. G. B. and J.R.), and the Intramural Research Program of the National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, and federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under Contract HHSN26120080001E. J.P.V. is an Australian Research Council Discovery Early Career Researcher Award Fellow, D. A. P. is a Wellcome Trust Senior Investigator, and J.R. is a National Health and Medical Research Council of Australia Fellow. NR 43 TC 17 Z9 17 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2014 VL 192 IS 6 BP 2875 EP 2884 DI 10.4049/jimmunol.1303142 PG 10 WC Immunology SC Immunology GA AC7IX UT WOS:000332702700036 PM 24563253 ER PT J AU Mu, J Tai, XG Iyer, SS Weissman, JD Singer, A Singer, DS AF Mu, Jie Tai, Xuguang Iyer, Shankar S. Weissman, Jocelyn D. Singer, Alfred Singer, Dinah S. TI Regulation of MHC Class I Expression by Foxp3 and Its Effect on Regulatory T Cell Function SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; AUTOIMMUNE-DISEASE; TRANSCRIPTION FACTOR; DNA-BINDING; COMPLEX; GENES; ENHANCEOSOME; MOLECULES; ELEMENTS; CANCER AB Expression of MHC class I molecules, which provide immune surveillance against intracellular pathogens, is higher on lymphoid cells than on any other cell types. In T cells, this is a result of activation of class I transcription by the T cell enhanceosome consisting of Runx1, CBF beta, and LEF1. We now report that MHC class I transcription in T cells also is enhanced by Foxp3, resulting in higher levels of class I in CD4(+)CD25(+) T regulatory cells than in conventional CD4(+)CD25(-) T cells. Interestingly, the effect of Foxp3 regulation of MHC class I transcription is cell type specific: Foxp3 increases MHC class I expression in T cells but represses it in epithelial tumor cells. In both cell types, Foxp3 targets the upstream IFN response element and downstream core promoter of the class I gene. Importantly, expression of MHC class I contributes to the function of CD4(+)CD25(+) T regulatory cells by enhancing immune suppression, both in in vitro and in vivo. These findings identify MHC class I genes as direct targets of Foxp3 whose expression augments regulatory T cell function. C1 [Mu, Jie; Tai, Xuguang; Iyer, Shankar S.; Weissman, Jocelyn D.; Singer, Alfred; Singer, Dinah S.] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Singer, DS (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B-36, Bethesda, MD 20892 USA. EM Dinah.Singer@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 39 TC 3 Z9 3 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2014 VL 192 IS 6 BP 2892 EP 2903 DI 10.4049/jimmunol.1302847 PG 12 WC Immunology SC Immunology GA AC7IX UT WOS:000332702700038 PM 24523508 ER PT J AU Belshe, RB Heineman, TC Bernstein, DI Bellamy, AR Ewell, M van der Most, R Deal, CD AF Belshe, Robert B. Heineman, Thomas C. Bernstein, David I. Bellamy, Abbie R. Ewell, Marian van der Most, Robbert Deal, Carolyn D. TI Correlate of Immune Protection Against HSV-1 Genital Disease in Vaccinated Women SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HSV vaccine; vaccine efficacy; protective antibodies ID SIMPLEX-VIRUS TYPE-1; SUBUNIT VACCINE; ANTIBODY-RESPONSE; HERPES; INFECTION; TRIAL; YOUNG AB Background. Previously we conducted a double-blind controlled, randomized efficacy field trial of gD-2 HSV vaccine adjuvanted with ASO4 in 8323 women. Subjects had been previously selected to be seronegative for HSV-1 and HSV-2. We found that vaccine was 82% protective against HSV-1 genital disease, but offered no significant protection against HSV-2 genital disease. Methods. To better understand the results of the efficacy study, post-vaccination anti-gD-2 antibody concentrations from all HSV infected subjects and matched uninfected controls were measured. Three models were used to determine whether these responses correlated with protection against HSV infection or disease. Similarly, cellular immune responses from a subset of subjects and matched controls were evaluated for a correlation with HSV protection. Results. Antibodies to gD-2 correlated with protection against HSV-1 infection with higher antibody concentration associated with higher efficacy. Cellular immune responses to gD-2 did not correlate with protection. Conclusions. The protection against HSV-1 infection observed in the Herpevac Trial for Women was associated with antibodies directed against the vaccine. C1 [Belshe, Robert B.] St Louis Univ, Sch Med, Div Infect Dis Allergy & Immunol, Dept Internal Med, St Louis, MO 63104 USA. [Heineman, Thomas C.; van der Most, Robbert] GlaxoSmithKline Biol, Global Clin Dev Vaccines, King Of Prussia, PA 19406 USA. [Bernstein, David I.] Cincinnati Childrens Hosp Med Ctr, Div Infect Dis, Cincinnati, OH 45229 USA. [Bellamy, Abbie R.; Ewell, Marian] EMMES Corp, Rockville, MD 20850 USA. [Deal, Carolyn D.] NIAID, Dept Hlth & Human Serv, NIH, DMID,STDB, Bethesda, MD 20892 USA. RP Belshe, RB (reprint author), St Louis Univ, Sch Med, Div Infect Dis Allergy & Immunol, 1100 S Grand Blvd,DRC 8, St Louis, MO 63104 USA. EM belsherb@slu.edu FU National Institute of Allergy and Infectious Diseases [N01-AI-45250]; GlaxoSmithKline FX This research was supported by a contract with the National Institute of Allergy and Infectious Diseases (N01-AI-45250) and by GlaxoSmithKline. NR 10 TC 30 Z9 30 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 15 PY 2014 VL 209 IS 6 BP 828 EP 836 DI 10.1093/infdis/jit651 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AC2PH UT WOS:000332343600004 PM 24285844 ER PT J AU Wentzensen, N Nason, M Schiffman, M Dodd, L Hunt, WC Wheeler, CM AF Wentzensen, Nicolas Nason, Martha Schiffman, Mark Dodd, Lori Hunt, William C. Wheeler, Cosette M. CA New Mexico HPV Pap Registry Steeri TI No Evidence for Synergy Between Human Papillomavirus Genotypes for the Risk of High-Grade Squamous Intraepithelial Lesions in a Large Population-Based Study SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE cervical cancer screening; cytology; human papillomavirus (HPV); multiple Infections ID CERVICAL-CANCER; MULTIPLE TYPES; UNITED-STATES; NEOPLASIA; INFECTION; WOMEN; VACCINATION; AGE AB Background. Multiple human papillomavirus (HPV) genotypes may be independently or synergistically associated with risk of high-grade squamous intraepithelial lesions (HSILs). We evaluated the risk of HSIL in women concomitantly infected with multiple HPV genotypes. Methods. A population-based stratified sample of 59 664 cervical cytology specimens from women residing in New Mexico were evaluated for cytologic abnormalities and HPV genotypes. We calculated the risk of HSIL in women infected with a single HPV genotype and the risk in those infected with multiple HPV genotypes. Results. The highest risk of HSIL was observed for HPV-16 (0.036), followed by HPV-33 (0.028), HPV-58 (0.024), and HPV-18 (0.022). For most types, we observed a greater risk of HSIL in women infected with multiple carcinogenic HPV types. In contrast, the risk of HSIL was similar in women infected with HPV-16 and other types, compared with women infected with HPV-16 only. We observed an increased but plateauing risk of HSIL in women infected with multiple types, compared with those infected with a single type, with risk ratios of 1.5 (95% confidence interval [CI], 1.2-1.8), 1.7 (95% CI, 1.3-2.4), and 1.4 (95% CI, 0.83-2.5) for women infected with 2, 3, and >= 4 genotypes, respectively. Conclusions. In the largest population-based study of HPV genotypes and cytologic outcomes so far, we did not see more than additive effects of HPV types on the risk of HSIL in women infected with multiple types. C1 [Wentzensen, Nicolas; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Nason, Martha; Dodd, Lori] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Hunt, William C.; Wheeler, Cosette M.] Univ New Mexico, Dept Pathol, Hlth Sci Ctr, Albuquerque, NM 87131 USA. RP Wheeler, CM (reprint author), Univ New Mexico, Dept Pathol, Hlth Sci Ctr, House Prevent Epidemiol HOPE Bldg 191, Albuquerque, NM 87131 USA. EM cwheeler@salud.unm.edu FU National Institutes of Health [U19AI084081, R01CA134779]; National Cancer Institute; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services FX This work was supported by the National Institutes of Health (awards U19AI084081 and R01CA134779 to C.M.W.) and by the Intramural Research Programs of the National Cancer Institute and National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services. HPV Linear Array reagents and equipment to automate HPV genotyping assays were provided by Roche Molecular Systems. NR 17 TC 9 Z9 12 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 15 PY 2014 VL 209 IS 6 BP 855 EP 864 DI 10.1093/infdis/jit577 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AC2PH UT WOS:000332343600007 PM 24179110 ER PT J AU Krishnan, S Wilson, EMP Sheikh, V Rupert, A Mendoza, D Yang, J Lempicki, R Migueles, SA Sereti, I AF Krishnan, Sonya Wilson, Eleanor M. P. Sheikh, Virginia Rupert, Adam Mendoza, Daniel Yang, Jun Lempicki, Richard Migueles, Stephen A. Sereti, Irini TI Evidence for Innate Immune System Activation in HIV Type 1-Infected Elite Controllers SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; Elite Controllers; Biomarkers; D-dimer; soluble Tissue Factor; Monocytes ID INCIDENT CARDIOVASCULAR-DISEASE; LONG-TERM NONPROGRESSORS; CORONARY-HEART-DISEASE; CD8(+) T-CELLS; ANTIRETROVIRAL THERAPY; D-DIMER; MYOCARDIAL-INFARCTION; TISSUE FACTOR; CLINICAL-IMPLICATIONS; INFECTED INDIVIDUALS AB Background. Elite controllers maintain high CD4(+) T-cell counts and suppress plasma human immunodeficiency virus (HIV) viremia in the absence of antiretroviral therapy (ART). It is unclear whether levels of biomarkers associated with coagulation, monocyte activation, and inflammation, which are linked to HIV-associated mortality, differ among elite controllers, ART recipients with suppressed viremia (plasma HIV type 1 RNA load, <50 copies/mL), and HIV-negative controls. Methods. A total of 68 elite controllers, 68 ART recipients with suppressed viremia, and 35 HIV-negative participants were evaluated. Levels of biomarkers in cryopreserved plasma were measured by enzyme-linked immunosorbent assay and electrochemiluminescence-based assay. Cryopreserved peripheral blood mononuclear cells were used to assess monocyte phenotype and function and interferon-inducible gene expression (IFIG). Nonparametric testing was used to compare median values among groups. Results. CD4(+) T-cell counts were similar between elite controllers and HIV-negative controls but significantly lower in ART recipients with suppressed viremia. Levels of C-reactive protein and interleukin 6 were higher and IFIG upregulated in both HIV-positive groups, compared with HIV-negative controls. D-dimer and soluble tissue factor levels were significantly elevated in elite controllers, compared with those in ART recipients with suppressed viremia and HIV-negative controls (P < .01). Monocytes from elite controllers (and ART recipients with suppressed viremia) expressed lower CCR2 and higher CX3CR1 levels than monocytes from HIV-negative controls. In addition, elite controllers had a significantly higher proportion of CD14(+)CD16(+) monocytes, compared with HIV-negative controls. Conclusion. Elite controllers maintain control of plasma HIV viremia and have evidence of an activated innate immune response. C1 [Krishnan, Sonya] NCI, Clin Res Directorate, Clin Monitoring Res Program, Frederick, MD 21701 USA. [Rupert, Adam] NCI, AIDS Monitoring Lab, Frederick, MD 21701 USA. [Yang, Jun; Lempicki, Richard] NCI, Appl & Dev Res Directorate, Sci Applicat Int Corp SAIC Frederick, Frederick, MD 21701 USA. [Wilson, Eleanor M. P.; Sheikh, Virginia; Mendoza, Daniel; Migueles, Stephen A.; Sereti, Irini] NIAID, NIH, Bethesda, MD 20892 USA. RP Sereti, I (reprint author), NIH, 10 Ctr Dr,Bldg 10,Rm 11B07A, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov RI Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Mendoza, Daniel/0000-0002-6362-0771; Wilson, Eleanor/0000-0002-4855-514X FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program, National Institute of Allergy and Infectious Diseases FX This work was supported by the National Cancer Institute, National Institutes of Health (contract HHSN261200800001E), and the Intramural Research Program, National Institute of Allergy and Infectious Diseases. NR 50 TC 44 Z9 44 U1 0 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 15 PY 2014 VL 209 IS 6 BP 931 EP 939 DI 10.1093/infdis/jit581 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AC2PH UT WOS:000332343600015 PM 24185941 ER PT J AU Drinkwater, DC Davidson-Moncada, J Heckendorn, E Myers, J Whitman, TJ AF Drinkwater, Dennis C. Davidson-Moncada, Jan Heckendorn, Emily Myers, Janet Whitman, Timothy J. TI A Patient With Ulcerated Nodules on His Face SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID PROLONGED VORICONAZOLE THERAPY; SQUAMOUS-CELL CARCINOMAS; TRIAZOLE ANTIFUNGAL AGENT; PHOTOSENSITIVITY C1 [Drinkwater, Dennis C.] Walter Reed Natl Mil Med Ctr, Dept Internal Med, Bethesda, MD 20889 USA. [Davidson-Moncada, Jan] NIH, Dept Hematol Oncol, Bethesda, MD 20892 USA. [Heckendorn, Emily] Walter Reed Natl Mil Med Ctr, Dept Pathol, Bethesda, MD 20889 USA. [Myers, Janet] US Naval Hosp Okinawa, Dept Pulm Med, Nakagami, Japan. [Whitman, Timothy J.] Walter Reed Natl Mil Med Ctr, Dept Infect Dis, Bethesda, MD 20889 USA. RP Whitman, TJ (reprint author), Walter Reed Natl Mil Med Ctr, Dept Infect Dis, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM timothy.j.whitman.mil@health.mil NR 12 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAR 15 PY 2014 VL 58 IS 6 BP 839 EP + DI 10.1093/cid/cit716 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AC2KQ UT WOS:000332330200016 PM 24573080 ER PT J AU Ketley, A Chen, CZ Li, X Arya, S Robinson, TE Granados-Riveron, J Udosen, I Morris, GE Holt, I Furling, D Chaouch, S Haworth, B Southall, N Shinn, P Zheng, W Austin, CP Hayes, CJ Brook, JD AF Ketley, Ami Chen, Catherine Z. Li, Xin Arya, Sukrat Robinson, Thelma E. Granados-Riveron, Javier Udosen, Inyang Morris, Glenn E. Holt, Ian Furling, Denis Chaouch, Soraya Haworth, Ben Southall, Noel Shinn, Paul Zheng, Wei Austin, Christopher P. Hayes, Christopher J. Brook, J. David TI High-content screening identifies small molecules that remove nuclear foci, affect MBNL distribution and CELF1 protein levels via a PKC-independent pathway in myotonic dystrophy cell lines SO HUMAN MOLECULAR GENETICS LA English DT Article ID EXPANDED-REPEAT TRANSCRIPTS; 3 UNTRANSLATED REGION; MUSCULAR-DYSTROPHY; TRIPLET-REPEAT; MESSENGER-RNA; IN-VIVO; TRINUCLEOTIDE REPEAT; RATIONAL DESIGN; SKELETAL-MUSCLE; CTG REPEAT AB Myotonic dystrophy (DM) is a multi-system neuromuscular disorder for which there is no treatment. We have developed a medium throughput phenotypic assay, based on the identification of nuclear foci in DM patient cell lines using in situ hybridization and high-content imaging to screen for potentially useful therapeutic compounds. A series of further assays based on molecular features of DM have also been employed. Two compounds that reduce and/or remove nuclear foci have been identified, Ro 31-8220 and chromomycin A3. Ro 31-8220 is a PKC inhibitor, previously shown to affect the hyperphosphorylation of CELF1 and ameliorate the cardiac phenotype in a DM1 mouse model. We show that the same compound eliminates nuclear foci, reduces MBNL1 protein in the nucleus, affects ATP2A1 alternative splicing and reduces steady-state levels of CELF1 protein. We demonstrate that this effect is independent of PKC activity and conclude that this compound may be acting on alternative kinase targets within DM pathophysiology. Understanding the activity profile for this compound is key for the development of targeted therapeutics in the treatment of DM. C1 [Ketley, Ami; Li, Xin; Arya, Sukrat; Robinson, Thelma E.; Granados-Riveron, Javier; Udosen, Inyang; Brook, J. David] Univ Nottingham, Queens Med Ctr, Sch Life Sci, Nottingham NG7 2UH, England. [Chen, Catherine Z.; Southall, Noel; Shinn, Paul; Zheng, Wei; Austin, Christopher P.; Hayes, Christopher J.] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Morris, Glenn E.; Holt, Ian] RJAH Orthopaed Hosp, Wolfson Ctr Inherited Neuromuscular Dis, Oswestry SY10 7AG, Shrops, England. [Morris, Glenn E.; Holt, Ian] Keele Univ, Inst Sci & Technol Med, Keele, Staffs, England. [Furling, Denis; Chaouch, Soraya] Univ Paris 06, UM 76, Inst Myol, F-75013 Paris, France. [Furling, Denis; Chaouch, Soraya] INSERM, U974, F-75013 Paris, France. [Furling, Denis; Chaouch, Soraya] CNRS, UMR7215, F-75013 Paris, France. [Haworth, Ben] Mol Devices, Wokingham RG41 5TS, Berks, England. [Hayes, Christopher J.] Univ Nottingham, Sch Chem, Nottingham NG7 2RD, England. RP Brook, JD (reprint author), Univ Nottingham, Queens Med Ctr, Sch Life Sci, Nottingham NG7 2UH, England. EM david.brook@nottingham.ac.uk RI Southall, Noel/H-8991-2012; Hayes, Christopher/B-6022-2016; Zheng, Wei/J-8889-2014; OI Southall, Noel/0000-0003-4500-880X; Hayes, Christopher/0000-0003-1692-3646; Zheng, Wei/0000-0003-1034-0757; Granados-Riveron, Javier T./0000-0002-0368-225X; Brook, John David/0000-0002-5946-6740 FU MRC DPFS; Muscular Dystrophy Campaign; Leverhulme Trust; Myotonic Dystrophy Support Group; Association Francaise contre les Myopathies; Marigold Foundation Research fellowship for CZC; Medical Research Council; intramural research of the National Centre for Advancing Translational Sciences, NIH FX This research was funded by an MRC DPFS award, the Muscular Dystrophy Campaign, the Leverhulme Trust, the Myotonic Dystrophy Support Group, the Association Francaise contre les Myopathies, intramural research of the National Centre for Advancing Translational Sciences, NIH, and a Marigold Foundation Research fellowship for CZC. Funding to pay the Open Access publication charges for this article was provided by the Medical Research Council. NR 50 TC 13 Z9 14 U1 0 U2 16 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 MAR 15 PY 2014 VL 23 IS 6 BP 1551 EP 1562 DI 10.1093/hmg/ddt542 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AB8MK UT WOS:000332044300013 PM 24179176 ER PT J AU Lai, YL Albert, PS AF Lai, Yinglei Albert, Paul S. TI Identifying multiple change points in a linear mixed effects model SO STATISTICS IN MEDICINE LA English DT Article DE change point; longitudinal data; linear mixed effects model; expectation-maximization algorithm; dynamic programming algorithm ID LONGITUDINAL DATA; SEGMENTATION AB Although change-point analysis methods for longitudinal data have been developed, it is often of interest to detect multiple change points in longitudinal data. In this paper, we propose a linear mixed effects modeling framework for identifying multiple change points in longitudinal Gaussian data. Specifically, we develop a novel statistical and computational framework that integrates the expectation-maximization and the dynamic programming algorithms. We conduct a comprehensive simulation study to demonstrate the performance of our method. We illustrate our method with an analysis of data from a trial evaluating a behavioral intervention for the control of type I diabetes in adolescents with HbA1c as the longitudinal response variable. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Lai, Yinglei] George Washington Univ, Dept Stat, Washington, DC 20052 USA. [Lai, Yinglei] George Washington Univ, Ctr Biostat, Washington, DC 20052 USA. [Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. RP Lai, YL (reprint author), George Washington Univ, Dept Stat, Rome Hall,Room 553,801 22nd St NW, Washington, DC 20052 USA. EM ylai@gwu.edu FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institute of Health; National Institute of General Medical Sciences of the National Institutes of Health [R01GM092963] FX This research was partially supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institute of Health. Research reported in this publication was also partially supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R01GM092963 (to Y.L.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 23 TC 1 Z9 1 U1 0 U2 9 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 MAR 15 PY 2014 VL 33 IS 6 BP 1015 EP 1028 DI 10.1002/sim.5996 PG 14 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 AA9DZ UT WOS:000331395300009 PM 24114935 ER PT J AU Cornwell, BR Overstreet, C Grillon, C AF Cornwell, B. R. Overstreet, C. Grillon, C. TI Spontaneous fast gamma activity in the septal hippocampal region correlates with spatial learning in humans SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Gamma activity; Hippocampus; Magnetoencephalography; Memory consolidation; Spatial learning; Virtual reality ID HIGH-FREQUENCY OSCILLATIONS; MEDIAL TEMPORAL-LOBE; VIRTUAL WATER MAZE; THETA-RHYTHM; MEMORY CONSOLIDATION; HUMAN CORTEX; NAVIGATION; RIPPLES; BRAIN; MAGNETOENCEPHALOGRAPHY AB Hippocampal neuronal populations exhibit multiple kinds of activity patterns, from the dominant theta rhythm during active exploration to high-frequency ripple-like activity during periods of relative inactivity. In animals, evidence is rapidly accruing that these high-frequency ripple activity patterns subserve retention of spatial learning performance. In a translational effort to address the possible function of offline hippocampal processes in humans, we measured spontaneous gamma activity during an awake rest period within a virtual spatial learning context. Whole-head magnetoencephalographic (MEG) recordings were taken while healthy participants (N=24) quietly rested (eyes open) between encoding and retrieval phases of a hippocampal-dependent virtual Morris water maze task. Results are that fast gamma activity (80-140 Hz) in the septal or posterior region of the hippocampus (bilaterally) was positively correlated across participants with subsequent within-session spatial learning rate. Fast gamma did not predict initial retrieval performance following rest, failing to provide evidence of a direct link between spontaneous high-frequency activity patterns during awake rest and consolidation of previous spatial memories. The findings nevertheless are consistent with a prospective role for offline human hippocampal processes in spatial learning and indicate that higher spontaneous gamma activity in the septal hippocampal region is related to faster updating of spatial knowledge in familiar virtual surroundings. Published by Elsevier B.V. C1 [Cornwell, B. R.] Swinburne Univ Technol, Brain & Psychol Sci Res Ctr, Hawthorn, Vic 3122, Australia. [Cornwell, B. R.; Overstreet, C.; Grillon, C.] NIMH, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. RP Cornwell, BR (reprint author), Swinburne Univ Technol, Mail H99,POB 218, Hawthorn, Vic 3122, Australia. EM bcornwell@swin.edu.au FU National Institute of Mental Health FX This work was funded by the Intramural Research Program of the National Institute of Mental Health. NR 45 TC 1 Z9 1 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAR 15 PY 2014 VL 261 BP 258 EP 264 DI 10.1016/j.bbr.2013.12.031 PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA AB0QK UT WOS:000331497000032 PM 24388977 ER PT J AU Bai, RL Basser, PJ Briber, RM Horkay, F AF Bai, Ruiliang Basser, Peter J. Briber, Robert M. Horkay, Ferenc TI NMR Water Self- Diffusion and Relaxation Studies on Sodium Polyacrylate Solutions and Gels in Physiologic Ionic Solutions SO JOURNAL OF APPLIED POLYMER SCIENCE LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; NUCLEAR-MAGNETIC-RESONANCE; POLYMER SOLVENT SYSTEMS; SPIN-LATTICE RELAXATION; FREE-VOLUME THEORIES; SINGLE-SIDED NMR; HYDRATION WATER; TRANSVERSE RELAXATION; STRUCTURAL-CHANGES; PROTON RELAXATION C1 [Bai, Ruiliang; Basser, Peter J.; Horkay, Ferenc] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. [Bai, Ruiliang] Univ Maryland, Inst Phys Sci & Technol, Biophys Program, College Pk, MD 20740 USA. [Briber, Robert M.] Univ Maryland, Dept Mat Sci & Engn, College Pk, MD 20740 USA. RP Bai, RL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. EM ruiliang.bai@nih.gov RI Briber, Robert/A-3588-2012 OI Briber, Robert/0000-0002-8358-5942 FU Intramural Research Program of the NICHD, NIH FX This research was supported by the Intramural Research Program of the NICHD, NIH. We thank the comments from Dr. Uzi Eliav (Tel Aviv University). NR 67 TC 8 Z9 8 U1 3 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-8995 EI 1097-4628 J9 J APPL POLYM SCI JI J. Appl. Polym. Sci. PD MAR 15 PY 2014 VL 131 IS 6 AR 40001 DI 10.1002/app.40001 PG 7 WC Polymer Science SC Polymer Science GA AA3PM UT WOS:000331004800017 ER PT J AU Kroesen, M Nierkens, S Ansems, M Wassink, M Orentas, RJ Boon, L den Brok, MH Hoogerbrugge, PM Adema, GJ AF Kroesen, Michiel Nierkens, Stefan Ansems, Marleen Wassink, Melissa Orentas, Rimas J. Boon, Louis den Brok, Martijn H. Hoogerbrugge, Peter M. Adema, Gosse J. TI A transplantable TH-MYCN transgenic tumor model in C57Bl/6 mice for preclinical immunological studies in neuroblastoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE neuroblastoma; immunotherapy; autologous mouse model; anti-GD2 mAb therapy; NK cell ID HIGH-RISK NEUROBLASTOMA; STEM-CELL TRANSPLANTATION; VACCINE-INDUCED IMMUNITY; ANTI-GD2 ANTIBODY; DENDRITIC CELLS; IMMUNOTHERAPEUTIC IMPLICATIONS; MURINE NEUROBLASTOMA; BONE-MARROW; CLASS-I; EXPRESSION AB Current multimodal treatments for patients with neuroblastoma (NBL), including anti-disialoganglioside (GD2) monoclonal antibody (mAb) based immunotherapy, result in a favorable outcome in around only half of the patients with advanced disease. To improve this, novel immunocombinational strategies need to be developed and tested in autologous preclinical NBL models. A genetically well-explored autologous mouse model for NBL is the TH-MYCN model. However, the immunobiology of the TH-MYCN model remains largely unexplored. We developed a mouse model using a transplantable TH-MYCN cell line in syngeneic C57Bl/6 mice and characterized the immunobiology of this model. In this report, we show the relevance and opportunities of this model to study immunotherapy for human NBL. Similar to human NBL cells, syngeneic TH-MYCN-derived 9464D cells endogenously express the tumor antigen GD2 and low levels of MHC Class I. The presence of the adaptive immune system had little or no influence on tumor growth, showing the low immunogenicity of the NBL cells. In contrast, depletion of NK1.1+ cells resulted in enhanced tumor outgrowth in both wild-type and Rag1(-/-) mice, showing an important role for NK cells in the natural anti-NBL immune response. Analysis of the tumor infiltrating leukocytes ex vivo revealed the presence of both tumor associated myeloid cells and T regulatory cells, thus mimicking human NBL tumors. Finally, anti-GD2 mAb mediated NBL therapy resulted in ADCC in vitro and delayed tumor outgrowth in vivo. We conclude that the transplantable TH-MYCN model represents a relevant model for the development of novel immunocombinatorial approaches for NBL patients. What's new? Natural killer (NK) cells may serve a role in immune defense against neuroblastoma, though limitations in existing models have prevented extensive study of the immunological characteristics of the disease. Here, to better understand the immunobiology of neuroblastoma, the TH-MYCN mouse model was adapted for immunological investigation. Tumor cells (9464D) derived from immunologically compatible C57Bl/6 TH-MYCN mice were found to express the tumor antigen GD2. In addition, depletion of NK cells was associated with tumor outgrowth in both wild-type and Rag1-/- C57Bl/6 mice, whereas immunotherapy targeted against GD2 decreased tumor growth. C1 [Kroesen, Michiel; Nierkens, Stefan; Ansems, Marleen; Wassink, Melissa; den Brok, Martijn H.; Adema, Gosse J.] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, Dept Tumor Immunol, NL-6525 ED Nijmegen, Netherlands. [Kroesen, Michiel; Hoogerbrugge, Peter M.] Radboud Univ Nijmegen, Nijmegen Med Ctr, Dept Pediat Oncol, NL-6525 ED Nijmegen, Netherlands. [Nierkens, Stefan] Univ Med Ctr Utrecht, Utrecht Ctr Diagnost Adv Immunol Res U DAIR, Dept Immunol, Utrecht, Netherlands. [Orentas, Rimas J.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Boon, Louis] Bioceros BV, Utrecht, Netherlands. RP Adema, GJ (reprint author), Nijmegen Ctr Mol Life Sci 278 TIL, Dept Tumor Immunol, Post Box 9101, NL-6500 HB Nijmegen, Netherlands. EM g.adema@ncmls.ru.nl RI Adema, G.J./H-8007-2014; Hoogerbrugge, Peter/H-8049-2014; den Brok, Martijn/O-1054-2013 FU Vrienden KOC Nijmegen, Villa Joep Foundation FX Grant sponsor: Vrienden KOC Nijmegen, Villa Joep Foundation NR 47 TC 9 Z9 9 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD MAR 15 PY 2014 VL 134 IS 6 BP 1335 EP 1345 DI 10.1002/ijc.28463 PG 11 WC Oncology SC Oncology GA 283CS UT WOS:000329223000008 PM 24038106 ER PT J AU Ryan, BM Zanetti, KA Robles, AI Schetter, AJ Goodman, J Hayes, RB Huang, WY Gunter, MJ Yeager, M Burdette, L Berndt, SI Harris, CC AF Ryan, Brid M. Zanetti, Krista A. Robles, Ana I. Schetter, Aaron J. Goodman, Julie Hayes, Richard B. Huang, Wen-Yi Gunter, Mark J. Yeager, Meredith Burdette, Laurie Berndt, Sonja I. Harris, Curtis C. TI Germline variation in NCF4, an innate immunity gene, is associated with an increased risk of colorectal cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE colorectal cancer; single nucleotide polymorphism; innate immunity; NCF4 ID INFLAMMATORY-BOWEL-DISEASE; POPULATION-BASED COHORT; GENOME-WIDE ASSOCIATION; PERIANAL CROHNS-DISEASE; SUSCEPTIBILITY LOCI; NADPH OXIDASE; COLON-CANCER; ULCERATIVE-COLITIS; ADVANCED ADENOMAS; METAANALYSIS AB Chronic inflammation has been implicated in the etiology of colorectal adenoma and cancer; however, few key inflammatory genes mediating this relationship have been identified. In this study, we investigated the association of germline variation in innate immunity genes in relation to the risk of colorectal neoplasia. Our study was based on the analysis of samples collected from the prostate, lung, colorectal and ovarian (PLCO) Cancer Screening Trial. We investigated the association between 196 tag single nucleotide polymorphisms (SNPs) in 20 key innate immunity genes with risk of advanced colorectal adenoma and cancer in 719 adenoma cases, 481 cancer cases and 719 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). After Bonferroni correction, the AG/GG genotype of rs5995355, which is upstream of NCF4, was associated with an increased risk of colorectal cancer (OR=2.43, 95% CI=1.73-3.39; p<0.0001). NCF4 is part of the NAPDH complex, a key factor in biochemical pathways and the innate immune response. While not definitive, our analyses suggest that the variant allele does not affect expression of NCF4, but rather modulates activity of the NADPH complex. Additional studies on the functional consequences of rs5995355 in NCF4 may help to clarify the mechanistic link between inflammation and colorectal cancer. What's new? A single nucleotide polymorphism (SNP) known as rs5995355 in the gene NCF4, a member of the NADPH oxidase complex, is associated with increased risk of inflammatory bowel disease. The NADPH system functions in the elimination of invading microorganisms and has never previously been linked to colorectal cancer. As this screen for colorectal adenoma and cancer-related gene variants reveals, however, the NCF4 germline SNP may share a unique association with colon cancer. The analysis suggests that the variant disrupts the functionality of the NADPH complex, possibly impeding the ability of neutrophils to repel infectious agents. C1 [Ryan, Brid M.; Zanetti, Krista A.; Robles, Ana I.; Schetter, Aaron J.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Zanetti, Krista A.] Div Canc Control & Populat Sci, Host Susceptibil Factors Branch, Epidemiol & Genom Res Program, Rockville, MD 20852 USA. [Goodman, Julie] Gradient Corp, Cambridge, MA 02138 USA. [Hayes, Richard B.] NYU, Langone Med Ctr, Inst Canc, Div Epidemiol,Dept Environm Med, New York, NY 10016 USA. [Huang, Wen-Yi; Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Gunter, Mark J.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London W2 1PG, England. [Yeager, Meredith; Burdette, Laurie] ATC, Core Genotyping Facil, Gaithersburg, MD 20877 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Bldg 37,Room 3068,37 Convent Dr,MSC 4258, Bethesda, MD 20892 USA. EM curtis_harris@nih.gov OI Hayes, Richard/0000-0002-0918-661X FU Center for Cancer Research; Division of Cancer Epidemiology and Genetics FX Grant sponsor: Center for Cancer Research and Division of Cancer Epidemiology and Genetics NR 48 TC 9 Z9 9 U1 2 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD MAR 15 PY 2014 VL 134 IS 6 BP 1399 EP 1407 DI 10.1002/ijc.28457 PG 9 WC Oncology SC Oncology GA 283CS UT WOS:000329223000014 PM 23982929 ER PT J AU Poliakov, E Strunnikova, NV Jiang, JK Martinez, B Parikh, T Lakkaraju, A Thomas, C Brooks, BP Redmond, TM AF Poliakov, Eugenia Strunnikova, Natalya V. Jiang, Jian-kang Martinez, Bianca Parikh, Toral Lakkaraju, Aparna Thomas, Craig Brooks, Brian P. Redmond, T. Michael TI Multiple A2E treatments lead to melanization of rod outer segment-challenged ARPE-19 cells SO MOLECULAR VISION LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; RETINYLIDENE-N-RETINYLETHANOLAMINE; MACULAR DEGENERATION; FUNDUS AUTOFLUORESCENCE; LIPOFUSCIN FLUOROPHORE; RPE CELLS; GEOGRAPHIC ATROPHY; MOUSE MODEL; MELANIN; ACCUMULATION AB Purpose: Daily phagocytosis of outer segments (OSs) and retinoid recycling by the RPE lead to the accumulation of storage bodies in the RPE containing autofluorescent lipofuscin, which consists of lipids and bisretinoids such as A2E and its oxidation products. Accumulation of A2E and its oxidation products is implicated in the pathogenesis of several retinal degenerative diseases. However, A2E accumulates in the RPE during normal aging. In this study, we used a cell model to determine the homeostatic mechanisms of RPE cells in response to A2E accumulation. Methods: To distinguish between pathologic and normal responses of the RPE to A2E accumulation, we treated established ARPE-19 cells (cultured for 3 weeks after reaching confluence) with low micromolar amounts of A2E for several weeks. We compared the lysosomal function, lysosomal pH, degree of OS digestion, and melanization of the treated cells to untreated control cells in response to a challenge of purified rod OSs (ROSs). A2E was analyzed with high-performance liquid chromatography (HPLC); and A2E and melanin were identified with mass spectrometry. Results: We found that post-confluent ARPE-19 cells took up and accumulated A2E under dim light conditions. Spectral analysis of the HPLC separations and mass spectrometry showed that A2E-fed cells contained A2E and oxidized A2E (furan-A2E). A2E accumulation led to a modest increase (up to 0.25 unit) in lysosomal pH in these cells. The specific activity of cathepsin D and lysosomal acid phosphatase was reduced in the A2E-treated cells, but ROS degradation was not impaired. We found that, upon challenge with ROSs, melanin pigment was induced in the lysosomal fraction of the A2E-treated ARPE-19 cells. Thus, the ARPE-19 cells responded to the A2E treatment and ROS challenge by producing a melanin-containing lysosome fraction. We speculate that this prevents them from becoming impaired in OS processing. Conclusions: We used a modified ARPE-19 cell model in which melanization was elicited as a response to chronic accumulation of A2E. We found that although A2E treatment led, as has been previously reported, to modest lysosomal alkalinization and lysosomal impairment of ARPE-19 cells, a potential homeostatic mechanism may involve production of a special type of lysosomes containing melanin. C1 [Poliakov, Eugenia; Martinez, Bianca; Parikh, Toral; Redmond, T. Michael] NEI, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Strunnikova, Natalya V.; Brooks, Brian P.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Jiang, Jian-kang; Thomas, Craig] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Lakkaraju, Aparna] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. RP Redmond, TM (reprint author), NEI, LRCMB, NIH, Bldg 6,Rm 117A,6 Ctr Dr MSC 0608, Bethesda, MD 20892 USA. EM redmondd@helix.nih.gov OI Redmond, T. Michael/0000-0002-1813-5291 FU Intramural Research Program of the National Eye Institute; National Center for Advancing Translational Sciences, National Institutes of Health; Howard Hughes Medical Institute FX This research was supported by the Intramural Research Program of the National Eye Institute, and of the National Center for Advancing Translational Sciences, National Institutes of Health. T.P. was supported by the Howard Hughes Medical Institute. We thank Dr. Robert N. Fariss and Dr. Maria M. Campos, Biological Imaging Core, NEI for assisting with confocal microscopy. NR 63 TC 6 Z9 7 U1 1 U2 2 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD MAR 14 PY 2014 VL 20 BP 285 EP 300 PG 16 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA AK3CV UT WOS:000338301400001 PM 24644403 ER PT J AU Abeykoon, A Wang, GH Chao, CC Chock, PB Gucek, M Ching, WM Yang, DCH AF Abeykoon, Amila Wang, Guanghui Chao, Chien-Chung Chock, P. Boon Gucek, Marjan Ching, Wei-Mei Yang, David C. H. TI Multimethylation of Rickettsia OmpB Catalyzed by Lysine Methyltransferases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Bacteria; Cell Surface Protein; Enzyme Catalysis; Mass Spectrometry (MS); Protein Methylation ID OUTER-MEMBRANE-PROTEIN; PROTEOMIC ANALYSIS; METHYLATION; PROWAZEKII; INFECTION; TYPHI; TRIMETHYLLYSINE; RECOGNITION; ANTIGENS; INVASION AB Background: Methylation of OmpB has been implicated in rickettsial virulence. Results: Native OmpBs purified from Rickettsia contain mono- and trimethyllysine at specific locations that coincide with those catalyzed by methyltransferases in vitro. Conclusion: The number of trimethyllysine clusters in OmpBs correlates with degree of virulence. Significance: This study provides new insight into methylation of OmpB and its correlation with virulence. Methylation of rickettsial OmpB (outer membrane protein B) has been implicated in bacterial virulence. Rickettsial methyltransferases RP789 and RP027-028 are the first biochemically characterized methyltransferases to catalyze methylation of outer membrane protein (OMP). Methylation in OMP remains poorly understood. Using semiquantitative integrated liquid chromatography-tandem mass spectroscopy, we characterize methylation of (i) recombinantly expressed fragments of Rickettsia typhi OmpB exposed in vitro to trimethyltransferases of Rickettsia prowazekii RP027-028 and of R. typhi RT0101 and to monomethyltransferases of R. prowazekii RP789 and of R. typhi RT0776, and (ii) native OmpBs purified from R. typhi and R. prowazekii strains Breinl, RP22, and Madrid E. We found that in vitro trimethylation occurs at relatively specific locations in OmpB with consensus motifs, KX(G/A/V/I)N and KT(I/L/F), whereas monomethylation is pervasive throughout OmpB. Native OmpB from virulent R. typhi contains mono- and trimethyllysines at locations well correlated with methylation in recombinant OmpB catalyzed by methyltransferases in vitro. Native OmpBs from highly virulent R. prowazekii strains Breinl and RP22 contain multiple clusters of trimethyllysine in contrast to a single cluster in OmpB from mildly virulent R. typhi. Furthermore, OmpB from the avirulent strain Madrid E contains mostly monomethyllysine and no trimethyllysine. The native OmpB from Madrid E was minimally trimethylated by RT0101 or RP027-028, consistent with a processive mechanism of trimethylation. This study provides the first in-depth characterization of methylation of an OMP at the molecular level and may lead to uncovering the link between OmpB methylation and rickettsial virulence. C1 [Abeykoon, Amila; Yang, David C. H.] Georgetown Univ, Dept Chem, Washington, DC 20057 USA. [Wang, Guanghui; Gucek, Marjan] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. [Chao, Chien-Chung; Ching, Wei-Mei] Naval Med Res Ctr, Viral & Rickettsial Dis Dept, Infect Dis Directorate, Silver Spring, MD 20910 USA. [Chock, P. Boon] NHLBI, Biochem Lab, Bethesda, MD 20892 USA. RP Yang, DCH (reprint author), Georgetown Univ, Dept Chem, Washington, DC 20057 USA. EM yangdc@georgetown.edu RI Yang, David/A-7294-2009 FU Naval Medical Logistic Command Award [N62645]; [6000.RAD1.J.A0310] FX The work was supported by Naval Medical Logistic Command Award N62645 (to Georgetown University) and Work Unit 6000.RAD1.J.A0310 (to the Naval Medical Research Center). NR 44 TC 8 Z9 8 U1 1 U2 9 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 MAR 14 PY 2014 VL 289 IS 11 BP 7691 EP 7701 DI 10.1074/jbc.M113.535567 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AC8CV UT WOS:000332761500037 PM 24497633 ER PT J AU Koorella, C Nair, JR Murray, ME Carlson, LM Watkins, SK Lee, KP AF Koorella, Chandana Nair, Jayakumar R. Murray, Megan E. Carlson, Louise M. Watkins, Stephanie K. Lee, Kelvin P. TI Novel Regulation of CD80/CD86-induced Phosphatidylinositol 3-Kinase Signaling by NOTCH1 Protein in Interleukin-6 and Indoleamine 2,3-Dioxygenase Production by Dendritic Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Dendritic Cells; Interleukin; NOTCH Pathway; PI 3-Kinase (PI3K); Signal Transduction; Indoleamine 2; 3-Dioxygenase ID NITRIC-OXIDE SYNTHASE; CD4(+) T-CELLS; MALIGNANT PLASMA-CELLS; TRANSCRIPTION FACTOR; TRYPTOPHAN CATABOLISM; DEPENDENT PATHWAY; STROMAL CELLS; CD28 FUNCTION; IN-VITRO; PTEN AB Background: Engagement of CD80/CD86 on dendritic cells by CD28 on T cells induces dendritic cell production of IL-6 and IDO. Results: The NOTCH pathway modulates activation of the PI3K pathway downstream of CD80/CD86 ligation and regulates IL-6 and IDO production. Conclusion: Cross-talk between NOTCH and PI3K pathways modulates dendritic cell production of IL-6 and IDO. Significance: Elucidating the molecular mechanism of NOTCH-PI3K cross-talk will have broad implications in human disease. Dendritic cells (DC) play a critical role in modulating antigen-specific immune responses elicited by T cells via engagement of the prototypic T cell costimulatory receptor CD28 by the cognate ligands CD80/CD86, expressed on DC. Although CD28 signaling in T cell activation has been well characterized, it has only recently been shown that CD80/CD86, which have no demonstrated binding domains for signaling proteins in their cytoplasmic tails, nonetheless also transduce signals to the DC. Functionally, CD80/CD86 engagement results in DC production of the pro-inflammatory cytokine IL-6, which is necessary for full T cell activation. However, ligation of CD80/CD86 by CTLA4 also induces DC production of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO), which depletes local pools of the essential amino acid tryptophan, resulting in blockade of T cell activation. Despite the significant role of CD80/CD86 in immunological processes and the seemingly opposing roles they play by producing IL-6 and IDO upon their activation, how CD80/CD86 signal remains poorly understood. We have now found that cross-linking CD80/CD86 in human DC activates the PI3K/AKT pathway. This results in phosphorylation/inactivation of its downstream target, FOXO3A, and alleviates FOXO3A-mediated suppression of IL-6 expression. A second event downstream of AKT phosphorylation is activation of the canonical NF-B pathway, which induces IL-6 expression. In addition to these downstream pathways, we unexpectedly found that CD80/CD86-induced PI3K signaling is regulated by previously unrecognized cross-talk with NOTCH1 signaling. This cross-talk is facilitated by NOTCH-mediated up-regulation of the expression of prolyl isomerase PIN1, which in turn increases enzyme activity of casein kinase II. Subsequently, phosphatase and tensin homolog (which suppresses PI3K activity) is inactivated via phosphorylation by casein kinase II. This results in full activation of PI3K signaling upon cross-linking CD80/CD86. Similar to IL-6, we have found that CD80/CD86-induced IDO production by DC at late time points is also dependent upon the PI3K AKT NF-B pathway and requires cross-talk with NOTCH signaling. These data further suggest that the same signaling pathways downstream of DC CD80/CD86 cross-linking induce early IL-6 production to enhance T cell activation, followed by later IDO production to self-limit this activation. In addition to characterizing the pathways downstream of CD80/CD86 in IL-6 and IDO production, identification of a novel cross-talk between NOTCH1 and PI3K signaling may provide new insights in other biological processes where PI3K signaling plays a major role. C1 [Koorella, Chandana; Nair, Jayakumar R.; Murray, Megan E.; Carlson, Louise M.; Lee, Kelvin P.] Roswell Pk Canc Inst, Dept Immunol, Buffalo, NY 14263 USA. [Watkins, Stephanie K.] NCI, Natl Inst Hlth, Frederick, MD 21702 USA. RP Lee, KP (reprint author), Roswell Pk Canc Inst, Dept Immunol, Buffalo, NY 14263 USA. EM Kelvin.Lee@roswellpark.org FU National Institutes of Health [R01 CA140622, R01 CA121044, R01 AI10015, T32 CA085183]; Multiple Myeloma Research Foundation FX This work was supported, in whole or in part, by National Institutes of Health Grants R01 CA140622, R01 CA121044, R01 AI10015, and T32 CA085183. This work was also supported by the Multiple Myeloma Research Foundation. NR 51 TC 17 Z9 19 U1 0 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 MAR 14 PY 2014 VL 289 IS 11 BP 7747 EP 7762 DI 10.1074/jbc.M113.519686 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AC8CV UT WOS:000332761500042 PM 24415757 ER PT J AU Jurgensen, HJ Johansson, K Madsen, DH Porse, A Melander, MC Sorensen, KR Nielsen, C Bugge, TH Behrendt, N Engelholm, LH AF Juergensen, Henrik J. Johansson, Kristina Madsen, Daniel H. Porse, Astrid Melander, Maria C. Sorensen, Kristine R. Nielsen, Christoffer Bugge, Thomas H. Behrendt, Niels Engelholm, Lars H. TI Complex Determinants in Specific Members of the Mannose Receptor Family Govern Collagen Endocytosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Collagen; Endocytosis; Extracellular Matrix; Protein Chimeras; Receptor Structure-Function; Intracellular Collagen Degradation; Mannose Receptor; Cancer Invasion; Mannose Receptor Family; uPARAP; Endo180 ID SECRETORY PHOSPHOLIPASES A(2); GELATIN-BINDING DOMAIN; UROKINASE RECEPTOR; MATRIX METALLOPROTEINASE-2; ENDOTHELIAL-CELLS; MEMBRANE-RECEPTOR; LECTIN RECEPTOR; DENDRITIC CELLS; IV COLLAGENASE; IN-VIVO AB Background: Mannose receptor family members are candidate mediators of intracellular collagen degradation. Results: Despite common candidate collagen-binding domains and endocytic capacity throughout the family, only uPARAP/Endo180 and MR internalize collagens. Conclusion: A multi-domain interplay in the active receptors governs collagen endocytosis. Significance: Identification of the principal collagen receptors allows elucidation of the biological importance of intracellular collagen degradation. Members of the well-conserved mannose receptor (MR) protein family have been functionally implicated in diverse biological and pathological processes. Importantly, a proposed common function is the internalization of collagen for intracellular degradation occurring during bone development, cancer invasion, and fibrosis protection. This functional relationship is suggested by a common endocytic capability and a candidate collagen-binding domain. Here we conducted a comparative investigation of each member's ability to facilitate intracellular collagen degradation. As expected, the family members uPARAP/Endo180 and MR bound collagens in a purified system and internalized collagens for degradation in cellular settings. In contrast, the remaining family members, PLA(2)R and DEC-205, showed no collagen binding activity and were unable to mediate collagen internalization. To pinpoint the structural elements discriminating collagen from non-collagen receptors, we constructed a series of receptor chimeras and loss- and gain-of-function mutants. Using this approach we identified a critical collagen binding loop in the suggested collagen binding region (an FN-II domain) in uPARAP/Endo180 and MR, which was different in PLA(2)R or DEC-205. However, we also found that an active FN-II domain was not a sufficient determinant to allow collagen internalization through these receptors. Nevertheless, this ability could be acquired by the transfer of a larger segment of uPARAP/Endo180 (the Cys-rich domain, the FN-II domain and two CTLDs) to DEC-205. These data underscore the importance of the FN-II domain in uPARAP/Endo180 and MR-mediated collagen internalization but at the same time uncover a critical interplay with flanking domains. C1 [Juergensen, Henrik J.; Johansson, Kristina; Madsen, Daniel H.; Porse, Astrid; Melander, Maria C.; Sorensen, Kristine R.; Nielsen, Christoffer; Behrendt, Niels; Engelholm, Lars H.] Rigshosp, Finsen Lab, Biotech Res & Innovat Ctr, DK-2200 Copenhagen, Denmark. [Juergensen, Henrik J.; Madsen, Daniel H.; Bugge, Thomas H.] NIDCR, Proteases & Tissue Remodeling Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Engelholm, LH (reprint author), Rigshosp, Finsen Lab, Copenhagen Bioctr, BRIC, Ole Maaloesvej 5, DK-2200 Copenhagen N, Denmark. EM lhe@finsenlab.dk OI Madsen, Daniel Hargboel/0000-0002-3183-6201; Engelholm, Lars/0000-0002-6616-1232 FU NIDCR Intramural Research Program; Danish Cancer Society; Danish Medical Research Council; Danish Cancer Research Foundation; Novo Nordisk Foundation; Danish National Research Foundation (Danish-Chinese Center for Proteases and Cancer); European Community [201279]; Lundbeck Foundation; "Grosserer Alfred Nielsen og Hustrus" foundation; Rigshospitalet/Copenhagen University Hospital FX This work was supported by the NIDCR Intramural Research Program (D. M. and T. H. B.), the Danish Cancer Society, the Danish Medical Research Council, the Danish Cancer Research Foundation, the Novo Nordisk Foundation, the Danish National Research Foundation (Danish-Chinese Center for Proteases and Cancer) and the European Community's Seventh Framework Programme FP7/2007-2011 under Grant agreement no 201279 (to M. C. M. and N. B.), by the Lundbeck Foundation (to D. H. M. and L. H. E.), the "Grosserer Alfred Nielsen og Hustrus" foundation (to L. H. E.). The work was also supported by personal grants from Rigshospitalet/Copenhagen University Hospital (to H. J. J. and A. P.). NR 67 TC 10 Z9 11 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 MAR 14 PY 2014 VL 289 IS 11 BP 7935 EP 7947 DI 10.1074/jbc.M113.512780 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AC8CV UT WOS:000332761500058 PM 24500714 ER PT J AU Matyas, GR Rice, KC Cheng, K Li, F Antoline, JFG Iyer, MR Jacobson, AE Mayorov, AV Beck, Z Torres, OB Alving, CR AF Matyas, Gary R. Rice, Kenner C. Cheng, Kejun Li, Fuying Antoline, Joshua F. G. Iyer, Malliga R. Jacobson, Arthur E. Mayorov, Alexander V. Beck, Zoltan Torres, Oscar B. Alving, Carl R. TI Facial recognition of heroin vaccine opiates: Type 1 cross-reactivities of antibodies induced by hydrolytically stable haptenic surrogates of heroin, 6-acetylmorphine, and morphine SO VACCINE LA English DT Article DE Haptens; Heroin; 6-Acetylmorphine; Morphine; Type 1 and type 2 cross-reactivity; Liposomes; Monophosphoryl lipid A; Tetanus toxoid; Vaccines to drugs of abuse ID CONJUGATE VACCINE; ADJUVANT SYSTEM; RELAPSE; BEHAVIORS; LIPOSOMES; ABUSE; RATS AB Novel synthetic compounds similar to heroin and its major active metabolites, 6-acetylmorphine and morphine, were examined as potential surrogate haptens for the ability to interface with the immune system for a heroin vaccine. Recent studies have suggested that heroin-like haptens must degrade hydrolytically to induce independent immune responses both to heroin and to the metabolites, resulting in antisera containing mixtures of antibodies (type 2 cross-reactivity). To test this concept, two unique hydrolytically stable haptens were created based on presumed structural facial similarities to heroin or to its active metabolites. After conjugation of a heroin-like hapten (DiAmHap) to tetanus toxoid and mixing with liposomes containing monophosphotyl lipid A, high titers of antibodies after two injections in mice had complementary binding sites that exhibited strong type 1 ("true") specific cross-reactivity with heroin and with both of its physiologically active metabolites. Mice immunized with each surrogate hapten exhibited reduced antinociceptive effects caused by injection of heroin. This approach obviates the need to create hydrolytically unstable synthetic heroin-like compounds to induce independent immune responses to heroin and its active metabolites for vaccine development. Facial recognition of hydrolytically stable surrogate haptens by antibodies together with type 1 cross-reactivities with heroin and its metabolites can help to guide synthetic chemical strategies for efficient development of a heroin vaccine. (C) 2014 Published by Elsevier Ltd. C1 [Matyas, Gary R.; Mayorov, Alexander V.; Beck, Zoltan; Torres, Oscar B.; Alving, Carl R.] Walter Reed Army Inst Res, US Mil HIV Res Program, Lab Adjuvant & Antigen Res, Silver Spring, MD 20910 USA. [Rice, Kenner C.; Cheng, Kejun; Li, Fuying; Antoline, Joshua F. G.; Jacobson, Arthur E.] Natl Inst Drug Abuse, Drug Design & Synth Sect, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Rice, Kenner C.; Cheng, Kejun; Li, Fuying; Antoline, Joshua F. G.; Jacobson, Arthur E.] NIAAA, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Rice, Kenner C.; Cheng, Kejun; Li, Fuying; Antoline, Joshua F. G.; Iyer, Malliga R.; Jacobson, Arthur E.] NIAAA, NIH, Bethesda, MD 20892 USA. [Mayorov, Alexander V.; Beck, Zoltan; Torres, Oscar B.] Henry M Jackson Fdn Adv Mil Med, US Mil HIV Res Program, Bethesda, MD 20817 USA. RP Alving, CR (reprint author), Walter Reed Army Inst Res, US Mil HIV Res Program, Lab Adjuvant & Antigen Res, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM calving@hivresearch.org OI Matyas, Gary/0000-0002-2074-2373 FU Henry M. Jackson Foundation for the Advancement of Military Medicine [W81XWH-07-2-067]; U.S. Army Medical Research and Materiel Command (MRMC); National Institute on Drug Abuse (NIH) [1DP1DA034787-01]; NIH Intramural Research Programs of the National Institute on Drug Abuse; National Institute of Alcohol Abuse and Alcoholism; NIH; DHHS FX This work was supported through a Cooperative Agreement Award (no. W81XWH-07-2-067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the U.S. Army Medical Research and Materiel Command (MRMC). The work was partially supported by an Avant Garde award to GRM from the National Institute on Drug Abuse (NIH grant no. 1DP1DA034787-01). The work of KC, FL, MRI, AEJ, and KCR was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism, NIH, DHHS. The authors thank Dr. Jay A. Berzofsky (NCI, NIH) for useful discussion of type 1 and type 2 cross-reactivity; Ms. Elaine Morrison, Ms. Courtney Tucker and Mr. Marcus Gallon provided outstanding technical assistance. Research was conducted in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals and adhered to principles stated in the Guide for the Care and Use of Laboratory Animals, NRC Publication, 1996 edition. The views expressed in this article are those of the authors and do not necessarily reflect the official policy of the Department of the Army, Department of Defense, or NIH, or the U.S. Government. NR 18 TC 7 Z9 7 U1 0 U2 3 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 MAR 14 PY 2014 VL 32 IS 13 BP 1473 EP 1479 DI 10.1016/j.vaccine.2014.01.028 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AG7SC UT WOS:000335617600009 PM 24486371 ER PT J AU Knight, JS Luo, W O'Dell, AA Yalavarthi, S Zhao, WP Subramanian, V Guo, CA Grenn, RC Thompson, PR Eitzman, DT Kaplan, MJ AF Knight, Jason S. Luo, Wei O'Dell, Alexander A. Yalavarthi, Srilakshmi Zhao, Wenpu Subramanian, Venkataraman Guo, Chiao Grenn, Robert C. Thompson, Paul R. Eitzman, Daniel T. Kaplan, Mariana J. TI Peptidylarginine Deiminase Inhibition Reduces Vascular Damage and Modulates Innate Immune Responses in Murine Models of Atherosclerosis SO CIRCULATION RESEARCH LA English DT Article DE atherosclerosis; immunology; interferon-; neutrophils; protein-arginine deiminase; thrombosis ID NEUTROPHIL EXTRACELLULAR TRAPS; E-DEFICIENT MICE; PLASMACYTOID DENDRITIC CELLS; DEEP-VEIN THROMBOSIS; CARDIOVASCULAR-DISEASE; INTERFERON-ALPHA; KNOCKOUT MICE; LUPUS; LESIONS; DNA AB Rationale: Neutrophil extracellular trap (NET) formation promotes vascular damage, thrombosis, and activation of interferon--producing plasmacytoid dendritic cells in diseased arteries. Peptidylarginine deiminase inhibition is a strategy that can decrease in vivo NET formation. Objective: To test whether peptidylarginine deiminase inhibition, a novel approach to targeting arterial disease, can reduce vascular damage and inhibit innate immune responses in murine models of atherosclerosis. Methods and Results:Apolipoprotein-E (Apoe)(-/-) mice demonstrated enhanced NET formation, developed autoantibodies to NETs, and expressed high levels of interferon- in diseased arteries. Apoe(-/-) mice were treated for 11 weeks with daily injections of Cl-amidine, a peptidylarginine deiminase inhibitor. Peptidylarginine deiminase inhibition blocked NET formation, reduced atherosclerotic lesion area, and delayed time to carotid artery thrombosis in a photochemical injury model. Decreases in atherosclerosis burden were accompanied by reduced recruitment of netting neutrophils and macrophages to arteries, as well as by reduced arterial interferon- expression. Conclusions: Pharmacological interventions that block NET formation can reduce atherosclerosis burden and arterial thrombosis in murine systems. These results support a role for aberrant NET formation in the pathogenesis of atherosclerosis through modulation of innate immune responses. C1 [Knight, Jason S.; O'Dell, Alexander A.; Yalavarthi, Srilakshmi; Grenn, Robert C.] Univ Michigan, Sch Med, Dept Rheumatol, Ann Arbor, MI USA. [Luo, Wei; Guo, Chiao; Eitzman, Daniel T.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. [Zhao, Wenpu; Kaplan, Mariana J.] NIAMSD, Syst Autoimmun Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Subramanian, Venkataraman; Thompson, Paul R.] Scripps Res Inst, Dept Chem, Jupiter, FL USA. RP Knight, JS (reprint author), Univ Michigan, Dept Internal Med, Div Rheumatol, 5520 MSRB 1,1150 W Med Ctr Dr,SPC 5680, Ann Arbor, MI 48109 USA. EM jsknight@umich.edu; mariana.kaplan@nih.gov FU National Institutes of Health (NIH) through Public Health Service grant [HL088419]; Rheumatology Research Foundation Rheumatology Scientist Development Award; NIH [GM079357, CA151304] FX This work was supported by the National Institutes of Health (NIH) through Public Health Service grant HL088419 (to M.J. Kaplan). J.S. Knight was supported by a Rheumatology Research Foundation Rheumatology Scientist Development Award. P.R. Thompson is supported by NIH grants GM079357 and CA151304. This article was prepared while W. Zhao and M.J. Kaplan were employed at the University of Michigan. The opinions expressed in this article are the authors' own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the US government. NR 48 TC 53 Z9 53 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD MAR 14 PY 2014 VL 114 IS 6 BP 947 EP 956 DI 10.1161/CIRCRESAHA.114.303312 PG 10 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AE0IF UT WOS:000333646900010 PM 24425713 ER PT J AU Killeen, GF Chitnis, N AF Killeen, Gerry F. Chitnis, Nakul TI Potential causes and consequences of behavioural resilience and resistance in malaria vector populations: a mathematical modelling analysis SO MALARIA JOURNAL LA English DT Article DE Plasmodium; Anopheles; Malaria; Behaviour; Resistance; Vector control; Endophagic; Exophagic; Endophilic; Exophilic ID INSECTICIDE-TREATED NETS; ANOPHELES-ARABIENSIS; BED NETS; ENTOMOPATHOGENIC FUNGI; PLASMODIUM-FALCIPARUM; TRANSMISSION DYNAMICS; HUMAN EXPOSURE; AEDES-AEGYPTI; MOSQUITO; TANZANIA AB Background: The ability of mosquitoes to evade fatal exposure to insecticidal nets and sprays represents the primary obstacle to eliminating malaria. However, it remains unclear which behaviours are most important for buffering mosquito and parasite populations against vector control. Methods: Simulated life histories were used to compare the impact of alternative feeding behaviour strategies upon overall lifetime feeding success, and upon temporal distributions of successful feeds and biting rates experienced by unprotected humans, in the presence and absence of insecticidal nets. Strictly nocturnal preferred feeding times were contrasted with 1) a wider preference window extending to dawn and dusk, and 2) crepuscular preferences wherein foraging is suppressed when humans sleep and can use nets but is maximal immediately before and after. Simulations with diversion and mortality parameters typical of endophagic, endophilic African vectors, such as Anopheles gambiae and Anopheles funestus, were compared with those for endophagic but exophilic species, such as Anopheles arabiensis, that also enter houses but leave earlier before lethal exposure to insecticide-treated surfaces occurs. Results: Insecticidal nets were predicted to redistribute successful feeding events to dawn and dusk where these were included in the profile of innately preferred feeding times. However, predicted distributions of biting unprotected humans were unaffected because extended host-seeking activity was redistributed to innately preferred feeding times. Recently observed alterations of biting activity distributions therefore reflect processes not captured in this model, such as evolutionary selection of heritably modified feeding time preferences or phenotypically plastic expression of feeding time preference caused by associative learning. Surprisingly, endophagy combined with exophily, among mosquitoes that enter houses but then feed and/or rest briefly before rapidly exiting, consistently attenuated predicted insecticide impact more than any feeding time preference trait. Conclusions: Regardless of underlying cause, recent redistributions of host-biting activity to dawn and dusk necessitate new outdoor control strategies. However, persistently indoor-feeding vectors, that evade intradomiciliary insecticide exposure, are at least equally important. Fortunately, recent evaluations of occupied houses or odour-baited stations, with baffled entrances that retain An. arabiensis within insecticide-treated structures, illustrate how endophagic but exophilic vectors may be more effectively tackled using existing insecticides. C1 [Killeen, Gerry F.] Ifakara Hlth Inst, Environm Hlth & Ecol Sci Themat Grp, Morogoro, Tanzania. [Killeen, Gerry F.] Univ Liverpool, Liverpool Sch Trop Med, Dept Vector Biol, Liverpool L3 5QA, Merseyside, England. [Chitnis, Nakul] Swiss Trop & Publ Hlth Inst, Dept Epidemiol & Publ Hlth, CH-4002 Basel, Switzerland. [Chitnis, Nakul] Univ Basel, Basel, Switzerland. [Chitnis, Nakul] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Killeen, GF (reprint author), Ifakara Hlth Inst, Environm Hlth & Ecol Sci Themat Grp, POB 53, Morogoro, Tanzania. EM gkilleen@ihi.or.tz RI Chitnis, Nakul/B-3105-2013 FU Bill & Melinda Gates Foundation [45114, 52644, OPP1032350]; European Union [265660] FX We thank O J Briet, F O Okumu and N J Govella for comments on the manuscript, as well as F C Collins and T L Russell for discussions that stimulated this analysis. The research leading to this manuscript has received funding from the Bill & Melinda Gates Foundation (award numbers 45114, 52644 and OPP1032350) and the European Union Seventh Framework Programme FP7/2007-2013 (grant agreement 265660). NR 66 TC 15 Z9 16 U1 5 U2 22 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 MAR 14 PY 2014 VL 13 AR 97 DI 10.1186/1475-2875-13-97 PG 16 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AF6CS UT WOS:000334802600003 PM 24629066 ER PT J AU Hasin, N Cusack, SA Ali, SS Fitzpatrick, DA Jones, GW AF Hasin, Naushaba Cusack, Sarah A. Ali, Shahin S. Fitzpatrick, David A. Jones, Gary W. TI Global transcript and phenotypic analysis of yeast cells expressing Ssa1, Ssa2, Ssa3 or Ssa4 as sole source of cytosolic Hsp70-Ssa chaperone activity SO BMC GENOMICS LA English DT Article DE Saccharomyces cerevisiae; Prion; Heat shock; Stress; Hsp70; Ssa1; Ssa2; Ssa3; Ssa4; Chaperone; Gene expression ID NUCLEOTIDE EXCHANGE FACTOR; HEAT-SHOCK PROTEINS; SACCHAROMYCES-CEREVISIAE; PRION PROPAGATION; MOLECULAR CHAPERONES; IN-VIVO; GUANIDINE-HYDROCHLORIDE; FUNCTIONAL SPECIFICITY; MAMMALIAN PRIONS; OXIDATIVE STRESS AB Background: Cytosolic Hsp70 is a ubiquitous molecular chaperone that is involved in responding to a variety of cellular stresses. A major function of Hsp70 is to prevent the aggregation of denatured proteins by binding to exposed hydrophobic regions and preventing the accumulation of amorphous aggregates. To gain further insight into the functional redundancy and specialisation of the highly homologous yeast Hsp70-Ssa family we expressed each of the individual Ssa proteins as the sole source of Hsp70 in the cell and assessed phenotypic differences in prion propagation and stress resistance. Additionally we also analysed the global gene expression patterns in yeast strains expressing individual Ssa proteins, using microarray and RT-qPCR analysis. Results: We confirm and extend previous studies demonstrating that cells expressing different Hsp70-Ssa isoforms vary in their ability to propagate the yeast [PSI+] prion, with Ssa3 being the most proficient. Of the four Ssa family members the heat inducible isoforms are more proficient in acquiring thermotolerance and we show a greater requirement than was previously thought, for cellular processes in addition to the traditional Hsp104 protein disaggregase machinery, in acquiring such thermotolerance. Cells expressing different Hsp70-Ssa isoforms also display differences in phenotypic response to exposure to cell wall damaging and oxidative stress agents, again with the heat inducible isoforms providing better protection than constitutive isoforms. We assessed global transcriptome profiles for cells expressing individual Hsp70-Ssa isoforms as the sole source of cytosolic Hsp70, and identified a significant difference in cellular gene expression between these strains. Differences in gene expression profiles provide a rationale for some phenotypic differences we observed in this study. We also demonstrate a high degree of correlation between microarray data and RT-qPCR analysis for a selection of genes. Conclusions: The Hsp70-Ssa family provide both redundant and variant-specific functions within the yeast cell. Yeast cells expressing individual members of the Hsp70-Ssa family as the sole source of Ssa protein display differences in global gene expression profiles. These changes in global gene expression may contribute significantly to the phenotypic differences observed between the Hsp70-Ssa family members. C1 [Hasin, Naushaba; Cusack, Sarah A.; Jones, Gary W.] Natl Univ Ireland Maynooth, Dept Biol, Yeast Genet Lab, Maynooth, Kildare, Ireland. [Hasin, Naushaba] NICHHD, Sect Format RNA, NIH, Bethesda, MD 20814 USA. [Ali, Shahin S.] ARS, Sustainable Perennial Crops Lab, USDA, Beltsville, MD USA. [Fitzpatrick, David A.] Natl Univ Ireland Maynooth, Dept Biol, Genome Evolut Lab, Maynooth, Kildare, Ireland. RP Jones, GW (reprint author), Natl Univ Ireland Maynooth, Dept Biol, Yeast Genet Lab, Maynooth, Kildare, Ireland. EM gary.jones@nuim.ie OI Fitzpatrick, David/0000-0001-7345-6998 FU Science Foundation Ireland [RFP/07/BIC493]; John and Pat Hume postgraduate scholarship; Toray Industries as part of a 3D-Gene(TM) Competition Award FX We thank Daniel Masison for plasmids, Elizabeth Craig and John Glover for antibodies, used in this study. This work was supported in part by Science Foundation Ireland grant RFP/07/BIC493 awarded to GWJ. NH was supported by a John and Pat Hume postgraduate scholarship. Microarray analysis was performed by Toray Industries as part of a 3D-Gene (TM) Competition Award to GWJ. NR 70 TC 10 Z9 11 U1 5 U2 17 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 MAR 14 PY 2014 VL 15 AR 194 DI 10.1186/1471-2164-15-194 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AD8QB UT WOS:000333529600003 PM 24628813 ER PT J AU Sen, SK Barb, JJ Cherukuri, PF Accame, DS Elkahloun, AG Singh, LN Lee-Lin, SQ Kolodgie, FD Cheng, Q Zhao, XQ Chen, MY Arai, AE Green, ED Mullikin, JC Munson, PJ Biesecker, LG AF Sen, Shurjo K. Barb, Jennifer J. Cherukuri, Praveen F. Accame, David S. Elkahloun, Abdel G. Singh, Larry N. Lee-Lin, Shih-Queen Kolodgie, Frank D. Cheng, Qi Zhao, XiaoQing Chen, Marcus Y. Arai, Andrew E. Green, Eric D. Mullikin, James C. Munson, Peter J. Biesecker, Leslie G. CA NISC Comparative Sequencing TI Identification of candidate genes involved in coronary artery calcification by transcriptome sequencing of cell lines SO BMC GENOMICS LA English DT Article DE Coronary artery calcification; RNA-Seq; Lymphoblastoid cell lines; Transcriptome profiling ID GENOME-WIDE ASSOCIATION; 2010 ACCF/AHA GUIDELINE; INTIMA-MEDIA THICKNESS; RNA-SEQ; DIFFERENTIAL EXPRESSION; ATHEROSCLEROSIS MESA; ASYMPTOMATIC ADULTS; CARDIOVASCULAR RISK; TASK-FORCE; DISEASE AB Background: Massively-parallel cDNA sequencing (RNA-Seq) is a new technique that holds great promise for cardiovascular genomics. Here, we used RNA-Seq to study the transcriptomes of matched coronary artery disease cases and controls in the ClinSeq (R) study, using cell lines as tissue surrogates. Results: Lymphoblastoid cell lines (LCLs) from 16 cases and controls representing phenotypic extremes for coronary calcification were cultured and analyzed using RNA-Seq. All cell lines were then independently re-cultured and along with another set of 16 independent cases and controls, were profiled with Affymetrix microarrays to perform a technical validation of the RNA-Seq results. Statistically significant changes (p < 0.05) were detected in 186 transcripts, many of which are expressed at extremely low levels (5-10 copies/cell), which we confirmed through a separate spike-in control RNA-Seq experiment. Next, by fitting a linear model to exon-level RNA-Seq read counts, we detected signals of alternative splicing in 18 transcripts. Finally, we used the RNA-Seq data to identify differential expression (p < 0.0001) in eight previously unannotated regions that may represent novel transcripts. Overall, differentially expressed genes showed strong enrichment (p = 0.0002) for prior association with cardiovascular disease. At the network level, we found evidence for perturbation in pathways involving both cardiovascular system development and function as well as lipid metabolism. Conclusions: We present a pilot study for transcriptome involvement in coronary artery calcification and demonstrate how RNA-Seq analyses using LCLs as a tissue surrogate may yield fruitful results in a clinical sequencing project. In addition to canonical gene expression, we present candidate variants from alternative splicing and novel transcript detection, which have been unexplored in the context of this disease. C1 [Sen, Shurjo K.; Cherukuri, Praveen F.; Accame, David S.; Elkahloun, Abdel G.; Singh, Larry N.; Lee-Lin, Shih-Queen; Green, Eric D.; Mullikin, James C.; Biesecker, Leslie G.; NISC Comparative Sequencing] NHGRI, NIH, Bethesda, MD 20892 USA. [Barb, Jennifer J.; Munson, Peter J.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. [Kolodgie, Frank D.; Cheng, Qi; Zhao, XiaoQing] CVPath Inst Inc, Gaithersburg, MD 20878 USA. [Chen, Marcus Y.; Arai, Andrew E.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM lesb@mail.nih.gov FU Intramural Research Program of the National Institutes of Health FX The authors thank Peter Chines, Nancy Hansen, Jamie Teer, and Aaron Quinlan for computational analyses, Robert Blakesley, Alice Young, Michael Erdos, Marjorie Lindhurst, Jacquelyn Idol, and Jennifer Johnston for help with experimental procedures, Julia Fekecs for help with preparing high-resolution graphics, Soma Chowdhury for proofreading, and Flavia Facio, David Ng, Clesson Turner, and the ClinSeq (R) clinical support and nursing staff for their help with the clinical aspects of this study. We thank Eric Olivares and the SEQanswers community (http://SEQanswers.com) for providing valuable advice. Above all, we are grateful to the many participants of the ClinSeq (R) study. This study is supported by funds from the Intramural Research Program of the National Institutes of Health. NR 32 TC 1 Z9 1 U1 1 U2 12 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 MAR 14 PY 2014 VL 15 AR 198 DI 10.1186/1471-2164-15-198 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AD8QB UT WOS:000333529600007 PM 24628908 ER PT J AU Lucifora, J Xia, YC Reisinger, F Zhang, K Stadler, D Cheng, XM Sprinzl, MF Koppensteiner, H Makowska, Z Volz, T Remouchamps, C Chou, WM Thasler, WE Huser, N Durantel, D Liang, TJ Munk, C Heim, MH Browning, JL Dejardin, E Dandri, M Schindler, M Heikenwalder, M Protzer, U AF Lucifora, Julie Xia, Yuchen Reisinger, Florian Zhang, Ke Stadler, Daniela Cheng, Xiaoming Sprinzl, Martin F. Koppensteiner, Herwig Makowska, Zuzanna Volz, Tassilo Remouchamps, Caroline Chou, Wen-Min Thasler, Wolfgang E. Hueser, Norbert Durantel, David Liang, T. Jake Muenk, Carsten Heim, Markus H. Browning, Jeffrey L. Dejardin, Emmanuel Dandri, Maura Schindler, Michael Heikenwalder, Mathias Protzer, Ulrike TI Specific and Nonhepatotoxic Degradation of Nuclear Hepatitis B Virus cccDNA SO SCIENCE LA English DT Article ID LYMPHOTOXIN-BETA-RECEPTOR; GENE-EXPRESSION; HEPATOCELLULAR-CARCINOMA; CYTIDINE DEAMINASES; HUMAN HEPATOCYTES; TRANSGENIC MICE; HBV INFECTION; FOREIGN DNA; IN-VITRO; REPLICATION AB Current antiviral agents can control but not eliminate hepatitis B virus (HBV), because HBV establishes a stable nuclear covatently closed circular DNA (cccDNA), Interferon-alpha treatment can clear HBV but is limited by systemic side effects. We describe how interferon-alpha can induce specific degradation of the nuclear viral DNA without hepatotoxicity and propose lymphotoxin-beta receptor activation as a therapeutic alternative. Interferon-alpha and lymphotoxin-beta receptor activation up-regulated APOBEC3A and APOBEC3B cytidine deaminases, respectively, in HBV-infected cells, primary hepatocytes, and human liver needle biopsies. HBV core protein mediated the interaction with nuclear cccDNA, resulting in cytidine deamination, apurinic/apyrimidinic site formation, and finally cccDNA degradation that prevented HBV reactivation. Genomic DNA was not affected. Thus, inducing nuclear deaminases-for example, by lymphotoxin-beta receptor activation-allows the development of new therapeutics that, in combination with existing antivirals, may cure hepatitis B. C1 [Lucifora, Julie; Xia, Yuchen; Reisinger, Florian; Zhang, Ke; Stadler, Daniela; Cheng, Xiaoming; Sprinzl, Martin F.; Koppensteiner, Herwig; Chou, Wen-Min; Schindler, Michael; Heikenwalder, Mathias; Protzer, Ulrike] Tech Univ Munich, Helmholtz Zentrum Munchen, Inst Virol, D-81675 Munich, Germany. [Lucifora, Julie; Dandri, Maura; Protzer, Ulrike] German Ctr Infect Res DZIF, Munich, Germany. [Lucifora, Julie; Dandri, Maura; Protzer, Ulrike] German Ctr Infect Res DZIF, Hamburg Sites, Germany. [Sprinzl, Martin F.] Univ Hosp Mainz, Dept Med 1, D-55131 Mainz, Germany. [Makowska, Zuzanna; Heim, Markus H.] Univ Basel Hosp, Dept Biomed, CH-4031 Basel, Switzerland. [Volz, Tassilo; Dandri, Maura] Univ Med Ctr Hamburg Eppendorf, Dept Internal Med, D-20246 Hamburg, Germany. [Remouchamps, Caroline; Dejardin, Emmanuel] Univ Liege, GIGA Res Lab Mol Immunol & Signal Transduct, B-4000 Liege, Belgium. [Thasler, Wolfgang E.] Univ Munich, Grosshadern Hosp, Dept Gen Visceral Transplantat Vasc & Thorac Surg, D-81377 Munich, Germany. [Hueser, Norbert] Tech Univ Munich, Univ Hosp Rechts Isar, Dept Surg, D-85748 Munich, Germany. [Durantel, David] Univ Lyon, LabEx DEVweCAN, Canc Res Ctr Lyon, INSERM,U1052,CNRS,UMR 5286, F-69007 Lyon, France. [Liang, T. Jake] NIDDK, Liver Dis Branch, Bethesda, MD 20892 USA. [Muenk, Carsten] Univ Dusseldorf, Fac Med, Clin Gastroenterol Hepatol & Infectiol, D-40225 Dusseldorf, Germany. [Browning, Jeffrey L.] Biogen Idec Inc, Dept Immunobiol, Cambridge, MA 02142 USA. RP Heikenwalder, M (reprint author), Tech Univ Munich, Helmholtz Zentrum Munchen, Inst Virol, D-81675 Munich, Germany. EM heikenwaelder@helmholtz-muenchen.de; protzer@tum.de RI Schindler, Michael/C-1647-2015; OI Schindler, Michael/0000-0001-8989-5813; Xia, Yuchen/0000-0001-8460-3893; Heim, Markus/0000-0002-7523-4894 FU Federation Beige Contre Le Cancer; European Research Council; German Research Foundation [SFB 841, SFB TR 36, SFB TR 22]; Peter-Hans Hofschneider Foundation; Helmholtz Alliances HAIT; PCCC; HTCR FX We thank R. Rester, T. Asen, K. Ackermann, K. Kappes, M. Feuerherd, R. Barer, R. Hillermann, U. Finkel, A. Krikoni, and F. Zhang for technical support; L. Terracciano for analysis of acute hepatitis patients; F. Chisari for HBV transgenic mice (HBV 1.3.32); T. Buch arid O. Prazeres da Costa for help with array analysis and data discussions; L. Allweiss and A. Groth for help in generating and treating humanized uPA-SCID mice; and Siemens Healthcare Diagnostics for reagents. Supported by grants from Federation Beige Contre Le Cancer (E.D.), a European Research Council starting grant (LiverCancerMechanism) (M.H.), the German Research Foundation (SFB 841 to M.D. SFB TR 36 to M.H. and SFB TR 22), the Peter-Hans Hofschneider Foundation and the Helmholtz Alliances HAIT (U.P.), and PCCC (M.H.). We acknowledge the support of the nonprofit foundation HTCR, winch holds human tissue on trust, making it broadly available for research on an ethical and legal basis. Patent application EP12006XXX has been filed at the European patent office: "Lymphotoxin signaling activation and its downstream mediators eliminate HBV ccc DNA." Microarray data have been submitted to the GEO database (www.ncbi.nlm.nih.gov/geo/) with accession number GSE46667. Human liver chimeric uPA-SCID mice were handled in accordance with protocols approved by the ethical committee of the city and state of Hamburg (permission number G12/015). Experiments with HBV-transgenic mice were performed in accordance with German legislation governing animal studies and the Principles of Laboratory Animal Care guidelines, NIH (55.1-1-54-2531.3-27-08). The study protocol for the animal experiment in fig. S128 was approved at the Southwest Foundation for Biomedical Research, San Antonio, TX (IACUC 869 PT, approved in 2004). NR 41 TC 204 Z9 219 U1 8 U2 66 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 MAR 14 PY 2014 VL 343 IS 6176 BP 1221 EP 1228 DI 10.1126/science.1243462 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC7RG UT WOS:000332728500030 PM 24557838 ER PT J AU Bitar, C Saba, N AF Bitar, Carole Saba, Nakhle TI Neutrophil numerals SO BLOOD LA English DT Editorial Material C1 [Bitar, Carole] Univ Balamand, Koura, Lebanon. [Saba, Nakhle] NIH, Bethesda, MD USA. RP Bitar, C (reprint author), Univ Balamand, Koura, Lebanon. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 13 PY 2014 VL 123 IS 11 BP 1635 EP 1635 DI 10.1182/blood-2013-12-541797 PG 1 WC Hematology SC Hematology GA AH0YW UT WOS:000335847700009 PM 24761452 ER PT J AU Bouska, A McKeithan, TW Deffenbacher, KE Lachel, C Wright, GW Iqbal, J Smith, LM Zhang, WW Kucuk, C Rinaldi, A Bertoni, F Fitzgibbon, J Fu, K Weisenburger, DD Greiner, TC Dave, BJ Gascoyne, RD Rosenwald, A Ott, G Campo, E Rimsza, LM Delabie, J Jaffe, ES Braziel, RM Connors, JM Staudt, LM Chan, WC AF Bouska, Alyssa McKeithan, Timothy W. Deffenbacher, Karen E. Lachel, Cynthia Wright, George W. Iqbal, Javeed Smith, Lynette M. Zhang, Weiwei Kucuk, Can Rinaldi, Andrea Bertoni, Francesco Fitzgibbon, Jude Fu, Kai Weisenburger, Dennis D. Greiner, Timothy C. Dave, Bhavana J. Gascoyne, Randy D. Rosenwald, Andreas Ott, German Campo, Elias Rimsza, Lisa M. Delabie, Jan Jaffe, Elaine S. Braziel, Rita M. Connors, Joseph M. Staudt, Louis M. Chan, Wing-Chung TI Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma SO BLOOD LA English DT Article ID B-CELL LYMPHOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; NF-KAPPA-B; GERMINAL CENTER; UNIPARENTAL DISOMY; CLONAL EVOLUTION; BINDING PROTEIN; GENE-EXPRESSION; BREAST-CANCER; REPRESSION AB Follicular lymphoma (FL), the second most common type of non-Hodgkin lymphoma in the western world, is characterized by the t(14; 18) translocation, which is present in up to 90% of cases. We studied 277 lymphoma samples (198 FL and 79 transformed FL [tFL]) using a single-nucleotide polymorphism array to identify the secondary chromosomal abnormalities that drive the development of FL and its transformation to diffuse large B-cell lymphoma. Common recurrent chromosomal abnormalities in FL included gains of 2, 5, 7, 6p, 8, 12, 17q, 18, 21, and X and losses on 6q and 17p. We also observed many frequent small abnormalities, including losses of 1p36.33-p36.31, 6q23.3-q24.1, and 10q23.1-q25.1 and gains of 2p16.1-p15, 8q24.13-q24.3, and 12q12-q13.13, and identified candidate genes that may be driving this selection. Recurrent abnormalities more frequent in tFL samples included gains of 3q27.3-q28 and chromosome 11 and losses of 9p21.3 and 15q. Four abnormalities, gain of X or Xp and losses of 6q23.2-24.1 or 6q13-15, predicted overall survival. Abnormalities associated with transformation of the disease likely impair immune surveillance, activate the nuclear factor-kappa B pathway, and deregulate p53 and B-cell transcription factors. C1 [Bouska, Alyssa; McKeithan, Timothy W.; Deffenbacher, Karen E.; Lachel, Cynthia; Iqbal, Javeed; Zhang, Weiwei; Kucuk, Can; Fu, Kai; Greiner, Timothy C.; Chan, Wing-Chung] Univ Nebraska Med Ctr, Omaha, NE USA. [Wright, George W.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Smith, Lynette M.] Univ Nebraska Med Ctr, Coll Publ Hlth Biostat, Omaha, NE USA. [Rinaldi, Andrea; Bertoni, Francesco] Oncol Res Inst, Lymphoma & Genom Res Program, Bellinzona, Switzerland. [Bertoni, Francesco] Oncol Inst Southern Switzerland, Lymphoma Unit, Bellinzona, Switzerland. [Fitzgibbon, Jude] Queen Mary Univ London, Barts Canc Inst, Ctr Haematooncol, London, England. [Weisenburger, Dennis D.] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA. [Dave, Bhavana J.] Univ Nebraska Med Ctr, Ctr Human Genet, Omaha, NE USA. [Gascoyne, Randy D.] British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 4E6, Canada. [Rosenwald, Andreas] Univ Wurzburg, D-97070 Wurzburg, Germany. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Germany. [Ott, German] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Campo, Elias] Hosp Clin Barcelona, Hematopathol Unit, Barcelona, Spain. [Rimsza, Lisa M.] Univ Arizona, Dept Pathol, Tucson, AZ USA. [Delabie, Jan] Univ Toronto, Dept Pathol, Toronto, ON, Canada. [Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Braziel, Rita M.] Oregon Hlth & Sci Univ, Portland, OR USA. [Connors, Joseph M.] British Columbia Canc Agcy, Div Med Oncol, Vancouver, BC V5Z 4E6, Canada. [Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Chan, WC (reprint author), Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Ctr Res Lymphoma & Leukemia, 983135 Nebraska Med Ctr, Omaha, NE 68198 USA. EM jchan@unmc.edu RI Kucuk, Can/K-3913-2015; Campo, elias/O-7192-2016; OI Delabie, Jan/0000-0001-5023-0689; Jaffe, Elaine/0000-0003-4632-0301; Bertoni, Francesco/0000-0001-5637-8983; Kucuk, Can/0000-0001-5540-9012; Campo, elias/0000-0001-9850-9793; McKeithan, Timothy/0000-0003-2242-3074 FU Lymphoma Research Foundation Follicular Lymphoma Initiative; National Institutes of Health Lymphoma SPORE [P50CA136411-01-(NC1)]; Oncosuisse grant [OCS-1939-8-2006]; Nelia et Amadeo Barletta Foundation (Lausanne, Switzerland) FX This work was supported by the Lymphoma Research Foundation Follicular Lymphoma Initiative (W.-C. C.), National Institutes of Health Lymphoma SPORE P50CA136411-01-(NC1) (W.-C.C.), Oncosuisse grant OCS-1939-8-2006 (F.B.), and the Nelia et Amadeo Barletta Foundation (Lausanne, Switzerland) (F.B.). NR 56 TC 20 Z9 20 U1 1 U2 6 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 MAR 13 PY 2014 VL 123 IS 11 BP 1681 EP 1690 DI 10.1182/blood-2013-05-500595 PG 10 WC Hematology SC Hematology GA AH0YW UT WOS:000335847700015 PM 24037725 ER PT J AU Yu, GQ Fadrosh, D Ma, B Ravel, J Goedert, JJ AF Yu, Guoqin Fadrosh, Doug Ma, Bing Ravel, Jacques Goedert, James J. TI Anal microbiota profiles in HIV-positive and HIV-negative MSM SO AIDS LA English DT Article DE anal; sexual activities; risk factors; HIV; MSM; human microbiome ID BURROWS-WHEELER TRANSFORM; HOMOSEXUAL-MEN; BACTERIAL VAGINOSIS; HUMAN-IMMUNODEFICIENCY; READ ALIGNMENT; GUT MICROBIOME; DIVERSITY; WOMEN; AIDS AB Objective: Because differences in anal microbial populations (microbiota) could affect acquisition of HIV or other conditions, especially among MSM, we profiled the microbiota of the anal canal, assessed its stability, and investigated associations with diversity and composition. Design: Microbiota profiles in anal swabs collected from 76 MSM (52 in 1989, swab-1; 66 1-5 years later, swab-2) were compared by HIV status (25 HIV-positive), T-cell subsets, and questionnaire data. Methods: Bacterial 16S rRNA genes were amplified, sequenced (Illumina MiSeq), and clustered into species-level operational taxonomic units (QIIME and Greengenes). Regression models and Wilcoxon tests were used for associations with alpha diversity (unique operational taxonomic units, Shannon's index). Composition was compared by Adonis (QIIME). Results: Most anal bacteria were Firmicutes (mean 60.6%, range 21.1-91.1%) or Bacteroidetes (29.4%, 4.1-70.8%). Alpha diversity did not change between the two swabs (N = 42 pairs). In swab-2, HIV-positives had lower alpha diversity (P <= 0.04) and altered composition, with fewer Firmicutes and more Fusobacteria taxa (P <= 0.03), not completely attributable to very low CD4(+) cell count (median 232 cells/mu l), prior AIDS clinical diagnosis (N = 17), or trimethoprim-sulfamethoxazole use (N = 6). Similar but weaker differences were observed in swab-1 (HIV-positive median 580 CD4(+) cells/mu l; no trimethoprim-sulfamethoxazole). Associations with T-cell subsets, smoking, and sexual practices were null or inconsistent. Conclusions: The anal microbiota of MSM was relatively stable over 1-5 years. However, with uncontrolled, advanced HIV infection, the microbiota had altered composition and reduced diversity partially attributable to antibiotics. Investigations of microbial community associations with other immune perturbations and clinical abnormalities are needed. C1 [Yu, Guoqin; Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Fadrosh, Doug; Ma, Bing; Ravel, Jacques] Univ Maryland, Sch Med, Inst Genom Sci, Baltimore, MD 21201 USA. RP Goedert, JJ (reprint author), 9609 Med Ctr Dr,Room 6E106 MSC 9767, Bethesda, MD 20892 USA. EM goedertj@mail.nih.gov RI Ma, Bing/C-8226-2014; OI Ma, Bing/0000-0002-3488-2393; Ravel, Jacques/0000-0002-0851-2233 FU National Cancer Institute FX Supported in part by the Intramural Research Program of the National Cancer Institute. NR 29 TC 15 Z9 15 U1 1 U2 37 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 MAR 13 PY 2014 VL 28 IS 5 BP 753 EP 760 DI 10.1097/QAD.0000000000000154 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AD6QU UT WOS:000333386700013 PM 24335481 ER PT J AU Solomon, BD AF Solomon, Benjamin D. TI Incidentalomas in Genomics and Radiology SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID RECOMMENDATIONS; EXOME AB The often-drawn analogy between incidental findings in genomics and radiology may give nonexperts a false impression of our ability to efficiently interpret genetic or genomic findings and to understand how they might affect a person's health. The availability of new technologies has made high-throughput genomic sequencing increasingly prevalent in both research and clinical fields. Such sequencing includes targeted methods, such as exome sequencing, which focuses on the functionally important regions of known genes, as well as whole-genome sequencing. As the use of these methods grows, it is important to accurately describe both their potential and their inherent challenges. One controversial area involves the handling of the range of medical information found through genomic sequencing.(1),(2) This may include genetic or genomic data that are unrelated to the primary reason for conducting sequencing but may be medically ... C1 [Solomon, Benjamin D.] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. [Solomon, Benjamin D.] Inova Translat Med Inst, Falls Church, VA USA. RP Solomon, BD (reprint author), NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. NR 5 TC 14 Z9 14 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 MAR 13 PY 2014 VL 370 IS 11 BP 988 EP 990 DI 10.1056/NEJMp1310471 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AC7ED UT WOS:000332689100004 PM 24620864 ER PT J AU Beuschlein, F Fassnacht, M Assie, G Calebiro, D Stratakis, CA Osswald, A Ronchi, CL Wieland, T Sbiera, S Faucz, FR Schaak, K Schmittfull, A Schwarzmayr, T Barreau, O Vezzosi, D Rizk-Rabin, M Zabel, U Szarek, E Salpea, P Forlino, A Vetro, A Zuffardi, O Kisker, C Diener, S Meitinger, T Lohse, MJ Reincke, M Bertherat, J Strom, TM Allolio, B AF Beuschlein, Felix Fassnacht, Martin Assie, Guillaume Calebiro, Davide Stratakis, Constantine A. Osswald, Andrea Ronchi, Cristina L. Wieland, Thomas Sbiera, Silviu Faucz, Fabio R. Schaak, Katrin Schmittfull, Anett Schwarzmayr, Thomas Barreau, Olivia Vezzosi, Delphine Rizk-Rabin, Marthe Zabel, Ulrike Szarek, Eva Salpea, Paraskevi Forlino, Antonella Vetro, Annalisa Zuffardi, Orsetta Kisker, Caroline Diener, Susanne Meitinger, Thomas Lohse, Martin J. Reincke, Martin Bertherat, Jerome Strom, Tim M. Allolio, Bruno TI Constitutive Activation of PKA Catalytic Subunit in Adrenal Cushing's Syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PROTEIN-KINASE-A; ADRENOCORTICAL TUMORS; REGULATORY SUBUNIT; SOMATIC MUTATIONS; CARNEY COMPLEX; GENE; HYPERPLASIA; EXPRESSION; MANAGEMENT; RECEPTOR AB BackgroundCorticotropin-independent Cushing's syndrome is caused by tumors or hyperplasia of the adrenal cortex. The molecular pathogenesis of cortisol-producing adrenal adenomas is not well understood. MethodsWe performed exome sequencing of tumor-tissue specimens from 10 patients with cortisol-producing adrenal adenomas and evaluated recurrent mutations in candidate genes in an additional 171 patients with adrenocortical tumors. We also performed genomewide copy-number analysis in 35 patients with cortisol-secreting bilateral adrenal hyperplasias. We studied the effects of these genetic defects both clinically and in vitro. ResultsExome sequencing revealed somatic mutations in PRKACA, which encodes the catalytic subunit of cyclic AMP-dependent protein kinase (protein kinase A [PKA]), in 8 of 10 adenomas (c.617AC in 7 and c.595_596insCAC in 1). Overall, PRKACA somatic mutations were identified in 22 of 59 unilateral adenomas (37%) from patients with overt Cushing's syndrome; these mutations were not detectable in 40 patients with subclinical hypercortisolism or in 82 patients with other adrenal tumors. Among 35 patients with cortisol-producing hyperplasias, 5 (including 2 first-degree relatives) carried a germline copy-number gain (duplication) of the genomic region on chromosome 19 that includes PRKACA. In vitro studies showed impaired inhibition of both PKA catalytic subunit mutants by the PKA regulatory subunit, whereas cells from patients with germline chromosomal gains showed increased protein levels of the PKA catalytic subunit; in both instances, basal PKA activity was increased. ConclusionsGenetic alterations of the catalytic subunit of PKA were found to be associated with human disease. Germline duplications of this gene resulted in bilateral adrenal hyperplasias, whereas somatic PRKACA mutations resulted in unilateral cortisol-producing adrenal adenomas. (Funded by the European Commission Seventh Framework Program and others.) Corticotropin-independent Cushing's syndrome occurs with adrenocortical tumors or hyperplasia. The authors report that germline duplications of PRKACA lead to bilateral adrenal hyperplasia, whereas somatic mutations lead to unilateral cortisol-producing adrenal adenomas. Endogenous hypercortisolism, referred to as Cushing's syndrome, is associated with substantial morbidity and mortality.(1) When Cushing's syndrome is severe, patients have catabolic symptoms such as muscle weakness, skin fragility, osteoporosis, and severe metabolic sequelae.(2) Hypersecretion of cortisol can be driven by an excess of pituitary or ectopic corticotropin or can be due to adrenocortical tumors or hyperplasias with corticotropin-independent cortisol production. Adrenal adenomas are common, with a prevalence of at least 3% among persons older than 50 years of age.(3) Whereas only a subset of these tumors is associated with overt Cushing's syndrome, some degree of cortisol excess is present, ... C1 [Beuschlein, Felix; Fassnacht, Martin; Osswald, Andrea; Sbiera, Silviu; Schaak, Katrin; Reincke, Martin] Univ Munich, Med Klin & Poliklin IV, Munich, Germany. [Meitinger, Thomas; Strom, Tim M.] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Meitinger, Thomas; Strom, Tim M.] Munich Heart Alliance, Deutsch Zentrum Herz Kreislauf Forsch, Munich, Germany. [Fassnacht, Martin; Sbiera, Silviu; Allolio, Bruno] Univ Wurzburg, Dept Med 1, Endocrine & Diabet Unit, Univ Hosp, D-97070 Wurzburg, Germany. [Fassnacht, Martin; Lohse, Martin J.; Allolio, Bruno] Univ Wurzburg, Comprehens Heart Failure Ctr, D-97070 Wurzburg, Germany. [Calebiro, Davide; Zabel, Ulrike; Lohse, Martin J.] Univ Wurzburg, Inst Pharmacol & Toxicol, D-97070 Wurzburg, Germany. [Calebiro, Davide; Kisker, Caroline; Lohse, Martin J.] Univ Wurzburg, Rudolf Virchow Ctr, D-97070 Wurzburg, Germany. [Calebiro, Davide; Kisker, Caroline; Lohse, Martin J.] Univ Wurzburg, Deutsch Forschungsgemeinschaft Res Ctr Expt Biome, D-97070 Wurzburg, Germany. [Ronchi, Cristina L.] Univ Wurzburg, Comprehens Canc Ctr Mainfranken, D-97070 Wurzburg, Germany. [Wieland, Thomas; Schmittfull, Anett; Schwarzmayr, Thomas; Diener, Susanne; Meitinger, Thomas; Strom, Tim M.] Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Assie, Guillaume; Barreau, Olivia; Vezzosi, Delphine; Rizk-Rabin, Marthe; Bertherat, Jerome] Univ Paris 05, Ctr Natl Rech Scientif, Unit Mixte Rech 8104, INSERM Unite 1016,Inst Cochin,Fac Med,Sorbonne Pa, Paris, France. [Assie, Guillaume; Barreau, Olivia; Bertherat, Jerome] Hop Cochin, Assistance Publique Hop Paris, Referral Ctr Rare Adrenal Dis, Dept Endocrinol, F-75674 Paris, France. [Stratakis, Constantine A.; Faucz, Fabio R.; Szarek, Eva; Salpea, Paraskevi] NICHHD, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Forlino, Antonella; Zuffardi, Orsetta] Univ Pavia, Dipartimento Med Mol, I-27100 Pavia, Italy. [Vetro, Annalisa] Policlin San Matteo, Fdn Ist Ricovoro & Cura Carattere Sci, Biotechnol Res Lab, I-27100 Pavia, Italy. RP Fassnacht, M (reprint author), Univ Hosp Wurzburg, Dept Med 1, Oberdurrbacherstr 6, D-97080 Wurzburg, Germany. EM fassnacht_m@ukw.de RI Lohse, Martin/A-7160-2012; Forlino, Antonella/H-5385-2015; Meitinger, Thomas/O-1318-2015; OI Lohse, Martin/0000-0002-0599-3510; Forlino, Antonella/0000-0002-6385-1182; Beuschlein, Felix/0000-0001-7826-3984; zuffardi, orsetta/0000-0002-1466-4559; calebiro, davide/0000-0002-3811-1553; Vetro, Annalisa/0000-0003-2437-7526; Ronchi, Cristina/0000-0001-5020-2071 FU European Commission FX Funded by the European Commission Seventh Framework Program and others. NR 37 TC 114 Z9 115 U1 2 U2 17 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 MAR 13 PY 2014 VL 370 IS 11 BP 1019 EP 1028 DI 10.1056/NEJMoa1310359 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AC7ED UT WOS:000332689100009 PM 24571724 ER PT J AU Forlino, A Vetro, A Garavelli, L Ciccone, R London, E Stratakis, CA Zuffardi, O AF Forlino, Antonella Vetro, Annalisa Garavelli, Livia Ciccone, Roberto London, Edra Stratakis, Constantine A. Zuffardi, Orsetta TI PRKACB and Carney Complex SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter AB The authors report that a gain of function in the catalytic subunit beta of the cyclic AMP-dependent protein kinase (protein kinase A), resulting from the presence of four copies of PRKACB (instead of the normal two), may lead to a Carney complex phenotype.To the Editor: Beuschlein et al. report a gain of function in PRKACA, the catalytic subunit alpha (C) of the cyclic AMP (cAMP)-dependent protein kinase (protein kinase A [PKA]) in cortisol-producing adenomas and micronodular adrenocortical hyperplasia.(1) Micronodular adrenocortical hyperplasia is also associated with Carney complex and inactivating mutations of the PKA regulatory subunit RI (encoded by PRKAR1A).(2),(3) We report the case of a young woman with Carney complex who presented at 19 years of age with acromegaly, pigmented spots, and myxomas (Figure 1A); she did not have Cushing's syndrome (see the Supplementary Appendix, available with the full text of ... C1 [Forlino, Antonella; Ciccone, Roberto; Zuffardi, Orsetta] Univ Pavia, I-27100 Pavia, Italy. [Vetro, Annalisa] Fdn Ist Ricovero & Cura Carattere Sci IRCCS Polic, Pavia, Italy. [Garavelli, Livia] IRCCS Arcispedale S Maria Nuova, Reggio Emilia, Italy. [London, Edra; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Forlino, A (reprint author), Univ Pavia, Via Palestro 3, I-27100 Pavia, Italy. EM stratakc@mail.nichd.nih.gov; zuffardi@unipv.it RI Forlino, Antonella/H-5385-2015; OI Forlino, Antonella/0000-0002-6385-1182; Vetro, Annalisa/0000-0003-2437-7526; zuffardi, orsetta/0000-0002-1466-4559 FU Intramural NIH HHS NR 3 TC 27 Z9 27 U1 0 U2 2 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 MAR 13 PY 2014 VL 370 IS 11 BP 1065 EP 1067 DI 10.1056/NEJMc1309730 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AC7ED UT WOS:000332689100016 PM 24571725 ER PT J AU Jalah, R Kulkarni, V Patel, V Rosati, M Alicea, C Bear, J Yu, L Guan, YJ Shen, XY Tomaras, GD LaBranche, C Montefiori, DC Prattipati, R Pinter, A Bess, J Lifson, JD Reed, SG Sardesai, NY Venzon, DJ Valentin, A Pavlakis, GN Felber, BK AF Jalah, Rashmi Kulkarni, Viraj Patel, Vainav Rosati, Margherita Alicea, Candido Bear, Jenifer Yu, Lei Guan, Yongjun Shen, Xiaoying Tomaras, Georgia D. LaBranche, Celia Montefiori, David C. Prattipati, Rajasekhar Pinter, Abraham Bess, Julian, Jr. Lifson, Jeffrey D. Reed, Steven G. Sardesai, Niranjan Y. Venzon, David J. Valentin, Antonio Pavlakis, George N. Felber, Barbara K. TI DNA and Protein Co-Immunization Improves the Magnitude and Longevity of Humoral Immune Responses in Macaques SO PLOS ONE LA English DT Article ID T-CELL RESPONSES; IMMUNODEFICIENCY VIRUS CHALLENGE; ELECTROPORATION IN-VIVO; HIV-1 VACCINE EFFICACY; RHESUS MACAQUES; GENE-TRANSFER; ENVELOPE GLYCOPROTEINS; SIVMAC251 CHALLENGE; B-CELL; PLASMID AB We tested the concept of combining DNA with protein to improve anti-HIV Env systemic and mucosal humoral immune responses. Rhesus macaques were vaccinated with DNA, DNA&protein co-immunization or DNA prime followed by protein boost, and the magnitude and mucosal dissemination of the antibody responses were monitored in both plasma and mucosal secretions. We achieved induction of robust humoral responses by optimized DNA vaccination delivered by in vivo electroporation. These responses were greatly increased upon administration of a protein boost. Importantly, a co-immunization regimen of DNA&protein injected in the same muscle at the same time induced the highest systemic binding and neutralizing antibodies to homologous or heterologous Env as well as the highest Env-specific IgG in saliva. Inclusion of protein in the vaccine resulted in more immunized animals with Env-specific IgG in rectal fluids. Inclusion of DNA in the vaccine significantly increased the longevity of systemic humoral immune responses, whereas protein immunization, either as the only vaccine component or as boost after DNA prime, was followed by a great decline of humoral immune responses overtime. We conclude that DNA&protein co-delivery in a simple vaccine regimen combines the strength of each vaccine component, resulting in improved magnitude, extended longevity and increased mucosal dissemination of the induced antibodies in immunized rhesus macaques. C1 [Jalah, Rashmi; Kulkarni, Viraj; Alicea, Candido; Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Frederick, MD 21701 USA. [Patel, Vainav; Rosati, Margherita; Bear, Jenifer; Valentin, Antonio; Pavlakis, George N.] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. [Yu, Lei; Guan, Yongjun] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Inst Human Virol, Baltimore, MD 21201 USA. [Shen, Xiaoying; Tomaras, Georgia D.] Duke Univ, Duke Human Vaccine Inst, Durham, NC USA. [Shen, Xiaoying; Tomaras, Georgia D.] Duke Univ, Dept Surg, Durham, NC USA. [Shen, Xiaoying; Tomaras, Georgia D.] Duke Univ, Dept Immunol Mol Genet & Microbiol, Durham, NC USA. [LaBranche, Celia; Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Prattipati, Rajasekhar; Pinter, Abraham] Univ Med & Dent New Jersey, Publ Hlth Res Inst, Newark, NJ 07103 USA. [Bess, Julian, Jr.; Lifson, Jeffrey D.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Reed, Steven G.] Infect Dis Res Inst, Seattle, WA USA. [Sardesai, Niranjan Y.] Inovio Pharmaceut Inc, Blue Bell, PA USA. [Venzon, David J.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. RP Pavlakis, GN (reprint author), NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. EM george.pavlakis@nih.gov; barbara.felber@nih.gov RI Tomaras, Georgia/J-5041-2016 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH); NCI/NIH [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases-NIH [HHSN27201100016C, R01AI102718]; Institute of Human Virology Faculty Development Fund; Bill and Melinda Gates Foundation [42387] FX This work was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH) (BKF and GNP); Federal funds from the NCI/NIH under Contract HHSN261200800001E (to JDL); National Institute of Allergy and Infectious Diseases-NIH Contract HHSN27201100016C (to GDT, XS, CL, and DCM), National Institute of Allergy and Infectious Diseases-NIH grant R01AI102718 (to AP), Institute of Human Virology Faculty Development Fund (to YG) and Bill and Melinda Gates Foundation Grant #42387 (to SGR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 17 Z9 17 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 MAR 13 PY 2014 VL 9 IS 3 AR e91550 DI 10.1371/journal.pone.0091550 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC9JS UT WOS:000332851300103 PM 24626482 ER PT J AU Correia, BE Bates, JT Loomis, RJ Baneyx, G Carrico, C Jardine, JG Rupert, P Correnti, C Kalyuzhniy, O Vittal, V Connell, MJ Stevens, E Schroeter, A Chen, M MacPherson, S Serra, AM Adachi, Y Holmes, MA Li, YX Klevit, RE Graham, BS Wyatt, RT Baker, D Strong, RK Crowe, JE Johnson, PR Schief, WR AF Correia, Bruno E. Bates, John T. Loomis, Rebecca J. Baneyx, Gretchen Carrico, Chris Jardine, Joseph G. Rupert, Peter Correnti, Colin Kalyuzhniy, Oleksandr Vittal, Vinayak Connell, Mary J. Stevens, Eric Schroeter, Alexandria Chen, Man MacPherson, Skye Serra, Andreia M. Adachi, Yumiko Holmes, Margaret A. Li, Yuxing Klevit, Rachel E. Graham, Barney S. Wyatt, Richard T. Baker, David Strong, Roland K. Crowe, James E., Jr. Johnson, Philip R. Schief, William R. TI Proof of principle for epitope-focused vaccine design SO NATURE LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; NEUTRALIZING ANTIBODY; COMPUTATIONAL DESIGN; SYSTEMATIC ANALYSIS; CIRCULAR-DICHROISM; GLOBAL BURDEN; PROTEIN; MOTAVIZUMAB; SCAFFOLDS; INFECTION AB Vaccines prevent infectious disease largely by inducing protective neutralizing antibodies against vulnerable epitopes. Several major pathogens have resisted traditional vaccine development, although vulnerable epitopes targeted by neutralizing antibodies have been identified for several such cases. Hence, new vaccine design methods to induce epitope-specific neutralizing antibodies are needed. Here we show, with a neutralization epitope from respiratory syncytial virus, that computational protein design can generate small, thermally and conformationally stable protein scaffolds that accurately mimic the viral epitope structure and induce potent neutralizing antibodies. These scaffolds represent promising leads for the research and development of a human respiratory syncytial virus vaccine needed to protect infants, young children and the elderly. More generally, the results provide proof of principle for epitope-focused and scaffold-based vaccine design, and encourage the evaluation and further development of these strategies for a variety of other vaccine targets, including antigenically highly variable pathogens such as human immunodeficiency virus and influenza. C1 [Correia, Bruno E.; Baneyx, Gretchen; Jardine, Joseph G.; Kalyuzhniy, Oleksandr; Vittal, Vinayak; Stevens, Eric; Schroeter, Alexandria; MacPherson, Skye; Serra, Andreia M.; Adachi, Yumiko; Klevit, Rachel E.; Baker, David; Schief, William R.] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Correia, Bruno E.] Univ Nova Lisboa, Inst Gulbenkian Ciencia, PhD Program Computat Biol, P-2780157 Oeiras, Portugal. [Correia, Bruno E.] Univ Nova Lisboa, Inst Tecnol Quim & Biol, P-2780157 Oeiras, Portugal. [Correia, Bruno E.] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA. [Bates, John T.; Crowe, James E., Jr.] Vanderbilt Univ, Vanderbilt Vaccine Ctr, Med Ctr, Nashville, TN 37232 USA. [Loomis, Rebecca J.; Connell, Mary J.; Johnson, Philip R.] Childrens Hosp Philadelphia, Res Inst, Philadelphia, PA 19104 USA. [Carrico, Chris; Rupert, Peter; Correnti, Colin; Strong, Roland K.] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. [Jardine, Joseph G.; MacPherson, Skye; Serra, Andreia M.; Li, Yuxing; Wyatt, Richard T.; Schief, William R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Jardine, Joseph G.; Kalyuzhniy, Oleksandr; MacPherson, Skye; Serra, Andreia M.; Adachi, Yumiko; Li, Yuxing; Wyatt, Richard T.; Schief, William R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Jardine, Joseph G.; Kalyuzhniy, Oleksandr; MacPherson, Skye; Serra, Andreia M.; Adachi, Yumiko; Li, Yuxing; Wyatt, Richard T.; Schief, William R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Chen, Man; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Crowe, James E., Jr.] Vanderbilt Univ Sch Med, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA. [Crowe, James E., Jr.] Vanderbilt Univ Sch Med, Dept Pediat, Nashville, TN 37232 USA. RP Schief, WR (reprint author), Univ Washington, Dept Biochem, Seattle, WA 98195 USA. EM schief@scripps.edu RI Crowe, James/B-5549-2009; Cheng, Yushao/E-6256-2011; Baker, David/K-8941-2012; Chiang, Vincent, Ming-Hsien/D-4312-2016; OI Crowe, James/0000-0002-0049-1079; Baker, David/0000-0001-7896-6217; Chiang, Vincent, Ming-Hsien/0000-0002-2029-7863; Carrico, Chris/0000-0003-0939-9006; Spencer, Skye/0000-0001-9570-9634 FU Fundacao para a Ciencia e a Tecnologia [SFRH/BD/32958/2006]; National Institutes of Health NRSA Training Grant [T32CA080416]; Children's Hospital of Philadelphia; Bill and Melinda Gates Foundation CAVD award; International AIDS Vaccine Initiative Neutralizing Antibody Consortium; International AIDS Vaccine Initiative Neutralizing Antibody Center; March of Dimes; National Institutes of Health [2T32GM007270, U54 AI 005714]; National Institute of Allergy and Infectious Diseases [P01AI094419, 5R21AI088554, 1UM1AI100663, 1R01AI102766-01A1]; National Institute of Allergy and Infectious Diseases from the Center for AIDS Research, University of California, San Diego [P30AI36214] FX We thank S. Menis, D. Kulp and D. Burton for comments on the manuscript, Y.-E. Ban, D. Alonso and K. E. Laidig for computing assistance, E. Gribben and R. Carnahan for assistance with mouse immunizations and C. Slaughter for assistance in statistical analysis. Adjuplex adjuvant was a gift from Advanced BioAdjuvants. The University of Washington has filed patents relating to immunogens in this manuscript. Materials and information will be provided under Materials Transfer Agreement (MTA). Support for this work was provided by Fundacao para a Ciencia e a Tecnologia fellowship SFRH/BD/32958/2006 (B. E. C.), National Institutes of Health NRSA Training Grant fellowship T32CA080416 (J.G.J.), The Children's Hospital of Philadelphia (P.R.J.), a Bill and Melinda Gates Foundation CAVD award (W. R. S., R. K. S. and D. B.), the International AIDS Vaccine Initiative Neutralizing Antibody Consortium (W. R. S. and D. B.), the International AIDS Vaccine Initiative Neutralizing Antibody Center (W. R. S. and R. T. W.), a grant from the March of Dimes (J.E.C.), National Institutes of Health grants 2T32GM007270 (V. V.) and U54 AI 005714 (R. E. K.), National Institute of Allergy and Infectious Diseases grants P01AI094419 (W. R. S. and R. K. S.), 5R21AI088554 (W. R. S.), 1UM1AI100663 (W. R. S. and R. T. W.), 1R01AI102766-01A1 (Y.L. and R. T. W.), P30AI36214 (from the Center for AIDS Research, University of California, San Diego, to Y.L.), and the National Institute of Allergy and Infectious Diseases Intramural Research Program (B. S. G.). This is manuscript 26069 from The Scripps Research Institute. NR 39 TC 112 Z9 114 U1 18 U2 97 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 MAR 13 PY 2014 VL 507 IS 7491 BP 201 EP 206 DI 10.1038/nature12966 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC6RJ UT WOS:000332651800032 PM 24499818 ER PT J AU Brun-Buisson, C Sun, JF Natanson, C AF Brun-Buisson, Christian Sun, Junfeng Natanson, Charles TI Mortality in Patients With Hypovolemic Shock Treated With Colloids or Crystalloids SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID HYDROXYETHYL STARCH; FLUID RESUSCITATION; SEVERE SEPSIS C1 [Brun-Buisson, Christian] GH Henri Mondor, Serv Reanimat Med, F-9010 Creteil, France. [Sun, Junfeng; Natanson, Charles] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Brun-Buisson, C (reprint author), GH Henri Mondor, Serv Reanimat Med, 51 Ave Lattre de Tassigny, F-9010 Creteil, France. EM christian.brun-buisson@hmn.aphp.fr NR 5 TC 5 Z9 5 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 12 PY 2014 VL 311 IS 10 BP 1068 EP 1069 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AC5QO UT WOS:000332575800029 PM 24618973 ER PT J AU Maltsev, AS Grishaev, A Roche, J Zasloff, M Bax, A AF Maltsev, Alexander S. Grishaev, Alexander Roche, Julien Zasloff, Michael Bax, Ad TI Improved Cross Validation of a Static Ubiquitin Structure Derived from High Precision Residual Dipolar Couplings Measured in a Drug-Based Liquid Crystalline Phase SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID C-13 CHEMICAL-SHIFT; MODEL-FREE ANALYSIS; PROTEIN-STRUCTURE; CORRELATED MOTIONS; SCALAR COUPLINGS; NMR-SPECTROSCOPY; BIOMOLECULAR NMR; BACKBONE MOTION; ORIENTED MEDIA; DYNAMICS AB The antibiotic squalamine forms a lyotropic liquid crystal at very low concentrations in water (0.3-3.5% w/v), which remains stable over a wide range of temperature (1-40 degrees C) and pH (4-8). Squalamine is positively charged, and comparison of the alignment of ubiquitin relative to 36 previously reported alignment conditions shows that it differs substantially from most of these, but is closest to liquid crystalline cetyl pyridinium bromide. High precision residual dipolar couplings (RDCs) measured for the backbone H-1-N-15, C-13', H-1(alpha)-C-13(alpha), and C-13'-C-13(alpha) one-bond interactions in the squalamine medium fit well to the static structural model previously derived from NMR data. Inclusion into the structure refinement procedure of these RDCs, together with H-1-N-15 and H-1(alpha)-C-13(alpha) RDCs newly measured in Pf1, results in improved agreement between alignment-induced changes in C-13' chemical shift, (3)J(HNH alpha) values, and C-13(alpha)-C-13(beta) RDCs and corresponding values predicted by the structure, thereby validating the high quality of the single-conformer structural model. This result indicates that fitting of a single model to experimental data provides a better description of the average conformation than does averaging over previously reported NMR-derived ensemble representations. The latter can capture dynamic aspects of a protein, thus making the two representations valuable complements to one another. C1 [Maltsev, Alexander S.; Grishaev, Alexander; Roche, Julien; Bax, Ad] NIDDKD, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. [Zasloff, Michael] Georgetown Univ Hosp, Washington, DC 20007 USA. RP Bax, A (reprint author), NIDDKD, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. EM bax@nih.gov RI Roche, Julien/O-3204-2013 OI Roche, Julien/0000-0003-3892-0200 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Intramural Antiviral Target Program of the Office of the Director, NIH FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and by the Intramural Antiviral Target Program of the Office of the Director, NIH. NR 38 TC 31 Z9 31 U1 4 U2 27 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAR 12 PY 2014 VL 136 IS 10 BP 3752 EP 3755 DI 10.1021/ja4132642 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA AD0KJ UT WOS:000332922600011 PM 24568736 ER PT J AU Goldszmid, RS Dzutsev, A Trinchieri, G AF Goldszmid, Romina S. Dzutsev, Amiran Trinchieri, Giorgio TI Host Immune Response to Infection and Cancer: Unexpected Commonalities SO CELL HOST & MICROBE LA English DT Review ID HEMATOPOIETIC STEM-CELLS; CHRONIC VIRAL-INFECTION; CD8(+) T-CELLS; DENDRITIC CELLS; I INTERFERON; SUPPRESSOR-CELLS; MYELOID CELLS; THERAPEUTIC INTERVENTION; TUMOR MICROENVIRONMENT; ANTITUMOR IMMUNITY AB Both microbes and tumors activate innate resistance, tissue repair, and adaptive immunity. Unlike acute infection, tumor growth is initially unapparent; however, inflammation and immunity affect all phases of tumor growth from initiation to progression and dissemination. Here, we discuss the shared features involved in the immune response to infection and cancer including modulation by commensal microbiota, reactive hematopoiesis, chronic immune responses and regulatory mechanisms to prevent collateral tissue damage. This comparative analysis of immunity to infection and cancer furthers our understanding of the basic mechanisms underlying innate resistance and adaptive immunity and their translational application to the design of new therapeutic approaches. C1 [Goldszmid, Romina S.; Dzutsev, Amiran; Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Dzutsev, Amiran] Leidos Biomed Res Inc, Frederick, MD 21701 USA. RP Trinchieri, G (reprint author), NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. EM trinchig@mail.nih.gov FU Intramural NIH HHS [Z01 BC010793-01] NR 102 TC 23 Z9 23 U1 1 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD MAR 12 PY 2014 VL 15 IS 3 BP 295 EP 305 DI 10.1016/j.chom.2014.02.003 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AD2WZ UT WOS:000333098600008 PM 24629336 ER PT J AU Wu, S Beard, WA Pedersen, LG Wilson, SH AF Wu, Sangwook Beard, William A. Pedersen, Lee G. Wilson, Samuel H. TI Structural Comparison of DNA Polymerase Architecture Suggests a Nucleotide Gateway to the Polymerase Active Site SO CHEMICAL REVIEWS LA English DT Review ID ESCHERICHIA-COLI; DEOXYRIBONUCLEIC-ACID; FAMILY POLYMERASES; CRYSTAL-STRUCTURES; LARGE FRAGMENT; BETA; MECHANISM; FIDELITY; REPLICATION; BINDING C1 [Wu, Sangwook; Pedersen, Lee G.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. [Beard, William A.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Pedersen, LG (reprint author), Univ N Carolina, Dept Chem, CB 3290, Chapel Hill, NC 27599 USA. EM lee_pedersen@unc.edu; wilson5@niehs.nih.gov FU NIH [HL-06350, P41 RR-01081]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01-ES050158, Z01-ES050161]; National Institutes of Health [1U19CA105010] FX L.G.P. acknowledges NIH grant HL-06350. This research was supported by Research Project Numbers Z01-ES050158 and Z01-ES050161 to S.H.W. by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, and was in association with the National Institutes of Health Grant 1U19CA105010. Structural images were produced using the Chimera package57 from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH P41 RR-01081) NR 57 TC 12 Z9 12 U1 2 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 EI 1520-6890 J9 CHEM REV JI Chem. Rev. PD MAR 12 PY 2014 VL 114 IS 5 BP 2759 EP 2774 DI 10.1021/cr3005179 PG 16 WC Chemistry, Multidisciplinary SC Chemistry GA AD0KL UT WOS:000332922800005 PM 24359247 ER PT J AU Kiris, E Wang, T Yanpallewar, S Dorsey, SG Becker, J Bavari, S Palko, ME Coppola, V Tessarollo, L AF Kiris, Erkan Wang, Ting Yanpallewar, Sudhirkumar Dorsey, Susan G. Becker, Jodi Bavari, Sina Palko, Mary Ellen Coppola, Vincenzo Tessarollo, Lino TI TrkA In Vivo Function Is Negatively Regulated by Ubiquitination SO JOURNAL OF NEUROSCIENCE LA English DT Article ID NERVE GROWTH-FACTOR; FACTOR RECEPTOR TRKA; NEUROPATHIC PAIN; CELL FATE; NEUROTROPHINS; GENE; MICE; INTERNALIZATION; ENDOCYTOSIS; DELETION AB TrkA is a tyrosine kinase receptor required for development and survival of the peripheral nervous system. In the adult, TrkA and its ligand NGF are peripheral pain mediators, particularly in inflammatory pain states. However, how TrkA regulates the function of nociceptive neurons and whether its activity levels may lead to sensory abnormalities is still unclear. Here we report the characterization of a 3 aa (KFG) domain that negatively regulates TrkA level and function in response to NGF. Deletion of this domain in mouse causes a reduction of TrkA ubiquitination leading to an increase in TrkA protein levels and activity. The number of dorsal root ganglia neurons is not affected by the mutation. However, mutant mice have enhanced thermal sensitivity and inflammatory pain. Together, these data suggest that ubiquitination is a mechanism used in nociceptive neurons to regulate TrkA level and function. Our results may enhance our understanding of how ubiquitination affects TrkA activation following noxious thermal stimulation and inflammatory pain. C1 [Kiris, Erkan; Wang, Ting; Yanpallewar, Sudhirkumar; Becker, Jodi; Palko, Mary Ellen; Tessarollo, Lino] NCI, Neural Dev Sect, Mouse Canc Genet Program, Frederick, MD 21702 USA. [Kiris, Erkan; Becker, Jodi] US Army Med Res Inst Infect Dis, Dept Target Discovery & Expt Microbiol, Frederick, MD 21702 USA. [Dorsey, Susan G.] Univ Maryland, Sch Nursing, Baltimore, MD 21201 USA. [Dorsey, Susan G.] Univ Maryland, Program Neurosci, Baltimore, MD 21201 USA. [Coppola, Vincenzo] Ohio State Univ, Wexner Med Ctr, Ctr Comprehens Canc, Dept MVIMG, Columbus, OH 43210 USA. RP Coppola, V (reprint author), Ohio State Univ, Wexner Med Ctr, Ctr Comprehens Canc, Dept MVIMG, Columbus, OH 43210 USA. EM Vincenzo.Coppola@osumc.edu; tessarol@mail.nih.gov RI Coppola, Vincenzo/E-2917-2011 OI Coppola, Vincenzo/0000-0001-6163-1779 FU National Cancer Institute, Center for Cancer Research, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health. We thank Eileen Southon and Susan Reid for technical help in generating the TrkA mutant mouse model, Colleen Barrick for technical help, and Allan Weissman for discussion and suggestions. We are grateful to Robert Stephens for the discussions at the start of the project and Juan Carlos Arevalo for sharing his unpublished results. NR 33 TC 8 Z9 8 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 12 PY 2014 VL 34 IS 11 BP 4090 EP 4098 DI 10.1523/JNEUROSCI.4294-13.2014 PG 9 WC Neurosciences SC Neurosciences & Neurology GA AC9UG UT WOS:000332879500029 PM 24623787 ER PT J AU Enama, ME Ledgerwood, JE Novik, L Nason, MC Gordon, IJ Holman, L Bailer, RT Roederer, M Koup, RA Mascola, JR Nabel, GJ Graham, BS AF Enama, Mary E. Ledgerwood, Julie E. Novik, Laura Nason, Martha C. Gordon, Ingelise J. Holman, LaSonji Bailer, Robert T. Roederer, Mario Koup, Richard A. Mascola, John R. Nabel, Gary J. Graham, Barney S. CA VRC 011 Study Team TI Phase I Randomized Clinical Trial of VRC DNA and rAd5 HIV-1 Vaccine Delivery by Intramuscular (IM), Subcutaneous (SC) and Intradermal (ID) Administration (VRC 011) SO PLOS ONE LA English DT Article ID T-CELL RESPONSES; CANDIDATE VACCINE; IMMUNOGENICITY EVALUATION; EFFICACY TRIAL; VIRUS; IMMUNIZATION; INFECTION; ANTIBODY; IMMUNITY; VECTORS AB Background: Phase 1 evaluation of the VRC HIV DNA and rAd5 vaccines delivered intramuscularly (IM) supported proceeding to a Phase 2 b efficacy study. Here we report comparison of the IM, subcutaneous (SC) and intradermal (ID) routes of administration. Methods: Sixty subjects were randomized to 6 schedules to evaluate the IM, SC or ID route for prime injections. Three schedules included DNA primes (Wks 0,4,8) and 3 schedules included rAd5 prime (Wk0); all included rAd5 IM boost (Wk24). DNA vaccine dosage was 4 mg IM or SC, but 0.4 mg ID, while all rAd5 vaccinations were 10(10) PU. All injections were administered by needle and syringe. Results: Overall, 27/30 subjects completed 3 DNA primes; 30/30 subjects completed rAd5 primes. Mild local pruritus (itchiness), superficial skin lesions and injection site nodules were associated with ID and SC, but not IM injections. All routes induced T-cell and antibody immune responses after rAd5 boosting. Overall, >95% had Env antibody and >80% had Env T-cell responses. Conclusions: The pattern of local reactogenicity following ID and SC injections differed from IM injections but all routes were well-tolerated. There was no evidence of an immunogenicity advantage following SC or ID delivery, supporting IM delivery as the preferred route of administration. C1 [Enama, Mary E.; Ledgerwood, Julie E.; Novik, Laura; Gordon, Ingelise J.; Holman, LaSonji; Bailer, Robert T.; Roederer, Mario; Koup, Richard A.; Mascola, John R.; Nabel, Gary J.; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Nason, Martha C.] NIAID, Biostat Res Branch, Div Clin Res, NIH, Bethesda, MD 20892 USA. RP Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bgraham@nih.gov FU U.S. Government FX This study was supported by U.S. Government funding for the intramural research conducted by the National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 6 Z9 6 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 MAR 12 PY 2014 VL 9 IS 3 AR e91366 DI 10.1371/journal.pone.0091366 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC9HN UT WOS:000332845300081 PM 24621858 ER PT J AU Steingrimsdottir, L Halldorsson, TI Siggeirsdottir, K Cotch, MF Einarsdottir, BO Eiriksdottir, G Sigurdsson, S Launer, LJ Harris, TB Gudnason, V Sigurdsson, G AF Steingrimsdottir, Laufey Halldorsson, Thorhallur I. Siggeirsdottir, Kristin Cotch, Mary Frances Einarsdottir, Berglind O. Eiriksdottir, Gudny Sigurdsson, Sigurdur Launer, Lenore J. Harris, Tamara B. Gudnason, Vilmundur Sigurdsson, Gunnar TI Hip Fractures and Bone Mineral Density in the Elderly-Importance of Serum 25-Hydroxyvitamin D SO PLOS ONE LA English DT Article ID VITAMIN-D SUPPLEMENTATION; GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK; RANDOMIZED CONTROLLED-TRIALS; OLDER-ADULTS; OSTEOPOROTIC FRACTURES; NONSPINE FRACTURES; MUSCLE STRENGTH; HEALTH OUTCOMES; DIETARY-INTAKE; RISK AB Background: The significance of serum 25-hydroxyvitamin D [25(OH) D] concentrations for hip fracture risk of the elderly is still uncertain. Difficulties reaching both frail and healthy elderly people in randomized controlled trials or large cohort studies may in part explain discordant findings. We determined hazard ratios for hip fractures of elderly men and women related to serum 25(OH) D, including both the frail and the healthy segment of the elderly population. Methods: The AGES-Reykjavik Study is a prospective study of 5764 men and women, age 66-96 years, based on a representative sample of the population of Reykjavik, Iceland. Participation was 71.8%. Hazard ratios of incident hip fractures and baseline bone mineral density were determined according to serum concentrations of 25(OH) D at baseline. Results: Mean follow-up was 5.4 years. Compared with referent values (50-75 nmol/L), hazard ratios for hip fractures were 2.24 (95% CI 1.63, 3.09) for serum 25(OH) D <30 nmol/L, adjusting for age, sex, body mass index, height, smoking, alcohol intake and season, and 2.08 (95% CI 1.51, 2.87), adjusting additionally for physical activity. No difference in risk was associated with 30-50 nmol/L or >= 75 nmol/L in either model compared with referent. Analyzing the sexes separately, hazard ratios were 2.61 (95% CI 1.47, 4.64) in men and 1.93 (95% CI 1.31, 2.84) in women. Values <30 nmol/L were associated with significantly lower bone mineral density of femoral neck compared with referent, z-scores -0.14 (95% CI - 0.27, -0.00) in men and -0.11 (95% CI -0.22, -0.01) in women. Conclusions: Our results lend support to the overarching importance of maintaining serum 25(OH) D above 30 nmol/L for bone health of elderly people while potential benefits of having much higher levels could not be detected. C1 [Steingrimsdottir, Laufey; Halldorsson, Thorhallur I.] Univ Iceland, Unit Nutr Res, Reykjavik, Iceland. [Steingrimsdottir, Laufey; Halldorsson, Thorhallur I.] Landspitali Univ Hosp, Reykjavik, Iceland. [Siggeirsdottir, Kristin; Einarsdottir, Berglind O.; Eiriksdottir, Gudny; Sigurdsson, Sigurdur; Gudnason, Vilmundur; Sigurdsson, Gunnar] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. [Launer, Lenore J.; Harris, Tamara B.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Gudnason, Vilmundur; Sigurdsson, Gunnar] Univ Iceland, Reykjavik, Iceland. RP Steingrimsdottir, L (reprint author), Univ Iceland, Unit Nutr Res, Reykjavik, Iceland. EM laufey@hi.is RI Gudnason, Vilmundur/K-6885-2015; Halldorsson, Tohrhallur/M-1823-2015; OI Gudnason, Vilmundur/0000-0001-5696-0084; Halldorsson, Tohrhallur/0000-0001-5115-0162; Cotch, Mary Frances/0000-0002-2046-4350 FU National Institutes of Health, USA [N01-AG-12100]; National Institute on Aging Intramural Research Program, the National Eye Institute USA [Z01-EY000401]; National Institutes of Health, Hjartavernd (The Icelandic Heart Association); Althingi (Icelandic Parliament) FX This study was funded by the National Institutes of Health, USA contract N01-AG-12100, and the National Institute on Aging Intramural Research Program, the National Eye Institute USA (Z01-EY000401), National Institutes of Health, Hjartavernd (The Icelandic Heart Association), and Althingi (Icelandic Parliament). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 4 Z9 4 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 12 PY 2014 VL 9 IS 3 AR e91122 DI 10.1371/journal.pone.0091122 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC9HN UT WOS:000332845300054 PM 24621578 ER PT J AU Connor, EM Smoyer, WE Davis, JM Zajicek, A Ulrich, L Purucker, M Hirschfeld, S AF Connor, Edward M. Smoyer, William E. Davis, Jonathan M. Zajicek, Anne Ulrich, Linda Purucker, Mary Hirschfeld, Steven TI Meeting the Demand for Pediatric Clinical Trials SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material AB High-quality, cost-ef ective pediatric clinical trials require a robust research and regulatory infrastructure and a properly trained workforce. C1 [Connor, Edward M.] George Washington Univ, Dept Pediat, Washington, DC 20010 USA. [Connor, Edward M.] George Washington Univ, Clin & Translat Sci Inst, Washington, DC 20010 USA. [Connor, Edward M.] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20010 USA. [Smoyer, William E.] Ohio State Univ, Nationwide Childrens Hosp, Res Inst, Ctr Clin & Translat Res, Columbus, OH 43205 USA. [Smoyer, William E.] Ohio State Univ, Dept Pediat, Columbus, OH 43205 USA. [Davis, Jonathan M.] Tufts Med Ctr, Floating Hosp Children, Dept Pediat, Boston, MA 02111 USA. [Davis, Jonathan M.] Tufts Med Ctr, Floating Hosp Children, Tufts Clin & Translat Sci Inst, Boston, MA 02111 USA. [Zajicek, Anne; Hirschfeld, Steven] Eunice Kennedy Shriver NICHD, Bethesda, MD 20892 USA. [Ulrich, Linda] US FDA, Off Orphan Prod Dev, Silver Spring, MD 20993 USA. [Purucker, Mary] NCATS, CTSA, Bethesda, MD 20892 USA. RP Connor, EM (reprint author), George Washington Univ, Dept Pediat, Washington, DC 20010 USA. EM econnor@childrensnational.org RI Hirschfeld, Steven/E-2987-2016 OI Hirschfeld, Steven/0000-0003-0627-7249 FU NCATS NIH HHS [UL1 TR000073, UL1 TR000075, UL1 TR001070, UL1TR000073, UL1TR000075, UL1TR001070] NR 7 TC 6 Z9 6 U1 0 U2 2 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD MAR 12 PY 2014 VL 6 IS 227 AR 227fs11 DI 10.1126/scitranslmed.3008043 PG 3 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AC6KD UT WOS:000332630500001 PM 24622511 ER PT J AU Cooley, BC Nevado, J Mellad, J Yang, D St Hilaire, C Negro, A Fang, F Chen, GB San, H Walts, AD Schwartzbeck, RL Taylor, B Lanzer, JD Wragg, A Elagha, A Beltran, LE Berry, C Feil, R Virmani, R Ladich, E Kovacic, JC Boehm, M AF Cooley, Brian C. Nevado, Jose Mellad, Jason Yang, Dan St Hilaire, Cynthia Negro, Alejandra Fang, Fang Chen, Guibin San, Hong Walts, Avram D. Schwartzbeck, Robin L. Taylor, Brandi Lanzer, Jan D. Wragg, Andrew Elagha, Abdalla Beltran, Leilani E. Berry, Colin Feil, Robert Virmani, Renu Ladich, Elena Kovacic, Jason C. Boehm, Manfred TI TGF-beta Signaling Mediates Endothelial-to-Mesenchymal Transition (EndMT) During Vein Graft Remodeling SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID SMOOTH-MUSCLE-CELLS; NEOINTIMAL FORMATION; INTIMAL HYPERPLASIA; IN-VIVO; FIBROSIS; MICE; EXPRESSION; DISEASE; MODEL; GENE AB Veins grafted into an arterial environment undergo a complex vascular remodeling process. Pathologic vascular remodeling often results in stenosed or occluded conduit grafts. Understanding this complex process is important for improving the outcome of patients with coronary and peripheral artery disease undergoing surgical revascularization. Using in vivo murine cell lineage-tracing models, we show that endothelial-derived cells contribute to neointimal formation through endothelial-to-mesenchymal transition (EndMT), which is dependent on early activation of the Smad2/3-Slug signaling pathway. Antagonism of transforming growth factor-beta (TGF-beta) signaling by TGF-beta neutralizing antibody, short hairpin RNA-mediated Smad3 or Smad2 knockdown, Smad3 haploinsufficiency, or endothelial cell-specific Smad2 deletion resulted in decreased EndMT and less neointimal formation compared to controls. Histological examination of postmortem human vein graft tissue corroborated the changes observed in our mouse vein graft model, suggesting that EndMT is operative during human vein graft remodeling. These data establish that EndMT is an important mechanism underlying neointimal formation in interpositional vein grafts, and identifies the TGF-beta-Smad2/3-Slug signaling pathway as a potential therapeutic target to prevent clinical vein graft stenosis. C1 [Cooley, Brian C.] Med Coll Wisconsin, Dept Orthopaed Surg, Milwaukee, WI 53226 USA. [Nevado, Jose] Univ Philippines, Coll Med, Natl Inst Hlth, Manila 1000, Philippines. [Nevado, Jose; Yang, Dan; St Hilaire, Cynthia; Negro, Alejandra; Fang, Fang; Chen, Guibin; San, Hong; Walts, Avram D.; Schwartzbeck, Robin L.; Taylor, Brandi; Lanzer, Jan D.; Wragg, Andrew; Elagha, Abdalla; Beltran, Leilani E.; Berry, Colin; Kovacic, Jason C.; Boehm, Manfred] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Mellad, Jason; Wragg, Andrew] Barts & London NHS Trust, William Harvey Res Inst, London EC1M 6BQ, England. [Elagha, Abdalla] Cairo Univ, Fac Med, Cardiovasc Dept, Cairo 11559, Egypt. [Berry, Colin] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8TA, Lanark, Scotland. [Feil, Robert] Univ Tubingen, Interfac Inst Biochem, D-72074 Tubingen, Germany. [Virmani, Renu; Ladich, Elena] CVPath Inst Inc, Gaithersburg, MD 20878 USA. [Kovacic, Jason C.] Icahn Sch Med,Mt, Zena & Michael A Wiener Cardiovasc Inst, New York, NY 10029 USA. RP Boehm, M (reprint author), Univ N Carolina, Dept Pathol, Chapel Hill, NC 27599 USA. EM boehmm@nhlbi.nih.gov RI St. Hilaire, Cynthia/I-4713-2014; Feil, Robert/B-8918-2014; OI Feil, Robert/0000-0002-7335-4841; Elagha, Abdalla/0000-0003-3136-2293 FU Intramural Research Program of the NHLBI; Commission on Higher Education; Philippine Council on Advanced Science and Technology Research and Development, Department of Science and Technology (PCASTRD-DOST) in the Philippines; NIH [K08HL111330]; Boehringer Ingelheim Fonds FX This project was funded by the Intramural Research Program of the NHLBI. J.N. was supported by the Commission on Higher Education and the Philippine Council on Advanced Science and Technology Research and Development, Department of Science and Technology (PCASTRD-DOST) in the Philippines. J.M. was supported by an NIH Marshall Scholarship. J.C.K. is supported by NIH grant K08HL111330. J.D.L. was supported by a Boehringer Ingelheim Fonds MD Fellowship. NR 40 TC 20 Z9 20 U1 0 U2 12 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD MAR 12 PY 2014 VL 6 IS 227 AR 227ra34 DI 10.1126/scitranslmed.3006927 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AC6KD UT WOS:000332630500006 PM 24622514 ER PT J AU Barber, MD Brubaker, L Burgio, KL Richter, HE Nygaard, I Weidner, AC Menefee, SA Lukacz, ES Norton, P Schaffer, J Nguyen, JN Borello-France, D Goode, PS Jakus-Waldman, S Spino, C Warren, LK Gantz, MG Meikle, SF AF Barber, Matthew D. Brubaker, Linda Burgio, Kathryn L. Richter, Holly E. Nygaard, Ingrid Weidner, Alison C. Menefee, Shawn A. Lukacz, Emily S. Norton, Peggy Schaffer, Joseph Nguyen, John N. Borello-France, Diane Goode, Patricia S. Jakus-Waldman, Sharon Spino, Cathie Warren, Lauren Klein Gantz, Marie G. Meikle, Susan F. CA Eunice Kennedy Shriver Natl Inst C TI Comparison of 2 Transvaginal Surgical Approaches and Perioperative Behavioral Therapy for Apical Vaginal Prolapse The OPTIMAL Randomized Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PELVIC ORGAN PROLAPSE; SACROSPINOUS LIGAMENT FIXATION; URGE URINARY-INCONTINENCE; CONSERVATIVE TREATMENT; STRESS-INCONTINENCE; CLINICAL-TRIALS; VAULT PROLAPSE; UNITED-STATES; WOMEN; SURGERY AB IMPORTANCE More than 300 000 surgeries are performed annually in the United States for pelvic organ prolapse. Sacrospinous ligament fixation (SSLF) and uterosacral ligament suspension (ULS) are commonly performed transvaginal surgeries to correct apical prolapse. Little is known about their comparative efficacy and safety, and it is unknown whether perioperative behavioral therapy with pelvic floor muscle training (BPMT) improves outcomes of prolapse surgery. OBJECTIVE To compare outcomes between (1) SSLF and ULS and (2) perioperative BPMT and usual care in women undergoing surgery for vaginal prolapse and stress urinary incontinence. DESIGN, SETTING, AND PARTICIPANTS Multicenter, 2 x 2 factorial, randomized trial of 374 women undergoing surgery to treat both apical vaginal prolapse and stress urinary incontinence was conducted between 2008 and 2013 at 9 US medical centers. Two-year follow-up rate was 84.5%. INTERVENTIONS The surgical intervention was transvaginal surgery including midurethral sling with randomization to SSLF (n = 186) or ULS (n = 188); the behavioral intervention was randomization to receive perioperative BPMT (n = 186) or usual care (n = 188). MAIN OUTCOMES AND MEASURES The primary outcome for the surgical intervention (surgical success) was defined as (1) no apical descent greater than one-third into vaginal canal or anterior or posterior vaginal wall beyond the hymen (anatomic success), (2) no bothersome vaginal bulge symptoms, and (3) no re-treatment for prolapse at 2 years. For the behavioral intervention, primary outcome at 6 months was urinary symptom scores (Urinary Distress Inventory; range 0-300, higher scores worse), and primary outcomes at 2 years were prolapse symptom scores (Pelvic Organ Prolapse Distress Inventory; range 0-300, higher scores worse) and anatomic success. RESULTS At 2 years, surgical group was not significantly associated with surgical success rates (ULS, 59.2%[93/157] vs SSLF, 60.5%[92/152]; unadjusted difference, -1.3%; 95% CI, -12.2% to 9.6%; adjusted odds ratio [OR], 0.9; 95% CI, 0.6 to 1.5) or serious adverse event rates (ULS, 16.5%[31/188] vs SSLF, 16.7%[31/186]; unadjusted difference, -0.2%; 95% CI, -7.7% to 7.4%; adjusted OR, 0.9; 95% CI, 0.5 to 1.6). Perioperative BPMT was not associated with greater improvements in urinary scores at 6 months (adjusted treatment difference, -6.7; 95% CI, -19.7 to 6.2), prolapse scores at 24 months (adjusted treatment difference, -8.0; 95% CI, -22.1 to 6.1), or anatomic success at 24 months. CONCLUSIONS AND RELEVANCE Two years after vaginal surgery for prolapse and stress urinary incontinence, neither ULS nor SSLF was significantly superior to the other for anatomic, functional, or adverse event outcomes. Perioperative BPMT did not improve urinary symptoms at 6 months or prolapse outcomes at 2 years. C1 [Barber, Matthew D.] Cleveland Clin, Obstet Gynecol & Womens Hlth Inst, Cleveland, OH 44195 USA. [Brubaker, Linda] Loyola Univ, Dept Obstet & Gynecol, Stritch Sch Med, Chicago, IL 60611 USA. [Brubaker, Linda] Loyola Univ, Dept Urol, Stritch Sch Med, Chicago, IL 60611 USA. [Burgio, Kathryn L.; Goode, Patricia S.] Univ Alabama Birmingham, Div Gerontol Geriatr & Palliat Care, Birmingham, AL USA. [Burgio, Kathryn L.; Goode, Patricia S.] Dept Vet Affairs, Birmingham, AL USA. [Richter, Holly E.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL USA. [Nygaard, Ingrid; Norton, Peggy] Univ Utah, Med Ctr, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. [Weidner, Alison C.] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Menefee, Shawn A.] Kaiser Permanente So Calif, Dept Obstet & Gynecol, San Diego, CA USA. [Lukacz, Emily S.] Univ Calif San Diego Hlth Syst, Dept Reprod Med, San Diego, CA USA. [Schaffer, Joseph] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. [Nguyen, John N.; Jakus-Waldman, Sharon] Kaiser Permanente So Calif, Dept Obstet & Gynecol, Downey, CA USA. [Borello-France, Diane] Duquesne Univ, Dept Phys Therapy, Pittsburgh, PA 15219 USA. [Spino, Cathie] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Warren, Lauren Klein; Gantz, Marie G.] RTI Int, Social Stat & Environm Sci, Res Triangle Pk, NC USA. [Meikle, Susan F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Barber, MD (reprint author), Cleveland Clin, Obstet Gynecol & Womens Hlth Inst, 9500 Euclid Ave,Desk A81, Cleveland, OH 44195 USA. EM barberm2@ccf.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 HD041249, U10 HD041250, U10 HD041261, U10 HD041267, U10 HD054136, U10 HD054214, U10 HD054215, U01 HD069031, U10 HD054241]; National Institutes of Health Office of Research on Women's Health FX This research was supported by grants U01 HD041249, U10 HD041250, U10 HD041261, U10 HD041267, U10 HD054136, U10 HD054214, U10 HD054215, U01 HD069031, and U10 HD054241 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health Office of Research on Women's Health. NR 38 TC 47 Z9 48 U1 1 U2 6 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 MAR 12 PY 2014 VL 311 IS 10 BP 1023 EP 1034 DI 10.1001/jama.2014.1719 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA AC5QO UT WOS:000332575800020 PM 24618964 ER PT J AU Batters, C Veigel, C Homsher, E Sellers, JR AF Batters, Christopher Veigel, Claudia Homsher, Earl Sellers, James R. TI To understand muscle you must take it apartle SO FRONTIERS IN PHYSIOLOGY LA English DT Review DE muscle; myosin; actomyosin; ATPase; electron microscopy; in vitro model ID MYOSIN MOTOR DOMAIN; FAMILIAL HYPERTROPHIC CARDIOMYOPATHY; BETA-CARDIAC MYOSIN; DEPENDENT ADENOSINE-TRIPHOSPHATASE; RABBIT SKELETAL ACTOMYOSIN; ESSENTIAL LIGHT-CHAIN; ACTIN-BASED MOTOR; S2 HINGE REGIONS; HAND-OVER-HAND; SMOOTH-MUSCLE AB Striated muscle is an elegant system for study at many levels. Much has been learned about the mechanism of contraction from studying the mechanical properties of intact and permeabilized (or skinned) muscle fibers. Structural studies using electron microscopy, X-ray diffraction or spectroscopic probes attached to various contractile proteins were possible because of the highly ordered sarcomeric arrangement of actin and myosin. However, to understand the mechanism of force generation at a molecular level, it is necessary to take the system apart and study the interaction of myosin with actin using in vitro assays. This reductionist approach has lead to many fundamental insights into how myosin powers muscle contraction. In addition, nature has provided scientists with an array of muscles with different mechanical properties and with a superfamily of myosin molecules. Taking advantage of this diversity in myosin structure and function has lead to additional insights into common properties of force generation. This review will highlight the development of the major assays and methods that have allowed this combined reductionist and comparative approach to be so fruitful. This review highlights the history of biochemical and biophysical studies of myosin and demonstrates how a broad comparative approach combined with reductionist studies have led to a detailed understanding of how myosin interacts with actin and uses chemical energy to generate force and movement in muscle contraction and motility in general. C1 [Batters, Christopher; Veigel, Claudia] Univ Munich, Dept Cellular Physiol, Munich, Germany. [Batters, Christopher; Veigel, Claudia] Univ Munich, Ctr Nanosci CeNS, Munich, Germany. [Homsher, Earl] Univ Calif Los Angeles, Dept Physiol, Los Angeles, CA 90024 USA. [Sellers, James R.] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. RP Sellers, JR (reprint author), NHLBI, Lab Mol Physiol, NIH, Bldg 50,Room 3523, Bethesda, MD 20892 USA. EM sellersj@nhlbi.nih.gov NR 157 TC 5 Z9 5 U1 4 U2 19 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD MAR 11 PY 2014 VL 5 AR 90 DI 10.3389/fphys.2014.00090 PG 14 WC Physiology SC Physiology GA AX3KX UT WOS:000346839300001 PM 24653704 ER PT J AU Klein, CJ Wu, YH Vogel, P Goebel, HH Bonnemann, C Zukosky, K Botuyan, MV Duan, XH Middha, S Atkinson, EJ Mer, G Dyck, PJ AF Klein, Christopher J. Wu, Yanhong Vogel, Peter Goebel, Hans H. Boennemann, Carsten Zukosky, Kristen Botuyan, Maria-Victoria Duan, Xiaohui Middha, Sumit Atkinson, Elizabeth J. Mer, Georges Dyck, Peter J. TI Ubiquitin ligase defect by DCAF8 mutation causes HMSN2 with giant axons SO NEUROLOGY LA English DT Article ID MARIE-TOOTH-DISEASE; NEUROFILAMENT ACCUMULATION; SEQUENCING DATA; NEUROPATHY; GIGAXONIN; SH3TC2 AB Objective:To identify the genetic cause of axonal hereditary motor and sensory neuropathy (HMSN2) with infrequent giant axons.Methods:We studied 11 members of a previously described HMSN2 family with infrequent giant axons and variable cardiomyopathy. Whole-exome sequencing (WES) was performed on 2 affected persons and 1 unaffected person. Sanger sequencing was utilized to confirm the identified novel variant tracking with the affected status. Linkage analysis and haplotype mapping were obtained to confirm the causal nature of the identified variant. Cotransfection of HEK293 cells and co-immunoprecipitation assay were performed to assess the impact of the identified mutant protein in the implicated ubiquitin ligase pathway.Results:Giant axons with neurofilament accumulations were found in 3 affected persons who had undergone nerve biopsy evaluations. Six novel variants were identified by WES, but only DCAF8 p.R317C tracked with affected status within the family. Linkage and haplotype analysis using microsatellite markers supported this variant as causal. The mutation is within the DCAF8 WD repeat region critical for its binding to DDB1. Functional analysis shows DCAF8 p.R317C reduces the association of DCAF8 and DDB1, which is important in Cul4-ubiquitin E3 function.Conclusions:Our results indicate that DCAF8 p.R317C mutation is responsible for this specific variety of HMSN2 with infrequent giant axons and mild cardiomyopathy. This mutation results in decreased DDB1-DCAF8 association, leading to an E3 ubiquitin ligase defect that is likely associated with neurofilament degradation. C1 [Klein, Christopher J.; Duan, Xiaohui; Dyck, Peter J.] Mayo Clin, Peripheral Nerve Lab, Rochester, MN 55905 USA. [Wu, Yanhong] Mayo Clin, Lab Med & Pathol, Rochester, MN USA. [Botuyan, Maria-Victoria; Mer, Georges] Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN USA. [Middha, Sumit; Atkinson, Elizabeth J.] Mayo Clin, Rochester, MN USA. [Vogel, Peter] St Georg Hosp, Dept Neurol, Hamburg, Germany. [Goebel, Hans H.] Charite, Dept Neuropathol, D-13353 Berlin, Germany. [Boennemann, Carsten; Zukosky, Kristen] NINDS, Neurogenet Branch, Bethesda, MD 20892 USA. RP Klein, CJ (reprint author), Mayo Clin, Peripheral Nerve Lab, Rochester, MN 55905 USA. EM klein.christopher@mayo.edu OI Middha, Sumit/0000-0003-4135-6268 FU NIH [NS065007] FX NIH grant (NS065007, C.J.K.), Mayo Clinic Center for Individualized Medicine. NR 22 TC 4 Z9 5 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR 11 PY 2014 VL 82 IS 10 BP 873 EP 878 DI 10.1212/WNL.0000000000000206 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA AH9TJ UT WOS:000336485100014 PM 24500646 ER PT J AU Lee, PR Marsh, EB AF Lee, Paul R. Marsh, Elisabeth B. TI Opinion & Special Articles: Mentoring in neurology Filling the residency gap in academic mentoring SO NEUROLOGY LA English DT Editorial Material ID MEDICINE AB Effective academic mentoring significantly affects a physician's choice of career, academic productivity, and professional trajectory. The mentoring relationship is necessary for the continued success of medical training. It is critical to cultivate a climate in which mentoring can thrive. In order to improve the quality and outcomes of mentoring, we must adopt a comprehensive plan. There are interventions at every level of training that will ensure that the current cohort of neurologists receives the requisite expertise needed to flourish and inspire future trainees. Professional organizations must articulate a comprehensive vision of mentoring. Institutions must create an infrastructure to support mentors. Mentors should work in active partnerships with their mentees to forge sustained, productive relationships. Mentees must actively contribute to their own mentoring. Proper mentorship will ensure a bright future for academic neurology. C1 [Lee, Paul R.] NINDS, NIH, Bethesda, MD 20892 USA. [Marsh, Elisabeth B.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. RP Marsh, EB (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. EM ebmarsh@jhmi.edu FU Intramural NIH HHS NR 10 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR 11 PY 2014 VL 82 IS 10 BP E85 EP E88 DI 10.1212/WNL.0000000000000190 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA AH9TJ UT WOS:000336485100002 PM 24616198 ER PT J AU Han, J Fujisawa, T Husain, SR Puri, RK AF Han, Jing Fujisawa, Toshio Husain, Syed R. Puri, Raj K. TI Identification and characterization of cancer stem cells in human head and neck squamous cell carcinoma SO BMC CANCER LA English DT Article DE HNSCC (head & neck squamous cell carcinoma); Stem-like cells; CD24; CD44; Salivary gland malignant neoplasms ID CD24 EXPRESSION; ALDEHYDE DEHYDROGENASE; MARKER; RESISTANCE; LINES; IMMUNOPHENOTYPES; GEMCITABINE; METASTASIS AB Background: Current evidence suggests that initiation, growth, and invasion of cancer are driven by a small population of cancer stem cells (CSC). Previous studies have identified CD44+ cells as cancer stem cells in head and neck squamous cell carcinoma (HNSCC). However, CD44 is widely expressed in most cells in HNSCC tumor samples and several cell lines tested. We previously identified a small population of CD24+/CD44+ cells in HNSCC. In this study, we examined whether this population of cells may represent CSC in HNSCC. Methods: CD24+/CD44+ cells from HNSCC cell lines were sorted by flow cytometry, and their phenotype was confirmed by qRT-PCR. Their self-renewal and differentiation properties, clonogenicity in collagen gels, and response to anticancer drugs were tested in vitro. The tumorigenicity potential of CD24+/CD44+ cells was tested in athymic nude mice in vivo. Results: Our results show that CD24+/CD44+ cells possessed stemness characteristics of self-renewal and differentiation. CD24+/CD44+ cells showed higher cell invasion in vitro and made higher number of colonies in collagen gels compared to CD24-/CD44+ HNSCC cells. In addition, the CD24+/CD44+ cells were more chemo-resistant to gemcitabine and cisplatin compared to CD24-/CD44+ cells. In vivo, CD24+/CD44+ cells showed a tendency to generate larger tumors in nude mice compared to CD24-/CD44+ cell population. Conclusion: Our study clearly demonstrates that a distinct small population of CD24+/CD44+ cells is present in HNSCC that shows stem cell-like properties. This distinct small population of cells should be further characterized and may provide an opportunity to target HNSCC CSC for therapy. C1 [Han, Jing; Husain, Syed R.; Puri, Raj K.] US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, NIH Bldg 29B,Rm 2NN20,29 Lincoln Dr, Bethesda, MD 20892 USA. EM raj.puri@fda.hhs.gov NR 39 TC 22 Z9 22 U1 1 U2 15 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 MAR 11 PY 2014 VL 14 AR 173 DI 10.1186/1471-2407-14-173 PG 11 WC Oncology SC Oncology GA AD7DF UT WOS:000333421100001 PM 24612587 ER PT J AU Morris, JC Tan, AR Olencki, TE Shapiro, GI Dezube, BJ Reiss, M Hsu, FJ Berzofsky, JA Lawrence, DP AF Morris, John C. Tan, Antoinette R. Olencki, Thomas E. Shapiro, Geoffrey I. Dezube, Bruce J. Reiss, Michael Hsu, Frank J. Berzofsky, Jay A. Lawrence, Donald P. TI Phase I Study of GC1008 (Fresolimumab): A Human Anti-Transforming Growth Factor-Beta (TGF beta) Monoclonal Antibody in Patients with Advanced Malignant Melanoma or Renal Cell Carcinoma SO PLOS ONE LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSDIFFERENTIATION; METASTATIC BREAST-CANCER; SOLID TUMORS; T-CELLS; PROGRESSION; INHIBITION; EFFICACY; SURVIVAL; VIVO; KERATOACANTHOMAS AB Background: In advanced cancers, transforming growth factor-beta (TGFb) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFb monoclonal antibody that neutralizes all isoforms of TGFb. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma. Methods: In this multi-center phase I trial, cohorts of patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at 0.1, 0.3, 1, 3, 10, or 15 mg/kg on days 0, 28, 42, and 56. Patients achieving at least stable disease were eligible to receive Extended Treatment consisting of 4 doses of GC1008 every 2 weeks for up to 2 additional courses. Pharmacokinetic and exploratory biomarker assessments were performed. Results: Twenty-nine patients, 28 with malignant melanoma and 1 with renal cell carcinoma, were enrolled and treated, 22 in the dose-escalation part and 7 in a safety cohort expansion. No dose-limiting toxicity was observed, and the maximum dose, 15 mg/kg, was determined to be safe. The development of reversible cutaneous keratoacanthomas/squamous-cell carcinomas (4 patients) and hyperkeratosis was the major adverse event observed. One malignant melanoma patient achieved a partial response, and six had stable disease with a median progression-free survival of 24 weeks for these 7 patients (range, 16.4-44.4 weeks). Conclusions: GC1008 had no dose-limiting toxicity up to 15 mg/kg. In patients with advanced malignant melanoma and renal cell carcinoma, multiple doses of GC1008 demonstrated acceptable safety and preliminary evidence of antitumor activity, warranting further studies of single agent and combination treatments. C1 [Morris, John C.; Berzofsky, Jay A.] NCI, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Morris, John C.; Berzofsky, Jay A.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Tan, Antoinette R.; Reiss, Michael] Canc Inst New Jersey, Dept Med, New Brunswick, NJ USA. [Olencki, Thomas E.] Ohio State Univ, Dept Med, Columbus, OH 43210 USA. [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Dezube, Bruce J.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Hsu, Frank J.] Genzyme Corp, Cambridge, MA USA. [Lawrence, Donald P.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Morris, JC (reprint author), Univ Cincinnati, Dept Med, Div Hematol Oncol, Vontz Ctr Mol Studies, ML0562, Cincinnati, OH 45221 USA. EM morri2j7@ucmail.uc.edu; berzofsj@mail.nih.gov FU Genzyme Corporation; Center for Cancer Research, National Cancer Institute (NCI); Genzyme FX This work was supported by Genzyme Corporation, and in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI). Genzyme provided financial support, the investigational agent GC1008, and supported study design, data collection and analysis, the decision to publish, and preparation of the manuscript. NR 50 TC 41 Z9 46 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 11 PY 2014 VL 9 IS 3 AR e90353 DI 10.1371/journal.pone.0090353 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC9GM UT WOS:000332842400014 PM 24618589 ER PT J AU Harel, A Kravitz, DJ Baker, CI AF Harel, Assaf Kravitz, Dwight J. Baker, Chris I. TI Task context impacts visual object processing differentially across the cortex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE object recognition; vision; fMRI; top-down processing; occipitotemporal cortex ID INFERIOR PREFRONTAL CORTEX; HUMAN FRONTOPARIETAL CORTEX; LATERAL OCCIPITAL COMPLEX; PARIETAL CORTEX; FUNCTIONAL MRI; WORKING-MEMORY; FMRI EVIDENCE; ATTENTIONAL MODULATION; EXTRASTRIATE CORTEX; FOCAL ATTENTION AB Perception reflects an integration of "bottom-up" (sensory-driven) and "top-down" (internally generated) signals. Although models of visual processing often emphasize the central role of feed-forward hierarchical processing, less is known about the impact of top-down signals on complex visual representations. Here, we investigated whether and how the observer's goals modulate object processing across the cortex. We examined responses elicited by a diverse set of objects under six distinct tasks, focusing on either physical (e.g., color) or conceptual properties (e.g., man-made). Critically, the same stimuli were presented in all tasks, allowing us to investigate how task impacts the neural representations of identical visual input. We found that task has an extensive and differential impact on object processing across the cortex. First, we found task-dependent representations in the ventral temporal and prefrontal cortex. In particular, although object identity could be decoded from the multivoxel response within task, there was a significant reduction in decoding across tasks. In contrast, the early visual cortex evidenced equivalent decoding within and across tasks, indicating task-independent representations. Second, task information was pervasive and present from the earliest stages of object processing. However, although the responses of the ventral temporal, prefrontal, and parietal cortex enabled decoding of both the type of task (physical/conceptual) and the specific task (e.g., color), the early visual cortex was not sensitive to type of task and could only be used to decode individual physical tasks. Thus, object processing is highly influenced by the behavioral goal of the observer, highlighting how top-down signals constrain and inform the formation of visual representations. C1 [Harel, Assaf; Kravitz, Dwight J.; Baker, Chris I.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Harel, A (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM assaf.harel@nih.gov OI Baker, Chris/0000-0001-6861-8964; Harel, Assaf/0000-0002-4899-6156 NR 74 TC 36 Z9 36 U1 5 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 MAR 11 PY 2014 VL 111 IS 10 BP E962 EP E971 DI 10.1073/pnas.1312567111 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC5MK UT WOS:000332564800014 PM 24567402 ER PT J AU Fekete, A Eszenyi, D Herczeg, M Pozsgay, V Borbas, A AF Fekete, Aniko Eszenyi, Daniel Herczeg, Mihaly Pozsgay, Vince Borbas, Aniko TI Preparation of synthetic oligosaccharide- conjugates of poly-beta-(1 -> 6)-N-acetyl glucosamine SO CARBOHYDRATE RESEARCH LA English DT Article DE Carbohydrate chemical synthesis; poly-beta-(1 -> 6)-N-acetyl glucosamine; Reductive amination; Glycoconjugate ID POLY-N-ACETYLGLUCOSAMINE; SURFACE POLYSACCHARIDE; STAPHYLOCOCCUS-AUREUS; INTERCELLULAR ADHESIN; OLIGOGLUCOSAMINES; EPIDERMIDIS; RESISTANCE; PATHOGENS; VACCINES AB Staphylococcus aureus and Staphylococcus epidermidis are prominent bacterial pathogens of nosocomial infections. Both microorganisms colonize medical devices by forming adherent biofilms. poly-beta-(1 -> 6)-N-acetyl-glucosamine (PNAG) is a surface polysaccharide antigen which was found on both S. aureus and S. epidermidis. Animal studies have proved that PNAG can elicit antibodies which protect against staphylococcal infections. We have presented the synthesis of di-, tetra-and hexasaccharide fragments of PNAG with formyl-heptyl aglycone and their attachment to bovine serum albumin (BSA) by reductive amination. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Fekete, Aniko; Herczeg, Mihaly] Univ Debrecen, Dept Organ Chem, H-4010 Debrecen, Hungary. [Pozsgay, Vince] NICHHD, NIH, Bethesda, MD 20892 USA. [Eszenyi, Daniel; Borbas, Aniko] Univ Debrecen, Dept Pharmaceut Chem, Med & Hlth Ctr, H-4010 Debrecen, Hungary. RP Fekete, A (reprint author), Univ Debrecen, Dept Organ Chem, POB 20, H-4010 Debrecen, Hungary. EM fekete.aniko@science.unideb.hu FU Hungarian Scientific Research Fund [PD73064] FX This work was supported by the Hungarian Scientific Research Fund (Project No. PD73064). NR 28 TC 4 Z9 5 U1 0 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 EI 1873-426X J9 CARBOHYD RES JI Carbohydr. Res. PD MAR 11 PY 2014 VL 386 BP 33 EP 40 DI 10.1016/j.carres.2013.12.022 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA AA5YM UT WOS:000331175800006 PM 24468971 ER PT J AU van Ryn, M Phelan, SM Arora, NK Haggstrom, DA Jackson, GL Zafar, SY Griffin, JM Zullig, LL Provenzale, D Yeazel, MW Jindal, RM Clauser, SB AF van Ryn, Michelle Phelan, Sean M. Arora, Neeraj K. Haggstrom, David A. Jackson, George L. Zafar, S. Yousuf Griffin, Joan M. Zullig, Leah L. Provenzale, Dawn Yeazel, Mark W. Jindal, Rahul M. Clauser, Steven B. TI Patient-Reported Quality of Supportive Care Among Patients With Colorectal Cancer in the Veterans Affairs Health Care System SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; OF-LIFE; DISTRESS MANAGEMENT; PROSTATE-CANCER; NCCN GUIDELINES; RECALL BIAS; DISPARITIES; ONCOLOGY; COMMUNICATION; COORDINATION AB Purpose High-quality supportive care is an essential component of comprehensive cancer care. We implemented a patient-centered quality of cancer care survey to examine and identify predictors of quality of supportive care for bowel problems, pain, fatigue, depression, and other symptoms among 1,109 patients with colorectal cancer. Patients and Methods Patients with new diagnosis of colorectal cancer at any Veterans Health Administration medical center nationwide in 2008 were ascertained through the Veterans Affairs Central Cancer Registry and sent questionnaires assessing a variety of aspects of patient-centered cancer care. We received questionnaires from 63% of eligible patients (N = 1,109). Descriptive analyses characterizing patient experiences with supportive care and binary logistic regression models were used to examine predictors of receipt of help wanted for each of the five symptom categories. Results There were significant gaps in patient-centered quality of supportive care, beginning with symptom assessment. In multivariable modeling, the impact of clinical factors and patient race on odds of receiving wanted help varied by symptom. Coordination of care quality predicted receipt of wanted help for all symptoms, independent of patient demographic or clinical characteristics. Conclusion This study revealed substantial gaps in patient-centered quality of care, difficult to characterize through quality measurement relying on medical record review alone. It established the feasibility of collecting patient-reported quality measures. Improving quality measurement of supportive care and implementing patient-reported outcomes in quality-measurement systems are high priorities for improving the processes and outcomes of care for patients with cancer. C1 [van Ryn, Michelle; Phelan, Sean M.] Mayo Clin, Rochester, MN 55905 USA. [Griffin, Joan M.] Vet Affairs Med Ctr, Durham, NC USA. [Yeazel, Mark W.] Univ Minnesota, Minneapolis, MN USA. [Arora, Neeraj K.; Clauser, Steven B.] NCI, Bethesda, MD 20892 USA. [Haggstrom, David A.] Richard L Roudebush Vet Affairs Med Ctr, Indianapolis, IN 46202 USA. [Haggstrom, David A.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Jackson, George L.; Zullig, Leah L.; Provenzale, Dawn] Durham Vet Affairs Med Ctr, Durham, NC USA. [Jackson, George L.; Zafar, S. Yousuf; Provenzale, Dawn] Duke Univ, Med Ctr, Durham, NC 27706 USA. [Zullig, Leah L.] Univ N Carolina, Chapel Hill, NC USA. [Jindal, Rahul M.] Walter Reed Army Med Ctr, Washington, DC 20307 USA. RP van Ryn, M (reprint author), Mayo Clin, Div Hlth Care Policy & Res, 200 First St SW, Rochester, MN 55905 USA. EM vanryn.michelle@mayo.edu FU Interagency Quality of Cancer Care Committee, Applied Research Branch, National Cancer Institute (NCI); Veterans Health Administration; NCI [5R25CA116339] FX Supported by the Interagency Quality of Cancer Care Committee, Applied Research Branch, National Cancer Institute (NCI), through an interagency agreement with the Veterans Health Administration and by NCI Grant No. 5R25CA116339 (L.L.Z.). NR 62 TC 12 Z9 12 U1 1 U2 3 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 MAR 10 PY 2014 VL 32 IS 8 BP 809 EP + DI 10.1200/JCO.2013.49.4302 PG 8 WC Oncology SC Oncology GA AC4IB UT WOS:000332483400018 PM 24493712 ER PT J AU Lu, KH Wood, ME Daniels, M Burke, C Ford, J Kauff, ND Kohlmann, W Lindor, NM Mulvey, TM Robinson, L Rubinstein, WS Stoffel, EM Snyder, C Syngal, S Merrill, JK Wollins, DS Hughes, KS AF Lu, Karen H. Wood, Marie E. Daniels, Molly Burke, Cathy Ford, James Kauff, Noah D. Kohlmann, Wendy Lindor, Noralane M. Mulvey, Therese M. Robinson, Linda Rubinstein, Wendy S. Stoffel, Elena M. Snyder, Carrie Syngal, Sapna Merrill, Janette K. Wollins, Dana Swartzberg Hughes, Kevin S. TI American Society of Clinical Oncology Expert Statement: Collection and Use of a Cancer Family History for Oncology Providers SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LI-FRAUMENI SYNDROME; COLORECTAL-CANCER; RISK-ASSESSMENT; LYNCH-SYNDROME; POLICY STATEMENT; BREAST-CANCER; GENETIC COUNSELORS; GERMLINE MUTATIONS; NATIONAL SOCIETY; OVARIAN-CANCER C1 [Lu, Karen H.; Daniels, Molly; Burke, Cathy] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Robinson, Linda] Simmons Comprehens Canc Ctr, Dallas, TX USA. [Wood, Marie E.] Univ Vermont, Burlington, VT 05405 USA. [Ford, James] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Kauff, Noah D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Kohlmann, Wendy] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Lindor, Noralane M.] Mayo Clin, Scottsdale, AZ USA. [Mulvey, Therese M.] Southcoast Ctr Canc Care, Fall River, MA USA. [Syngal, Sapna] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Hughes, Kevin S.] Massachusetts Gen Hosp, Avon Comprehens Breast Evaluat Ctr, Boston, MA 02114 USA. [Rubinstein, Wendy S.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Stoffel, Elena M.] Univ Michigan, Ann Arbor, MI 48109 USA. [Snyder, Carrie] Creighton Univ, Omaha, NE 68178 USA. [Merrill, Janette K.; Wollins, Dana Swartzberg] Amer Soc Clin Oncol, Alexandria, VA USA. RP Wood, ME (reprint author), Univ Vermont, Hem Onc, Given E214,89 Beaumont, Burlington, VT 05405 USA. EM marie.wood@uvm.edu OI Daniels, Molly/0000-0002-5093-5539; Kauff, Noah/0000-0001-7242-6156; Hughes, Kevin/0000-0003-4084-6484 FU NCI NIH HHS [P50 CA083639, P30 CA016672] NR 51 TC 43 Z9 46 U1 1 U2 3 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 MAR 10 PY 2014 VL 32 IS 8 BP 833 EP + DI 10.1200/JCO.2013.50.9257 PG 9 WC Oncology SC Oncology GA AC4IB UT WOS:000332483400022 PM 24493721 ER PT J AU Freidlin, B Sun, ZX Gray, R Korn, EL AF Freidlin, Boris Sun, Zhuoxin Gray, Robert Korn, Edward L. TI Reply to S. Goteti et al SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID RANDOMIZED CLINICAL-TRIALS; ONCOLOGY C1 [Freidlin, Boris; Korn, Edward L.] NCI, Bethesda, MD 20892 USA. [Sun, Zhuoxin; Gray, Robert] Dana Farber Canc Inst, Eastern Cooperat Oncol Grp, Boston, MA 02115 USA. RP Freidlin, B (reprint author), NCI, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 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 MAR 10 PY 2014 VL 32 IS 8 BP 856 EP 856 DI 10.1200/JCO.2013.53.8934 PG 1 WC Oncology SC Oncology GA AC4IB UT WOS:000332483400029 PM 24493728 ER PT J AU Murphy, E Steenbergen, C AF Murphy, Elizabeth Steenbergen, Charles TI Estrogen regulation of protein expression and signaling pathways in the heart SO BIOLOGY OF SEX DIFFERENCES LA English DT Review DE Cardiac; Estrogen; Ischemia-reperfusion; Metabolism ID ISCHEMIA-REPERFUSION INJURY; PRESSURE-OVERLOAD HYPERTROPHY; TERM CALORIC RESTRICTION; MALE-FEMALE DIFFERENCES; RECEPTOR-ALPHA; GENDER-DIFFERENCES; MOUSE HEART; ER-BETA; ISCHEMIA/REPERFUSION INJURY; TRIACYLGLYCERIDE DYNAMICS AB Sex differences in cardiovascular disease and cardiac physiology have been reported in humans as well as in animal models. Premenopausal women have reduced cardiovascular disease compared to men, but the incidence of cardiovascular disease in women increases following menopause. Sex differences in cardiomyocytes likely contribute to the differences in male-female physiology and response to disease. Sex differences in the heart have been noted in electrophysiology, contractility, signaling, metabolism, and cardioprotection. These differences appear to be due, at least in part, to differences in gene and protein expression as well as in posttranslational protein modifications. This review will focus primarily on estrogen-mediated male-female differences in protein expression and signaling pathways in the heart and cardiac cells. It should be emphasized that these basic differences are not intrinsically beneficial or detrimental per se; the difference can be good or bad depending on the context and circumstances. C1 [Murphy, Elizabeth] NHLBI, Lab Cardiac Physiol, Syst Biol Ctr, NIH, Bethesda, MD 20824 USA. [Steenbergen, Charles] JHMI, Dept Pathol, Baltimore, MD 21231 USA. RP Murphy, E (reprint author), NHLBI, Lab Cardiac Physiol, Syst Biol Ctr, NIH, Bethesda, MD 20824 USA. EM murphy1@mail.nih.gov FU ZIA [HL002065, HL006059]; [5R01 HL039752] FX EM was supported by ZIA HL002065 and ZIA HL006059. CS was supported by 5R01 HL039752. NR 81 TC 10 Z9 10 U1 1 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2042-6410 J9 BIOL SEX DIFFER JI Biol. Sex Differ. PD MAR 10 PY 2014 VL 5 AR 6 DI 10.1186/2042-6410-5-6 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity SC Endocrinology & Metabolism; Genetics & Heredity GA AE0OD UT WOS:000333664700001 PM 24612699 ER PT J AU Pusapati, GV Hughes, CE Dorn, KV Zhang, DP Sugianto, P Aravind, L Rohatgi, R AF Pusapati, Ganesh V. Hughes, Casey E. Dorn, Karolin V. Zhang, Dapeng Sugianto, Priscilla Aravind, L. Rohatgi, Rajat TI EFCAB7 and IQCE Regulate Hedgehog Signaling by Tethering the EVC-EVC2 Complex to the Base of Primary Cilia SO DEVELOPMENTAL CELL LA English DT Article ID VAN-CREVELD-SYNDROME; WEYERS ACRODENTAL DYSOSTOSIS; PROTEOMIC ANALYSIS; PROTEINS; DISSOCIATION; MUTATIONS; INTERACTS; EVC/EVC2; EVC AB The Hedgehog (Hh) pathway depends on primary cilia in vertebrates, but the signaling machinery within cilia remains incompletely defined. We report the identification of a complex between two ciliary proteins, EFCAB7 and IQCE, which positively regulates the Hh pathway. The EFCAB7-IQCE module anchors the EVC-EVC2 complex in a signaling microdomain at the base of cilia. EVC and EVC2 genes are mutated in Ellis van Creveld and Weyers syndromes, characterized by impaired Hh signaling in skeletal, cardiac, and orofacial tissues. EFCAB7 binds to a C-terminal disordered region in EVC2 that is deleted in Weyers patients. EFCAB7 depletion mimics the Weyers cellular phenotype-the mislocalization of EVC-EVC2 within cilia and impaired activation of the transcription factor GLI2. Evolutionary analysis suggests that emergence of these complexes might have been important for adaptation of an ancient organelle, the cilium, for an animal-specific signaling network. C1 [Pusapati, Ganesh V.; Hughes, Casey E.; Dorn, Karolin V.; Sugianto, Priscilla; Rohatgi, Rajat] Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA. [Pusapati, Ganesh V.; Hughes, Casey E.; Dorn, Karolin V.; Sugianto, Priscilla; Rohatgi, Rajat] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Zhang, Dapeng; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov; rrohatgi@stanford.edu FU March of Dimes Foundation [6-FY13-104]; National Institutes of Health [DP2GM105448]; Pew Foundation; Sontag Foundation; Intramural Research Program of the National Institutes of Health, Department of Health, and Human Services FX We thank A. Lebensohn for purification of the GBP protein used in all the anti-GFP IP experiments and for help with the CRISPR/Cas9 system, G. Luchetti for insightful discussions and EvC complex experiments in 293T cells, E. Nigg (anti-CEP164) and J. Eggenschwiler (anti-GLI2) for reagents, and X. Ge for help with immunofluorescence. This work was supported by the March of Dimes Foundation (6-FY13-104), the National Institutes of Health (DP2GM105448), and the Pew Foundation and the Sontag Foundation. D.Z. and L.A. are supported by funds of the Intramural Research Program of the National Institutes of Health, Department of Health, and Human Services. NR 25 TC 20 Z9 21 U1 0 U2 2 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 MAR 10 PY 2014 VL 28 IS 5 BP 483 EP 496 DI 10.1016/j.devcel.2014.01.021 PG 14 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA AD6XU UT WOS:000333405600004 PM 24582806 ER PT J AU Galiwango, RM Lubyayi, L Musoke, R Kalibbala, S Buwembo, M Kasule, J Serwadda, D Gray, RH Reynolds, SJ Chang, LW AF Galiwango, Ronald M. Lubyayi, Lawrence Musoke, Richard Kalibbala, Sarah Buwembo, Martin Kasule, Jjingo Serwadda, David Gray, Ronald H. Reynolds, Steven J. Chang, Larry W. TI Field Evaluation of PIMA Point-of-Care CD4 Testing in Rakai, Uganda SO PLOS ONE LA English DT Article ID ANTIRETROVIRAL THERAPY; SOUTH-AFRICA; ANALYZER; SERVICE; MORTALITY; COUNTS AB Objective: To assess the accuracy of PIMA Point-of-Care (POC) CD4 testing in rural Rakai, Uganda. Methods: 903 HIV positive persons attending field clinics provided a venous blood sample assessed on site using PIMA analyzers per manufacturer's specifications. The venous samples were then run on FACSCalibur flow cytometry at a central facility. The Bland-Altman method was used to estimate mean bias and 95% limits of agreement (LOA). Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were calculated for a CD4 threshold of <350 and <500 cells/uL for antiretroviral eligibility. Results: There was a high correlation between PIMA and FACSCalibur CD4 counts (r = 0.943, p<0.001). Relative to FACSCalibur, the PIMA POC CD4 had negative mean bias of -34.6 cells/uL (95% LOA: -219.8 to 150.6) overall. The dispersion at CD4<350 cells/uL was 5.1 cells/uL (95% LOA: -126.6 to 136.8). For a threshold of CD4<350 cells/uL, PIMA venous blood had a sensitivity of 88.6% (95% CI 84.8-92.4%), specificity of 87.5% (95% CI 84.9-90.1%), NPV of 94.9% (95% CI 93.1-96.7%), and PPV of 74.4% (95% CI 69.6-79.2%). PIMA sensitivity and PPV significantly increased to 96.1% and 88.3% respectively with increased threshold of 500 cells/uL. Conclusions: Overall, PIMA POC CD4 counts demonstrated negative bias compared to FACSCalibur. PIMA POC sensitivity improved significantly at a higher CD4 threshold of 500 than a 350 cells/uL threshold. C1 [Galiwango, Ronald M.; Lubyayi, Lawrence; Musoke, Richard; Kalibbala, Sarah; Buwembo, Martin; Kasule, Jjingo] Rakai Hlth Sci Program, Kalisizo, Uganda. [Gray, Ronald H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Reynolds, Steven J.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Reynolds, Steven J.; Chang, Larry W.] Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. [Serwadda, David] Makerere Univ, Coll Hlth Sci, Sch Publ Hlth, Kampala, Uganda. RP Chang, LW (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. EM lchang8@jhmi.edu FU CDC Uganda; PEPFAR Uganda; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We acknowledge CDC Uganda for the funding support that availed the PIMAs to our institution and PEPFAR Uganda that supports the treatment program. This work was supported in part (SJR) by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in the study design, data collection, analysis, decision to publish or preparation of the manuscript. NR 18 TC 10 Z9 10 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 10 PY 2014 VL 9 IS 3 AR e88928 DI 10.1371/journal.pone.0088928 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC9FH UT WOS:000332839300008 PM 24614083 ER PT J AU Thein, S Tao-Cheng, JH Li, Y Bayer, KU Reese, TS Dosemeci, A AF Thein, Soe Tao-Cheng, Jung-Hwa Li, Yan Bayer, K. Ulrich Reese, Thomas S. Dosemeci, Ayse TI CaMKII Mediates Recruitment and Activation of the Deubiquitinase CYLD at the Postsynaptic Density SO PLOS ONE LA English DT Article ID PROTEIN-KINASE-II; HIPPOCAMPAL-NEURONS; PHOSPHORYLATION; UBIQUITINATION; DEGRADATION; INHIBITOR; PROTEASOMES; STARGAZIN; MECHANISM; PROMOTES AB NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy. Recruitment of CYLD, a deubiquitinase specific for K63-linked polyubiquitins, is blocked by pre-treatment with tatCN21, a CaMKII inhibitor, at a concentration that inhibits the translocation of CaMKII to the PSD. Furthermore, CaMKII co-immunoprecipitates with CYLD from solubilized PSD fractions, indicating an association between the proteins. Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity. Activation of CaMKII in isolated PSDs promotes phosphorylation of CYLD on the same residues and also enhances endogenous deubiquitinase activity specific for K63-linked polyubiquitins. Since K63-linked polyubiquitin conjugation to proteins inhibits their interaction with proteasomes, CaMKII-mediated recruitment and upregulation of CYLD is expected to remove K63-linked polyubiquitins and facilitate proteasomal degradation at the PSD. C1 [Thein, Soe; Reese, Thomas S.; Dosemeci, Ayse] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. [Tao-Cheng, Jung-Hwa] NINDS, EM Facil, Bethesda, MD 20892 USA. [Li, Yan] NINDS, Prot Peptide Sequencing Facil, Bethesda, MD 20892 USA. [Bayer, K. Ulrich] Univ Colorado Denver, Sch Med, Dept Pharmacol, Aurora, CO USA. RP Thein, S (reprint author), NINDS, Neurobiol Lab, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM theinsh@mail.nih.gov; dosemeca@mail.nih.gov FU Intramural Research Program NINDS, National Institutes of Health (NIH); NIH [R01 NS081248] FX This research was supported by the Intramural Research Program NINDS, National Institutes of Health (NIH) and NIH grant R01 NS081248 (to KUB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 7 Z9 7 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 10 PY 2014 VL 9 IS 3 AR e91312 DI 10.1371/journal.pone.0091312 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC9FH UT WOS:000332839300111 PM 24614225 ER PT J AU Wang, RP Sun, PD AF Wang, Ruipeng Sun, Peter D. TI Natural Killer Cell-Mediated Shedding of ULBP2 SO PLOS ONE LA English DT Article ID SOLUBLE UL16-BINDING PROTEIN-2; NKG2D LIGAND EXPRESSION; CLINICAL-SIGNIFICANCE; POOR-PROGNOSIS; CUTTING EDGE; NK CELLS; T-CELLS; RECEPTOR; APOPTOSIS; ACTIVATION AB UL16 binding proteins (ULBPs) are a family of cell surface proteins that are present in transformed and stressed cells and ligands for NKG2D. Soluble NKG2D ligands have been found in sera from cancer patients with their protein concentrations correlated with poor cancer prognosis. Here we show, for the first time, that human tumor cells lost their surface expression of ULBP2, but not ULBP1 and ULBP3, during NK cell-mediated cytolysis. In contrast to spontaneous shedding of NKG2D ligands, NK cytolysis-mediated shedding of ULBP2 was linked to target cell apoptosis, although both resulted from metalloproteinase cleavages. Inhibition of ULBP2 shedding by a metalloproteinase inhibitor BB-94 lead to reduced NK cell-mediated cytotoxicity and cytokine production. These results illustrate a regulation of NK cell effector functions through cytolysis-induced NKG2D ligand shedding. Consequently, compounds inhibiting NKG2D ligand shedding may offer therapeutic means to reduce excessive pathogenic NK cell activities. C1 [Wang, Ruipeng; Sun, Peter D.] NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Sun, PD (reprint author), NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM psun@nih.gov FU National Institute of Allergy and Infectious Diseases FX The funding is provided by the National Institute of Allergy and Infectious Diseases Intramural research funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 3 Z9 4 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 10 PY 2014 VL 9 IS 3 AR e91133 DI 10.1371/journal.pone.0091133 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC9FH UT WOS:000332839300083 PM 24614922 ER PT J AU Gomez-Rodriguez, J Wohlfert, EA Handon, R Meylan, F Wu, JZ Anderson, SM Kirby, MR Belkaid, Y Schwartzberg, PL AF Gomez-Rodriguez, Julio Wohlfert, Elizabeth A. Handon, Robin Meylan, Francoise Wu, Julie Z. Anderson, Stacie M. Kirby, Martha R. Belkaid, Yasmine Schwartzberg, Pamela L. TI Itk-mediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR-1; TRANSCRIPTION FACTORS; FATE DECISIONS; IN-VIVO; DIFFERENTIATION; MTOR; ACTIVATION; INTERLEUKIN-2; PATHWAYS; ANTIGEN AB A proper balance between Th17 and T regulatory cells (T-reg cells) is critical for generating protective immune responses while minimizing autoimmunity. We show that the Tec family kinase Itk (IL2-inducible T cell kinase), a component of T cell receptor (TCR) signaling pathways, influences this balance by regulating cross talk between TCR and cytokine signaling. Under both Th17 and Treg cell differentiation conditions, Itk. (-)/(-). CD4+ T cells develop higher percentages of functional FoxP(3+) cells, associated with increased sensitivity to IL-2. Itk(-)/(-) CD4+ T cells also preferentially develop into Treg cells in vivo. We find that Itk- deficient T cells exhibit reduced TCR-induced phosphorylation of mammalian target of rapamycin (mTOR) targets, accompanied by downstream metabolic alterations. Surprisingly, Itk(-)/(-) cells also exhibit reduced IL-2-induced mTOR activation, despite increased STAT5 phosphorylation. We demonstrate that in wild-type CD4+ T cells, TCR stimulation leads to a dose-dependent repression of Pten. However, at low TCR stimulation or in the absence of Itk, Pten is not effectively repressed, thereby uncoupling STAT5 phosphorylation and phosphoinositide-3-kinase (PI3K) pathways. Moreover, Itk- deficient CD4+ T cells show impaired TCR-mediated induction of Myc and miR- 19b, known repressors of Pten. Our results demonstrate that Itk helps orchestrate positive feedback loops integrating multiple T cell signaling pathways, suggesting Itk as a potential target for altering the balance between Th17 and Treg cells. C1 [Gomez-Rodriguez, Julio; Handon, Robin; Wu, Julie Z.; Anderson, Stacie M.; Kirby, Martha R.; Schwartzberg, Pamela L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Wohlfert, Elizabeth A.; Belkaid, Yasmine] NIAID, Bethesda, MD 20892 USA. [Meylan, Francoise] NIAMSD, Bethesda, MD 20892 USA. [Wu, Julie Z.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Schwartzberg, PL (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM pams@mail.nih.gov FU National Human Genome Research Institute; National Institute of Allergy and Infectious Diseases; National Institute of Arthritis and Musculoskeletal and Skin Disease FX This work was supported by funds from the intramural programs of the National Human Genome Research Institute, National Institute of Allergy and Infectious Diseases, and National Institute of Arthritis and Musculoskeletal and Skin Diseases. NR 60 TC 39 Z9 40 U1 5 U2 14 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 MAR 10 PY 2014 VL 211 IS 3 BP 529 EP 543 DI 10.1084/jem.20131459 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AC8JH UT WOS:000332778800012 PM 24534190 ER PT J AU Song, MO Mattie, MD Lee, CH Freedman, JH AF Song, Min Ok Mattie, Michael D. Lee, Chang-Ho Freedman, Jonathan H. TI The role of Nrf1 and Nrf2 in the regulation of copper-responsive transcription SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Nrf1; Nrf2; ARE; Transcription; Copper; Metallothionein-1 ID OXIDATIVE STRESS; HEPG2 CELLS; NRF2-REGULATED GENES; INDUCIBLE EXPRESSION; ELEMENT; ACTIVATION; TOXICITY; PATHWAY; MICE; IDENTIFICATION AB Recent evidences indicated Nrf2 is more potent than Nrfl in the activation of antioxidant genes. However, the roles of Nrf proteins in the regulation of copper-responsive transcription have not been well addressed. We took the toxicogenomic approach and the present network and Gene Ontology analyses results showed that Nrfl and Nrf2 are distinctively involved in copper-responsive transcriptional regulation in HepG2 transcriptome. Cells deficient in either Nrfl or Nrf2 were more susceptible to copper exposure than wild type cells. Nrfl and Nrf2 null cells were transfected with the luciferase reporters containing either ARE(s) or a combination of ARE(s) and MREs, and then treated with copper. In Nrf2-null (Nrf2(-/-)) cells, copper did not activate transcription of reporter genes, whereas Nrfl deficiency did not affect copper-inducible activation. Ectopic expression of Nrf2 restored copper-inducible transcription in Nrf2(-/-) cells. However, the changes in the intrinsic mRNA levels of MT-1 in Nrf null cells following copper treatment showed that Nrfl and Nrf2 equally contributed to MT-1 activation after 4 h, while Nrfl involved more than Nrf2 following 24 h exposure. These results suggest that while Nrf2 is crucial for MRE/ARE-mediated transcription in response to copper, Nrfl may activate MT-1 expression by a mechanism different from that Nr12 employs. (C) 2014 Elsevier Inc. All rights reserved. C1 [Song, Min Ok; Lee, Chang-Ho] Gangneung Wonju Natl Univ, Coll Nat Sci, Dept Biol, Gangneung Si 210702, Gangwon Do, South Korea. [Mattie, Michael D.] Duke Univ, Nicholas Sch Environm, Durham, NC 27708 USA. [Freedman, Jonathan H.] NIEHS, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. RP Song, MO (reprint author), Agensys Inc, 1545 17th St, Santa Monica, CA 90404 USA. EM rotisong@gmail.com; mmattie@agensys.com FU Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health [Z01ES102046]; Natural Science Research Institute of Gangneung-Wonju National University FX The authors would like to thank Dr. Glen Andrews (University of Kansas Medical Center) for providing the mouse MT-1-based Luc reporter plasmids and Dr. Jefferson Y. Chan (University of California-Irvine) for the Nrfl and Nrf2-1- cell lines. This work was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health (Z01ES102046) and by Natural Science Research Institute of Gangneung-Wonju National University (to C.-H. Lee). NR 37 TC 12 Z9 12 U1 0 U2 9 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 EI 1090-2422 J9 EXP CELL RES JI Exp. Cell Res. PD MAR 10 PY 2014 VL 322 IS 1 BP 39 EP 50 DI 10.1016/j.yexcr.2014.01.013 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AB8QU UT WOS:000332055900005 PM 24462598 ER PT J AU Lyu, XM Fang, WY Cai, LM Zheng, H Ye, YF Zhang, L Li, JB Peng, H Cho, WCS Wang, EN Marincola, FM Yao, KT Cai, HB Li, JL Li, X AF Lyu, Xiaoming Fang, Weiyi Cai, Longmei Zheng, Hang Ye, Yanfen Zhang, Lan Li, Jinbang Peng, Hong Cho, William C. S. Wang, Ena Marincola, Francesco M. Yao, Kaitai Cai, Hongbing Li, Jiliang Li, Xin TI TGF beta R2 is a major target of miR-93 in nasopharyngeal carcinoma aggressiveness SO MOLECULAR CANCER LA English DT Article DE miR-93; TGF beta R2; Aggressiveness; PI3K/Akt; Nasopharyngeal carcinoma ID FACTOR-BETA RECEPTOR; OVARIAN-CANCER CELLS; TGF-BETA; GROWTH-FACTOR; HEPATOCELLULAR-CARCINOMA; BREAST-CANCER; MESENCHYMAL TRANSITION; MICRORNA CLUSTER; TUMOR-SUPPRESSOR; COLON-CANCER AB Background: MiR-17-92 cluster and its paralogues have emerged as crucial regulators of many oncogenes and tumor suppressors. Transforming growth factor-beta receptor II (TGF beta R2), as an important tumor suppressor, is involved in various cancer types. However, it is in cancer that only two miRNAs of this cluster and its paralogues have been reported so far to regulate TGF beta R2. MiR-93 is oncogenic, but its targetome in cancer has not been fully defined. The role of miR-93 in nasopharyngeal carcinoma (NPC) still remains largely unknown. Methods: We firstly evaluated the clinical signature of TGF beta R2 down-regulation in clinical samples, and next used a miRNA expression profiling analysis followed by multi-validations, including Luciferase reporter assay, to identify miRNAs targeting TGF beta R2 in NPC. In vitro and in vivo studies were performed to further investigate the effects of miRNA-mediated TGF beta R2 down-regulation on NPC aggressiveness. Finally, mechanism studies were conducted to explore the associated pathway and genes influenced by this miRNA-mediated TGF beta R2 down-regulation. Results: TGF beta R2 was down-regulated in more than 50% of NPC patients. It is an unfavorable prognosis factor contributing to clinical NPC aggressiveness. A cluster set of 4 TGF beta R2-associated miRNAs was identified; they are all from miR-17-92 cluster and its paralogues, of which miR-93 was one of the most significant miRNAs, directly targeting TGF beta R2, promoting cell proliferation, invasion and metastasis in vitro and in vivo. Moreover, miR-93 resulted in the attenuation of Smad-dependent TGF-beta signaling and the activation of PI3K/Akt pathway by suppressing TGF beta R2, further promoting NPC cell uncontrolled growth, invasion, metastasis and EMT-like process. Impressively, the knockdown of TGF beta R2 by siRNA displayed a consentaneous phenocopy with the effect of miR-93 in NPC cells, supporting TGF beta R2 is a major target of miR-93. Our findings were also substantiated by investigation of the clinical signatures of miR-93 and TGF beta R2 in NPC. Conclusion: The present study reports an involvement of miR-93-mediated TGF beta R2 down-regulation in NPC aggressiveness, thus giving extended insights into molecular mechanisms underlying cancer aggressiveness. Approaches aimed at blocking miR-93 may serve as a promising therapeutic strategy for treating NPC patients. C1 [Lyu, Xiaoming; Fang, Weiyi; Cai, Longmei; Zheng, Hang; Ye, Yanfen; Li, Jinbang; Yao, Kaitai; Li, Xin] Southern Med Univ, Canc Res Inst, Guangzhou, Guangdong, Peoples R China. [Lyu, Xiaoming; Fang, Weiyi; Cai, Longmei; Zheng, Hang; Ye, Yanfen; Li, Jinbang; Yao, Kaitai; Li, Xin] Southern Med Univ, Prov Key Lab Funct Prote, Guangzhou, Guangdong, Peoples R China. [Cai, Hongbing] Southern Med Univ, Sch Chinese Tradit Med, Guangzhou, Guangdong, Peoples R China. [Zhang, Lan; Peng, Hong] Southern Med Univ, Nanfang Hosp, Dept Otorhinolaryngol, Guangzhou, Guangdong, Peoples R China. [Zheng, Hang] Southern Med Univ, Nanfang Hosp, Dept Oncol, Guangzhou, Guangdong, Peoples R China. [Cho, William C. S.] Queen Elizabeth Hosp, Dept Clin Oncol, Guangzhou, Hong Kong, Peoples R China. [Wang, Ena; Marincola, Francesco M.] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Li, Jiliang] Southern Med Univ, Sch Biotechnol, Guangzhou, Guangdong, Peoples R China. [Li, Jiliang] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Mol Oncol Labs,Dept Oncol, Oxford OX3 9DU, England. RP Cai, HB (reprint author), Southern Med Univ, Sch Chinese Tradit Med, Guangzhou, Guangdong, Peoples R China. EM chbing2008@126.com; ji-liang.li@imm.ox.ac.uk; xinli268@gmail.com FU National Natural Science Foundation of China [30973292, 30872856, 30371535, 81171959]; Natural Science Foundation of Guangdong Province [S2011010004157, S2013010016388] FX This work was financially supported by grants from National Natural Science Foundation of China (No. 30973292, No. 30872856, No. 30371535 and No. 81171959) and Natural Science Foundation of Guangdong Province (No. S2011010004157 and No. S2013010016388). In addition, we appreciate Miss. CunCun Yuan, Mr. Yaoyong Lu, and Dr. Ying He to provide helpful technical assistances in the present study. NR 70 TC 30 Z9 31 U1 0 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD MAR 8 PY 2014 VL 13 AR 51 DI 10.1186/1476-4598-13-51 PG 14 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA AF2KY UT WOS:000334542200001 PM 24606633 ER PT J AU Lee, KP Choi, S Hong, JH Ahuja, M Graham, S Ma, R So, I Shin, DM Muallem, S Yuan, JP AF Lee, Kyu Pil Choi, Seok Hong, Jeong Hee Ahuja, Malini Graham, Sarabeth Ma, Rong So, Insuk Shin, Dong Min Muallem, Shmuel Yuan, Joseph P. TI Molecular Determinants Mediating Gating of Transient Receptor Potential Canonical (TRPC) Channels by Stromal Interaction Molecule 1 (STIM1) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Calcium; Calcium Signaling; Gating; Signaling; TRP Channels; Gating Mechanism; STIM1 ID STORE-OPERATED CHANNELS; PLASMA-MEMBRANE; ORAI CHANNELS; CA2+ INFLUX; MECHANISTIC INSIGHTS; CRAC CHANNELS; DOMAIN; ENTRY; CALCIUM; OLIGOMERIZATION AB Background: STIM1 gates TRPC channels, but the interacting domains are unknown. Results: The TRPC N and C terminus coiled coil domains interact to restrict access of STIM1. Their dissociation by cell stimulation promotes STIM1 interaction. Conclusion: The STIM1 Orai1-activating region (SOAR) domain interacts with the TRPC C terminus CCD to open the channels. Significance: The findings reveal how STIM1 opens the TRPC channels to control receptor-stimulated Ca2+ influx. Transient receptor potential canonical (TRPC) channels mediate a critical part of the receptor-evoked Ca2+ influx. TRPCs are gated open by the endoplasmic reticulum Ca2+ sensor STIM1. Here we asked which stromal interaction molecule 1 (STIM1) and TRPC domains mediate the interaction between them and how this interaction is used to open the channels. We report that the STIM1 Orai1-activating region domain of STIM1 interacts with the TRPC channel coiled coil domains (CCDs) and that this interaction is essential for opening the channels by STIM1. Thus, disruption of the N-terminal (NT) CCDs by triple mutations eliminated TRPC surface localization and reduced binding of STIM1 to TRPC1 and TRPC5 while increasing binding to TRPC3 and TRPC6. Single mutations in TRPC1 NT or C-terminal (CT) CCDs reduced interaction and activation of TRPC1 by STIM1. Remarkably, single mutations in the TRPC3 NT CCD enhanced interaction and regulation by STIM1. Disruption in the TRPC3 CT CCD eliminated regulation by STIM1 and the enhanced interaction caused by NT CCD mutations. The NT CCD mutations converted TRPC3 from a TRPC1-dependent to a TRPC1-independent, STIM1-regulated channel. TRPC1 reduced the FRET between BFP-TRPC3 and TRPC3-YFP and between CFP-TRPC3-YFP upon stimulation. Accordingly, knockdown of TRPC1 made TRPC3 STIM1-independent. STIM1 dependence of TRPC3 was reconstituted by the TRPC1 CT CCD alone. Knockout of Trpc1 and Trpc3 similarly inhibited Ca2+ influx, and inhibition of Trpc3 had no further effect on Ca2+ influx in Trpc1(-/-) cells. Cell stimulation enhanced the formation of Trpc1-Stim1-Trpc3 complexes. These findings support a model in which the TRPC3 NT and CT CCDs interact to shield the CT CCD from interaction with STIM1. The TRPC1 CT CCD dissociates this interaction to allow the STIM1 Orai1-activating region within STIM1 access to the TRPC3 CT CCD and regulation of TRPC3 by STIM1. These studies provide evidence that the TRPC channel CCDs participate in channel gating. C1 [Lee, Kyu Pil] Chungnam Natl Univ, Coll Vet Med, Dept Physiol, Taejon 305764, South Korea. [Choi, Seok; Hong, Jeong Hee; Ahuja, Malini; Muallem, Shmuel] NIDCR, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Graham, Sarabeth; Ma, Rong; Yuan, Joseph P.] Univ N Texas, Hlth Sci Ctr, Cardiovasc Res Inst, Dept Integrat Physiol, Ft Worth, TX 76107 USA. [So, Insuk] Seoul Natl Univ, Coll Med, Dept Physiol & Biophys, Seoul 110799, South Korea. [Shin, Dong Min] Yonsei Univ, Dept Oral Biol, PLUS Project BK21, Seoul 120752, South Korea. [Choi, Seok] Chosun Univ, Coll Med, Dept Physiol, Kwangju 501759, South Korea. RP Muallem, S (reprint author), NIDCR, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM shmuel.muallem@nih.gov RI rchnds, rchnds/D-7595-2016 FU National Institute of Health [Z1A-DE000735, Z01-ES101684, 5R00HL093297]; National Research Foundation of Korea (NRF) [NRF-2013R1A1A1010783, 20070056092, 2012R1A2A1A01003487]; Korean government FX This work was funded, in whole or in part, by intramural National Institute of Health grant Z1A-DE000735 (to S. M.); National Institutes of Health Grant Z01-ES101684 (to L. B.); and National Institutes of Health Grant 5R00HL093297 (to J. P. Y.). This work was also supported by National Research Foundation of Korea (NRF) grants (MSIP) NRF-2013R1A1A1010783 (to K. P. L.) and 20070056092 and 2012R1A2A1A01003487 (to D. M. S.) funded by the Korean government. NR 34 TC 28 Z9 28 U1 2 U2 9 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 MAR 7 PY 2014 VL 289 IS 10 BP 6372 EP 6382 DI 10.1074/jbc.M113.546556 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AC3BG UT WOS:000332389400006 PM 24464579 ER PT J AU Chawla, LS Amdur, RL Shaw, AD Faselis, C Palant, CE Kimmel, PL AF Chawla, Lakhmir S. Amdur, Richard L. Shaw, Andrew D. Faselis, Charles Palant, Carlos E. Kimmel, Paul L. TI Association between AKI and Long-Term Renal and Cardiovascular Outcomes in United States Veterans SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID ACUTE KIDNEY INJURY; ACUTE MYOCARDIAL-INFARCTION; CRITICALLY-ILL PATIENTS; CARDIAC-SURGERY; CLINICAL-TRIALS; NIDDK WORKSHOP; FAILURE; MORTALITY; DISEASE; RISK AB Background and objectives AKI is associated with major adverse kidney events (MAKE): death, new dialysis, and worsened renal function. CKD (arising from worsened renal function) is associated with a higher risk of major adverse cardiac events (MACE): myocardial infarction (MI), stroke, and heart failure. Therefore, the study hypothesis was that veterans who develop AKI during hospitalization for an MI would be at higher risk of subsequent MACE and MAKE. Design, setting, participants, & measurements Patients in the Veterans Affairs (VA) database who had a discharge diagnosis with International Classification of Diseases, Ninth Revision, code of 584.xx (AKI) or 410.xx (MI) and were admitted to a VA facility from October 1999 through December 2005 were selected for analysis. Three groups of patients were created on the basis of the index admission diagnosis and serum creatinine values: AKI, MI, or MI with AKI. Patients with mean baseline estimated GFR<45 ml/min per 1.73 m(2) were excluded. The primary outcomes assessed were mortality, MAKE, and MACE during the study period (maximum of 6 years). The combination of MAKE and MACE-major adverse renocardiovascular events (MARCE)-was also assessed. Results A total of 36,980 patients were available for analysis. Mean age +/- SD was 66.8 +/- 11.4 years. The most deaths occurred in the MI+AKI group (57.5%), and the fewest (32.3%) occurred in patients with an uncomplicated MI admission. In both the unadjusted and adjusted time-to-event analyses, patients with AKI and AKI+MI had worse MARCE outcomes than those who had MI alone (adjusted hazard ratios, 1.37 [95% confidence interval, 1.32 to 1.42] and 1.92 [1.86 to 1.99], respectively). Conclusions Veterans who develop AKI in the setting of MI have worse long-term outcomes than those with AKI or MI alone. Veterans with AKI alone have worse outcomes than those diagnosed with an MI in the absence of AKI. C1 [Chawla, Lakhmir S.; Amdur, Richard L.; Faselis, Charles; Palant, Carlos E.] Vet Affairs Med Ctr, Res & Med Serv, Washington, DC 20422 USA. [Chawla, Lakhmir S.] George Washington Univ, Dept Med, Div Renal Dis & Hypertens, Washington, DC USA. [Chawla, Lakhmir S.] George Washington Univ, Dept Anesthesiol & Crit Care Med, Washington, DC USA. [Amdur, Richard L.] Georgetown Univ, Sch Med, Dept Psychiat, Washington, DC USA. [Amdur, Richard L.] Georgetown Univ, Sch Med, Dept Surg, Washington, DC USA. [Shaw, Andrew D.] Duke Univ, Med Ctr, Dept Anesthesiol, Durham, NC 27710 USA. [Shaw, Andrew D.] Vet Affairs Med Ctr, Durham, NC USA. [Kimmel, Paul L.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Chawla, LS (reprint author), 900 23rd St NW,G-105, Washington, DC 20037 USA. EM chawla@gwu.edu NR 42 TC 58 Z9 60 U1 0 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD MAR 7 PY 2014 VL 9 IS 3 BP 448 EP 456 DI 10.2215/CJN.02440213 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA AC4VD UT WOS:000332518300006 PM 24311708 ER PT J AU Sajgo, S Ghinia, MG Shi, M Liu, P Dong, LJ Parmhans, N Popescu, O Badea, TC AF Sajgo, Szilard Ghinia, Miruna Georgiana Shi, Melody Liu, Pinghu Dong, Lijin Parmhans, Nadia Popescu, Octavian Badea, Tudor Constantin TI Dre - Cre Sequential Recombination Provides New Tools for Retinal Ganglion Cell Labeling and Manipulation in Mice SO PLOS ONE LA English DT Article ID SITE-SPECIFIC RECOMBINATION; TRANSCRIPTION FACTORS BRN3A; TRANSGENIC MOUSE LINE; MEDIATED RECOMBINATION; DNA RECOMBINATION; MAMMALIAN-CELLS; COMBINATORIAL EXPRESSION; SOMATOSENSORY NEURONS; FLUORESCENT PROTEINS; COMPETENCE STATE AB Background: Genetic targeting methods have greatly advanced our understanding of many of the 20 Retinal Ganglion Cell (RGC) types conveying visual information from the eyes to the brain. However, the complexity and partial overlap of gene expression patterns in RGCs call for genetic intersectional or sparse labeling strategies. Loci carrying the Cre recombinase in conjunction with conditional knock-out, reporter or other genetic tools can be used for targeted cell type ablation and functional manipulation of specific cell populations. The three members of the Pou4f family of transcription factors, Brn3a, Brn3b and Brn3c, expressed early during RGC development and in combinatorial pattern amongst RGC types are excellent candidates for such gene manipulations. Methods and Findings: We generated conditional Cre knock-in alleles at the Brn3a and Brn3b loci, Brn3a(CKOCre) and Brn3b(CKOCre). When crossed to mice expressing the Dre recombinase, the endogenous Brn3 gene expressed by Brn3a(CKOCre) or Brn3b(CKOCre) is removed and replaced with a Cre recombinase, generating Brn3a(Cre) and Brn3b(Cre) knock-in alleles. Surprisingly both Brn3a(Cre) and Brn3b(Cre) knock-in alleles induce early ubiquitous recombination, consistent with germline expression. However in later stages of development, their expression is limited to the expected endogenous pattern of the Brn3a and Brn3b genes. We use the Brn3a(Cre) and Brn3b(Cre) alleles to target a Cre dependent Adeno Associated Virus (AAV) reporter to RGCs and demonstrate its use in morphological characterization, early postnatal gene delivery and tracing the expression of Brn3 genes in RGCs. Conclusions: Dre recombinase effectively recombines the Brn3a(CKOCre) and Brn3b(CKOCre) alleles containing its roxP target sites. Sequential Dre to Cre recombination reveals Brn3a and Brn3b expression in early mouse development. The generated Brn3a(Cre) and Brn3b(Cre) alleles are useful tools that can target exogenously delivered Cre dependent reagents to RGCs in early postnatal development, opening up a large range of potential applications. C1 [Sajgo, Szilard; Ghinia, Miruna Georgiana; Shi, Melody; Liu, Pinghu; Dong, Lijin; Parmhans, Nadia; Badea, Tudor Constantin] NEI, NIH, Bethesda, MD 20892 USA. [Sajgo, Szilard; Ghinia, Miruna Georgiana; Popescu, Octavian] Univ Babes Bolyai, Dept Biol, R-3400 Cluj Napoca, Romania. [Popescu, Octavian] Acad Romana, Inst Biol, Bucharest, Romania. RP Badea, TC (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM badeatc@mail.nih.gov FU National Institutes of Health; European Union doctoral fellowship system through POSDRU Program [107/1.5/S/76841] FX This study was supported by the National Institutes of Health. Partial funding was provided to M.G.G. by the European Union doctoral fellowship system through POSDRU Program 107/1.5/S/76841. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 76 TC 8 Z9 8 U1 2 U2 11 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 MAR 7 PY 2014 VL 9 IS 3 AR e91435 DI 10.1371/journal.pone.0091435 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC4IY UT WOS:000332485800136 PM 24608965 ER PT J AU Bitan, M He, WS Zhang, MJ Abdel-Azim, H Ayas, MF Bielorai, B Carpenter, PA Cairo, MS Diaz, MA Horan, JT Jodele, S Kitko, CL Schultz, KR Kletzel, M Kasow, KA Lehmann, LE Mehta, PA Shah, N Pulsipher, MA Prestidge, T Seber, A Shenoy, S Woolfrey, AE Yu, LC Davies, SM AF Bitan, Menachem He, Wensheng Zhang, Mei-Jie Abdel-Azim, Hisham Ayas, Mouhab Fakhreddine Bielorai, Bella Carpenter, Paul A. Cairo, Mitchell S. Angel Diaz, Miguel Horan, John T. Jodele, Sonata Kitko, Carrie L. Schultz, Kirk R. Kletzel, Morris Kasow, Kimberly A. Lehmann, Leslie E. Mehta, Parinda A. Shah, Nirali Pulsipher, Michael A. Prestidge, Tim Seber, Adriana Shenoy, Shalini Woolfrey, Ann E. Yu, Lolie C. Davies, Stella M. TI Transplantation for children with acute myeloid leukemia: a comparison of outcomes with reduced intensity and myeloablative regimens SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; ALLOGENEIC TRANSPLANTATION; CURRENT CONTROVERSIES; SURVIVAL; DISEASE; THERAPY; FAILURE; RECEIVE; VIEW AB The safety and efficacy of reduced-intensity conditioning (RIC) regimens for the treatment of pediatric acute myeloid leukemia is unknown. We compared the outcome of allogeneic hematopoietic cell transplantation in children with acute myeloid leukemia using RIC regimens with those receiving myeloablative-conditioning (MAC) regimens. A total of 180 patients were evaluated (39 with RIC and 141 with MAC regimens). Results of univariate and multivariate analysis showed no significant differences in the rates of acute and chronic graft-versus-host disease, leukemia-free, and overall survival between treatment groups. The 5-year probabilities of overall survival with RIC and MAC regimens were 45% and 48%, respectively (P = .99). Moreover, relapse rates were not higher with RIC compared with MAC regimens (39% vs 39%; P = .95), and recipients of MAC regimens were not at higher risk for transplant-related mortality compared with recipients of RIC regimens (16% vs 16%; P = .73). After carefully controlled analyses, we found that in this relatively modest study population, the data supported a role for RIC regimens for acute myeloid leukemia in children undergoing allogeneic hematopoietic cell transplantation. The data also provided justification for designing a carefully controlled randomized clinical trial that examines the efficacy of regimen intensity in this population. C1 [Bitan, Menachem] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Pediat Hematol Oncol, IL-69978 Tel Aviv, Israel. [He, Wensheng] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Zhang, Mei-Jie] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Zhang, Mei-Jie] Childrens Hosp Los Angeles, Div Hematol Oncol & Blood Marrow Transplant Res I, Los Angeles, CA USA. [Abdel-Azim, Hisham] Univ So Calif, Dept Pediat, Keck Sch Med, Los Angeles, CA 90089 USA. [Ayas, Mouhab Fakhreddine] King Faisal Specialist Hosp & Res Ctr, Dept Pediat Hematol Oncol, Riyadh 11211, Saudi Arabia. [Bielorai, Bella] Chaim Sheba Med Ctr, Dept Pediat Hematol Oncol & BMT, IL-52621 Tel Hashomer, Israel. [Carpenter, Paul A.; Woolfrey, Ann E.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Pediat, Valhalla, NY 10595 USA. [Angel Diaz, Miguel] Hosp Nino Jesus, Unidad Trasplante Hematopoyet, Madrid, Spain. [Horan, John T.] Childrens Healthcare Atlanta Egleston, Atlanta, GA USA. [Jodele, Sonata; Mehta, Parinda A.; Davies, Stella M.] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH 45229 USA. [Kitko, Carrie L.] Univ Michigan, Pediat & Communicable Dis Blood & Marrow Transpla, Ann Arbor, MI 48109 USA. [Schultz, Kirk R.] British Columbia Childrens Hosp, Vancouver, BC, Canada. [Kletzel, Morris] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL USA. [Kasow, Kimberly A.] Univ North Carolina Hosp, Div Pediat Hematol Oncol, Chapel Hill, NC USA. [Lehmann, Leslie E.] Dana Farber Canc Inst, Pediat Stem Cell Transplant Unit, Boston, MA 02115 USA. [Shah, Nirali] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Pulsipher, Michael A.] Univ Utah, Primary Childrens Med Ctr, Div Hematol Hematol Malignancies, Huntsman Canc Inst, Salt Lake City, UT USA. [Prestidge, Tim] Starship Childrens Hosp, Auckland, New Zealand. [Seber, Adriana] Inst Oncol Pediat, Sao Paulo, Brazil. [Shenoy, Shalini] Washington Univ, St Louis Childrens Hosp, Pediat Stem Cell Transplant Program, St Louis, MO 63110 USA. [Yu, Lolie C.] Louisiana State Univ, Div Hematol Oncol, Childrens Hosp, New Orleans, LA USA. RP Davies, SM (reprint author), Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave,MLC 11027, Cincinnati, OH 45229 USA. EM stella.davies@cchmc.org FU Public Health Service grant from the National Cancer Institute [U24-CA76518]; National Heart Lung and Blood Institute; National Institute of Allergy and Infectious Diseases; Health Resources and Services Administration [HHSH234200637051C] FX This study was funded by Public Health Service grant (U24-CA76518) from the National Cancer Institute, the National Heart Lung and Blood Institute, the National Institute of Allergy and Infectious Diseases, and the Health Resources and Services Administration (HHSH234200637051C). NR 24 TC 16 Z9 17 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 6 PY 2014 VL 123 IS 10 BP 1615 EP 1620 DI 10.1182/blood-2013-10-535716 PG 6 WC Hematology SC Hematology GA AH0XR UT WOS:000335844600030 PM 24435046 ER PT J AU Gan, L O'Hanlon, TP Gordon, AS Rider, LG Miller, FW Burbelo, PD AF Gan, Lu O'Hanlon, Terrance P. Gordon, Aaron S. Rider, Lisa G. Miller, Frederick W. Burbelo, Peter D. TI Twins discordant for myositis and systemic lupus erythematosus show markedly enriched autoantibodies in the affected twin supporting environmental influences in pathogenesis SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article ID AUTOIMMUNE-DISEASES; MONOZYGOTIC TWINS; JUVENILE DERMATOMYOSITIS; MOLECULAR PATHWAYS; ANTI-INTERFERON; EXPRESSION; POLYMYOSITIS; INFECTIONS; RELATIVES; PROFILES AB Background: Studies of twin pairs discordant for autoimmune conditions provide a unique opportunity to explore contributing factors triggered by complex gene-environment interactions. Methods: In this cross-sectional study, thirty-one monozygotic or dizygotic twin pairs discordant for myositis or systemic lupus erythematosus (SLE), along with matched healthy controls were evaluated for antibodies against a panel of 21 autoantigens. Results: Autoantibody profiling revealed that 42% of the affected twins showed significant seropositivity against autoantigens in the panel. In many of these affected twins, but none of healthy controls, there were high levels of autoantibodies detected against two or more autoantigens commonly seen in systemic autoimmune diseases including Ro52, Ro60, RNP-70 K and/or RNP-A. In contrast, only 10% (3/31) of the unaffected twins showed seropositivity and these immunoreactivities were against single autoantigens not seen in systemic autoimmune diseases. While no significant differences in autoantibodies were detected between the affected or unaffected twins against thyroid peroxidase, transglutaminase and several cytokines, 23% of the affected twins with myositis showed autoantibodies against the gastric ATPase. Analysis of the monozygotic twins separately also revealed a higher frequencies of autoantibodies in the affected twins compared to the unaffected twins (P = 0.046). Lastly, clinical analysis of both the affected monozygotic and dizygotic twins revealed that the autoantibody seropositive affected twins had a greater global disease activity score compared to seronegative affected twins (P = 0.019). Conclusion: The findings of significantly more autoantibodies in the affected twins with myositis and SLE compared to the unaffected twins are consistent with potential non-genetic factors playing a role in autoantibody production and pathogenesis of these autoimmune disorders. C1 [Gan, Lu; O'Hanlon, Terrance P.; Rider, Lisa G.; Miller, Frederick W.] Natl Inst Environm Hlth Sci, Environm Autoimmun Grp, Bethesda, MD 20892 USA. [Gordon, Aaron S.; Burbelo, Peter D.] Natl Inst Dent & Craniofacial Res, Dental Clin Res Core, NIH, Bethesda, MD USA. RP Miller, FW (reprint author), Natl Inst Environm Hlth Sci, Environm Autoimmun Grp, Bethesda, MD 20892 USA. EM millerf@mail.nih.gov; burbelop@nidcr.nih.gov RI Gan, Lu/L-5395-2014; OI Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 FU Intramural Research Program of the NIH, Division of Intramural Research, National Institute of Dental and Craniofacial Research; National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the NIH, Division of Intramural Research, National Institute of Dental and Craniofacial Research and National Institute of Environmental Health Sciences. NR 47 TC 5 Z9 5 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD MAR 6 PY 2014 VL 15 AR 67 DI 10.1186/1471-2474-15-67 PG 11 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA AG1LM UT WOS:000335176800001 PM 24602337 ER PT J AU Zhou, Q Yang, D Ombrello, AK Zavialov, AV Toro, C Zavialov, AV Stone, DL Chae, JJ Rosenzweig, SD Bishop, K Barron, KS Kuehn, HS Hoffmann, P Negro, A Tsai, WXL Cowen, EW Pei, W Milner, JD Silvin, C Heller, T Chin, DT Patronas, NJ Barber, JS Lee, CCR Wood, GM Ling, A Kelly, SJ Kleiner, DE Mullikin, JC Ganson, NJ Kong, HH Hambleton, S Candotti, F Quezado, MM Calvo, KR Alao, H Barham, BK Jones, A Meschia, JF Worrall, BB Kasner, SE Rich, SS Goldbach-Mansky, R Abinun, M Chalom, E Gotte, AC Punaro, M Pascual, V Verbsky, JW Torgerson, TR Singer, NG Gershon, TR Ozen, S Karadag, O Fleisher, TA Remmers, EF Burgess, SM Moir, SL Gadina, M Sood, R Hershfield, MS Boehm, M Kastner, DL Aksentijevich, I AF Zhou, Qing Yang, Dan Ombrello, Amanda K. Zavialov, Andrey V. Toro, Camilo Zavialov, Anton V. Stone, Deborah L. Chae, Jae Jin Rosenzweig, Sergio D. Bishop, Kevin Barron, Karyl S. Kuehn, Hye Sun Hoffmann, Patrycja Negro, Alejandra Tsai, Wanxia L. Cowen, Edward W. Pei, Wuhong Milner, Joshua D. Silvin, Christopher Heller, Theo Chin, David T. Patronas, Nicholas J. Barber, John S. Lee, Chyi-Chia R. Wood, Geryl M. Ling, Alexander Kelly, Susan J. Kleiner, David E. Mullikin, James C. Ganson, Nancy J. Kong, Heidi H. Hambleton, Sophie Candotti, Fabio Quezado, Martha M. Calvo, Katherine R. Alao, Hawwa Barham, Beverly K. Jones, Anne Meschia, James F. Worrall, Bradford B. Kasner, Scott E. Rich, Stephen S. Goldbach-Mansky, Raphaela Abinun, Mario Chalom, Elizabeth Gotte, Alisa C. Punaro, Marilynn Pascual, Virginia Verbsky, James W. Torgerson, Troy R. Singer, Nora G. Gershon, Timothy R. Ozen, Seza Karadag, Omer Fleisher, Thomas A. Remmers, Elaine F. Burgess, Shawn M. Moir, Susan L. Gadina, Massimo Sood, Raman Hershfield, Michael S. Boehm, Manfred Kastner, Daniel L. Aksentijevich, Ivona TI Early- Onset Stroke and Vasculopathy Associated with Mutations in ADA2 SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID AICARDI-GOUTIERES SYNDROME; GROWTH-FACTOR; DISEASE; ATHEROSCLEROSIS; MACROPHAGES; MONOCYTES AB BackgroundWe observed a syndrome of intermittent fevers, early-onset lacunar strokes and other neurovascular manifestations, livedoid rash, hepatosplenomegaly, and systemic vasculopathy in three unrelated patients. We suspected a genetic cause because the disorder presented in early childhood. MethodsWe performed whole-exome sequencing in the initial three patients and their unaffected parents and candidate-gene sequencing in three patients with a similar phenotype, as well as two young siblings with polyarteritis nodosa and one patient with small-vessel vasculitis. Enzyme assays, immunoblotting, immunohistochemical testing, flow cytometry, and cytokine profiling were performed on samples from the patients. To study protein function, we used morpholino-mediated knockdowns in zebrafish and short hairpin RNA knockdowns in U937 cells cultured with human dermal endothelial cells. ResultsAll nine patients carried recessively inherited mutations in CECR1 (cat eye syndrome chromosome region, candidate 1), encoding adenosine deaminase 2 (ADA2), that were predicted to be deleterious; these mutations were rare or absent in healthy controls. Six patients were compound heterozygous for eight CECR1 mutations, whereas the three patients with polyarteritis nodosa or small-vessel vasculitis were homozygous for the p.Gly47Arg mutation. Patients had a marked reduction in the levels of ADA2 and ADA2-specific enzyme activity in the blood. Skin, liver, and brain biopsies revealed vasculopathic changes characterized by compromised endothelial integrity, endothelial cellular activation, and inflammation. Knockdown of a zebrafish ADA2 homologue caused intracranial hemorrhages and neutropenia phenotypes that were prevented by coinjection with nonmutated (but not with mutated) human CECR1. Monocytes from patients induced damage in cocultured endothelial-cell layers. ConclusionsLoss-of-function mutations in CECR1 were associated with a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy or vasculitis. (Funded by the National Institutes of Health Intramural Research Programs and others.) Adenosine deaminase 2 (ADA2) is an enzyme involved in purine metabolism and a growth factor that influences the development of endothelial cells and leukocytes. This study shows that defects in ADA2 cause recurrent fevers, vascular pathologic features, and mild immunodeficiency. Patients with autoinflammatory disease sometimes present with clinical findings that encompass multiple organ systems.(1) Three unrelated children presented to the National Institutes of Health (NIH) Clinical Center with intermittent fevers, recurrent lacunar strokes, elevated levels of acute-phase reactants, livedoid rash, hepatosplenomegaly, and hypogammaglobulinemia. Collectively, these findings do not easily fit with any of the known inherited autoinflammatory diseases. Hereditary or acquired vascular disorders can have protean manifestations yet be caused by mutations in a single gene. Diseases such as the Aicardi-Goutieres syndrome,(2),(3) polypoidal choroidal vasculopathy,(4) sickle cell anemia,(5) livedoid vasculopathy,(6) and the small-vessel vasculitides(7),(8) are examples of systemic ... C1 [Zhou, Qing; Ombrello, Amanda K.; Toro, Camilo; Stone, Deborah L.; Chae, Jae Jin; Bishop, Kevin; Hoffmann, Patrycja; Pei, Wuhong; Silvin, Christopher; Chin, David T.; Wood, Geryl M.; Mullikin, James C.; Candotti, Fabio; Barham, Beverly K.; Jones, Anne; Remmers, Elaine F.; Burgess, Shawn M.; Sood, Raman; Kastner, Daniel L.; Aksentijevich, Ivona] NHGRI, Bethesda, MD 20892 USA. [Yang, Dan; Negro, Alejandra; Boehm, Manfred] NHLBI, Bethesda, MD 20892 USA. [Rosenzweig, Sergio D.; Barron, Karyl S.; Milner, Joshua D.; Barber, John S.; Moir, Susan L.] NIAID, Bethesda, MD 20892 USA. [Kuehn, Hye Sun; Patronas, Nicholas J.; Ling, Alexander; Calvo, Katherine R.; Fleisher, Thomas A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Tsai, Wanxia L.; Goldbach-Mansky, Raphaela; Gadina, Massimo] NIAMSD, Bethesda, MD 20892 USA. [Cowen, Edward W.; Lee, Chyi-Chia R.; Kleiner, David E.; Kong, Heidi H.; Quezado, Martha M.] NCI, Bethesda, MD 20892 USA. [Heller, Theo; Alao, Hawwa] NIDDK, Bethesda, MD 20892 USA. [Zavialov, Andrey V.; Zavialov, Anton V.] Univ Turku, Turku, Finland. [Kelly, Susan J.; Ganson, Nancy J.; Hershfield, Michael S.] Duke Univ Med Ctr, Durham, NC USA. [Gershon, Timothy R.] Univ N Carolina Neurosci Ctr, Chapel Hill, NC USA. [Hambleton, Sophie; Abinun, Mario] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England. [Meschia, James F.] Mayo Clin Florida, Jacksonville, FL USA. [Worrall, Bradford B.; Rich, Stephen S.] Univ Virginia, Charlottesville, VA USA. [Kasner, Scott E.] Univ Penn, Philadelphia, PA 19104 USA. [Chalom, Elizabeth] Barnabas Hlth, W Orange, NJ USA. [Gotte, Alisa C.; Punaro, Marilynn] Texas Scottish Rite Hosp Crippled Children, Dallas, TX USA. [Pascual, Virginia] Baylor Inst Immunol Res, Dallas, TX USA. [Verbsky, James W.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Torgerson, Troy R.] Univ Washington, Seattle, WA 98195 USA. [Torgerson, Troy R.] Seattle Childrens Res Inst, Seattle, WA 98195 USA. [Singer, Nora G.] Metro Hlth Med Ctr, Cleveland, OH USA. [Singer, Nora G.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Ozen, Seza; Karadag, Omer] Hacettepe Univ, Fac Med, TR-06100 Ankara, Turkey. RP Aksentijevich, I (reprint author), NHGRI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM askentii@exchange.nih.gov; askentii@exchange.nih.gov RI Zavialov, Anton/C-7664-2015; Yu, Xiaomin/I-6407-2016; OI Zavialov, Anton/0000-0001-6191-5931; Singer, Nora/0000-0001-7041-723X; Calvo, Katherine/0000-0002-0771-4191; Kong, Heidi/0000-0003-4424-064X; Gershon, Timothy/0000-0001-7034-6400 FU National Institutes of Health (NIH) Intramural Research Programs; National Human Genome Research Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Heart, Lung, and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute; Undiagnosed Diseases Program of the Common Fund of the Office of the Director of the NIH; NIH Clinical Center; Sigma Tau Pharmaceuticals; Finnish Academy FX Supported by the National Institutes of Health (NIH) Intramural Research Programs, including the Intramural Research Programs of the National Human Genome Research Institute, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Cancer Institute, the Undiagnosed Diseases Program of the Common Fund of the Office of the Director of the NIH, and the NIH Clinical Center; and by grants from Sigma Tau Pharmaceuticals (to Dr. Hershfield) and the Finnish Academy (to Drs. Andrey and Anton Zavialov). NR 25 TC 96 Z9 99 U1 6 U2 25 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 MAR 6 PY 2014 VL 370 IS 10 BP 911 EP 920 DI 10.1056/NEJMoa1307361 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AC2EB UT WOS:000332309800008 PM 24552284 ER PT J AU Bayro, MJ Chen, B Yau, WM Tycko, R AF Bayro, Marvin J. Chen, Bo Yau, Wai-Ming Tycko, Robert TI Site-Specific Structural Variations Accompanying Tubular Assembly of the HIV-1 Capsid Protein SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE human immunodeficiency virus; AIDS; solid-state NMR; electron microscopy; automated resonance assignment ID SOLID-STATE NMR; NUCLEAR-MAGNETIC-RESONANCE; TERMINAL DIMERIZATION DOMAIN; ANGLE-SPINNING NMR; 3-DIMENSIONAL STRUCTURE; MOLECULAR-STRUCTURE; CRYSTAL-STRUCTURE; AMYLOID FIBRILS; TORSION ANGLES; CYCLOPHILIN-A AB The 231-residue capsid (CA) protein of human immunodeficiency virus type 1 (HIV-1) spontaneously self-assembles into tubes with a hexagonal lattice that is believed to mimic the surface lattice of conical capsid cores within intact virions. We report the results of solid-state nuclear magnetic resonance (NMR) measurements on HIV-1 CA tubes that provide new information regarding changes in molecular structure that accompany CA self-assembly, local dynamics within CA tubes, and possible mechanisms for the generation of lattice curvature. This information is contained in site-specific assignments of signals in two- and three-dimensional solid-state NMR spectra, conformation-dependent N-15 and C-13 NMR chemical shifts, detection of highly dynamic residues under solution NMR conditions, measurements of local variations in transverse spin relaxation rates of amide H-1 nuclei, and quantitative measurements of site-specific N-15-N-15 dipole dipole couplings. Our data show that most of the CA sequence is conformationally ordered and relatively rigid in tubular assemblies and that structures of the N-terminal domain (NTD) and the C-terminal domain (CTD) observed in solution are largely retained. However, specific segments, including the N-terminal 13-hairpin, the cyclophilin A binding loop, the inter-domain linker, segments involved in intermolecular NTD CTD interactions, and the C-terminal tail, have substantial static or dynamical disorder in tubular assemblies. Other segments, including the 310-helical segment in CTD, undergo clear conformational changes. Structural variations associated with curvature of the CA lattice appear to be localized in the inter-domain linker and intermolecular NTD CTD interface, while structural variations within NTD hexamers, around local 3-fold symmetry axes, and in CTD CTD dimerization interfaces are less significant. Published by Elsevier Ltd. C1 [Bayro, Marvin J.; Yau, Wai-Ming; Tycko, Robert] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Chen, Bo] Univ Cent Florida, Dept Phys, Orlando, FL 32816 USA. RP Tycko, R (reprint author), NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov RI Chen, Bo/F-3573-2015; Bayro, Marvin/Q-4643-2016 OI Bayro, Marvin/0000-0003-1482-9381 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, a component of the National Institutes of Health; National Institutes of Health Intramural AIDS Targeted Antiviral Program; Air Force Office of Scientific Research [FA955013-1-0150]; National Institutes of Health [EB-002026] FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, a component of the National Institutes of Health, and by the National Institutes of Health Intramural AIDS Targeted Antiviral Program. M.J.B. acknowledges postdoctoral support by the Intramural AIDS Research Fellowship Program. B.C. acknowledges support from the Air Force Office of Scientific Research, award number FA955013-1-0150. NMR spectra at 21.1 T were acquired at the Massachusetts Institute of Technology/Harvard Center for Magnetic Resonance, supported by National Institutes of Health grant EB-002026. We thank Lalit Deshmukh and Guillermo Bermejo for helpful discussions regarding solution NMR spectroscopy of CA and Xplor-NIH calculations, respectively. NR 61 TC 21 Z9 21 U1 2 U2 35 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD MAR 6 PY 2014 VL 426 IS 5 SI SI BP 1109 EP 1127 DI 10.1016/j.jmb.2013.12.021 PG 19 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AD0FG UT WOS:000332909300010 PM 24370930 ER PT J AU Zhang, FQ Wang, GQ Shugart, YY Xu, Y Liu, CX Wang, LF Lu, TL Yan, H Ruan, YY Chang, ZH Tian, L Jin, CH Yuan, JM Wang, ZQ Zhu, W Cao, LM Liu, YS Yue, WH Zhang, D AF Zhang, Fuquan Wang, Guoqiang Shugart, Yin Yao Xu, Yong Liu, Chenxing Wang, Lifang Lu, Tianlan Yan, Hao Ruan, Yanyan Chang, Zaohuo Tian, Lin Jin, Chunhui Yuan, Janmin Wang, Zhiqiang Zhu, Wei Cao, Leiming Liu, Yansong Yue, Weihua Zhang, Dai TI Association analysis of a functional variant in ATXN2 with schizophrenia SO NEUROSCIENCE LETTERS LA English DT Article DE Schizophrenia; ATXN2; rs7969300 ID POLYGLUTAMINE EXPANSIONS; ATAXIN-2; PROTEIN; REPEAT; RISK; MICE AB Schizophrenia (SZ) is a severe mental disorder characterized by multiple neurodevelopmental dysfunctions including a breakdown of thinking process and a deficit of typical emotional responses. Ataxin-2 (ATXN2) plays vital roles in cell proliferation and growth, and functional mutations of ATXN2 cause neurodegenerative phenotypes, including spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS). To explore the possible role of ATXN2 in SZ, we conducted a two-stage study to examine the association of ATXN2 polymorphisms with SZ in the Han Chinese population. Association analysis of seven SNPs in 768 patients and 1348 controls revealed two associated SNPs, including rs630511 (P= 1.76E-4) and rs7969300 (P= 5.08E-4). We examined these two SNPs in a validation sample of 1957 patients and 1509 controls, and observed an association of rs7969300 with SZ (P=5.03E-3). The SNP rs7969300 is a non-synonymous SNP causing a Ser to Asn substitution, which is predicted to increase the protein stability of ATXN2. Our data suggest that the ATXN2 gene may confer vulnerability for SZ, adding further evidence for the genetic variants within the developmental pathway in the illness. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Zhang, Fuquan; Wang, Guoqiang; Chang, Zaohuo; Tian, Lin; Jin, Chunhui; Yuan, Janmin; Wang, Zhiqiang; Zhu, Wei; Cao, Leiming; Liu, Yansong] Wuxi Mental Hlth Ctr, Wuxi, Jiangsu, Peoples R China. [Zhang, Fuquan; Liu, Chenxing; Wang, Lifang; Lu, Tianlan; Yan, Hao; Ruan, Yanyan; Yue, Weihua; Zhang, Dai] Peking Univ, Inst Mental Hlth, Beijing 100191, Peoples R China. [Zhang, Fuquan; Liu, Chenxing; Wang, Lifang; Lu, Tianlan; Yan, Hao; Ruan, Yanyan; Yue, Weihua; Zhang, Dai] Minist Hlth, Key Lab Mental Hlth, Beijing, Peoples R China. [Shugart, Yin Yao] NIMH, Unit Stat Genom, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Xu, Yong] Shanxi Med Univ, Hosp 1, Dept Psychiat, Taiyuan, Peoples R China. RP Yue, WH (reprint author), Peking Univ, Inst Mental Hlth, 51 Hua Yuan Bei Rd, Beijing 100191, Peoples R China. EM dyue@bjmu.edu.cn; daizhang@bjmu.edu.cn FU National High-Tech Research and Development Program of China [2009AA022702]; National Natural Science Foundation of China [81000578, 81071087, 81071088]; National Basic Research Program of China [2011CB707805]; International Science & Technology Cooperation Program of China [2010DFB30820]; Intramural Research Program of NIMH, NIH, USA FX We would sincerely thank the schizophrenia participants, their families and the healthy volunteers for their participation, and all the medical staff involved in specimen collection. The views expressed in this presentation do not necessarily represent the views of the NIMH, NIH, HHS, or the United States Government. This work was supported by research grants from the National High-Tech Research and Development Program of China (2009AA022702), the National Natural Science Foundation of China (81000578, 81071087 and 81071088), the National Basic Research Program of China (2011CB707805) and the International Science & Technology Cooperation Program of China (2010DFB30820). YYS is supported by the Intramural Research Program of NIMH, NIH, USA. NR 25 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAR 6 PY 2014 VL 562 BP 24 EP 27 DI 10.1016/j.neulet.2013.12.001 PG 4 WC Neurosciences SC Neurosciences & Neurology GA AD0FM UT WOS:000332909900005 PM 24333172 ER PT J AU Tragante, V Barnes, MR Ganesh, SK Lanktree, MB Guo, W Franceschini, N Smith, EN Johnson, T Holmes, MV Padmanabhan, S Karczewski, KJ Almoguera, B Barnard, J Baumert, J Chang, YPC Elbers, CC Farrall, M Fischer, ME Gaunt, TR Gho, JMIH Gieger, C Goel, A Gong, Y Isaacs, A Kleber, ME Leach, IM McDonough, CW Meijs, MFL Melander, O Nelson, CP Nolte, IM Pankratz, N Price, TS Shaffer, J Shah, S Tomaszewski, M van der Most, PJ Van Iperen, EPA Vonk, JM Witkowska, K Wong, COL Zhang, L Beitelshees, AL Berenson, GS Bhatt, DL Brown, M Burt, A Cooper-DeHoff, RM Connell, JM Cruickshanks, KJ Curtis, SP Davey-Smith, G Delles, C Gansevoort, RT Guo, XQ Haiqing, S Hastie, CE Hofker, MH Hovingh, GK Kim, DS Kirkland, SA Klein, BE Klein, R Li, YR Maiwald, S Newton-Cheh, C O'Brien, ET Onland-Moret, NC Palmas, W Parsa, A Penninx, BW Pettinger, M Vasan, RS Ranchalis, JE Ridker, PM Rose, LM Sever, P Shimbo, D Steele, L Stolk, RP Thorand, B Trip, MD van Duijn, CM Verschuren, WM Wijmenga, C Wyatt, S Young, JH Zwinderman, AH Bezzina, CR Boerwinkle, E Casas, JP Caulfield, MJ Chakravarti, A Chasman, DI Davidson, KW Doevendans, PA Dominiczak, AF FitzGerald, GA Gums, JG Fornage, M Hakonarson, H Halder, I Hillege, HL Illig, T Jarvik, GP Johnson, JA Kastelein, JJP Koenig, W Kumari, M Marz, W Murray, SS O'Connell, JR Oldehinkel, AJ Pankow, JS Rader, DJ Redline, S Reilly, MP Schadt, EE Kottke-Marchant, K Snieder, H Snyder, M Stanton, AV Tobin, MD Uitterlinden, AG van der Harst, P van der Schouw, YT Samani, NJ Watkins, H Johnson, AD Reiner, AP Zhu, XF de Bakker, PIW Levy, D Asselbergs, FW Munroe, PB Keating, BJ AF Tragante, Vinicius Barnes, Michael R. Ganesh, Santhi K. Lanktree, Matthew B. Guo, Wei Franceschini, Nora Smith, Erin N. Johnson, Toby Holmes, Michael V. Padmanabhan, Sandosh Karczewski, Konrad J. Almoguera, Berta Barnard, John Baumert, Jens Chang, Yen-Pei Christy Elbers, Clara C. Farrall, Martin Fischer, Mary E. Gaunt, Tom R. Gho, Johannes M. I. H. Gieger, Christian Goel, Anuj Gong, Yan Isaacs, Aaron Kleber, Marcus E. Leach, Irene Mateo McDonough, Caitrin W. Meijs, Matthijs F. L. Melander, Olle Nelson, Christopher P. Nolte, Ilja M. Pankratz, Nathan Price, Tom S. Shaffer, Jonathan Shah, Sonia Tomaszewski, Maciej van der Most, Peter J. Van Iperen, Erik P. A. Vonk, Judith M. Witkowska, Kate Wong, Caroline O. L. Zhang, Li Beitelshees, Amber L. Berenson, Gerald S. Bhatt, Deepak L. Brown, Morris Burt, Amber Cooper-DeHoff, Rhonda M. Connell, John M. Cruickshanks, Karen J. Curtis, Sean P. Davey-Smith, George Delles, Christian Gansevoort, Ron T. Guo, Xiuqing Haiqing, Shen Hastie, Claire E. Hofker, Marten H. Hovingh, G. Kees Kim, Daniel S. Kirkland, Susan A. Klein, Barbara E. Klein, Ronald Li, Yun R. Maiwald, Steffi Newton-Cheh, Christopher O'Brien, Eoin T. Onland-Moret, N. Charlotte Palmas, Walter Parsa, Afshin Penninx, Brenda W. Pettinger, Mary Vasan, Ramachandran S. Ranchalis, Jane E. Ridker, Paul M. Rose, Lynda M. Sever, Peter Shimbo, Daichi Steele, Laura Stolk, Ronald P. Thorand, Barbara Trip, Mieke D. van Duijn, Cornelia M. Verschuren, W. Monique Wijmenga, Cisca Wyatt, Sharon Young, J. Hunter Zwinderman, Aeilko H. Bezzina, Connie R. Boerwinkle, Eric Casas, Juan P. Caulfield, Mark J. Chakravarti, Aravinda Chasman, Daniel I. Davidson, Karina W. Doevendans, Pieter A. Dominiczak, Anna F. FitzGerald, Garret A. Gums, John G. Fornage, Myriam Hakonarson, Hakon Halder, Indrani Hillege, Hans L. Illig, Thomas Jarvik, Gail P. Johnson, Julie A. Kastelein, John J. P. Koenig, Wolfgang Kumari, Meena Maerz, Winfried Murray, Sarah S. O'Connell, Jeffery R. Oldehinkel, Albertine J. Pankow, James S. Rader, Daniel J. Redline, Susan Reilly, Muredach P. Schadt, Eric E. Kottke-Marchant, Kandice Snieder, Harold Snyder, Michael Stanton, Alice V. Tobin, Martin D. Uitterlinden, Andre G. van der Harst, Pim van der Schouw, Yvonne T. Samani, Nilesh J. Watkins, Hugh Johnson, Andrew D. Reiner, Alex P. Zhu, Xiaofeng de Bakker, Paul I. W. Levy, Daniel Asselbergs, Folkert W. Munroe, Patricia B. Keating, Brendan J. TI Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; HUMAN PREFRONTAL CORTEX; FACTOR-KAPPA-B; ESSENTIAL-HYPERTENSION; SUSCEPTIBILITY LOCUS; CANDIDATE GENES; COMMON VARIANTS; DRUG DISCOVERY; PULSE PRESSURE AB Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped similar to 50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 x 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification. C1 [Tragante, Vinicius; Gho, Johannes M. I. H.; Meijs, Matthijs F. L.; Doevendans, Pieter A.; Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, NL-3584 CX Utrecht, Netherlands. [Tragante, Vinicius; Elbers, Clara C.; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, NL-3584 CX Utrecht, Netherlands. [Barnes, Michael R.] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, Inst Hlth Biomed Res Unit, London EC1M 6BQ, England. [Ganesh, Santhi K.] Univ Michigan Hlth Syst, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Ganesh, Santhi K.] Univ Michigan Hlth Syst, Dept Human Genet, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Lanktree, Matthew B.] McMaster Univ, Dept Med, Hamilton, ON L8S 4L8, Canada. [Guo, Wei; Zhu, Xiaofeng] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Franceschini, Nora] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Smith, Erin N.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Smith, Erin N.] Univ Calif San Diego, Radys Childrens Hosp, La Jolla, CA 92093 USA. [Johnson, Toby; Witkowska, Kate; Wong, Caroline O. L.; Caulfield, Mark J.; Munroe, Patricia B.] Queen Mary Univ London, London EC1M 6BQ, England. [Johnson, Toby; Witkowska, Kate; Wong, Caroline O. L.; Caulfield, Mark J.; Munroe, Patricia B.] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Barts & London Genome Ctr, London EC1M 6BQ, England. [Holmes, Michael V.; Steele, Laura; Keating, Brendan J.] Univ Penn, Dept Surg, Perelman Sch Med, Philadelphia, PA 19104 USA. [Padmanabhan, Sandosh; Dominiczak, Anna F.] Univ Glasgow, BHF, Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland. [Karczewski, Konrad J.; Snyder, Michael] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. [Almoguera, Berta; Li, Yun R.; Keating, Brendan J.] Childrens Hosp Philadelphia, Abramson Res Ctr, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Barnard, John; Zhang, Li] Cleveland Clin, Lerner Res Inst, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA. [Baumert, Jens; Thorand, Barbara] Helmholtz Zentrum Mu nchen, German Res Ctr Environm Hlth, Inst Epidemiol2, D-85764 Neuherberg, Germany. [Chang, Yen-Pei Christy] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Chang, Yen-Pei Christy] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Elbers, Clara C.; Hofker, Marten H.; Onland-Moret, N. Charlotte; van der Schouw, Yvonne T.; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, NL-3584 CX Utrecht, Netherlands. [Farrall, Martin; Goel, Anuj; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Farrall, Martin; Goel, Anuj; Watkins, Hugh] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford OX3 9DU, England. [Fischer, Mary E.; Cruickshanks, Karen J.; Klein, Barbara E.; Klein, Ronald] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI 53726 USA. [Gaunt, Tom R.; Davey-Smith, George] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England. [Gieger, Christian] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, D-85764 Neuherberg, Germany. [Gong, Yan; McDonough, Caitrin W.; Cooper-DeHoff, Rhonda M.; Johnson, Julie A.] Univ Florida, Dept Pharmacotherapy & Translat Res, Gainesville, FL 32610 USA. [Gong, Yan; McDonough, Caitrin W.; Cooper-DeHoff, Rhonda M.; Johnson, Julie A.] Univ Florida, Ctr Pharmacogenom, Gainesville, FL 32610 USA. [Isaacs, Aaron; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, NL-3015 GE Rotterdam, Netherlands. [Kleber, Marcus E.; Jarvik, Gail P.; Maerz, Winfried] Heidelberg Univ, Med Fac Mannheim, Med Clin 5, D-68167 Mannheim, Germany. [Leach, Irene Mateo; van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands. [Melander, Olle] Lund Univ, Dept Clin Sci, S-20502 Malmo, Sweden. [Melander, Olle] Skane Univ Hosp, Ctr Emergency Med, S-20502 Malmo, Sweden. [Nelson, Christopher P.; Tomaszewski, Maciej; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England. [Nelson, Christopher P.; Samani, Nilesh J.] Glenfield Hosp, NIHR, Lecister Cardiovasc Biomed Res Unit, Leicester LE3 9QP, Leics, England. [Nolte, Ilja M.; van der Most, Peter J.; Vonk, Judith M.; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands. [Pankratz, Nathan] Univ Minnesota, Dept Lab Med & Pathol, Inst Human Genet, Minneapolis, MN 55455 USA. [Price, Tom S.] Inst Psychiat, MRC, SGDP Ctr, London SE5 8AF, England. [Shaffer, Jonathan; Shimbo, Daichi] Columbia Univ, Dept Med, New York, NY 10032 USA. [Shah, Sonia] UCL, Genet Inst, Dept Genet Evolut & Environm, London WC1E 6BT, England. [Van Iperen, Erik P. A.; van der Harst, Pim; Asselbergs, Folkert W.] ICIN, Durrer Ctr Cardiogenet Res, Netherlands Heart Inst, NL-3511 GC Utrecht, Netherlands. [Van Iperen, Erik P. A.; Zwinderman, Aeilko H.] Univ Amsterdam, Acad Med Ctr, Dept Clin Epidemiol Biostat & Bioinformat, NL-1105 AZ Amsterdam, Netherlands. [Beitelshees, Amber L.; Haiqing, Shen; Parsa, Afshin] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. 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[Bezzina, Connie R.] Univ Amsterdam, Acad Med Ctr, Mol & Expt Cardiol Grp, NL-1105 AZ Amsterdam, Netherlands. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol, Houston, TX 77030 USA. [Casas, Juan P.] London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, London WC1E 7HT, England. [Casas, Juan P.] UCL, Dept Epidemiol & Publ Hlth, Genet Epidemiol Grp, London WC1E 6BT, England. [Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, Ctr Complex Dis Genom, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Davidson, Karina W.] Columbia Univ, Dept Med, New York, NY 10032 USA. [Davidson, Karina W.] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. [FitzGerald, Garret A.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Gums, John G.] Univ Florida, Dept Pharmacotherapy & Translat Res, Gainesville, FL 32610 USA. [Gums, John G.] Univ Florida, Dept Community Hlth, Gainesville, FL 32610 USA. [Gums, John G.] Univ Florida, Dept Family Med, Gainesville, FL 32610 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Div Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA. [Halder, Indrani] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15261 USA. [Illig, Thomas] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany. [Illig, Thomas] Hannover Med Sch, Hannover Unified Biobank, D-30625 Hannover, Germany. [Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89081 Ulm, Germany. [Kumari, Meena] UCL, Dept Epidemiol & Publ Hlth, Div Populat Hlth, London WC1E 7HB, England. [Jarvik, Gail P.] Synlab Serv GmbH, Synlab Acad, D-69214 Mannheim, Germany. [Maerz, Winfried] Med Univ Graz, Inst Clin Med, A-8036 Graz, Austria. [Maerz, Winfried] Med Univ Graz, Chem Lab Diagnost, A-8036 Graz, Austria. [Murray, Sarah S.] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92037 USA. [Oldehinkel, Albertine J.] Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, NL-9700 RB Groningen, Netherlands. [Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Rader, Daniel J.; Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Redline, Susan] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Schadt, Eric E.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA. [Kottke-Marchant, Kandice] Cleveland Clin, Pathol & Lab Med Inst, Cleveland, OH 44195 USA. [Stanton, Alice V.] Royal Coll Surgeons Ireland, Dublin 2, Ireland. [Tobin, Martin D.] Univ Leicester, Dept Hlth Sci, Leicester LE1 7RH, Leics, England. [Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands. [Johnson, Andrew D.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [de Bakker, Paul I. W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. [de Bakker, Paul I. W.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Framingham, MA 01702 USA. [Asselbergs, Folkert W.] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London WC1E 6BT, England. [Keating, Brendan J.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Munroe, PB (reprint author), Queen Mary Univ London, London EC1M 6BQ, England. EM p.b.munroe@qmul.ac.uk; bkeating@mail.med.upenn.edu RI Wijmenga, Cisca/D-2173-2009; de Bakker, Paul/B-8730-2009; Onland-Moret, N. Charlotte/G-9185-2011; Thorand, Barbara/B-5349-2014; Johnson, Andrew/G-6520-2013; Padmanabhan, Sandosh/S-3963-2016; van der Schouw, Yvonne/F-8327-2014; Shah, Sonia/N-7547-2013; Price, Thomas/B-7372-2008; Stanton, Alice/F-4697-2012; Jarvik, Gail/N-6476-2014; Gaunt, Tom/O-3918-2014; Davey Smith, George/A-7407-2013; OI de Bakker, Paul/0000-0001-7735-7858; Thorand, Barbara/0000-0002-8416-6440; van der Schouw, Yvonne/0000-0002-4605-435X; Shah, Sonia/0000-0001-5860-4526; Price, Thomas/0000-0001-7356-2109; Jarvik, Gail/0000-0002-6710-8708; Gaunt, Tom/0000-0003-0924-3247; Davey Smith, George/0000-0002-1407-8314; Stanton, Alice/0000-0002-4961-165X; Wijmenga, Cisca/0000-0002-5635-1614; Johnson, Toby/0000-0002-5998-3270; Karczewski, Konrad/0000-0003-2878-4671; Padmanabhan, Sandosh/0000-0003-3869-5808; Ramachandran, Vasan/0000-0001-7357-5970; Gieger, Christian/0000-0001-6986-9554; Watkins, Hugh/0000-0002-5287-9016; Pankow, James/0000-0001-7076-483X; Kleber, Marcus/0000-0003-0663-7275 FU British Heart Foundation [FS/11/35/28871, FS/12/33/29561, FS/12/8/29377, FS/14/12/30540, PG/07/085/23349, PG/09/022/26739, SP/08/002/24118]; Medical Research Council [MR/K006584/1, G0802432, G0902313, G9521010, MC_UU_12013/1, MC_UU_12013/8, MR/K013351/1]; NCATS NIH HHS [UL1 TR000064, UL1 TR000124]; NHLBI NIH HHS [R01 HL074730]; NIA NIH HHS [R01 AG016592, R01 AG021917, R37 AG011099]; NIDDK NIH HHS [P30 DK063491, P30 DK072488]; NIGMS NIH HHS [U01 GM074492]; Wellcome Trust [090532] NR 114 TC 50 Z9 51 U1 3 U2 29 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAR 6 PY 2014 VL 94 IS 3 BP 349 EP 360 DI 10.1016/j.ajhg.2013.12.016 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA AC6DK UT WOS:000332611400009 PM 24560520 ER PT J AU Liu, MY Chen, KQ Yoshimura, T Liu, Y Gong, WH Le, YY Gao, JL Zhao, JH Wang, JM Wang, AM AF Liu, Mingyong Chen, Keqiang Yoshimura, Teizo Liu, Ying Gong, Wanghua Le, Yingying Gao, Ji-Liang Zhao, Jianhua Wang, Ji Ming Wang, Aimin TI Formylpeptide Receptors Mediate Rapid Neutrophil Mobilization to Accelerate Wound Healing SO PLOS ONE LA English DT Article ID HOST-DEFENSE; GRO-ALPHA; IN-VIVO; MICE; INFLAMMATION; CHEMOKINES; ACCUMULATION; RECRUITMENT; MIGRATION; CXCR1/2 AB Wound healing is a multi-phased pathophysiological process requiring chemoattractant receptor-dependent accumulation of myeloid cells in the lesion. Two G protein-coupled formylpeptide receptors Fpr1 and Fpr2 mediate rapid neutrophil infiltration in the liver of Listeria-infected mice by sensing pathogen-derived chemotactic ligands. These receptors also recognize host-derived chemotactic peptides in inflammation and injury. Here we report the capacity of Fprs to promote the healing of sterile skin wound in mice by initiating neutrophil infiltration. We found that in normal miceneutrophils rapidly infiltrated the dermis in the wound before the production of neutrophil-specific chemokines by the injured tissue. In contrast, rapid neutrophil infiltration was markedly reduced with delayed wound closure in mice deficient in both Fprs. In addition, we detected Fpr ligand activity that chemoattracted neutrophils into the wound tissue. Our study thus demonstrates that Fprs are critical for normal healing of the sterile skin wound by mediating the first wave of neutrophil infiltration. C1 [Liu, Mingyong; Zhao, Jianhua] Third Mil Med Univ, Daping Hosp, Dept Spine Surg, Chongqing, Peoples R China. [Liu, Mingyong; Chen, Keqiang; Yoshimura, Teizo; Liu, Ying; Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Liu, Ying] Natl Ctr Nanosci & Technol, Beijing, Peoples R China. [Gong, Wanghua] Sci Applicat Int Corp Frederick, Basic Res Program, Frederick, MD USA. [Le, Yingying] Chinese Acad Sci, Shanghai Inst Biol Sci, Key Lab Food Safety Res, Inst Nutr Sci, Shanghai, Peoples R China. [Gao, Ji-Liang] NIAID, Lab Mol Immunol, Bethesda, MD 20892 USA. [Wang, Aimin] Third Mil Med Univ, Ctr Orthoped, Daping Hosp, Chongqing, Peoples R China. RP Liu, MY (reprint author), Third Mil Med Univ, Daping Hosp, Dept Spine Surg, Chongqing, Peoples R China. EM mingyong_liu@163.com OI Zhao, Jianhua/0000-0001-5758-3479 FU National Natural Science Foundation of China (NSFC) [81070981, 201111606]; National Cancer Institute (NCI), National Institutes of Health (NIH) [HHSN261200800001E]; Intramural Research Program of the NCI, NIH, United States of America FX This project was supported in part by the National Natural Science Foundation of China (NSFC, No. 81070981 and 201111606). This project was also funded in part with Federal funds from the National Cancer Institute (NCI), National Institutes of Health (NIH), under Contract No. HHSN261200800001E and was supported in part by the Intramural Research Program of the NCI, NIH, United States of America. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 8 Z9 9 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 6 PY 2014 VL 9 IS 3 AR e90613 DI 10.1371/journal.pone.0090613 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC4ID UT WOS:000332483600068 PM 24603667 ER PT J AU Wu, XY Cai, H Kallianpur, A Li, HL Yang, G Gao, J Xiang, YB Ji, BT Yu-Tang Zheng, W Shu, XO AF Wu, Xiaoyan Cai, Hui Kallianpur, Asha Li, Honglan Yang, Gong Gao, Jing Xiang, Yong-Bing Ji, Bu-Tian Yu-Tang Zheng, Wei Shu, Xiao-Ou TI Impact of Premature Ovarian Failure on Mortality and Morbidity among Chinese Women SO PLOS ONE LA English DT Article ID ISCHEMIC-HEART-DISEASE; NATURAL MENOPAUSE; BREAST-CANCER; AGE; HEALTH; ESTRONE; RISK; ANDROSTENEDIONE; REPRODUCIBILITY; QUESTIONNAIRE AB Objective: To evaluate associations of premature ovarian failure (POF) with mortality and morbidity in Asian populations. Methods: We identified 1,003 cases of POF among 36,402 postmenopausal women who participated in the Shanghai Women's Health Study, a population-based cohort study. Cox regression and logistic regression models were applied in data analysis. Results: After adjustment for potential confounding factors, we found that POF increased the risk of total and cancer-specific mortality (HR (95% CIs): 1.29 (1.08-1.54) and 1.38 (1.05-1.81), respectively). POF was also associated with high prevalence of autoimmune disease (OR (95% CI): 1.56 (1.04-2.35)) but decreased incidence of breast cancer (OR (95% CI): 0.59 (0.38-0.91)). Similar results were observed when hormone replacement therapy users were excluded from the analysis. POF is associated with high waist-to-hip ratio. Conclusions: Our results suggest that women with POF experience increased mortality and that these women may benefit from heightened surveillance and appropriate interventions. C1 [Wu, Xiaoyan; Cai, Hui; Kallianpur, Asha; Yang, Gong; Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37212 USA. [Wu, Xiaoyan; Cai, Hui; Kallianpur, Asha; Yang, Gong; Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Kallianpur, Asha] Vanderbilt Univ, Sch Med, Div Gen Internal Med & Publ Hlth, Dept Med, Nashville, TN 37212 USA. [Li, Honglan; Gao, Jing; Xiang, Yong-Bing; Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Ji, Bu-Tian] NCI, Occupat Epidemiol Branch, NIH, Bethesda, MD 20892 USA. RP Shu, XO (reprint author), Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37212 USA. EM Xiao-ou.shu@vanderbilt.edu FU US National Institutes of Health (NHI) [R37 CA 070867, R01 HL079123] FX Funding support for this work was provided by US National Institutes of Health (NHI) grants R37 CA 070867 (PI: W Zheng) and R01 HL079123 (PI: XO Shu). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 6 Z9 11 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 MAR 6 PY 2014 VL 9 IS 3 AR e89597 DI 10.1371/journal.pone.0089597 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC4ID UT WOS:000332483600014 PM 24603759 ER PT J AU Wen, H Gomella, AA Patel, A Wolfe, DE Lynch, SK Xiao, XH Morgan, N AF Wen, Han Gomella, Andrew A. Patel, Ajay Wolfe, Douglas E. Lynch, Susanna K. Xiao, Xianghui Morgan, Nicole TI Boosting phase contrast with a grating Bonse-Hart interferometer of 200 nanometre grating period SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES LA English DT Article DE X-ray; grating; phase contrast; absolute phase; interferometer; compact source ID X-RAY SOURCES; FABRICATION AB We report on a grating Bonse-Hart interferometer for phase-contrast imaging with hard X-rays. The method overcomes limitations in the level of sensitivity that can be achieved with the well-known Talbot grating interferometer, and without the stringent spectral filtering at any given incident angle imposed by the classic Bonse-Hart interferometer. The device operates in the far-field regime, where an incident beam is split by a diffraction grating into two widely separated beams, which are redirected by a second diffraction grating to merge at a third grating, where they coherently interfere. The wide separation of the interfering beams results in large phase contrast, and in some cases absolute phase images are obtained. Imaging experiments were performed using diffraction gratings of 200 nm period, at 22.5 keV and 1.5% spectral bandwidth on a bending-magnetic beamline. Novel design and fabrication process were used to achieve the small grating period. Using a slitted incident beam, we acquired absolute and differential phase images of lightly absorbing samples. An advantage of this method is that it uses only phase modulating gratings, which are easier to fabricate than absorption gratings of the same periods. C1 [Wen, Han; Gomella, Andrew A.; Patel, Ajay; Lynch, Susanna K.; Morgan, Nicole] NHLBI, NIH, Bethesda, MD 20892 USA. [Wolfe, Douglas E.] Penn State Univ, Dept Mat Sci & Engn, State Coll, PA USA. [Xiao, Xianghui] Argonne Natl Lab, Adv Photon Source, Lemont, IL USA. RP Wen, H (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM wenh@nhlbi.nih.gov RI Wen, Han/G-3081-2010 OI Wen, Han/0000-0001-6844-2997 FU Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health [HL006143-01]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357] FX The work was funded by the Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, under project no. HL006143-01. Use of the Advanced Photon Source at Argonne National Laboratory was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. DE-AC02-06CH11357. NR 21 TC 1 Z9 1 U1 2 U2 16 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1364-503X EI 1471-2962 J9 PHILOS T R SOC A JI Philos. Trans. R. Soc. A-Math. Phys. Eng. Sci. PD MAR 6 PY 2014 VL 372 IS 2010 AR 20130028 DI 10.1098/rsta.2013.0028 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC2XM UT WOS:000332379600005 PM 24470412 ER PT J AU Tibes, R Mesa, RA AF Tibes, Raoul Mesa, Ruben A. TI Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies SO JOURNAL OF HEMATOLOGY & ONCOLOGY LA English DT Review DE Myelofibrosis; Targeted therapy; Hedgehog pathway inhibitors; Janus kinase inhibitors ID INTERNATIONAL WORKING GROUP; PROGNOSTIC SCORING SYSTEM; BASAL-CELL CARCINOMA; TYROSINE KINASE JAK2; QUALITY-OF-LIFE; MURINE YOLK-SAC; MYELOPROLIFERATIVE NEOPLASMS; MYELOID METAPLASIA; POLYCYTHEMIA-VERA; STEM-CELLS AB Treatment of myelofibrosis (MF), a BCR-ABL-negative myeloproliferative neoplasm, is challenging. The only current potentially curative option, allogeneic hematopoietic stem cell transplant, is recommended for few patients. The remaining patients are treated with palliative therapies to manage MF-related anemia and splenomegaly. Identification of a mutation in the Janus kinase 2 (JAK2) gene (JAK2 V617F) in more than half of all patients with MF has prompted the discovery and clinical development of inhibitors that target JAK2. Although treatment with JAK2 inhibitors has been shown to improve symptom response and quality of life in patients with MF, these drugs do not alter the underlying disease; therefore, novel therapies are needed. The hedgehog (Hh) signaling pathway has been shown to play a role in normal hematopoiesis and in the tumorigenesis of hematologic malignancies. Moreover, inhibitors of the Hh pathway have been shown to inhibit growth and self-renewal capacity in preclinical models of MF. In a mouse model of MF, combined inhibition of the Hh and JAK pathways reduced JAK2 mutant allele burden, reduced bone marrow fibrosis, and reduced white blood cell and platelet counts. Preliminary clinical data also suggest that inhibition of the Hh pathway, alone or in combination with JAK2 inhibition, may enable disease modification in patients with MF. Future studies, including one combining the Hh pathway inhibitor sonidegib and the JAK2 inhibitor ruxolitinib, are underway in patients with MF and will inform whether this combination approach can lead to true disease modification. C1 [Tibes, Raoul; Mesa, Ruben A.] Mayo Clin, Ctr Canc, NCI Designated Comprehens Canc Ctr, Scottsdale, AZ 85259 USA. RP Tibes, R (reprint author), Mayo Clin, Ctr Canc, NCI Designated Comprehens Canc Ctr, 13400 E Shea Blvd, Scottsdale, AZ 85259 USA. EM tibes.raoul@mayo.edu FU Novartis Pharmaceuticals Corporation FX The authors thank Jillian Brechbiel, PhD, and Karen Miller-Moslin, PhD, for medical editorial assistance with this manuscript. Financial support for editorial assistance was provided by Novartis Pharmaceuticals Corporation. NR 110 TC 15 Z9 15 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8722 J9 J HEMATOL ONCOL JI J. Hematol. Oncol. PD MAR 5 PY 2014 VL 7 AR 18 DI 10.1186/1756-8722-7-18 PG 12 WC Oncology; Hematology SC Oncology; Hematology GA AG2SF UT WOS:000335265800001 PM 24598114 ER PT J AU Akarolo-Anthony, SN Dal Maso, L Igbinoba, F Mbulaiteye, SM Adebamowo, CA AF Akarolo-Anthony, Sally N. Dal Maso, Luigino Igbinoba, Festus Mbulaiteye, Sam M. Adebamowo, Clement A. TI Cancer burden among HIV-positive persons in Nigeria: preliminary findings from the Nigerian AIDS-cancer match study SO INFECTIOUS AGENTS AND CANCER LA English DT Article DE HIV; Cancer; AIDS-cancer match; Registry linkage; Nigeria ID IMMUNODEFICIENCY-VIRUS-INFECTION; KAPOSIS-SARCOMA; ANTIRETROVIRAL THERAPY; SOUTH-AFRICA; SPECTRUM; UGANDA; EPIDEMIOLOGY; MALIGNANCIES; REGISTRY; POPULATION AB Background: Although Nigeria has a large HIV epidemic, the impact of HIV on cancer in Nigerians is unknown. Methods: We conducted a registry linkage study using a probabilistic matching algorithm among a cohort of HIV positive persons registered at health facilities where the Institute of Human Virology Nigeria (IHVN) provides HIV prevention and treatment services. Their data was linked to data from 2009 to 2012 in the Abuja Cancer Registry. Match compatible files with first name, last name, sex, date of birth and unique HIV cohort identification numbers were provided by each registry and used for the linkage analysis. We describe demographic characteristics of the HIV clients and compute Standardized Incidence Ratios (SIRs) to evaluate the association of various cancers with HIV infection. Results: Between 2005 and 2012, 17,826 persons living with HIV (PLWA) were registered at IHVN. Their median age (Interquartile range (IQR)) was 33 (27-40) years; 41% (7246/17826) were men and 59% (10580/17826) were women. From 2009 to 2012, 2,029 clients with invasive cancers were registered at the Abuja Cancer Registry. The median age (IQR) of the cancer clients was 45 (35-68) years. Among PLWA, 39 cancer cases were identified, 69% (27/39) were incident cancers and 31% (12/39) were prevalent cancers. The SIR (95% CI) for the AIDS Defining Cancers were 5.7 (4.1, 7.2) and 2.0 (0.4, 3.5), for Kaposi Sarcoma and Cervical Cancer respectively. Conclusion: The risk of Kaposi Sarcoma but not Cervical Cancer or Non-Hodgkin's Lymphoma, was significantly increased among HIV positive persons, compared to the general population in Nigeria. C1 [Akarolo-Anthony, Sally N.; Adebamowo, Clement A.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Akarolo-Anthony, Sally N.; Adebamowo, Clement A.] Inst Human Virol, Off Strateg Informat & Res, Abuja, Nigeria. [Dal Maso, Luigino] IRCCS, Aviano Canc Ctr, Epidemiol & Biostat Unit, Aviano, Italy. [Igbinoba, Festus] Natl Hosp Abuja, Abuja Canc Registry, Abuja, Nigeria. [Mbulaiteye, Sam M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Adebamowo, Clement A.] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Adebamowo, Clement A.] Univ Maryland, Sch Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. RP Akarolo-Anthony, SN (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 677 Huntington Ave, Boston, MA 02115 USA. EM sna094@mail.harvard.edu OI Adebamowo, Sally/0000-0003-4713-2433; dal maso, luigino/0000-0001-6163-200X FU IHV-UM Capacity Development for Research into AIDS Associated Malignancies (CADRE), a U.S. National Institutes of Health [NIH/NCI D43CA153792-01] FX We thank Serraino Diego for his contribution to the registry linkage analysis. This research was supported by the IHV-UM Capacity Development for Research into AIDS Associated Malignancies (CADRE), a U.S. National Institutes of Health grant (NIH/NCI D43CA153792-01) awarded to CAA. NR 35 TC 9 Z9 9 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-9378 J9 INFECT AGENTS CANCER JI Infect. Agents Cancer PD MAR 5 PY 2014 VL 9 AR 1 DI 10.1186/1750-9378-9-1 PG 7 WC Oncology; Immunology SC Oncology; Immunology GA AD3SC UT WOS:000333165300001 PM 24597902 ER PT J AU Moreno, E Moreno-Delgado, D Navarro, G Hoffmann, HM Fuentes, S Rosell-Vilar, S Gasperini, P Rodriguez-Ruiz, M Medrano, M Mallol, J Cortes, A Casado, V Lluis, C Ferre, S Ortiz, J Canela, E McCormick, PJ AF Moreno, Estefania Moreno-Delgado, David Navarro, Gemma Hoffmann, Hanne M. Fuentes, Silvia Rosell-Vilar, Santi Gasperini, Paola Rodriguez-Ruiz, Mar Medrano, Mireia Mallol, Josefa Cortes, Antoni Casado, Vicent Lluis, Carme Ferre, Sergi Ortiz, Jordi Canela, Enric McCormick, Peter J. TI Cocaine Disrupts Histamine H-3 Receptor Modulation of Dopamine D-1 Receptor Signaling: sigma(1)-D-1-H-3 Receptor Complexes as Key Targets for Reducing Cocaine's Effects SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PROXIMITY LIGATION ASSAY; SIGMA-1 RECEPTORS; STRIATAL SLICES; BETA-ARRESTINS; AGONISTS; RAT; HETEROMERS; DISEASE; ACTIVATION; MECHANISMS AB The general effects of cocaine are not well understood at the molecular level. What is known is that the dopamine D-1 receptor plays an important role. Here we show that a key mechanism may be cocaine's blockade of the histamine H-3 receptor-mediated inhibition of D-1 receptor function. This blockade requires the sigma(1) receptor and occurs upon cocaine binding to sigma(1)-D-1-H-3 receptor complexes. The cocaine-mediated disruption leaves an uninhibited D-1 receptor that activates G(s), freely recruits beta-arrestin, increases p-ERK 1/2 levels, and induces cell death when over activated. Using in vitro assays with transfected cells and in ex vivo experiments using both rats acutely treated or self-administered with cocaine along with mice depleted of sigma(1) receptor, we show that blockade of sigma(1) 1 receptor by an antagonist restores the protective H-3 receptor-mediated brake on D-1 receptor signaling and prevents the cell death from elevated D-1 receptor signaling. These findings suggest that a combination therapy of sigma R-1 antagonists with H-3 receptor agonists could serve to reduce some effects of cocaine. C1 [Moreno, Estefania; Moreno-Delgado, David; Navarro, Gemma; Gasperini, Paola; Rodriguez-Ruiz, Mar; Medrano, Mireia; Mallol, Josefa; Cortes, Antoni; Casado, Vicent; Lluis, Carme; Canela, Enric; McCormick, Peter J.] Univ Barcelona, Fac Biol, Ctr Invest Biomed Red Enfermedades Neurodegenerat, E-08028 Barcelona, Spain. [Moreno, Estefania; Moreno-Delgado, David; Navarro, Gemma; Gasperini, Paola; Rodriguez-Ruiz, Mar; Medrano, Mireia; Mallol, Josefa; Cortes, Antoni; Casado, Vicent; Lluis, Carme; Canela, Enric; McCormick, Peter J.] Univ Barcelona, Fac Biol, Inst Biomed, E-08028 Barcelona, Spain. [Moreno, Estefania; Moreno-Delgado, David; Navarro, Gemma; Gasperini, Paola; Rodriguez-Ruiz, Mar; Medrano, Mireia; Mallol, Josefa; Cortes, Antoni; Casado, Vicent; Lluis, Carme; Canela, Enric; McCormick, Peter J.] Univ Barcelona, Fac Biol, Dept Biochem & Mol Biol, E-08028 Barcelona, Spain. [Hoffmann, Hanne M.; Fuentes, Silvia; Rosell-Vilar, Santi; Ortiz, Jordi] Univ Autonoma Barcelona, Fac Med, Inst Neurosci, Bellaterra 08193, Spain. [Hoffmann, Hanne M.; Fuentes, Silvia; Rosell-Vilar, Santi; Ortiz, Jordi] Univ Autonoma Barcelona, Fac Med, Dept Biochem & Mol Biol, Bellaterra 08193, Spain. [Ferre, Sergi] Natl Inst Drug Abuse, NIH, Dept Hlth & Human Serv, Intramural Res Program, Baltimore, MD 21224 USA. [McCormick, Peter J.] Univ E Anglia, Sch Pharm, Norwich NR4 7TJ, Norfolk, England. RP McCormick, PJ (reprint author), Univ E Anglia, Sch Pharm, Norwich Res Pk, Norwich NR4 7TJ, Norfolk, England. EM p.mccormick@uea.ac.uk RI McCormick, Peter/E-7387-2012; Ferre, Sergi/K-6115-2014; Ortiz, Jordi/E-9018-2011; Fuentes Garcia, Silvia/B-4827-2014; Casado, Vicent/K-1660-2014; Canela, Enric I./M-8726-2013 OI McCormick, Peter/0000-0002-2225-5181; Ferre, Sergi/0000-0002-1747-1779; Ortiz, Jordi/0000-0002-9748-2290; Moreno, Estefania/0000-0002-2491-5753; Canela, Enric I./0000-0003-4992-7440 FU Spanish Ministerio de Ciencia y Tecnologia [SAF2010-18472, SAF2011-23813, SAF2006-08240, SAF2009-12510]; Spanish Ministerio de Ciencia y Tecnologia (Red de Trastornos Adictivos) [RD06/0001/0015]; Intramural Funds of the National Institute on Drug Abuse FX This study was supported by grants from the Spanish Ministerio de Ciencia y Tecnologia (SAF2010-18472, SAF2011-23813, SAF2006-08240, SAF2009-12510, and Red de Trastornos Adictivos RD06/0001/0015) and by Intramural Funds of the National Institute on Drug Abuse to S. Ferre. P.J.M. is a Ramon y Cajal Fellow. We thank Jasmina Jimenez for technical help (University of Barcelona). We thank Laboratorios Esteve (Barcelona, Spain) for providing sigma 1 receptor KO and WT mice brains. NR 53 TC 18 Z9 19 U1 0 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 5 PY 2014 VL 34 IS 10 BP 3545 EP 3558 DI 10.1523/JNEUROSCI.4147-13.2014 PG 14 WC Neurosciences SC Neurosciences & Neurology GA AC7HN UT WOS:000332698900010 PM 24599455 ER PT J AU Nienborg, H Cumming, BG AF Nienborg, Hendrikje Cumming, Bruce G. TI Decision-Related Activity in Sensory Neurons May Depend on the Columnar Architecture of Cerebral Cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article DE choice probability; decision; orientation discrimination; striate cortex; V1 ID VISUAL AREA MT; INFERIOR TEMPORAL CORTEX; CHOICE-RELATED ACTIVITY; PSYCHOPHYSICAL PERFORMANCE; FUNCTIONAL-ORGANIZATION; NEURAL ACTIVITY; TASK STRATEGY; V1 NEURONS; V2 NEURONS; MACAQUE MT AB Many studies have reported correlations between the activity of sensory neurons and animals' judgments in discrimination tasks. Here, we suggest that such neuron-behavior correlations may require a cortical map for the task relevant features. This would explain why studies using discrimination tasks based on disparity in area V1 have not found these correlations: V1 contains no map for disparity. This scheme predicts that activity of V1 neurons correlates with decisions in an orientation-discrimination task. To test this prediction, we trained two macaque monkeys in a coarse orientation discrimination task using band-pass-filtered dynamic noise. The two orientations were always 90 apart and task difficulty was controlled by varying the orientation bandwidth of the filter. While the trained animals performed this task, we recordedfromorientation-selectiveV1 neurons (n = 82, n = 31 for Monkey 1, n = 51 for Monkey 2). For both monkeys, we observed significant correlation (quantified as "choice probabilities") of the V1 activity with the monkeys' perceptual judgments (mean choice probability 0.54, p = 10(-5)). In one of these animals, we had previously measured choice probabilities in a disparity discrimination task in V1, which had been at chance (0.49, not significantly different from 0.5). The choice probabilities in this monkey for the orientation discrimination task were significantly larger than those for the disparity discrimination task (p = 0.032). These results are predicted by our suggestion that choice probabilities are only observed for cortical sensory neurons that are organized in maps for the task-relevant feature. C1 [Nienborg, Hendrikje] NEI, Lab Sensorimotor Res, NIH, Bethesda, MD 20892 USA. [Nienborg, Hendrikje; Cumming, Bruce G.] Univ Tubingen, Werner Reichardt Ctr Integrat Neurosci, D-72076 Tubingen, Germany. RP Nienborg, H (reprint author), Werner Reichardt Ctr Integrat Neurosci, Otfried Mueller Str 25, D-72076 Tubingen, Germany. EM hendrikje.nienborg@cin.uni-tuebingen.de FU Intramural Research Program of the National Institutes of Health-National Eye Institute; European Research Council FX This work was supported by the Intramural Research Program of the National Institutes of Health-National Eye Institute and a Starting Independent Researcher grant to H.N. from the European Research Council (project acronym: NEUROOPTOGEN). We thank Denise Parker and Beth Nagy for excellent animal care. NR 50 TC 21 Z9 21 U1 0 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 5 PY 2014 VL 34 IS 10 BP 3579 EP 3585 DI 10.1523/JNEUROSCI.2340-13.2014 PG 7 WC Neurosciences SC Neurosciences & Neurology GA AC7HN UT WOS:000332698900012 PM 24599457 ER PT J AU Wang, MH Wang, X Zhao, L Ma, WX Rodriguez, IR Fariss, RN Wong, WT AF Wang, Minhua Wang, Xu Zhao, Lian Ma, Wenxin Rodriguez, Ignacio R. Fariss, Robert N. Wong, Wai T. TI Macroglia-Microglia Interactions via TSPO Signaling Regulates Microglial Activation in the Mouse Retina SO JOURNAL OF NEUROSCIENCE LA English DT Article DE DBI; gliosis; microglia; Muller cells; retina; TSPO ID DIAZEPAM-BINDING INHIBITOR; PERIPHERAL BENZODIAZEPINE-RECEPTOR; PROTEIN 18 KDA; CULTURED RAT ASTROCYTES; GANGLION-CELL APOPTOSIS; AMINO-ACID-SEQUENCE; TRANSLOCATOR PROTEIN; MACULAR DEGENERATION; CHOLESTEROL TRANSPORT; STEROID-BIOSYNTHESIS AB Chronic retinal inflammation in the form of activated microglia and macrophages are implicated in the etiology of neurodegenerative diseases of the retina, including age-related macular degeneration, diabetic retinopathy, and glaucoma. However, molecular biomarkers and targeted therapies for immune cell activation in these disorders are currently lacking. To address this, we investigated the involvement and role of translocator protein (TSPO), a biomarker of microglial and astrocyte gliosis in brain degeneration, in the context of retinal inflammation. Here, we find that TSPO is acutely and specifically upregulated in retinal microglia in separate mouse models of retinal inflammation and injury. Concomitantly, its endogenous ligand, diazepam-binding inhibitor (DBI), is upregulated in the macroglia of the mouse retina such as astrocytes and Muller cells. In addition, we discover that TSPO-mediated signaling in microglia via DBI-derived ligands negatively regulates features of microglial activation, including reactive oxygen species production, TNF-alpha expression and secretion, and microglial proliferation. The inducibility and effects of DBI-TSPO signaling in the retina reveal a mechanism of coordinated macroglia-microglia interactions, the function of which is to limit the magnitude of inflammatory responses after their initiation, facilitating a return to baseline quiescence. Our results indicate that TSPO is a promising molecular marker for imaging inflammatory cell activation in the retina and highlight DBI-TSPO signaling as a potential target for immodulatory therapies. C1 [Wang, Minhua; Wang, Xu; Zhao, Lian; Ma, Wenxin; Wong, Wai T.] NEI, NIH, Unit Neuron Glia Interact Retinal Dis, Bethesda, MD 20892 USA. [Rodriguez, Ignacio R.] NEI, NIH, Mech Retinal Dis Sect, Lab Retinal Cell & Mol Biol, Bethesda, MD 20892 USA. [Fariss, Robert N.] NEI, NIH, Bethesda, MD 20892 USA. RP Wong, WT (reprint author), NEI, NIH, Unit Neuron Glia Interact Retinal Dis, Bldg 6,Room 215, Bethesda, MD 20892 USA. EM wongw@nei.nih.gov RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU National Eye Institute Intramural Research Program, National Institutes of Health FX This study was supported by funds from the National Eye Institute Intramural Research Program, National Institutes of Health. NR 85 TC 40 Z9 40 U1 2 U2 9 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 5 PY 2014 VL 34 IS 10 BP 3793 EP 3806 DI 10.1523/JNEUROSCI.3153-13.2014 PG 14 WC Neurosciences SC Neurosciences & Neurology GA AC7HN UT WOS:000332698900031 PM 24599476 ER PT J AU Perrin, BS Tian, Y Fu, RQ Grant, CV Chekmenev, EY Wieczorek, WE Dao, AE Hayden, RM Burzynski, CM Venable, RM Sharma, M Opella, SJ Pastor, RW Cotten, ML AF Perrin, B. Scott, Jr. Tian, Ye Fu, Riqiang Grant, Christopher V. Chekmenev, Eduard Y. Wieczorek, William E. Dao, Alexander E. Hayden, Robert M. Burzynski, Caitlin M. Venable, Richard M. Sharma, Mukesh Opella, Stanley J. Pastor, Richard W. Cotten, Myriam L. TI High-Resolution Structures and Orientations of Antimicrobial Peptides Piscidin 1 and Piscidin 3 in Fluid Bilayers Reveal Tilting, Kinking, and Bilayer Immersion SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID SOLID-STATE NMR; MOLECULAR-DYNAMICS SIMULATION; MEMBRANE-ACTIVE PEPTIDES; ALIGNED LIPID-BILAYERS; AUSTRALIAN TREE FROG; HYBRID STRIPED BASS; ANTIBACTERIAL PEPTIDES; MODEL MEMBRANES; CHARGE-DISTRIBUTION; PORE FORMATION AB While antimicrobial peptides (AMPs) have been widely investigated as potential therapeutics, high-resolution structures obtained under biologically relevant conditions are lacking. Here, the high-resolution structures of the homologous 22-residue long AMPs piscidin 1 (p1) and piscidin 3 (p3) are determined in fluid-phase 3:1 phosphatidylcholine/phosphatidylglycerol (PC/PG) and 1:1 phosphatidylethanolamine/phosphatidylglycerol (PE/PG) bilayers to identify molecular features important for membrane destabilization in bacterial cell membrane mimics. Structural refinement of H-1-N-15 dipolar couplings and N-15 chemical shifts measured by oriented sample solid-state NMR and all-atom molecular dynamics (MD) simulations provide structural and orientational information of high precision and accuracy about these interfacially bound alpha-helical peptides. The tilt of the helical axis, tau, is between 83 degrees and 93 degrees with respect to the bilayer normal for all systems and analysis methods. The average azimuthal rotation, rho, is 235 degrees, which results in burial of hydrophobic residues in the bilayer. The refined NMR and MD structures reveal a slight kink at G13 that delineates two helical segments characterized by a small difference in their T angles (<10 degrees) and significant difference in their rho angles (similar to 25 degrees). Remarkably, the kink, at the end of a G(X)(4)G motif highly conserved among members of the piscidin family, allows p1 and p3 to adopt rho angles that maximize their hydrophobic moments. Two structural features differentiate the more potent pl from p3: p1 has a larger rho angle and less N-terminal fraying. The peptides have comparable depths of insertion in PC/PG, but p3 is 1.2 angstrom more deeply inserted than p1 in PE/PG. In contrast to the ideal a-helical structures typically assumed in mechanistic models of AMPs, p1 and p3 adopt disrupted alpha-helical backbones that correct for differences in the amphipathicity of their N- and C-ends, and their centers of mass lie similar to 1.2-3.6 angstrom below the plane defined by the C2 atoms of the lipid acyl chains. C1 [Perrin, B. Scott, Jr.; Venable, Richard M.; Pastor, Richard W.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Tian, Ye; Grant, Christopher V.; Opella, Stanley J.] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. [Fu, Riqiang; Chekmenev, Eduard Y.] Natl High Magnet Field Lab, Tallahassee, FL 32310 USA. [Wieczorek, William E.; Dao, Alexander E.; Hayden, Robert M.; Burzynski, Caitlin M.; Cotten, Myriam L.] Hamilton Coll, Dept Chem, Clinton, NY 13323 USA. [Sharma, Mukesh] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Cotten, ML (reprint author), Hamilton Coll, Dept Chem, Clinton, NY 13323 USA. EM mcotten@hamilton.edu OI Chekmenev, Eduard/0000-0002-8745-8801 FU National Science Foundation [CHE-0832571]; NIH, National Heart, Lung and Blood Institute; National Institutes of Health [P41EB002031]; NSF [DMR-1157490]; State of Florida; U.S. Department of Energy FX This research was supported in part by a grant from the National Science Foundation (CHE-0832571) and the Intramural Research Program of the NIH, National Heart, Lung and Blood Institute, and utilized the high-performance computational capabilities at the National Institutes of Health, Bethesda, MD (NHLBI LoBoS cluster). This work also utilized the Center for NMR Spectroscopy and Imaging of Proteins at the University of California, San Diego supported by the National Institutes of Health (P41EB002031). The authors are grateful for NMR time received at the National High Magnetic Field Laboratory (NHMFL) supported by the NSF Cooperative Agreement DMR-1157490, the State of Florida, and the U.S. Department of Energy. NR 92 TC 27 Z9 28 U1 3 U2 71 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAR 5 PY 2014 VL 136 IS 9 BP 3491 EP 3504 DI 10.1021/ja411119m PG 14 WC Chemistry, Multidisciplinary SC Chemistry GA AC7CN UT WOS:000332684700029 PM 24410116 ER PT J AU Li, YL Freudenthal, BD Beard, WA Wilson, SH Schlick, T AF Li, Yunlang Freudenthal, Bret D. Beard, William A. Wilson, Samuel H. Schlick, Tamar TI Optimal and Variant Metal-Ion Routes in DNA Polymerase beta's Conformational Pathways SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ACTIVE-SITE; MOLECULAR-DYNAMICS; NUCLEOTIDE INCORPORATION; MINOR-GROOVE; MECHANISM; SUBSTRATE; FIDELITY; CORRECT; CANCER; ENERGY AB To interpret recent structures of the R283K mutant of human DNA repair enzyme DNA polymerase beta (pol beta) differing in the number of Mg2+ ions, we apply transition path sampling (TPS) to assess the effect of differing ion placement on the transition from the open one-metal to the closed two-metal state. We find that the closing pathway depends on the initial ion position, both in terms of the individual transition states and associated energies. The energy barrier of the conformational pathway varies from 25 to 58 kJ/mol, compared to the conformational energy barrier of 42 kJ/mol for the wild-type poi beta reported previously. Moreover, we find a preferred ion route located in the center of the enzyme, parallel to the DNA. Within this route, the conformational pathway is similar to that of the overall open to closed transition of pol beta, but outside it, especially when the ion starts near active site residues Arg258 and Asp 190, the conformational pathway diverges significantly. Our findings should apply generally to pol beta since R283K is relatively far from the active site; further experimental and computational work are required to confirm this. Our studies also underscore the common feature that less active mutants have less stable closed states than their open states, in marked contrast to the wild-type enzyme, where the closed state is significantly more stable than the open form. C1 [Li, Yunlang; Schlick, Tamar] NYU, Dept Chem, New York, NY 10012 USA. [Li, Yunlang; Schlick, Tamar] NYU, Courant Inst Math Sci, New York, NY 10012 USA. [Freudenthal, Bret D.; Beard, William A.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Schlick, T (reprint author), NYU, Dept Chem, 251 Mercer St, New York, NY 10012 USA. EM schlick@nyu.edu FU NIH, National Institute of Environmental Health Sciences [Z01-ES050158]; NIH [1U19CA105010] FX We thank Dr. Ravi Radhakrishnan for providing the initial scripts for transition path sampling simulations. This work was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (project number Z01-ES050158) and was in association with NIH grant 1U19CA105010. The computations in this study were conducted using the resources of the CCNI supported by the New York State Foundation for Science, Technology and Innovation (NYSTAR), and the Dell computer cluster by New York University Information Technology Services (NYU ITS). Molecular images were generated using the VMD35 programs. NR 48 TC 4 Z9 4 U1 0 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAR 5 PY 2014 VL 136 IS 9 BP 3630 EP 3639 DI 10.1021/ja412701f PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA AC7CN UT WOS:000332684700044 PM 24511902 ER PT J AU Lim, U Kocarnik, JM Bush, WS Matise, TC Caberto, C Park, SL Carlson, CS Deelman, E Duggan, D Fesinmeyer, M Haiman, CA Henderson, BE Hindorff, LA Kolonel, LN Peters, U Stram, DO Tiirikainen, M Wilkens, LR Wu, CY Kooperberg, C Le Marchand, L AF Lim, Unhee Kocarnik, Jonathan M. Bush, William S. Matise, Tara C. Caberto, Christian Park, Sungshim Lani Carlson, Christopher S. Deelman, Ewa Duggan, David Fesinmeyer, Megan Haiman, Christopher A. Henderson, Brian E. Hindorff, Lucia A. Kolonel, Laurence N. Peters, Ulrike Stram, Daniel O. Tiirikainen, Maarit Wilkens, Lynne R. Wu, Chunyuan Kooperberg, Charles Le Marchand, Loic TI Pleiotropy of Cancer Susceptibility Variants on the Risk of Non-Hodgkin Lymphoma: The PAGE Consortium SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; CHRONIC LYMPHOCYTIC-LEUKEMIA; MANTLE CELL LYMPHOMA; 2ND PRIMARY CANCERS; MULTIETHNIC COHORT; FOLLICULAR LYMPHOMA; INFLAMMATION GENES; COMPLEX DISEASES; COMMON VARIANTS; LOCI AB Background: Risk of non-Hodgkin lymphoma (NHL) is higher among individuals with a family history or a prior diagnosis of other cancers. Genome-wide association studies (GWAS) have suggested that some genetic susceptibility variants are associated with multiple complex traits (pleiotropy). Objective: We investigated whether common risk variants identified in cancer GWAS may also increase the risk of developing NHL as the first primary cancer. Methods: As part of the Population Architecture using Genomics and Epidemiology (PAGE) consortium, 113 cancer risk variants were analyzed in 1,441 NHL cases and 24,183 controls from three studies (BioVU, Multiethnic Cohort Study, Women's Health Initiative) for their association with the risk of overall NHL and common subtypes [diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL)] using an additive genetic model adjusted for age, sex and ethnicity. Study-specific results for each variant were meta-analyzed across studies. Results: The analysis of NHL subtype-specific GWAS SNPs and overall NHL suggested a shared genetic susceptibility between FL and DLBCL, particularly involving variants in the major histocompatibility complex region (rs6457327 in 6p21.33: FL OR = 1.29, p = 0.013; DLBCL OR = 1.23, p = 0.013; NHL OR = 1.22, p = 5.9 x E-05). In the pleiotropy analysis, six risk variants for other cancers were associated with NHL risk, including variants for lung (rs401681 in TERT: OR per C allele = 0.89, p = 3.7 x E-03; rs4975616 in TERT: OR per A allele = 0.90, p = 0.01; rs3131379 in MSH5: OR per T allele = 1.16, p = 0.03), prostate (rs7679673 in TET2: OR per C allele = 0.89, p = 5.7 x E-03; rs10993994 in MSMB: OR per T allele = 1.09, p = 0.04), and breast (rs3817198 in LSP1: OR per C allele = 1.12, p = 0.01) cancers, but none of these associations remained significant after multiple test correction. Conclusion: This study does not support strong pleiotropic effects of non-NHL cancer risk variants in NHL etiology; however, larger studies are warranted. C1 [Lim, Unhee; Caberto, Christian; Kolonel, Laurence N.; Tiirikainen, Maarit; Wilkens, Lynne R.; Le Marchand, Loic] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96822 USA. [Kocarnik, Jonathan M.; Carlson, Christopher S.; Peters, Ulrike; Wu, Chunyuan; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Bush, William S.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37235 USA. [Matise, Tara C.; Deelman, Ewa] Rutgers State Univ, Dept Genet, Piscataway, NJ USA. [Park, Sungshim Lani; Haiman, Christopher A.; Henderson, Brian E.; Stram, Daniel O.] Univ So Calif, Dept Prevent Med, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Los Angeles, CA 90089 USA. [Duggan, David] Translat Genom Res Inst, Phoenix, AZ USA. [Fesinmeyer, Megan] Seattle Childrens Res Inst, Ctr Child Hlth Behav & Dev, Seattle, WA USA. [Hindorff, Lucia A.] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA. RP Lim, U (reprint author), Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96822 USA. EM ulim@cc.hawaii.edu OI Bush, William/0000-0002-9729-6519; Tiirikainen, Maarit/0000-0002-8124-3818 FU National Human Genome Research Institute (NHGRI); NHGRI PAGE program [U01HG004802, U01HG004790, U01HG004798-01]; Johns Hopkins University from NHLBI [N01-HV-48195]; Centers for Disease Control and Prevention; Vanderbilt CTSA from NCATS/NIH [UL1 TR000445]; NHGRI; National Cancer Institute [R37CA54281, R01 CA63, P01CA33619, U01CA136792, U01CA98758]; National Heart, Lung, and Blood Institute; NIH; U.S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 4210726, 42129-32, 44221]; NCI [R25CA94880]; PAGE Coordinating Center [U01HG004801-01]; [U01HG004803]; [U01HG004798]; [U01HG004801] FX The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI), and U01HG004801 (Coordinating Center), and their respective NHGRI ARRA supplements. The complete list of PAGE members can be found at http://www.pagestudy.org. The data and materials included in this report result from collaboration between the following studies: The "Epidemiologic Architecture for Genes Linked to Environment (EAGLE)'' is funded through the NHGRI PAGE program (U01HG004798-01 and its NHGRI ARRA supplement). Genotyping services for select NHANES III SNPs presented here were also provided by the Johns Hopkins University under federal contract number (N01-HV-48195) from NHLBI. The study participants derive from the National Health and Nutrition Examination Surveys (NHANES), and these studies are supported by the Centers for Disease Control and Prevention. The dataset used for the analyses described were obtained from Vanderbilt University Medical Center's BioVU which is supported by institutional funding and by the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH. The Multiethnic Cohort study (MEC) characterization of epidemiological architecture is funded through the NHGRI PAGE program (U01HG004802 and its NHGRI ARRA supplement). The MEC study is funded through the National Cancer Institute (R37CA54281, R01 CA63, P01CA33619, U01CA136792, and U01CA98758). Funding support for the "Epidemiology of putative genetic variants: The Women's Health Initiative'' study is provided through the NHGRI PAGE program (U01HG004790 and its NHGRI ARRA supplement). The WHI program is funded by the National Heart, Lung, and Blood Institute; NIH; and U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 4210726, 42129-32, and 44221. A full listing of WHI investigators can be found at: http://www.whiscience.org/publications/WHI_investigators_shortlist. pdf. Additional support for Dr. Kocarnik was provided by R25CA94880 from NCI. Assistance with phenotype harmonization, SNP selection and annotation, data cleaning, data management, integration and dissemination, and general study coordination was provided by the PAGE Coordinating Center (U01HG004801-01 and its NHGRI ARRA supplement). The National Institutes of Mental Health also contributes to the support for the Coordinating Center. The funders had no role in study design, data collection and analysis, or preparation of the manuscript. NR 41 TC 4 Z9 4 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 5 PY 2014 VL 9 IS 3 AR e89791 DI 10.1371/journal.pone.0089791 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC4GP UT WOS:000332479400028 PM 24598796 ER PT J AU Luo, K Zhang, H Zavala, F Biragyn, A Espinosa, DA Markham, RB AF Luo, Kun Zhang, Hong Zavala, Fidel Biragyn, Arya Espinosa, Diego A. Markham, Richard B. TI Fusion of Antigen to a Dendritic Cell Targeting Chemokine Combined with Adjuvant Yields a Malaria DNA Vaccine with Enhanced Protective Capabilities SO PLOS ONE LA English DT Article ID PLASMODIUM-YOELII SPOROZOITES; FALCIPARUM CIRCUMSPOROZOITE PROTEIN; CD8(+) T-CELLS; IMMUNE-RESPONSES; LIVER STAGES; IRRADIATED SPOROZOITES; RHESUS MACAQUES; IN-VITRO; ANTITUMOR IMMUNITY; GENITAL HERPES AB Although sterilizing immunity to malaria can be elicited by irradiated sporozoite vaccination, no clinically practical subunit vaccine has been shown to be capable of preventing the approximately 600,000 annual deaths attributed to this infection. DNA vaccines offer several potential advantages for a disease that primarily affects the developing world, but new approaches are needed to improve the immunogenicity of these vaccines. By using a novel, lipid-based adjuvant, Vaxfectin, to attract immune cells to the immunization site, in combination with an antigen-chemokine DNA construct designed to target antigen to immature dendritic cells, we elicited a humoral immune response that provided sterilizing immunity to malaria challenge in a mouse model system. The chemokine, MIP3 alpha CCL20, did not significantly enhance the cellular infiltrate or levels of cytokine or chemokine expression at the immunization site but acted with Vaxfectin to reduce liver stage malaria infection by orders of magnitude compared to vaccine constructs lacking the chemokine component. The levels of protection achieved were equivalent to those observed with irradiated sporozoites, a candidate vaccine undergoing development for further large scale clinical trial. Only vaccination with the combined regimen of adjuvant and chemokine provided 80-100% protection against the development of bloodstream infection. Treating the immunization process as requiring the independent steps of 1) attracting antigen-presenting cells to the site of immunization and 2) specifically directing vaccine antigen to the immature dendritic cells that initiate the adaptive immune response may provide a rational strategy for the development of a clinically applicable malaria DNA vaccine. C1 [Luo, Kun; Zhang, Hong; Zavala, Fidel; Espinosa, Diego A.; Markham, Richard B.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21218 USA. [Biragyn, Arya] NIA, Immunoregulat Sect, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. RP Markham, RB (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21218 USA. EM rmarkham@jhsph.edu OI Espinosa, Diego A./0000-0002-4364-5031 FU National Institutes of Health [AI073619]; Johns Hopkins University Malaria Research Institute FX This work was supported by grants from the National Institutes of Health (Grant #AI073619) and the Johns Hopkins University Malaria Research Institute (http://malaria.jhsph.edu). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 94 TC 5 Z9 5 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 MAR 5 PY 2014 VL 9 IS 3 AR e90413 DI 10.1371/journal.pone.0090413 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC4GP UT WOS:000332479400072 PM 24599116 ER PT J AU Olson, SH Parmley, J Soos, C Gilbert, M Latorre-Margalef, N Hall, JS Hansbro, PM Leighton, F Munster, V Joly, D AF Olson, Sarah H. Parmley, Jane Soos, Catherine Gilbert, Martin Latorre-Margalef, Neus Hall, Jeffrey S. Hansbro, Phillip M. Leighton, Frederick Munster, Vincent Joly, Damien TI Sampling Strategies and Biodiversity of Influenza A Subtypes in Wild Birds SO PLOS ONE LA English DT Article ID PATHOGENIC AVIAN INFLUENZA; MIGRATORY BIRDS; VIRUS; SURVEILLANCE; WATERFOWL; PREVALENCE; PREDICTION; RICHNESS; PATTERNS; DUCKS AB Wild aquatic birds are recognized as the natural reservoir of avian influenza A viruses (AIV), but across high and low pathogenic AIV strains, scientists have yet to rigorously identify most competent hosts for the various subtypes. We examined 11,870 GenBank records to provide a baseline inventory and insight into patterns of global AIV subtype diversity and richness. Further, we conducted an extensive literature review and communicated directly with scientists to accumulate data from 50 non-overlapping studies and over 250,000 birds to assess the status of historic sampling effort. We then built virus subtype sample-based accumulation curves to better estimate sample size targets that capture a specific percentage of virus subtype richness at seven sampling locations. Our study identifies a sampling methodology that will detect an estimated 75% of circulating virus subtypes from a targeted bird population and outlines future surveillance and research priorities that are needed to explore the influence of host and virus biodiversity on emergence and transmission. C1 [Olson, Sarah H.; Gilbert, Martin] Wildlife Conservat Soc, Bronx, NY USA. [Parmley, Jane] Univ Guelph, Dept Pathobiol, Canadian Cooperat Wildlife Hlth Ctr, Guelph, ON N1G 2W1, Canada. [Soos, Catherine] Environm Canada, Sci & Technol Branch, Saskatoon, SK, Canada. [Latorre-Margalef, Neus] Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst EEMiS, Kalmar, Sweden. [Latorre-Margalef, Neus] Univ Georgia, Coll Vet Med, Dept Populat Hlth, Southeastern Cooperat Wildlife Dis Study, Athens, GA USA. [Hall, Jeffrey S.] USGS, Natl Wildlife Hlth Ctr, Madison, WI USA. [Hansbro, Phillip M.] Univ Newcastle, Prior Res Ctr Asthma & Resp Dis, Newcastle, NSW 2300, Australia. [Hansbro, Phillip M.] Hunter Med Res Inst, Newcastle, NSW, Australia. [Leighton, Frederick] Univ Saskatchewan, Western Coll Vet Med, Canadian Cooperat Wildlife Hlth Ctr, Saskatoon, SK S7N 0W0, Canada. [Munster, Vincent] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. [Joly, Damien] Metabiota, Nanaimo, BC, Canada. RP Joly, D (reprint author), Metabiota, Nanaimo, BC, Canada. EM djoly@metabiota.com OI Hall, Jeffrey/0000-0001-5599-2826; Munster, Vincent/0000-0002-2288-3196 FU Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health; National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); Department of Health and Human Services [HHSN266200700007C] FX This study was made possible by the generous support of the American people through the United States Agency for International Development (USAID) Emerging Pandemic Threats program, PREDICT project. VJM is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health. Additional funding for this work was provided by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), and the Department of Health and Human Services under contract HHSN266200700007C. Journal access was provided by in-kind support from the University of Wisconsin-Madison Center for Sustainability and the Global Environment (SAGE). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 15 Z9 15 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 MAR 5 PY 2014 VL 9 IS 3 AR e90826 DI 10.1371/journal.pone.0090826 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC4GP UT WOS:000332479400137 PM 24599502 ER PT J AU Onwuamah, CK Ekama, SO Audu, RA Ezechi, OC Poirier, MC Odeigah, PGC AF Onwuamah, Chika K. Ekama, Sabdat O. Audu, Rosemary A. Ezechi, Oliver C. Poirier, Miriam C. Odeigah, Peter G. C. TI Exposure of Allium cepa Root Cells to Zidovudine or Nevirapine Induces Cytogenotoxic Changes SO PLOS ONE LA English DT Article ID REVERSE-TRANSCRIPTASE INHIBITORS; HUMAN LYMPHOBLASTOID-CELLS; UNINFECTED CHILDREN BORN; HIV-INFECTED WOMEN; IN-VITRO EXPOSURE; PERINATAL EXPOSURE; UTERO EXPOSURE; TRANSMISSION; GENOTOXICITY; CARCINOMA AB Antiretroviral drugs have proved useful in the clinical management of HIV-infected persons, though there are concerns about the effects of exposure to these DNA-reactive drugs. We investigated the potential of the plant model Allium cepa root tip assay to demonstrate the cytogenotoxicity of zidovudine and nevirapine and as a replace-reduce-refine programme amenable to resource-poor research settings. Cells mitotic index were determined in squashed root cells from Allium cepa bulbs exposed to zidovudine or nevirapine for 48 hr. The concentration of zidovudine and nevirapine inhibiting 50% root growth after 96 hr exposure was 65.0 mu M and 92.5 mu M respectively. Root length of all antiretroviral-exposed roots after 96 hr exposure was significantly shorter than the unexposed roots while additional root growth during a subsequent 48 hr recovery period in the absence of drug was not significantly different. By ANOVA, there was a significant association between percentage of cells in mitosis and zidovudine dose (p = 0.004), but not nevirapine dose (p = 0.68). Chromosomal aberrations such as sticky chromosomes, chromatin bridges, multipolar mitoses and binucleated cells were observed in root cells exposed to zidovudine and nevirapine for 48 hr. The most notable chromosomal aberration was drug-related increases in sticky chromosomes. Overall, the study showed inhibition in root length growth, changes in the mitotic index, and the induction of chromosomal aberrations in Allium bulbs treated for 96 hr or 48 hr with zidovudine and nevirapine. The study reveals generalized cytogenotoxic damage induced by exposure to zidovudine and nevirapine, and further show that the two compounds differ in their effects on mitosis and the types of chromosomal aberrations induced. C1 [Onwuamah, Chika K.; Audu, Rosemary A.] Nigerian Inst Med Res, Human Virol Lab, Lagos, Nigeria. [Ekama, Sabdat O.; Ezechi, Oliver C.] Nigerian Inst Med Res, Div Clin Sci, Lagos, Nigeria. [Poirier, Miriam C.] NCI, Carcinogen DNA Interact Sect, LCBG, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Odeigah, Peter G. C.] Univ Lagos, Dept Cell Biol & Genet, Lagos, Nigeria. RP Onwuamah, CK (reprint author), Nigerian Inst Med Res, Human Virol Lab, Lagos, Nigeria. EM chikaonwuamah@yahoo.com FU Intramural research program of the Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA FX This work was self-sponsored by Dr Onwuamah as part of his doctoral research. Dr Poirier also provided some reagents and she is supported by the Intramural research program of the Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 18 TC 0 Z9 0 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 MAR 5 PY 2014 VL 9 IS 3 AR e90296 DI 10.1371/journal.pone.0090296 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC4GP UT WOS:000332479400060 PM 24599327 ER PT J AU Zarin, DA Tse, T Menikoff, J AF Zarin, Deborah A. Tse, Tony Menikoff, Jerry TI Federal Human Research Oversight of Clinical Trials in the United States SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Zarin, Deborah A.; Tse, Tony] NIH, Natl Lib Med, Bethesda, MD 20894 USA. [Menikoff, Jerry] US Dept HHS, Off Human Res Protect, Rockville, MD USA. RP Zarin, DA (reprint author), NIH, 8600 Rockville Pike,Bldg 38A,Room 07N719, Bethesda, MD 20894 USA. EM dzarin@mail.nih.gov FU Intramural NIH HHS [Z99 LM999999] NR 4 TC 2 Z9 2 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 5 PY 2014 VL 311 IS 9 BP 960 EP 961 DI 10.1001/jama.2013.284306 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AC0FS UT WOS:000332170800026 PM 24595782 ER PT J AU Faroqi-Shah, Y Kling, T Solomon, J Liu, SY Park, G Braun, A AF Faroqi-Shah, Yasmeen Kling, Therese Solomon, Jeffrey Liu, Siyuan Park, Grace Braun, Allen TI Lesion analysis of language production deficits in aphasia SO APHASIOLOGY LA English DT Article DE Inferior frontal gyrus; Insula; Planum temporale.; Superior temporal gyrus; Lesion analysis; Repetition; Aphasia; Sentence production ID SENSORY-MOTOR INTEGRATION; SPEECH PRODUCTION; PLANUM TEMPORALE; BASAL GANGLIA; BROCAS AREA; SENTENCE COMPREHENSION; CONDUCTION APHASIA; ANTERIOR INSULA; STROKE PATIENTS; NEURAL BASIS AB Background: Three aspects of language production are impaired to different degrees in individuals with post-stroke aphasia: ability to repeat words and nonwords, name pictures, and produce sentences. These impairments often persist into the chronic stages, and the neuroanatomical distribution of lesions associated with chronicity of each of these impairments is incompletely understood. Aims: The primary objective of this study was to investigate the lesion correlates of picture naming, sentence production, and nonword repetition deficits in the same participant group because most prior lesion studies have mapped single language impairments. The broader goal of this study was to investigate the extent and degree of overlap and uniqueness among lesions resulting in these deficits in order to advance the current understanding of functional subdivision of neuroanatomical regions involved in language production. Methods & Procedures: In this study, lesion-symptom mapping was used to determine if specific cortical regions are associated with nonword repetition, picture naming, and sentence production scores. Structural brain images and behavioural performance of 31 individuals with post-stroke left hemisphere lesions and a diagnosis of aphasia were used in the lesion analysis. Outcomes & Results: Each impairment was associated with mostly unique, but a few shared lesions. Overall, sentence and repetition deficits were associated with left anterior perisylvian lesions, including the pars opercularis and triangularis of the inferior frontal lobe, anterior superior temporal gyrus, anterior portions of the supramarginal gyrus, the putamen, and anterior portions of the insula. In contrast, impaired picture naming was associated with posterior perisylvian lesions including major portions of the inferior parietal lobe and middle temporal gyrus. The distribution of lesions in the insula was consistent with this antero-posterior perisylvian gradient. Significant voxels in the posterior planum temporale were associated with a combination of all three deficits. Conclusions: These findings emphasise the participation of each perisylvian region in multiple linguistic functions, suggesting a many(functions)-to-many(networks) framework while also identifying functional subdivisions within each region. C1 [Faroqi-Shah, Yasmeen] Univ Maryland, Dept Hearing & Speech Sci, College Pk, MD 20742 USA. [Kling, Therese] Johns Hopkins Univ Hosp, Baltimore, MD 21205 USA. [Solomon, Jeffrey] Med Numer, Germantown, MD USA. [Liu, Siyuan; Park, Grace; Braun, Allen] NIDCD, Bethesda, MD USA. RP Faroqi-Shah, Y (reprint author), Univ Maryland, Dept Hearing & Speech Sci, College Pk, MD 20742 USA. EM yfshah@umd.edu NR 104 TC 2 Z9 2 U1 8 U2 27 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0268-7038 EI 1464-5041 J9 APHASIOLOGY JI Aphasiology PD MAR 4 PY 2014 VL 28 IS 3 BP 258 EP 277 DI 10.1080/02687038.2013.853023 PG 20 WC Clinical Neurology SC Neurosciences & Neurology GA AH3DK UT WOS:000336001900001 ER PT J AU Li, JJ Agarwal, SK Alonso, A Blecker, S Chamberlain, AM London, SJ Loehr, LR McNeill, AM Poole, C Soliman, EZ Heiss, G AF Li, Jingjing Agarwal, Sunil K. Alonso, Alvaro Blecker, Saul Chamberlain, Alanna M. London, Stephanie J. Loehr, Laura R. McNeill, Ann Marie Poole, Charles Soliman, Elsayed Z. Heiss, Gerardo TI Airflow Obstruction, Lung Function, and Incidence of Atrial Fibrillation The Atherosclerosis Risk in Communities (ARIC) Study SO CIRCULATION LA English DT Article DE atrial fibrillation; forced expiratory volume; pulmonary disease; chronic obstructive; respiratory physiological phenomena; risk factors; vital capacity ID ACQUIRED PNEUMONIA; PULMONARY VEINS; ISCHEMIC-STROKE; HEART-DISEASE; COPD; INFLAMMATION; EPIDEMIOLOGY; HYPERTENSION; ASSOCIATION; PREVALENCE AB Background Reduced low forced expiratory volume in 1 second (FEV1) is reportedly associated with an increased risk of atrial fibrillation (AF). Extant reports do not provide separate estimates for never smokers or for blacks, who incongruously have lower AF incidence than whites. Methods and Results We examined 15 004 middle-aged blacks and whites enrolled in the Atherosclerosis Risk in Communities (ARIC) cohort study. Standardized spirometry data were collected at the baseline examination. Incident AF was identified from the first among the following: International Classification of Diseases codes for AF on hospital discharge records or death certificates or 12-lead ECGs performed during 3 triennial follow-up visits. Over an average follow-up of 17.5 years, a total of 1691 participants (11%) developed new-onset AF. The rate of incident AF was inversely associated with FEV1 in each of the 4 race and sex groups. After multivariable adjustment for traditional cardiovascular disease risk factors and height, hazard ratios of AF comparing the lowest with the highest quartile of FEV1 were 1.37 (95% confidence interval, 1.02-1.83) for white women, 1.49 (95% confidence interval, 1.16-1.91) for white men, 1.63 (95% confidence interval, 1.00-2.66) for black women, and 2.36 (95% confidence interval, 1.30-4.29) for black men. The above associations were observed across all smoking status categories. Moderate/severe airflow obstruction (FEV1/forced vital capacity <0.70 and FEV1 < 80% of predicted value) was also associated with higher AF incidence. Conclusions In this large population-based study with a long-term follow-up, reduced FEV1 and obstructive respiratory disease were associated with a higher AF incidence after adjustment for measured confounders. C1 [Li, Jingjing; Loehr, Laura R.; McNeill, Ann Marie; Poole, Charles; Heiss, Gerardo] Univ N Carolina, Chapel Hill, NC USA. [Agarwal, Sunil K.] Johns Hopkins Univ, Baltimore, MD 21287 USA. [Alonso, Alvaro] Univ Minnesota, Minneapolis, MN USA. [Blecker, Saul] NYU, Med Ctr, New York, NY 10016 USA. [Chamberlain, Alanna M.] Mayo Clin, Rochester, MN USA. [London, Stephanie J.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Soliman, Elsayed Z.] Wake Forest Univ, Winston Salem, NC 27109 USA. RP Agarwal, SK (reprint author), Johns Hopkins Univ, 2020 E Monument St,Room B-321, Baltimore, MD 21287 USA. EM sunilagarwal@jhu.edu RI Alonso, Alvaro/A-4917-2010; OI Alonso, Alvaro/0000-0002-2225-8323; London, Stephanie/0000-0003-4911-5290 FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022]; NHLBI [T32-HL-007779, IRC1HL099452-01]; American Heart Association [09SDG2280087]; National Institutes of Health/NHLBI [T32HL007024] FX This research was sponsored by National Heart, Lung, and Blood Institute (NHLBI) contracts N01-HC-55015, -55016, -55018, -55019, -55020, -55021, and -55022. Dr Chamberlain was supported by NHLBI grant T32-HL-007779. Additional funding for this study was provided by grants 09SDG2280087 from the American Heart Association and IRC1HL099452-01 from the NHLBI. Dr Agarwal is supported by a National Institutes of Health/NHLBI T32HL007024 Cardiovascular Epidemiology Training Grant. NR 45 TC 22 Z9 22 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 4 PY 2014 VL 129 IS 9 BP 971 EP 980 DI 10.1161/CIRCULATIONAHA.113.004050 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AB9UF UT WOS:000332140500009 PM 24344084 ER PT J AU Kojima, G Bell, CL Chen, R Ross, GW Abbott, RD Launer, L Lui, F Masaki, K AF Kojima, Gotaro Bell, Christina L. Chen, Randi Ross, G. Webster Abbott, Robert D. Launer, Lenore Lui, Felix Masaki, Kamal TI Low Dietary Vitamin D in Mid-Life Predicts Total Mortality in Men with Hypertension: The Honolulu Heart Program SO JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION LA English DT Article DE vitamin D; mortality; hypertension; Japan; ethnology; Asian Americans ID SERUM 25-HYDROXYVITAMIN D; CARDIOVASCULAR-DISEASE MORTALITY; RANDOMIZED CONTROLLED-TRIAL; ALL-CAUSE MORTALITY; JAPANESE ANCESTRY; D DEFICIENCY; POSTMENOPAUSAL WOMEN; GENERAL-POPULATION; ANGIOTENSIN-II; BLOOD-PRESSURE AB Background: Vitamin D deficiency was associated with total mortality in previous epidemiological studies. Little is known about the effects of dietary vitamin D intake on mortality. We examined the association between mid-life dietary vitamin D intake and 45-year total mortality. Methods: The Honolulu Heart Program is a longitudinal cohort study of 8006 Japanese American men in Hawaii aged 45 to 68 at baseline (1965-1968). Mid-life dietary vitamin D intake was calculated from 24-hour dietary recall using Nutritionist IV v3 software. We divided subjects into quartiles of dietary vitamin D. Total mortality data were available over 45years through 2010. Results: Age-adjusted total mortality rates were higher in the lower quartiles of dietary vitamin D intake compared to the highest (p for trend = 0.011). Using Cox regression, low dietary vitamin D was significantly associated with total mortality; quartile (Q) 1 hazard ratio (HR) = 1.14, 95% confidence interval (95% CI) = 1.07-1.22, p < 0.001; Q2 HR = 1.11, 95% CI = 1.04-1.18, p = 0.002; and Q3 HR = 1.08, 95% CI = 1.01-1.15, p = 0.027; Q4 = reference. After adjusting for age, kilocalories, cardiovascular risk factors, and prevalent chronic diseases, only Q2 remained significant (HR = 1.08, 95% CI = 1.00-1.15, p = 0.037). Among hypertensive subjects only, those in the lower 2 quartiles had higher total mortality; Q1 HR = 1.12, 95% CI = 1.01-1.25, p = 0.039, and Q2 HR = 1.13, 95% CI = 1.02-1.26, p = 0.025, compared to Q4. There was no significant relationship in subjects without hypertension. Conclusions: Low dietary vitamin D intake in mid-life was a weak predictor of total mortality over 45years of follow-up. We found a significant association between low dietary vitamin D intake and higher total mortality only among hypertensive subjects. Vitamin D may have cardioprotective effects. C1 [Kojima, Gotaro; Bell, Christina L.; Ross, G. Webster; Abbott, Robert D.; Lui, Felix; Masaki, Kamal] Univ Hawaii, John A Burns Sch Med, Dept Geriatr Med, John A Hartford Fdn Ctr Excellence Geriatr, Honolulu, HI 96817 USA. [Bell, Christina L.; Chen, Randi; Masaki, Kamal] Kuakini Med Ctr, Honolulu, HI USA. [Ross, G. Webster] Vet Affairs Pacific Isl Hlth Care Syst, Honolulu, HI USA. [Abbott, Robert D.] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. [Launer, Lenore] NIA, Bethesda, MD 20892 USA. RP Kojima, G (reprint author), Univ Hawaii, John A Burns Sch Med, Dept Geriatr Med, 347 N Kuakini St HPM-9, Honolulu, HI 96817 USA. EM gotarokojima@yahoo.co.jp FU National Heart, Lung, and Blood Institute [N01-HC-05102]; National Institute on Aging [N01-AG-4254-2149, U01-AG019349, R01-AG-038707, R01-AG-027060]; Hawaii Community Foundation [2004-0463]; office for Research and Development, Department of Veterans Affairs FX This study was supported by contract N01-HC-05102 from The National Heart, Lung, and Blood Institute; contract N01-AG-4254-2149, and grants U01-AG019349, R01-AG-038707 and R01-AG-027060 from the National Institute on Aging; the Hawaii Community Foundation (grant 2004-0463); and the office for Research and Development, Department of Veterans Affairs. The views expressed in this article do not necessarily represent those of the federal government. NR 41 TC 0 Z9 0 U1 2 U2 5 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0731-5724 EI 1541-1087 J9 J AM COLL NUTR JI J. Am. Coll. Nutr. PD MAR 4 PY 2014 VL 33 IS 2 BP 129 EP 135 DI 10.1080/07315724.2013.875363 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AE7DV UT WOS:000334157800007 PM 24724770 ER PT J AU Marshall, RS Festa, JR Cheung, YK Pavol, MA Derdeyn, CP Clarke, WR Videen, TO Grubb, RL Slane, K Powers, WJ Lazar, RM AF Marshall, Randolph S. Festa, Joanne R. Cheung, Ying-Kuen Pavol, Marykay A. Derdeyn, Colin P. Clarke, William R. Videen, Tom O. Grubb, Robert L. Slane, Kevin Powers, William J. Lazar, Ronald M. CA RECON Investigators TI Randomized Evaluation of Carotid Occlusion and Neurocognition (RECON) trial Main results SO NEUROLOGY LA English DT Article ID HEMODYNAMIC CEREBRAL-ISCHEMIA; INTRACRANIAL BYPASS-SURGERY; COGNITIVE IMPAIRMENT; AGE; STENOSIS; STATINS; ADULTS; ATORVASTATIN; PERFORMANCE; POPULATION AB Objective:To determine whether extracranial-intracranial (EC-IC) bypass can improve cognition over 2 years compared to best medical therapy alone in patients with symptomatic internal carotid artery (ICA) occlusion and increased oxygen extraction fraction (OEF) on PET.Methods:Patients underwent O-15 PET and were randomized if OEF ratio was >1.13 on the occluded side. Using blinded baseline and 2-year cognitive assessments, age-adjusted composite z scores were generated from subtests sensitive to right/left hemisphere plus global cognitive functioning. Multiple regression predicted 2-year cognitive change.Results:Eighty-nine patients were enrolled; 41 had increased OEF and were randomized. Two died, 2 were lost to follow-up, and 2 refused 2-year testing. Of the 35 remaining, 6 had ipsilateral stroke or death, leaving 13 surgical and 16 medical patients. Controlling for age, education, and depression, there was no difference in 2-year cognitive change between the medical and surgical arms (95% confidence interval -0.5 to 0.5, p = 0.9). In post hoc analysis of 26 patients with no stroke in the follow-up period, cognitive improvement was associated with less impaired PET OEF at baseline (p = 0.045).Conclusion:Cognitive improvement following bypass surgery was not superior to medical therapy among patients with recently symptomatic carotid occlusion and increased OEF. Among those with no recurrent stroke, less hemodynamic impairment at baseline was associated with greater cognitive gain in both groups. Reversing cognitive impairment in hemodynamic failure remains an open challenge.Classification of evidence:This study provides Class II evidence that for patients with symptomatic ICA occlusion and increased OEF on PET, EC-IC bypass compared to no bypass does not improve cognitive function after 2 years. C1 [Marshall, Randolph S.; Cheung, Ying-Kuen; Pavol, Marykay A.; Slane, Kevin; Lazar, Ronald M.] Columbia Univ, Med Ctr, New York, NY 10027 USA. [Festa, Joanne R.] St Lukes Roosevelt Med Ctr New York, New York, NY USA. [Cheung, Ying-Kuen] NINDS, Bethesda, MD 20892 USA. [Derdeyn, Colin P.; Videen, Tom O.; Grubb, Robert L.] Washington Univ, St Louis, MO USA. [Clarke, William R.] Univ Iowa, Iowa City, IA USA. [Powers, William J.] Univ N Carolina, Chapel Hill, NC USA. RP Marshall, RS (reprint author), Columbia Univ, Med Ctr, New York, NY 10027 USA. EM rsm2@columbia.edu FU NINDS NIH HHS [5U01NS041895, NS048212, NS42167] NR 41 TC 16 Z9 17 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR 4 PY 2014 VL 82 IS 9 BP 744 EP 751 DI 10.1212/WNL.0000000000000167 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA AG9OD UT WOS:000335748100007 PM 24477109 ER PT J AU Houghton, LC AF Houghton, L. C. TI Becoming dedicated to the scarf: biocultural markers of growing up British-Bangladeshi. SO AMERICAN JOURNAL OF HUMAN BIOLOGY LA English DT Meeting Abstract C1 [Houghton, L. C.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 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 1042-0533 EI 1520-6300 J9 AM J HUM BIOL JI Am. J. Hum. Biol. PD MAR 4 PY 2014 VL 26 IS 2 BP 268 EP 268 PG 1 WC Anthropology; Biology SC Anthropology; Life Sciences & Biomedicine - Other Topics GA AB0DH UT WOS:000331461500053 ER PT J AU Robbins, JB Schneerson, R Kubler-Kielb, J Keith, JM Trollfors, B Vinogradov, E Shiloach, J AF Robbins, John B. Schneerson, Rachel Kubler-Kielb, Joanna Keith, Jerry M. Trollfors, Birger Vinogradov, Evgeny Shiloach, Joseph TI Toward a new vaccine for pertussis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE new pertussis vaccine; lipooligosaccharide conjugate ID PROTEIN CONJUGATE VACCINE; INFLUENZAE TYPE-B; BORDETELLA-PERTUSSIS; MONOCLONAL-ANTIBODIES; WHOOPING-COUGH; TOXOID VACCINE; BACTERICIDAL ANTIBODIES; CAPSULAR POLYSACCHARIDE; SEROLOGIC RESPONSE; HOUSEHOLD EXPOSURE AB To overcome the limitations of the current pertussis vaccines, those of limited duration of action and failure to induce direct killing of Bordetella pertussis, a synthetic scheme was devised for preparing a conjugate vaccine composed of the Bordetella bronchiseptica core oligosaccharide with one terminal trisaccharide to aminooxylated BSA via their terminal ketodeoxyoctanate residues. Conjugate-induced antibodies, by a fraction of an estimated human dose injected into young outbred mice as a saline solution, were bactericidal against B. pertussis, and their titers correlated with their ELISA values. The carrier protein is planned to be genetically altered pertussis toxoid. Such conjugates are easy to prepare, stable, and should add both to the level and duration of immunity induced by current vaccine-induced pertussis antibodies and reduce the circulation of B. pertussis. C1 [Kubler-Kielb, Joanna] NICHHD, NIH, Bethesda, MD 20892 USA. [Shiloach, Joseph] NIDDK, NIH, Bethesda, MD 20892 USA. [Trollfors, Birger] Sahlgrenska Hosp, Dept Pediat, S-41345 Gothenburg, Sweden. [Vinogradov, Evgeny] CNR, Ottawa, ON K1A 0R6, Canada. EM johnbennettrobbins@gmail.com NR 87 TC 13 Z9 13 U1 0 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 MAR 4 PY 2014 VL 111 IS 9 BP 3213 EP 3216 DI 10.1073/pnas.1324149111 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC5KR UT WOS:000332560300019 PM 24556987 ER PT J AU Ishibashi, T Dangkulwanich, M Coello, Y Lionberger, TA Lubkowska, L Ponticelli, AS Kashlev, M Bustamante, C AF Ishibashi, Toyotaka Dangkulwanich, Manchuta Coello, Yves Lionberger, Troy A. Lubkowska, Lucyna Ponticelli, Alfred S. Kashlev, Mikhail Bustamante, Carlos TI Transcription factors IIS and IIF enhance transcription efficiency by differentially modifying RNA polymerase pausing dynamics SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE optical tweezers; Pol II; yeast; enzyme kinetics ID SACCHAROMYCES-CEREVISIAE TFIIF; STRUCTURAL BASIS; CHROMATIN TEMPLATES; NUCLEOSOMAL BARRIER; ELONGATION; INITIATION; FIDELITY; CLEAVAGE; YEAST; BACKTRACKING AB Transcription factors IIS (TFIIS) and IIF (TFIIF) are known to stimulate transcription elongation. Here, we use a single-molecule transcription elongation assay to study the effects of both factors. We find that these transcription factors enhance overall transcription elongation by reducing the lifetime of transcriptional pauses and that TFIIF also decreases the probability of pause entry. Furthermore, we observe that both factors enhance the processivity of RNA polymerase II through the nucleosomal barrier. The effects of TFIIS and TFIIF are quantitatively described using the linear Brownian ratchet kinetic model for transcription elongation and the backtracking model for transcriptional pauses, modified to account for the effects of the transcription factors. Our findings help elucidate the molecular mechanisms by which transcription factors modulate gene expression. C1 [Ishibashi, Toyotaka; Dangkulwanich, Manchuta; Coello, Yves; Lionberger, Troy A.; Bustamante, Carlos] Univ Calif Berkeley, Jason L Choy Lab Single Mol Biophys, Berkeley, CA 94720 USA. [Ishibashi, Toyotaka; Dangkulwanich, Manchuta; Coello, Yves; Lionberger, Troy A.; Bustamante, Carlos] Univ Calif Berkeley, Calif Inst Quantitat Biosci, Berkeley, CA 94720 USA. [Dangkulwanich, Manchuta; Lionberger, Troy A.; Bustamante, Carlos] Univ Calif Berkeley, Kavli Energy NanoSci Inst, Berkeley, CA 94720 USA. [Dangkulwanich, Manchuta; Bustamante, Carlos] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. [Lionberger, Troy A.; Bustamante, Carlos] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA. [Lionberger, Troy A.; Bustamante, Carlos] Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA. [Bustamante, Carlos] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Dangkulwanich, Manchuta; Lionberger, Troy A.; Bustamante, Carlos] Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA. [Lubkowska, Lucyna; Kashlev, Mikhail] NCI, Ctr Canc Res, Frederick, MD 21702 USA. [Ponticelli, Alfred S.] SUNY Buffalo, Sch Med & Biomed Sci, Dept Biochem, Buffalo, NY 14214 USA. RP Ishibashi, T (reprint author), Univ Calif Berkeley, Jason L Choy Lab Single Mol Biophys, Berkeley, CA 94720 USA. EM toyotakaishibashi@gmail.com; carlosb@berkeley.edu OI Ishibashi, Toyotaka/0000-0001-8015-2319; Coello, Yves/0000-0001-6243-5403 FU National Institutes of Health [R01-GM032543]; US Department of Energy, Office of Basic Energy Sciences, Division of Materials Sciences and Engineering [DE-AC02-05CH11231] FX We thank Ms. Lian Lash-Rosenberg, Ms. Tran Do, and Dr. Cesar Diaz Celis for experimental assistance. We also thank Dr. Chen Yang for providing us a fraction of purified TFIIF. This work was supported in part by grants from the National Institutes of Health (R01-GM032543) (to C. B.) and the US Department of Energy, Office of Basic Energy Sciences, Division of Materials Sciences and Engineering under Contract DE-AC02-05CH11231 (to C.B.). NR 40 TC 18 Z9 19 U1 3 U2 19 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 MAR 4 PY 2014 VL 111 IS 9 BP 3419 EP 3424 DI 10.1073/pnas.1401611111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC5KR UT WOS:000332560300056 PM 24550488 ER PT J AU Roche, J Louis, JM Grishaev, A Ying, JF Bax, A AF Roche, Julien Louis, John M. Grishaev, Alexander Ying, Jinfa Bax, Adriaan TI Dissociation of the trimeric gp41 ectodomain at the lipid-water interface suggests an active role in HIV-1 Env-mediated membrane fusion SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hemagglutinin; HIV-1 fusion inhibitor; RDC; N-15 relaxation; chemical shift ID ENVELOPE GLYCOPROTEIN; ATOMIC-STRUCTURE; VIRAL MEMBRANE; VIRUS ENVELOPE; ENTRY; CONFORMATION; INHIBITION; CAPTURE; CORE AB The envelope glycoprotein gp41 mediates the process of membrane fusion that enables entry of the HIV-1 virus into the host cell. The actual fusion process involves a switch from a homotrimeric prehairpin intermediate conformation, consisting of parallel coiled-coil helices, to a postfusion state where the ectodomains are arranged as a trimer of helical hairpins, adopting a six-helix bundle (6HB) state. Here, we show by solution NMR spectroscopy that a water-soluble 6HB gp41 ectodomain binds to zwitterionic detergents that contain phosphocholine or phosphatidylcholine head groups and phospholipid vesicles that mimic T-cell membrane composition. Binding results in the dissociation of the 6HB and the formation of a monomeric state, where its two a-helices, N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR), become embedded in the lipid-water interface of the virus and host cell. The atomic structure of the gp41 ectodomain monomer, based on NOE distance restraints and residual dipolar couplings, shows that the NHR and CHR helices remain mostly intact, but they completely lose interhelical contacts. The high affinity of the ectodomain helices for phospholipid surfaces suggests that unzippering of the prehairpin intermediate leads to a state where the NHR and CHR helices become embedded in the host cell and viral membranes, respectively, thereby providing a physical force for bringing these membranes into close juxtaposition before actual fusion. C1 [Roche, Julien; Louis, John M.; Grishaev, Alexander; Ying, Jinfa; Bax, Adriaan] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM bax@nih.gov RI Roche, Julien/O-3204-2013 OI Roche, Julien/0000-0003-3892-0200 FU National Institutes of Health Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases; Intramural AIDS-Targeted Antiviral Program of the Office of the Director, National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases MS facility FX We thank Annie Aniana for help with protein expression and purification and Robert Blumenthal and Leonid Chernomordik for helpful discussions, and we acknowledge support from the National Institute of Diabetes and Digestive and Kidney Diseases MS facility. This work was funded by the National Institutes of Health Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, National Institutes of Health. NR 42 TC 22 Z9 23 U1 2 U2 28 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 MAR 4 PY 2014 VL 111 IS 9 BP 3425 EP 3430 DI 10.1073/pnas.1401397111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC5KR UT WOS:000332560300057 PM 24550514 ER PT J AU Liao, W Spolski, R Li, P Du, N West, EE Ren, M Mitra, S Leonard, WJ AF Liao, Wei Spolski, Rosanne Li, Peng Du, Ning West, Erin E. Ren, Min Mitra, Suman Leonard, Warren J. TI Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID INTERLEUKIN-9-PRODUCING T-CELLS; GERMINAL CENTER FORMATION; FOLLICULAR-HELPER-CELLS; IMMUNE-RESPONSES; T(H)17 CELLS; TGF-BETA; INFLAMMATION; GENERATION; INDUCTION; STAT5 AB Interleukin 9 (IL-9) is a gamma(c)-family cytokine that is highly produced by T-helper 9 (Th9) cells and regulates a range of immune responses, including allergic inflammation. Here we show that IL-2-JAK3-STAT5 signaling is required for Th9 differentiation, with critical STAT5 binding sites in the Il9 (the gene encoding IL-9) promoter. IL-2 also inhibited B cell lymphoma 6 (BCL6) expression, and overexpression of BCL6 impaired Th9 differentiation. In contrast, IL-21 induced BCL6 and diminished IL-9 expression in wild-type but not Bcl6(-/-) cells, and Th9 differentiation was increased in Il21(-/-) and Il21r(-/-) T cells. Interestingly, BCL6 bound in proximity to many STAT5 and STAT6 binding sites, including at the Il9 promoter. Moreover, there was increased BCL6 and decreased STAT binding at this site in cells treated with blocking antibodies to IL-2 and the IL-2 receptor, suggesting a possible BCL6-STAT5 binding competition that influences IL-9 production. BCL6 binding was also increased when cells were Th9-differentiated in the presence of IL-21. Thus, our data reveal not only direct IL-2 effects via STAT5 at the Il9 gene, but also opposing actions of IL-2 and IL-21 on BCL6 expression, with increased BCL6 expression inhibiting IL-9 production. These data suggest a model in which increasing BCL6 expression decreases efficient Th9 differentiation, indicating possible distinctive approaches for controlling this process. C1 [Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NHLBI, Ctr Immunol, 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, NHLBI, National Institutes of Health FX We thank Dr. Jian-Xin Lin (National Heart, Lung, and Blood Institute, Bethesda) for critical comments, Drs. Art Shaffer and Louis Staudt (National Cancer Institute, Bethesda) for Bcl6-/- mice and the human BCL6 retroviral expression vector, Dr. Lothar Hennighausen (National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda) for the Stat5a/Stat5bfl/fl mice, and the DNA Sequencing Core, NHLBI for generating ChIP-Seq and RNA-Seq libraries. This work was supported by the Division of Intramural Research, NHLBI, National Institutes of Health. NR 41 TC 28 Z9 30 U1 0 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 MAR 4 PY 2014 VL 111 IS 9 BP 3508 EP 3513 DI 10.1073/pnas.1301138111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC5KR UT WOS:000332560300071 PM 24550509 ER PT J AU Ma, HW Thapa, A Morris, L Redmond, TM Baehr, W Ding, XQ AF Ma, Hongwei Thapa, Arjun Morris, Lynsie Redmond, T. Michael Baehr, Wolfgang Ding, Xi-Qin TI Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CELL-DEATH; DEVELOPMENTAL EXPRESSION; RETINITIS-PIGMENTOSA; OPSIN EXPRESSION; DOWN-REGULATION; GENE DELIVERY; RECEPTOR; ACTIVATION; APOPTOSIS; METAMORPHOSIS AB Cone phototransduction and survival of cones in the human macula is essential for color vision and for visual acuity. Progressive cone degeneration in age-related macular degeneration, Stargardt disease, and recessive cone dystrophies is a major cause of blindness. Thyroid hormone (TH) signaling, which regulates cell proliferation, differentiation, and apoptosis, plays a central role in cone opsin expression and patterning in the retina. Here, we investigated whether TH signaling affects cone viability in inherited retinal degeneration mouse models. Retinol isomerase RPE65-deficient mice [a model of Leber congenital amaurosis (LCA) with rapid cone loss] and cone photoreceptor function loss type 1 mice (severe recessive achromatopsia) were used to determine whether suppressing TH signaling with antithyroid treatment reduces cone death. Further, cone cyclic nucleotide-gated channel B subunit-deficient mice (moderate achromatopsia) and guanylate cyclase 2e-deficient mice (LCA with slower cone loss) were used to determine whether triiodothyronine (T3) treatment (stimulating TH signaling) causes deterioration of cones. We found that cone density in retinol isomerase RPE65-deficient and cone photoreceptor function loss type 1 mice increased about sixfold following antithyroid treatment. Cone density in cone cyclic nucleotide-gated channel B subunit-deficient and guanylate cyclase 2e-deficient mice decreased about 40% following T3 treatment. The effect of TH signaling on cone viability appears to be independent of its regulation on cone opsin expression. This work demonstrates that suppressing TH signaling in retina dystrophy mouse models is protective of cones, providing insights into cone preservation and therapeutic interventions. C1 [Ma, Hongwei; Thapa, Arjun; Morris, Lynsie; Ding, Xi-Qin] Univ Oklahoma, Hlth Sci Ctr, Dept Cell Biol, Oklahoma City, OK 73104 USA. [Redmond, T. Michael] NEI, Lab Retinal Cell & Mol Biol, Bethesda, MD 20892 USA. [Baehr, Wolfgang] Univ Utah, John A Moran Eye Ctr, Salt Lake City, UT 84132 USA. RP Ding, XQ (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Cell Biol, Oklahoma City, OK 73104 USA. EM xi-qin-ding@ouhsc.edu OI Redmond, T. Michael/0000-0002-1813-5291 FU National Center for Research Resources [P20RR017703]; National Eye Institute [P30EY12190, R01EY019490, R01EY08123]; Oklahoma Center for the Advancement of Science and Technology FX We thank Drs. Cheryl Craft and Muna Naash for providing antibodies for M-opsin, cone arrestin, and S-opsin. This work was supported by grants from the National Center for Research Resources (P20RR017703), the National Eye Institute (P30EY12190, R01EY019490, and R01EY08123), and the Oklahoma Center for the Advancement of Science and Technology. NR 39 TC 11 Z9 12 U1 0 U2 14 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 MAR 4 PY 2014 VL 111 IS 9 BP 3602 EP 3607 DI 10.1073/pnas.1317041111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC5KR UT WOS:000332560300087 PM 24550448 ER PT J AU Gerlic, M Croker, BA Cengia, LH Moayeri, M Kile, BT Masters, SL AF Gerlic, Motti Croker, Ben A. Cengia, Louise H. Moayeri, Mahtab Kile, Benjamin T. Masters, Seth L. TI NLRP1a Expression in Srebp-1a-Deficient Mice SO CELL METABOLISM LA English DT Letter ID PYROPTOSIS C1 [Gerlic, Motti; Cengia, Louise H.; Kile, Benjamin T.; Masters, Seth L.] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia. [Gerlic, Motti; Kile, Benjamin T.; Masters, Seth L.] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia. [Croker, Ben A.] Harvard Univ, Boston Childrens Hosp, Sch Med, Div Hematol Oncol, Boston, MA 02115 USA. [Moayeri, Mahtab] NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Masters, SL (reprint author), Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia. EM masters@wehi.edu.au OI gerlic, mordechay/0000-0001-9518-1833; Croker, Ben/0000-0002-0885-3599; Kile, Benjamin/0000-0002-8836-8947; masters, seth/0000-0003-4763-576X NR 6 TC 1 Z9 2 U1 0 U2 3 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 MAR 4 PY 2014 VL 19 IS 3 BP 345 EP 346 DI 10.1016/j.cmet.2014.02.002 PG 2 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA AC3DP UT WOS:000332395500001 PM 24606891 ER PT J AU Maio, N Singh, A Uhrigshardt, H Saxena, N Tong, WH Rouault, TA AF Maio, Nunziata Singh, Anamika Uhrigshardt, Helge Saxena, Neetu Tong, Wing-Hang Rouault, Tracey A. TI Cochaperone Binding to LYR Motifs Confers Specificity of Iron Sulfur Cluster Delivery SO CELL METABOLISM LA English DT Article ID SUCCINATE-DEHYDROGENASE; SCAFFOLD PROTEIN; CLINICAL-FEATURES; IN-VIVO; CHAPERONE; COMPLEX; GENE; PARAGANGLIOMA; BIOGENESIS; DOMAIN AB Iron sulfur (Fe-S) clusters, preassembled on the ISCU scaffold, are transferred to target proteins or to intermediate scaffolds by a dedicated chaperone-cochaperone system. However, the molecular mechanisms that underlie substrate discrimination and guide delivery of nascent clusters to specific subsets of Fe-S recipients are poorly understood. Here, we identified interacting partners of the cochaperone HSC20 and discovered that LYR motifs are molecular signatures of specific recipient Fe-S proteins or accessory factors that assist Fe-S cluster delivery. In succinate dehydrogenase B, two LYR motifs engage the ISCU-HSC20-HSPA9 complex to aid incorporation of three Fe-S clusters within the final structure of complex II. Moreover, we show that members of the LYR motif family which assist assembly of complexes II or III, SDHAF1 and LYRM7, respectively, are HSC20 binding partners. Our studies unveil a network of interactions between HSC20 and LYR motif-containing proteins that are key to the assembly and function of complexes I, II, and III. C1 [Maio, Nunziata; Singh, Anamika; Uhrigshardt, Helge; Saxena, Neetu; Tong, Wing-Hang; Rouault, Tracey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rouault@mail.nih.gov FU Eunice Kennedy Shriver NICHD Intramural Research Program FX We are grateful to members of our lab for constructive discussions; to Drs. J.S. Bonifacino, R. Mattera, and Y. Prabhu for providing advice on the Y2H assay; to Dr. A. Banerjee for insights into the structural aspects of our work; and to A. Sharma for the gift of antibodies to the epitope tags. This work was supported by the Eunice Kennedy Shriver NICHD Intramural Research Program. NR 50 TC 35 Z9 37 U1 0 U2 6 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 MAR 4 PY 2014 VL 19 IS 3 BP 445 EP 457 DI 10.1016/j.cmet.2014.01.015 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA AC3DP UT WOS:000332395500014 PM 24606901 ER PT J AU Gruschus, JM Byrd, RA Randazzo, PA AF Gruschus, James M. Byrd, R. Andrew Randazzo, Paul A. TI The Importance of Seeing Surface (Effects) SO STRUCTURE LA English DT Editorial Material ID MEMBRANE; GTPASE; RAS; RECOGNITION; BINDING; ARF1 AB In this issue of Structure, Liu and colleagues describe an experimentally rigorous and innovative approach for understanding the role of membranes in the function and regulation of peripheral membrane proteins. This work is the beginning of a new era of experimental work that promises many advances relevant to molecular mechanisms and therapeutic targeting of this important class of proteins. C1 [Gruschus, James M.] NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Byrd, R. Andrew] NCI, Struct Biophys Lab, NIH, Bethesda, MD 20892 USA. [Randazzo, Paul A.] NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Randazzo, PA (reprint author), NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM randazzp@mail.nih.gov RI Byrd, R. Andrew/F-8042-2015 OI Byrd, R. Andrew/0000-0003-3625-4232 FU Intramural NIH HHS [Z99 CA999999, ZIA BC007365-19]; NCI NIH HHS [Z01 BC007365] NR 13 TC 1 Z9 1 U1 2 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD MAR 4 PY 2014 VL 22 IS 3 BP 363 EP 365 DI 10.1016/j.str.2014.02.005 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AD1WZ UT WOS:000333025700002 PM 24607142 ER PT J AU Xiao, Q Freedman, ND Ren, J Hollenbeck, AR Abnet, CC Park, Y AF Xiao, Q. Freedman, N. D. Ren, J. Hollenbeck, A. R. Abnet, C. C. Park, Y. TI Intakes of folate, methionine, vitamin B6, and vitamin B12 with risk of esophageal and gastric cancer in a large cohort study SO BRITISH JOURNAL OF CANCER LA English DT Article DE folate; one-carbon metabolism pathway; esophageal cancer; gastric cancer ID HEALTH-AMERICAN-ASSOCIATION; RETIRED-PERSONS DIET; NATIONAL-INSTITUTES; NUTRIENT INTAKE; ADENOCARCINOMAS; POLYMORPHISMS; CARCINOMA; OBESITY; MTHFR AB Background: Nutrients in the one-carbon metabolism pathway may be involved in carcinogenesis. Few cohort studies have investigated the intakes of folate and related nutrients in relation to gastric and esophageal cancer. Methods: We prospectively examined the association between self-reported intakes of folate, methionine, vitamin B6, and vitamin B12 and gastric and esophageal cancer in 492 293 men and women. Results: We observed an elevated risk of esophageal squamous cell carcinoma with low intake of folate (relative risk (95% confidence interval): Q1 vs Q3, 1.91 (1.17, 3.10)), but no association with high intake. Folate intake was not associated with esophageal adenocarcinoma, gastric cardia adenocarcinoma, or non-cardia gastric adenocarcinoma. The intakes of methionine, vitamin B6, and vitamin B12 were not associated with esophageal and gastric cancer. Conclusion: Low intake of folate was associated with increased risk of esophageal squamous cell carcinoma. C1 [Xiao, Q.; Freedman, N. D.; Abnet, C. C.; Park, Y.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ren, J.] Natl Canc Ctr, Natl Off Canc Prevent & Control, Beijing, Peoples R China. [Hollenbeck, A. R.] AARP, Washington, DC USA. RP Xiao, Q (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM qian.xiao@nih.gov RI Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015; OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098; Park, Yikyung/0000-0002-6281-489X FU NIH, National Cancer Institute, Department of Health and Human Services; Florida Department of Health, Tallahassee, Florida, USA FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Department of Health and Human Services. Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA. Cancer incidence data from California were collected by the California Cancer Registry, California Department of Public Health's Cancer Surveillance and Research Branch, Sacramento, California, USA. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, Lansing, Michigan, USA. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System (Miami, Florida, USA) under contract with the Florida Department of Health, Tallahassee, Florida, USA. The views expressed herein are solely those of the authors and do not necessarily reflect those of the FCDC or FDOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Health Sciences Center School of Public Health, New Orleans, Louisiana, USA. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health, Trenton, New Jersey, USA. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry, Raleigh, North Carolina, USA. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania, USA. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services, Phoenix, Arizona, USA. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, Texas, USA. Cancer incidence data from Nevada were collected by the Nevada Central Cancer Registry, State Health Division, State of Nevada Department of Health and Human Services, Las Vegas, Nevada, USA. We are indebted to the participants in the NIH-AARP Diet and Health Study for their outstanding cooperation. We also thank Sigurd Hermansen and Kerry Grace Morrissey from Westat for study outcome ascertainment and management and Leslie Carroll at Information Management Services for data support and analysis. Guarantor of the article: XQ. NR 25 TC 11 Z9 11 U1 1 U2 16 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 MAR 4 PY 2014 VL 110 IS 5 BP 1328 EP 1333 DI 10.1038/bjc.2014.17 PG 6 WC Oncology SC Oncology GA AC9EB UT WOS:000332836000028 PM 24481406 ER PT J AU Jenkins, MR Stinchcombe, JC Au-Yeung, BB Asano, Y Ritter, AT Weiss, A Griffiths, GM AF Jenkins, Misty R. Stinchcombe, Jane C. Au-Yeung, Byron B. Asano, Yukako Ritter, Alex T. Weiss, Arthur Griffiths, Gillian M. TI Distinct structural and catalytic roles for Zap70 in formation of the immunological synapse in CTL SO ELIFE LA English DT Article ID T-CELL-RECEPTOR; SEVERE COMBINED IMMUNODEFICIENCY; NATURAL-KILLER-CELLS; MEDIATED CYTOTOXICITY; TYROSINE PHOSPHORYLATION; ACTIN POLYMERIZATION; GRANULE POLARIZATION; SECRETORY GRANULES; RETROGRADE FLOW; ZAP-70 KINASE AB T cell receptor (TCR) activation leads to a dramatic reorganisation of both membranes and receptors as the immunological synapse forms. Using a genetic model to rapidly inhibit Zap70 catalytic activity we examined synapse formation between cytotoxic T lymphocytes and their targets. In the absence of Zap70 catalytic activity Vav-1 activation occurs and synapse formation is arrested at a stage with actin and integrin rich interdigitations forming the interface between the two cells. The membranes at the synapse are unable to flatten to provide extended contact, and Lck does not cluster to form the central supramolecular activation cluster (cSMAC). Centrosome polarisation is initiated but aborts before reaching the synapse and the granules do not polarise. Our findings reveal distinct roles for Zap70 as a structural protein regulating integrin-mediated control of actin vs its catalytic activity that regulates TCR-mediated control of actin and membrane remodelling during formation of the immunological synapse. C1 [Jenkins, Misty R.; Stinchcombe, Jane C.; Asano, Yukako; Ritter, Alex T.; Griffiths, Gillian M.] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England. [Au-Yeung, Byron B.; Weiss, Arthur] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Au-Yeung, Byron B.; Weiss, Arthur] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. [Ritter, Alex T.] NIH, Howard Hughes Med Inst, Bethesda, MD 20892 USA. [Au-Yeung, Byron B.; Weiss, Arthur] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA USA. RP Griffiths, GM (reprint author), Univ Cambridge, Cambridge Inst Med Res, Cambridge, England. EM gg305@cam.ac.uk OI Griffiths, Gillian/0000-0003-0434-5842; Au-Yeung, Byron/0000-0002-6446-9102 FU Wellcome Trust [075880, 100140]; Howard Hughes Medical Institute; Australian National Health and Medical Research Council (NHMRC) Biomedical Fellowship [567082]; Arthritis Foundation [5476]; NIAMS, National Institutes of Health [RC2AR058947] FX Wellcome Trust 075880, 100140 Gillian M Griffiths; Howard Hughes Medical Institute Arthur Weiss; Australian National Health and Medical Research Council (NHMRC) Biomedical Fellowship 567082 Misty R Jenkins; Arthritis Foundation 5476 Byron B Au-Yeung; NIAMS, National Institutes of Health RC2AR058947 Arthur Weiss NR 62 TC 11 Z9 11 U1 0 U2 9 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAR 4 PY 2014 VL 3 AR e01310 DI 10.7554/eLife.01310 PG 21 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AC6IQ UT WOS:000332625800001 PM 24596147 ER PT J AU de Koning, HJ Meza, R Plevritis, SK ten Haaf, K Munshi, VN Jeon, J Erdogan, SA Kong, CY Han, SS van Rosmalen, J Choi, SE Pinsky, PF de Gonzalez, AB Berg, CD Black, WC Tammemagi, MC Hazelton, WD Feuer, EJ McMahon, PM AF de Koning, Harry J. Meza, Rafael Plevritis, Sylvia K. ten Haaf, Kevin Munshi, Vidit N. Jeon, Jihyoun Erdogan, Saadet Ayca Kong, Chung Yin Han, Summer S. van Rosmalen, Joost Choi, Sung Eun Pinsky, Paul F. de Gonzalez, Amy Berrington Berg, Christine D. Black, William C. Tammemaegi, Martin C. Hazelton, William D. Feuer, Eric J. McMahon, Pamela M. TI Benefits and Harms of Computed Tomography Lung Cancer Screening Strategies: A Comparative Modeling Study for the US Preventive Services Task Force SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID LOW-DOSE CT; UNITED-STATES; SMOKING ABSTINENCE; SELECTION CRITERIA; NELSON TRIAL; POPULATION; MORTALITY; PROSTATE; STAGE; RISK AB Background: The optimum screening policy for lung cancer is unknown. Objective: To identify efficient computed tomography (CT) screening scenarios in which relatively more lung cancer deaths are averted for fewer CT screening examinations. Design: Comparative modeling study using 5 independent models. Data Sources: The National Lung Screening Trial; the Prostate, Lung, Colorectal, and Ovarian Cancer Screening trial; the Surveillance, Epidemiology, and End Results program; and the U.S. Smoking History Generator. Target Population: U.S. cohort born in 1950. Time Horizon: Cohort followed from ages 45 to 90 years. Perspective: Societal. Intervention: 576 scenarios with varying eligibility criteria (age, pack-years of smoking, years since quitting) and screening intervals. Outcome Measures: Benefits included lung cancer deaths averted or life-years gained. Harms included CT examinations, false-positive results (including those obtained from biopsy/surgery), overdiagnosed cases, and radiation-related deaths. Results of Best-Case Scenario: The most advantageous strategy was annual screening from ages 55 through 80 years for ever-smokers with a smoking history of at least 30 pack-years and ex-smokers with less than 15 years since quitting. It would lead to 50% (model ranges, 45% to 54%) of cases of cancer being detected at an early stage (stage I/II), 575 screening examinations per lung cancer death averted, a 14% (range, 8.2% to 23.5%) reduction in lung cancer mortality, 497 lung cancer deaths averted, and 5250 life-years gained per the 100 000-member cohort. Harms would include 67 550 false-positive test results, 910 biopsies or surgeries for benign lesions, and 190 overdiagnosed cases of cancer (3.7% of all cases of lung cancer [model ranges, 1.4% to 8.3%]). Results of Sensitivity Analysis: The number of cancer deaths averted for the scenario varied across models between 177 and 862; the number of overdiagnosed cases of cancer varied between 72 and 426. Limitations: Scenarios assumed 100% screening adherence. Data derived from trials with short duration were extrapolated to lifetime follow-up. Conclusion: Annual CT screening for lung cancer has a favorable benefit-harm ratio for individuals aged 55 through 80 years with 30 or more pack-years' exposure to smoking. C1 Erasmus MC, NL-3000 CA Rotterdam, Netherlands. Univ Michigan, Ann Arbor, MI 48109 USA. Stanford Univ, Stanford, CA 94305 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NCI, Bethesda, MD 20892 USA. Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. Brock Univ, St Catharines, ON L2S 3A1, Canada. RP de Koning, HJ (reprint author), Erasmus MC, Dept Publ Hlth, POB 2040, NL-3000 CA Rotterdam, Netherlands. EM h.dekoning@erasmusmc.nl RI Berg , Christine/K-1047-2014 FU National Cancer Institute FX Primary Funding Source: National Cancer Institute. NR 42 TC 120 Z9 121 U1 7 U2 24 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 MAR 4 PY 2014 VL 160 IS 5 BP 311 EP + DI 10.7326/M13-2316 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA AC8OT UT WOS:000332793900003 PM 24379002 ER PT J AU Kim, WC Ma, CA Li, WM Chohan, M Wilson, DM Lee, CH AF Kim, Wan Cheol Ma, Conan Li, Wai-Ming Chohan, Manbir Wilson, David M., III Lee, Chow H. TI Altered Endoribonuclease Activity of Apurinic/Apyrimidinic Endonuclease 1 Variants Identified in the Human Population SO PLOS ONE LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; EXCISION-REPAIR PATHWAY; DNA-REPAIR; GENETIC POLYMORPHISMS; CANCER-RISK; BREAST-CANCER; MESSENGER-RNA; APE1; APE1/REF-1; SITE AB Apurinic/apyrimidinic endonuclease 1 (APE1) is the major mammalian enzyme in the DNA base excision repair pathway and cleaves the DNA phosphodiester backbone immediately 5' to abasic sites. APE1 also has 3'-5' DNA exonuclease and 3' DNA phosphodiesterase activities, and regulates transcription factor DNA binding through its redox regulatory function. The human APE1 has recently been shown to endonucleolytically cleave single-stranded regions of RNA. Towards understanding the biological significance of the endoribonuclease activity of APE1, we examined eight different amino acid substitution variants of APE1 previously identified in the human population. Our study shows that six APE1 variants, D148E, Q51H, I64V, G241R, R237A, and G306A, exhibit a 76-85% reduction in endoribonuclease activity against a specific coding region of the c-myc RNA, yet fully retain the ability to cleave apurinic/apyrimidinic DNA. We found that two APE1 variants, L104R and E126D, exhibit a unique RNase inhibitor-resistant endoribonuclease activity, where the proteins cleave c-myc RNA 3' of specific single-stranded guanosine residues. Expression of L104R and E126D APE1 variants in bacterial Origami cells leads to a 60-80% reduction in colony formation and a 1.5-fold increase in cell doubling time, whereas the other variants, which exhibit diminished endoribonuclease activity, had no effect. These data indicate that two human APE1 variants exhibit a unique endoribonuclease activity, which correlates with their ability to induce cytotoxicity or slow down growth in bacterial cells and supports the notion of their biological functionality. C1 [Kim, Wan Cheol; Ma, Conan; Li, Wai-Ming; Chohan, Manbir; Lee, Chow H.] Univ British Columbia, Chem Program, Prince George, BC, Canada. [Wilson, David M., III] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Lee, CH (reprint author), Univ British Columbia, Chem Program, Prince George, BC, Canada. EM chow.lee@unbc.ca FU Natural Sciences & Engineering Research Council [227158]; Intramural Research Program at the NIH, National Institute on Aging FX This research was supported by a Discovery Grant (#227158) from Natural Sciences & Engineering Research Council to CHL, and in part by the Intramural Research Program at the NIH, National Institute on Aging to DMWIII. The funders had no role in study design, decision to publish, or preparation of the manuscript. NR 22 TC 3 Z9 4 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 4 PY 2014 VL 9 IS 3 AR e90837 DI 10.1371/journal.pone.0090837 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC4FD UT WOS:000332475500104 PM 24595156 ER PT J AU Afilalo, J Alexander, KP Mack, MJ Maurer, MS Green, P Allen, LA Popma, JJ Ferrucci, L Forman, DE AF Afilalo, Jonathan Alexander, Karen P. Mack, Michael J. Maurer, Mathew S. Green, Philip Allen, Larry A. Popma, Jeffrey J. Ferrucci, Luigi Forman, Daniel E. TI Frailty Assessment in the Cardiovascular Care of Older Adults SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiovascular disease; elderly; frailty ID PHYSICAL PERFORMANCE BATTERY; AORTIC-VALVE IMPLANTATION; LOWER-EXTREMITY FUNCTION; AMERICAN-HEART-ASSOCIATION; IANA TASK-FORCE; GAIT SPEED; CARDIAC-SURGERY; BODY-COMPOSITION; ELDERLY-PATIENTS; MUSCLE STRENGTH C1 [Afilalo, Jonathan] McGill Univ, Jewish Gen Hosp, Div Cardiol, Montreal, PQ H3T 1E2, Canada. [Afilalo, Jonathan] McGill Univ, Jewish Gen Hosp, Div Clin Epidemiol, Montreal, PQ H3T 1E2, Canada. [Alexander, Karen P.] Duke Univ, Med Ctr, Div Cardiol, Durham, NC 27710 USA. [Mack, Michael J.] Heart Hosp Baylor Plano, Div Cardiothorac Surg, Baylor Hlth Care Syst, Plano, TX USA. [Maurer, Mathew S.; Green, Philip] Columbia Univ, Med Ctr, Div Cardiol, New York, NY USA. [Allen, Larry A.] Univ Colorado, Sch Med, Div Cardiol, Aurora, CO USA. [Popma, Jeffrey J.] Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. [Ferrucci, Luigi] NIA, NIH, Baltimore, MD 21224 USA. [Forman, Daniel E.] Brigham & Womens Hosp, Div Cardiovasc Med, VA Boston Healthcare Ctr, Boston, MA 02115 USA. RP Afilalo, J (reprint author), McGill Univ, Jewish Gen Hosp, Div Cardiol, 3755 Cote St Catherine Rd,E-222, Montreal, PQ H3T 1E2, Canada. EM jonathan.afilalo@mcgill.ca FU NHLBI NIH HHS [K23 HL121142]; NIA NIH HHS [L30 AG040558] NR 110 TC 148 Z9 153 U1 10 U2 24 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 MAR 4 PY 2014 VL 63 IS 8 BP 747 EP 762 DI 10.1016/j.jacc.2013.09.070 PG 16 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AB3WM UT WOS:000331720900002 PM 24291279 ER PT J AU Forbes, CE Poore, JC Krueger, F Barbey, AK Solomon, J Grafman, J AF Forbes, Chad E. Poore, Joshua C. Krueger, Frank Barbey, Aron K. Solomon, Jeffrey Grafman, Jordan TI The role of executive function and the dorsolateral prefrontal cortex in the expression of neuroticism and conscientiousness SO SOCIAL NEUROSCIENCE LA English DT Article DE Personality; DLPC; Executive function; Neuroticism; Conscientiousness; Self-control ID GENERAL INTELLIGENCE; PERSONALITY-TRAITS; EMOTION REGULATION; BRAIN VOLUME; EXTROVERSION; FMRI; METAANALYSIS; SOFTWARE; AMYGDALA; INJURY AB The current study examined how specific neurological systems contribute to the expression of multiple personality dimensions. We used individuals with traumatic brain injuries to examine the contribution of the dorsolateral prefrontal cortex (DLPFC)a region important for executive function and attentionto the expression of neuroticism and conscientiousness factors and facets. Results from Voxel-Based Lesion-Symptom Mapping analyses revealed that focal damage to the left DLPFC (Brodmann's area 9) was associated with high neuroticism and low conscientious factor and facet scores (anxiety and self-discipline, respectively). Compared with lesioned and normal controls, veterans with damage in left DLPFC also reported higher neuroticism and lower conscientiousness facet scores, slower reaction times on the California Computerized Assessment Package assessment, and lower scores on the Delis-Kaplan executive function battery. Findings suggest that while neuroticism and conscientiousness remain psychometrically independent personality dimensions, their component facets may rely on a common neurocognitive infrastructure and executive function resources in general. C1 [Forbes, Chad E.; Poore, Joshua C.; Krueger, Frank; Barbey, Aron K.; Solomon, Jeffrey; Grafman, Jordan] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Forbes, Chad E.] Univ Delaware, Dept Psychol, Newark, DE 19716 USA. [Forbes, Chad E.] Ctr Clin, Bethesda, MD USA. [Forbes, Chad E.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Poore, Joshua C.] Charles Stark Draper Lab Inc, Boston, MA USA. [Krueger, Frank] George Mason Univ, Dept Mol Neurosci, Fairfax, VA 22030 USA. [Solomon, Jeffrey] Expert Image Anal LLC, Potomac, MD USA. [Grafman, Jordan] Rehabil Inst Chicago, Chicago, IL 60611 USA. [Grafman, Jordan] Northwestern Univ, Feinberg Sch Med, Alzheimers Dis Res Ctr, Dept Phys Med & Rehabil, Evanston, IL 60208 USA. [Grafman, Jordan] Northwestern Univ, Feinberg Sch Med, Alzheimers Dis Res Ctr, Dept Psychiat & Behav Sci, Evanston, IL 60208 USA. [Grafman, Jordan] Northwestern Univ, Feinberg Sch Med, Alzheimers Dis Res Ctr, Dept Cognit Neurol, Evanston, IL 60208 USA. [Grafman, Jordan] Northwestern Univ, Dept Psychol, Evanston, IL 60208 USA. RP Forbes, CE (reprint author), Univ Delaware, Dept Psychol, 111 Wolf Hall, Newark, DE 19716 USA. EM cforbes@psych.udel.edu; jgrafman@northwestern.edu RI Barbey, Aron/L-7312-2015; OI Barbey, Aron/0000-0002-6092-0912; Grafman, Jordan H./0000-0001-8645-4457 FU Intramural Research Training Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health; US Army Medical Research and Material Command [DAMD17-01-1-0675] FX This work was supported by the Intramural Research Training Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, and a project grant from the US Army Medical Research and Material Command administrated by the Henry M. Jackson Foundation [Vietnam Head Injury Study Phase III: A 30-year post-injury follow-up study: Grant number: DAMD17-01-1-0675]. The authors are grateful to all the Vietnam veterans who participated in this study. NR 52 TC 8 Z9 10 U1 3 U2 39 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1747-0919 EI 1747-0927 J9 SOC NEUROSCI-UK JI Soc. Neurosci. PD MAR 4 PY 2014 VL 9 IS 2 BP 139 EP 151 DI 10.1080/17470919.2013.871333 PG 13 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AA2NZ UT WOS:000330932600004 PM 24405294 ER PT J AU Hunt, MJO Weissfeld, L Boudreau, RM Aizenstein, H Newman, AB Simonsick, EM Van Domelen, DR Thomas, F Yaffe, K Rosano, C AF Hunt, Megan J. Olson Weissfeld, Lisa Boudreau, Robert M. Aizenstein, Howard Newman, Anne B. Simonsick, Eleanor M. Van Domelen, Dane R. Thomas, Fridtjof Yaffe, Kristine Rosano, Caterina TI A variant of sparse partial least squares for variable selection and data exploration SO FRONTIERS IN NEUROINFORMATICS LA English DT Article DE high-dimensional; multicollinearity; over-fitting; SPLS; inference; tuning parameters; network; MRI ID FUNCTIONING OLDER-ADULTS; GRAY-MATTER ATROPHY; CARDIOVASCULAR HEALTH; MR-IMAGES; BRAIN; REGRESSION; MEMORY; ABNORMALITIES; SEGMENTATION; PREVALENCE AB When data are sparse and/or predictors multicollinear, current implementation of sparse partial least squares (SPLS) does not give estimates for non-selected predictors nor provide a measure of inference. In response, an approach termed "all-possible" SPLS is proposed, which fits a SPLS model for all tuning parameter values across a set grid. Noted is the percentage of time a given predictor is chosen, as well as the average non-zero parameter estimate. Using a "large" number of multicollinear predictors, simulation confirmed variables not associated with the outcome were least likely to be chosen as sparsity increased across the grid of tuning parameters, while the opposite was true for those strongly associated. Lastly, variables with a weak association were chosen more often than those with no association, but less often than those with a strong relationship to the outcome. Similarly, predictors most strongly related to the outcome had the largest average parameter estimate magnitude, followed by those with a weak relationship, followed by those with no relationship. Across two independent studies regarding the relationship between volumetric MRI measures and a cognitive test score, this method confirmed a priori hypotheses about which brain regions would be selected most often and have the largest average parameter estimates. In conclusion, the percentage of time a predictor is chosen is a useful measure for ordering the strength of the relationship between the independent and dependent variables, serving as a form of inference. The average parameter estimates give further insight regarding the direction and strength of association. As a result, all-possible SPLS gives more information than the dichotomous output of traditional SPLS, making it useful when undertaking data exploration and hypothesis generation for a large number of potential predictors. C1 [Hunt, Megan J. Olson; Weissfeld, Lisa] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15213 USA. [Boudreau, Robert M.; Rosano, Caterina] Univ Pittsburgh, Ctr Aging & Populat Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Aizenstein, Howard] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. [Aizenstein, Howard] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15213 USA. [Aizenstein, Howard] Univ Pittsburgh, Dept Clin & Translat Sci, Pittsburgh, PA 15213 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Simonsick, Eleanor M.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Van Domelen, Dane R.] Emory Univ, Dept Biostat, Atlanta, GA 30322 USA. [Thomas, Fridtjof] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat Neurol & Epidemiol, San Francisco, CA 94143 USA. RP Rosano, C (reprint author), Univ Pittsburgh, Ctr Aging & Populat Hlth, Dept Epidemiol, 130 N Bellefield St, Pittsburgh, PA 15213 USA. EM rosanoc@edc.pitt.edu RI Newman, Anne B./C-6408-2013; OI Van Domelen, Dane/0000-0003-0051-7790; Newman, Anne B./0000-0002-0106-1150; Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010; Boudreau, Robert/0000-0003-0162-5187 FU National Institute on Aging (NIA) [AG-023629]; National Science Foundation [DGE-0940903]; NIA [AG-023629, N01-AG-6-2103, N01-AG-6-2106, NO1-AG-6-2101, R01-AG028050, AG-15928, AG-20098, AG-027058]; NINR [R01-NR012459]; NIH, National Institute on Aging; National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-85239, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, P30-AG-024827-01, HL080295]; National Institute of Neurological Disorders and Stroke (NINDS); NHLBI [R01-HL-075366]; University of Pittsburgh Claude D. Pepper Older Americans Independence Center [P30-AG-024827-07] FX This work was supported by the National Institute on Aging (NIA) AG-023629 and the National Science Foundation Graduate Research Fellowship DGE-0940903. Health ABC was supported by NIA contracts N01-AG-6-2103, N01-AG-6-2106 and NO1-AG-6-2101; NIA grant R01-AG028050 and NINR grant R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. CHS was supported by contract numbers N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, P30-AG-024827-01 and grant number HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with added contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG-15928, AG-20098, AG-027058 and AG-023629 from the NIA, R01-HL-075366 from the NHLBI and the University of Pittsburgh Claude D. Pepper Older Americans Independence Center P30-AG-024827-07. A full list of principal CHS investigators and institutions can be found at https://chs-nhlbi.org/pi. NR 41 TC 0 Z9 0 U1 1 U2 1 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5196 J9 FRONT NEUROINFORM JI Front. Neuroinformatics PD MAR 3 PY 2014 VL 8 AR 18 DI 10.3389/fninf.2014.00018 PG 9 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA AZ3CU UT WOS:000348106200001 ER PT J AU Dal Monte, O Noble, PL Costa, VD Averbeck, BB AF Dal Monte, Olga Noble, Pamela L. Costa, Vincent D. Averbeck, Bruno B. TI Oxytocin enhances attention to the eye region in rhesus monkeys SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE oxytocin; eyes; facial expression; free-viewing; gaze; eye tracking; intranasal oxytocin; rhesus macaques ID AUTISM SPECTRUM DISORDERS; INTRANASAL OXYTOCIN; EMOTIONAL FACES; FACIAL EXPRESSIONS; AMYGDALA; HUMANS; GAZE; RECOGNITION; PATTERNS; MACAQUE AB Human and non-human primates rely on the ability to perceive and interpret facial expressions to guide effective social interactions. The neuropeptide oxytocin (OT) has been shown to have a critical role in the perception of social cues, and in humans to increase the number of saccades to the eye region. To develop a useful primate model for the effects of OT on information processing, we investigated the influence of OT on gaze behavior during face processing in rhesus macaques. Forty-five minutes after a single intranasal dose of either 24IU OT or saline, monkeys completed a free-viewing task during which they viewed pictures of conspecifics displaying one of three facial expressions (neutral, open-mouth threat or bared-teeth) for 5s. The monkey was free to explore the face on the screen while the pattern of eye movements was recorded. OT did not increase overall fixations to the face compared to saline. Rather, when monkeys freely viewed conspecific faces, OT increased fixations to the eye region relative to the mouth region. This effect of OT was particularly pronounced when face position on the screen was manipulated so that the eye region was not the first facial feature seen by the monkeys. Together these findings are consistent with prior evidence in humans that intranasal administration of OT specifically enhances visual attention to the eye region compared to other informative facial features, thus validating the use of non-human primates to mechanistically explore how OT modulates social information processing and behavior. C1 [Dal Monte, Olga; Noble, Pamela L.; Costa, Vincent D.; Averbeck, Bruno B.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Dal Monte, Olga] Univ Turin, Dept Neuropsychol, Turin, Italy. RP Averbeck, BB (reprint author), NIMH, Neuropsychol Lab, NIH, 49 Convent Dr MSC 4415, Bethesda, MD 20892 USA. EM averbeckbb@mail.nih.gov OI dal monte, olga/0000-0002-7823-4769; Costa, Vincent/0000-0002-5412-8945 FU National Institute of Health, NIMH FX This research was supported by the Intramural Research Program of the National Institute of Health, NIMH. NR 55 TC 12 Z9 12 U1 4 U2 9 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD MAR 3 PY 2014 VL 8 AR 41 DI 10.3389/fnins.2014.00041 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AW7FL UT WOS:000346430000001 PM 24624055 ER PT J AU Riou, LM Broisat, A Ghezzi, C Finet, G Rioufol, G Gharib, AM Pettigrew, RI Ohayon, J AF Riou, Laurent M. Broisat, Alexis Ghezzi, Catherine Finet, Gerard Rioufol, Gilles Gharib, Ahmed M. Pettigrew, Roderic I. Ohayon, Jacques TI Effects of mechanical properties and atherosclerotic artery size on biomechanical plaque disruption - Mouse vs. human SO JOURNAL OF BIOMECHANICS LA English DT Article DE Plaque disruption; Mouse; Human; Mechanical properties; Artery size ID APOE-DEFICIENT MICE; E-KNOCKOUT MICE; MURINE MODELS; CIRCUMFERENTIAL STRESS; CORONARY-ARTERIES; CAP THICKNESS; RUPTURE; LESIONS; BEHAVIOR; AORTA AB Mouse models of atherosclerosis are extensively being used to study the mechanisms of atherosclerotic plaque development and the results are frequently extrapolated to humans. However, major differences have been described between murine and human atherosclerotic lesions and the determination of similarities and differences between these species has been largely addressed recently. This study takes over and extends previous studies performed by our group and related to the biomechanical characterization of both mouse and human atherosclerotic lesions. Its main objective was to determine the distribution and amplitude of mechanical stresses including peak cap stress (PCS) in aortic vessels from atherosclerotic apoE(-/-) mice, in order to evaluate whether such biomechanical data would be in accordance with the previously suggested lack of plaque rupture in this model. Successful finite element analysis was performed from the zero-stress configuration of aortic arch sections and mainly indicated (1) the modest role of atherosclerotic lesions in the observed increase in residual parietal stresses in apoE(-/-) mouse vessels and (2) the low amplitude of murine PCS as compared to humans. Overall, the results from the present study support the hypothesis that murine biomechanical properties and artery size confer less propensity to rupture for mouse lesions in comparison with those of humans. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Riou, Laurent M.; Broisat, Alexis; Ghezzi, Catherine] Fac Med Grenoble, Radiopharmaceut Bioclin, INSERM, UMR S 1039, Grenoble, France. [Finet, Gerard; Rioufol, Gilles] Hosp Civils Lyon, Dept Hemodynam & Intervent Cardiol, Lyon, France. [Finet, Gerard; Rioufol, Gilles] Univ Lyon 1, INSERM, U886, F-69365 Lyon, France. [Gharib, Ahmed M.; Pettigrew, Roderic I.] NIDDK, Lab Integrat Cardiovasc Imaging Sci, NIH, Bethesda, MD 20892 USA. [Pettigrew, Roderic I.; Ohayon, Jacques] UJF, CNRS, Lab TIMC IMAG DyCTiM, UMR 5525,In3S, Grenoble, France. [Ohayon, Jacques] Univ Savoie, Polytech Annecy Chambery, Le Bourget Du Lac, France. RP Pettigrew, RI (reprint author), UJF, CNRS, Lab TIMC IMAG DyCTiM, UMR 5525,In3S, Grenoble, France. EM rpettig@mail.nih.gov; jacques.ohayon@imag.fr RI Riou, Laurent/M-4562-2014; GHEZZI, Catherine/M-5185-2014; Ohayon, Jacques/M-6576-2014; Gharib, Ahmed/O-2629-2016 OI Riou, Laurent/0000-0002-9240-4680; Gharib, Ahmed/0000-0002-2476-481X FU Agence Nationale de la Recherche (ANR), France FX Financial support was provided by the Agence Nationale de la Recherche (ANR), France (ATHEBIOMECH 2007-2009 and MELANII 2009-2013 projects). The authors thank Dr. Nicolas Mesnier (TIMC Laboratory, Grenoble, France) for computational support, and Dr Alain Tedgui (Inserm U970, Paris, France) for helpful discussions. NR 47 TC 4 Z9 4 U1 0 U2 7 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 MAR 3 PY 2014 VL 47 IS 4 SI SI BP 765 EP 772 DI 10.1016/j.jbiomech.2014.01.020 PG 8 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA AE5BV UT WOS:000334003700002 PM 24491495 ER PT J AU Chen, ZX Golovnina, K Sultana, H Kumar, S Oliver, B AF Chen, Zhen-Xia Golovnina, Kseniya Sultana, Hina Kumar, Satish Oliver, Brian TI Transcriptional effects of gene dose reduction SO BIOLOGY OF SEX DIFFERENCES LA English DT Review DE Sex; Monosomy; X chromosome; Dosage compensation; Buffering; Feedback; Feed-forward; MSL complex ID COPY NUMBER VARIATION; DROSOPHILA DOSAGE COMPENSATION; X-CHROMOSOME; CAENORHABDITIS-ELEGANS; SEX-CHROMOSOMES; HUMAN GENOME; EXPRESSION; MELANOGASTER; EVOLUTION; COMPLEX AB Large-scale gene dose reductions usually lead to abnormal phenotypes or death. However, male mammals, Drosophila, and Caenorhabditis elegans have only one X chromosome and thus can be considered as monosomic for a major chromosome. Despite the deleterious effects brought about by such gene dose reduction in the case of an autosome, X chromosome monosomy in males is natural and innocuous. This is because of the nearly full transcriptional compensation for X chromosome genes in males, as opposed to no or partial transcriptional compensation for autosomal one-dose genes arising due to deletions. Buffering, the passive absorption of disturbance due to enzyme kinetics, and feedback responses triggered by expression change contribute to partial compensation. Feed-forward mechanisms, which are active responses to genes being located on the X, rather than actual gene dose are important contributors to full X chromosome compensation. In the last decade, highthroughput techniques have provided us with the tools to effectively and quantitatively measure the small-fold transcriptional effects of dose reduction. This is leading to a better understanding of compensatory mechanisms. C1 [Chen, Zhen-Xia; Golovnina, Kseniya; Sultana, Hina; Kumar, Satish; Oliver, Brian] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Chen, ZX (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM zhen-xia.chen@nih.gov FU National Institutes of Health (NIDDK) FX This work was supported by the Intramural Research Programs of the National Institutes of Health (NIDDK). NR 55 TC 4 Z9 4 U1 3 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2042-6410 J9 BIOL SEX DIFFER JI Biol. Sex Differ. PD MAR 3 PY 2014 VL 5 AR 5 DI 10.1186/2042-6410-5-5 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity SC Endocrinology & Metabolism; Genetics & Heredity GA AE0OC UT WOS:000333664600001 PM 24581086 ER PT J AU Deshpande, RA Williams, GJ Limbo, O Williams, RS Kuhnlein, J Lee, JH Classen, S Guenther, G Russell, P Tainer, JA Paull, TT AF Deshpande, Rajashree A. Williams, Gareth J. Limbo, Oliver Williams, R. Scott Kuhnlein, Jeff Lee, Ji-Hoon Classen, Scott Guenther, Grant Russell, Paul Tainer, John A. Paull, Tanya T. TI ATP-driven Rad50 conformations regulate DNA tethering, end resection, and ATM checkpoint signaling SO EMBO JOURNAL LA English DT Article DE DNA damage signaling; DNA repair; double-strand breaks; protein-DNA interactions ID DOUBLE-STRAND-BREAK; KINASE-ACTIVITY; MRE11/RAD50 COMPLEX; CRYSTAL-STRUCTURE; FISSION YEAST; MRN COMPLEX; REPAIR; MRE11; BINDING; RECOMBINATION AB The Mre11-Rad50 complex is highly conserved, yet the mechanisms by which Rad50 ATP-driven states regulate the sensing, processing and signaling of DNA double-strand breaks are largely unknown. Here we design structure-based mutations in Pyrococcus furiosus Rad50 to alter protein core plasticity and residues undergoing ATP-driven movements within the catalytic domains. With this strategy we identify Rad50 separation-of-function mutants that either promote or destabilize the ATP-bound state. Crystal structures, X-ray scattering, biochemical assays, and functional analyses of mutant PfRad50 complexes show that the ATP-induced closed conformation promotes DNA end binding and end tethering, while hydrolysis-induced opening is essential for DNA resection. Reducing the stability of the ATP-bound state impairs DNA repair and Tel1 (ATM) checkpoint signaling in Schizosaccharomyces pombe, double-strand break resection in Saccharomyces cerevisiae, and ATM activation by human Mre11-Rad50-Nbs1 in vitro, supporting the generality of the P.furiosus Rad50 structure-based mutational analyses. These collective results suggest that ATP-dependent Rad50 conformations switch the Mre11-Rad50 complex between DNA tethering, ATM signaling, and 5 strand resection, revealing molecular mechanisms regulating responses to DNA double-strand breaks. C1 [Deshpande, Rajashree A.; Kuhnlein, Jeff; Lee, Ji-Hoon; Paull, Tanya T.] Univ Texas Austin, Inst Cellular & Mol Biol, Howard Hughes Med Inst, Dept Mol Genet & Microbiol, Austin, TX 78712 USA. [Williams, Gareth J.; Guenther, Grant; Tainer, John A.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA. [Limbo, Oliver; Russell, Paul; Tainer, John A.] Scripps Res Inst, La Jolla, CA 92037 USA. [Williams, R. Scott] NIEHS, Dept Hlth & Human Serv, Struct Biol Lab, US Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. [Classen, Scott] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA. [Tainer, John A.] Skaggs Inst Chem Biol, La Jolla, CA USA. RP Paull, TT (reprint author), Univ Texas Austin, Inst Cellular & Mol Biol, Howard Hughes Med Inst, Dept Mol Genet & Microbiol, Austin, TX 78712 USA. EM jat@scripps.edu; tpaull@mail.utexas.edu RI Williams, Robert/A-6059-2015 FU NIH [CA094008, CA092584, CA117638, CA077325]; US National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) [1Z01ES102765-01]; United States Department of Energy program Integrated Diffraction Analysis Technologies; NIH MINOS [R01GM105404] FX We thank members of the Paull, Tainer, and Russell laboratories for comments, Christophe Redon for the gamma H2A antibody, Antony Carr for the TAP-Rad50 S. pombe strain, and Tom Wilson, Jim Haber, Sang Eun Lee, and Tom Petes for S. cerevisiae strains. This study was supported by NIH grants CA094008 to T.P., CA092584 to J.T. and T.P., CA117638 to J.T. and P.R., CA077325 to P.R., and intramural research program of the US National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) (1Z01ES102765-01) to R.S.W. The SIBYLS beamline (BL12.3.1) at the Advanced Light Source is supported by United States Department of Energy program Integrated Diffraction Analysis Technologies and NIH MINOS R01GM105404. Mass spectroscopy was performed by the Protein and Metabolite Analysis Facility at UT Austin. NR 55 TC 40 Z9 41 U1 0 U2 11 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 MAR 3 PY 2014 VL 33 IS 5 BP 482 EP 500 DI 10.1002/embj.201386100 PG 19 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AC3CC UT WOS:000332391600010 PM 24493214 ER PT J AU Jha, A Ahuja, M Patel, S Brailoiu, E Muallem, S AF Jha, Archana Ahuja, Malini Patel, Sandip Brailoiu, Eugen Muallem, Shmuel TI Convergent regulation of the lysosomal two-pore channel-2 by Mg2+, NAADP, PI(3,5) P2 and multiple protein kinases SO EMBO JOURNAL LA English DT Article DE channel; lysosome; Mg2+; NAADP; TPC2 ID ADENINE-DINUCLEOTIDE PHOSPHATE; MOBILIZES CALCIUM; ACIDIC ORGANELLES; SENSITIVE CA2+; ION CHANNELS; RELEASE; TRAFFICKING; SIGNALS; CELLS; TPC2 AB Lysosomal Ca2+ homeostasis is implicated in disease and controls many lysosomal functions. A key in understanding lysosomal Ca2+ signaling was the discovery of the two-pore channels (TPCs) and their potential activation by NAADP. Recent work concluded that the TPCs function as a PI(3,5)P-2 activated channels regulated by mTORC1, but not by NAADP. Here, we identified Mg2+ and the MAPKs, JNK and P38 as novel regulators of TPC2. Cytoplasmic Mg2+ specifically inhibited TPC2 outward current, whereas lysosomal Mg2+ partially inhibited both outward and inward currents in a lysosomal lumen pH-dependent manner. Under controlled Mg2+, TPC2 is readily activated by NAADP with channel properties identical to those in response to PI(3,5)P-2. Moreover, TPC2 is robustly regulated by P38 and JNK. Notably, NAADP-mediated Ca2+ release in intact cells is regulated by Mg2+, PI(3,5)P-2, and P38/JNK kinases, thus paralleling regulation of TPC2 currents. Our data affirm a key role for TPC2 in NAADP-mediated Ca2+ signaling and link this pathway to Mg2+ homeostasis and MAP kinases, pointing to roles for lysosomal Ca2+ in cell growth, inflammation and cancer. C1 [Jha, Archana; Ahuja, Malini; Muallem, Shmuel] NIDCR, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Patel, Sandip] UCL, Dept Cell & Dev Biol, London, England. [Brailoiu, Eugen] Temple Univ, Sch Med, Dept Pharmacol, Philadelphia, PA 19122 USA. RP Brailoiu, E (reprint author), Temple Univ, Sch Med, Dept Pharmacol, Philadelphia, PA 19122 USA. EM ebrailou@temple.edu; shmuel.muallem@nih.gov RI Patel, Sandip/O-9591-2015 OI Patel, Sandip/0000-0001-7247-2013 FU National Institutes of Health [HL090804]; NIH/NIDCR [DE000735-03] FX This work was supported in part by National Institutes of Health Grants HL090804 to E.B. and by NIH/NIDCR intramural grant DE000735-03 to S.M. NR 50 TC 55 Z9 56 U1 2 U2 8 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 MAR 3 PY 2014 VL 33 IS 5 BP 501 EP 511 DI 10.1002/embj.201387035 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AC3CC UT WOS:000332391600011 PM 24502975 ER PT J AU Robbins, HA Li, Y Porras, C Pawlita, M Ghosh, A Rodriguez, AC Schiffman, M Wacholder, S Kemp, TJ Gonzalez, P Schiller, J Lowy, D Esser, M Matys, K Quint, W van Doorn, LJ Herrero, R Pinto, LA Hildesheim, A Waterboer, T Safaeian, M AF Robbins, Hilary A. Li, Yan Porras, Carolina Pawlita, Michael Ghosh, Arpita Rodriguez, Ana Cecilia Schiffman, Mark Wacholder, Sholom Kemp, Troy J. Gonzalez, Paula Schiller, John Lowy, Douglas Esser, Mark Matys, Katie Quint, Wim van Doorn, Leen-Jan Herrero, Rolando Pinto, Ligia A. Hildesheim, Allan Waterboer, Tim Safaeian, Mahboobeh TI Glutathione S-transferase L1 multiplex serology as a measure of cumulative infection with human papillomavirus SO BMC INFECTIOUS DISEASES LA English DT Article ID SQUAMOUS-CELL CARCINOMA; NEUTRALIZING EPITOPES; ANTIBODY-RESPONSES; IMMUNE-RESPONSES; PARTICLE VACCINE; YOUNG-WOMEN; COSTA-RICA; ASSAY; HPV; CANCER AB Background: Several assays are used to measure type-specific serological responses to human papillomavirus (HPV), including the bead-based glutathione S-transferase (GST)-L1 multiplex serology assay and virus-like particle (VLP)-based ELISA. We evaluated the high-throughput GST-L1, which is increasingly used in epidemiologic research, as a measure of cumulative HPV infection and future immune protection among HPV-unvaccinated women. Methods: We tested enrollment sera from participants in the control arm of the Costa Rica Vaccine Trial (n = 488) for HPV16 and HPV18 using GST-L1, VLP-ELISA, and two assays that measure neutralizing antibodies (cLIA and SEAP-NA). With statistical adjustment for sampling, we compared GST-L1 serostatus to established HPV seropositivity correlates and incident cervical HPV infection using odds ratios. We further compared GST-L1 to VLP-ELISA using pair-wise agreement statistics and by defining alternate assay cutoffs. Results: Odds of HPV16 GST-L1 seropositivity increased with enrollment age (OR = 1.20 per year, 95% CI 1.03-1.40) and lifetime number of sexual partners (OR = 2.06 per partner, 95% CI 1.49-2.83), with similar results for HPV18. GST-L1 seropositivity did not indicate protection from incident infection over 4 years of follow-up (HPV16 adjusted OR = 1.72, 95% CI 0.95-3.13; HPV18 adjusted OR = 0.38, 95% CI 0.12-1.23). Seroprevalence by GST-L1 (HPV16 and HPV18, respectively) was 5.0% and 5.2%, compared to 19.4% and 23.8% by VLP-ELISA, giving positive agreement of 39.2% and 20.8%. Lowering GST-L1 seropositivity cutoffs improved GST-L1/VLP-ELISA positive agreement to 68.6% (HPV16) and 61.5% (HPV18). Conclusions: Our data support GST-L1 as a marker of cumulative HPV infection, but not immune protection. At lower seropositivity cutoffs, GST-L1 better approximates VLP-ELISA. C1 [Robbins, Hilary A.; Li, Yan; Schiffman, Mark; Wacholder, Sholom; Hildesheim, Allan; Safaeian, Mahboobeh] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Li, Yan] Univ Maryland, Joint Program Survey Methodol, College Pk, MD 20742 USA. [Porras, Carolina; Rodriguez, Ana Cecilia; Gonzalez, Paula; Herrero, Rolando] Fdn INCIENSA, Proyecto Epidemiol Guanacaste, Guanacaste, Costa Rica. [Pawlita, Michael; Waterboer, Tim] German Canc Res Ctr, Heidelberg, Germany. [Ghosh, Arpita] Publ Hlth Fdn India, New Delhi, India. [Kemp, Troy J.; Pinto, Ligia A.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, HPV Immunol Lab, Frederick, MD USA. [Gonzalez, Paula; Herrero, Rolando] Int Agcy Res Canc, F-69372 Lyon, France. [Schiller, John; Lowy, Douglas] NCI, Ctr Canc Res, NIH, Rockville, MD USA. [Esser, Mark] MedImmune, Gaithersburg, MD USA. [Matys, Katie] PPD Vaccines & Biol Ctr Excellence, Wayne, PA USA. [Quint, Wim; van Doorn, Leen-Jan] DDL Diagnost Lab, Rijswijk, Netherlands. RP Robbins, HA (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. EM hilary.robbins@nih.gov RI Hildesheim, Allan/B-9760-2015; Waterboer, Tim/G-1252-2010; OI Hildesheim, Allan/0000-0003-0257-2363; Pawlita, Michael/0000-0002-4720-8306 FU NCI [N01-CP-11005]; National Institutes of Health Office of Research on Women's Health; Ministry of Health of Costa Rica FX The Costa Rica HPV Vaccine Trial is a long-standing collaboration between investigators in Costa Rica and the National Cancer Institute (NCI). The trial is sponsored and funded by the NCI (contract N01-CP-11005), with funding support from the National Institutes of Health Office of Research on Women's Health, and done with support from the Ministry of Health of Costa Rica. Vaccine was provided for our trial by GlaxoSmithKline Biologicals, under a Clinical Trials Agreement with the NCI. GlaxoSmithKline also provided support for aspects of the trial associated with regulatory submission needs of the company under US Food and Drug Administration BB-IND 7920. This study was designed, conducted, and written by NCI investigators with input from investigators at GlaxoSmithKline. NR 44 TC 7 Z9 7 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD MAR 3 PY 2014 VL 14 AR 120 DI 10.1186/1471-2334-14-120 PG 11 WC Infectious Diseases SC Infectious Diseases GA AC6KH UT WOS:000332631000001 PM 24588945 ER PT J AU Mikawa, T Maruyama, T Okamoto, K Nakagama, H Lleonart, ME Tsusaka, T Hori, K Murakami, I Izumi, T Takaori-Kondo, A Yokode, M Peters, G Beach, D Kondoh, H AF Mikawa, Takumi Maruyama, Takeshi Okamoto, Koji Nakagama, Hitoshi Lleonart, Matilde E. Tsusaka, Takeshi Hori, Kousuke Murakami, Itsuo Izumi, Taisuke Takaori-Kondo, Akifumi Yokode, Masayuki Peters, Gordon Beach, David Kondoh, Hiroshi TI Senescence-inducing stress promotes proteolysis of phosphoglycerate mutase via ubiquitin ligase Mdm2 SO JOURNAL OF CELL BIOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; CELLULAR SENESCENCE; TUMOR SUPPRESSION; ENOLASE ACTIVITY; P53 MUTATIONS; CANCER CELLS; LIFE-SPAN; IN-VIVO; EXPRESSION; DEGRADATION AB Despite the well-documented clinical significance of the Warburg effect, it remains unclear how the aggressive glycolytic rates of tumor cells might contribute to other hallmarks of cancer, such as bypass of senescence. Here, we report that, during oncogene- or DNA damage-induced senescence, Pak1 -mediated phosphorylation of phosphoglycerate mutase (PGAM) predisposes the glycolytic enzyme to ubiquitin-mediated degradation. We identify Mdm2 as a direct binding partner and ubiquitin ligase for PGAM in cultured cells and in vitro. Mutations in PGAM and Mdm2 that abrogate ubiquitination of PGAM restored the proliferative potential of primary cells under stress conditions and promoted neoplastic transformation. We propose that Mdm2, a downstream effector of p53, attenuates the Warburg effect via ubiquitination and degradation of PGAM. C1 [Mikawa, Takumi; Maruyama, Takeshi; Tsusaka, Takeshi; Hori, Kousuke; Murakami, Itsuo; Kondoh, Hiroshi] Kyoto Univ, Grad Sch Med, Dept Geriatr Med, Kyoto 6068507, Japan. [Takaori-Kondo, Akifumi] Kyoto Univ, Grad Sch Med, Dept Hematol Oncol, Kyoto 6068507, Japan. [Okamoto, Koji; Nakagama, Hitoshi] Natl Canc Ctr, Res Inst, Div Canc Dev Syst, Tokyo 1040045, Japan. [Lleonart, Matilde E.] Hosp Vall deHebron, Dept Pathol, Barcelona 08035, Spain. [Izumi, Taisuke] NCI, Viral Mutat Sect, HIV Drug Resistance Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Yokode, Masayuki] Kyoto Univ Hosp, Translat Res Ctr, Dept Clin Innovat Med, Kyoto 6068507, Japan. [Peters, Gordon] London Res Inst, Canc Res UK, London WC2A 3LY, England. [Beach, David] Inst Cell & Mol Sci, Ctr Cutaneous Biol, London E1 2AT, England. RP Kondoh, H (reprint author), Kyoto Univ, Grad Sch Med, Dept Geriatr Med, Kyoto 6068507, Japan. EM hkondoh@kuhp.kyoto-u.ac.jp RI Izumi, Taisuke/J-5607-2014 OI Izumi, Taisuke/0000-0002-9694-1459 FU Global COE program; Japan Society for the Promotion of Science; Ministry of Education, Culture, Sports, Science, and Technology of Japan [20590696, 23390186]; Japan Science and Technology Agency [8447, 5485]; Japan Science and Technology Agency (JST) Core Research for Evolutional Science and Technology FX T. Maruyama was supported by a postdoctoral fellowship from the Global COE program "Center for Frontier Medicine." This work was supported in part by grants from the Global COE program "Center for Frontier Medicine," from the Japan Society for the Promotion of Science, from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (grants No. 20590696 and No. 23390186), from the Japan Science and Technology Agency (grants No. 8447 and No. 5485), and from Japan Science and Technology Agency (JST) Core Research for Evolutional Science and Technology (CREST No. 18 to H. Kondoh). NR 61 TC 12 Z9 13 U1 0 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD MAR 3 PY 2014 VL 204 IS 5 BP 729 EP 745 DI 10.1083/jcb.201306149 PG 17 WC Cell Biology SC Cell Biology GA AC3OC UT WOS:000332430100011 PM 24567357 ER PT J AU Jeff, JM Armstrong, LL Ritchie, MD Denny, JC Kho, AN Basford, MA Wolf, WA Pacheco, JA Li, RL Chisholm, RL Roden, DM Hayes, MG Crawford, DC AF Jeff, Janina M. Armstrong, Loren L. Ritchie, Marylyn D. Denny, Joshua C. Kho, Abel N. Basford, Melissa A. Wolf, Wendy A. Pacheco, Jennifer A. Li, Rongling Chisholm, Rex L. Roden, Dan M. Hayes, M. Geoffrey Crawford, Dana C. TI Admixture Mapping and Subsequent Fine-Mapping Suggests a Biologically Relevant and Novel Association on Chromosome 11 for Type 2 Diabetes in African Americans SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; ELECTRONIC MEDICAL-RECORDS; EMERGE NETWORK; RISK LOCI; SUSCEPTIBILITY; VARIANT; VISUALIZATION; METAANALYSIS; ANCESTRY; GENETICS AB Type 2 diabetes (T2D) is a complex metabolic disease that disproportionately affects African Americans. Genome-wide association studies (GWAS) have identified several loci that contribute to T2D in European Americans, but few studies have been performed in admixed populations. We first performed a GWAS of 1,563 African Americans from the Vanderbilt Genome-Electronic Records Project and Northwestern University NUgene Project as part of the electronic Medical Records and Genomics (eMERGE) network. We successfully replicate an association in TCF7L2, previously identified by GWAS in this African American dataset. We were unable to identify novel associations at p<5.0x10(-8) by GWAS. Using admixture mapping as an alternative method for discovery, we performed a genome-wide admixture scan that suggests multiple candidate genes associated with T2D. One finding, TCIRG1, is a T-cell immune regulator expressed in the pancreas and liver that has not been previously implicated for T2D. We performed subsequent fine-mapping to further assess the association between TCIRG1 and T2D in >5,000 African Americans. We identified 13 independent associations between TCIRG1, CHKA, and ALDH3B1 genes on chromosome 11 and T2D. Our results suggest a novel region on chromosome 11 identified by admixture mapping is associated with T2D in African Americans. C1 [Jeff, Janina M.] Vanderbilt Univ, Charles Bronfman Inst Personalized Med, Icahn Sch Med Mt Sinai, Nashville, TN 37235 USA. [Crawford, Dana C.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37235 USA. [Denny, Joshua C.; Roden, Dan M.] Vanderbilt Univ, Dept Med, Div Clin Pharmacol, Nashville, TN 37235 USA. [Denny, Joshua C.] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37235 USA. [Basford, Melissa A.; Roden, Dan M.] Vanderbilt Univ, Off Personalized Med, Nashville, TN 37235 USA. [Roden, Dan M.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37235 USA. [Kho, Abel N.] Northwestern Univ, Div Gen Internal Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Armstrong, Loren L.; Hayes, M. Geoffrey] Northwestern Univ, Div Endocrinol Metab & Mol Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Pacheco, Jennifer A.; Chisholm, Rex L.; Hayes, M. Geoffrey] Northwestern Univ, Ctr Genet Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Wolf, Wendy A.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Li, Rongling] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. [Ritchie, Marylyn D.] Penn State Univ, Dept Biochem & Mol Biol, Ctr Syst Genom, University Pk, PA 16802 USA. RP Crawford, DC (reprint author), Vanderbilt Univ, Ctr Human Genet Res, 221 Kirkland Hall, Nashville, TN 37235 USA. EM crawford@chgr.mc.vanderbilt.edu FU NIH/NHGRI [U01HG004609, U01HG04603]; NCATS/NIH [UL1 TR000445] FX This work was supported by NIH/NHGRI U01HG004609 (Northwestern University as part of eMERGE) and U01HG04603 (Vanderbilt University as part of eMERGE, also serving as the Administrative Coordinating Center). A portion of the dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center's BioVU which is supported by institutional funding and by the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH. As part of the cooperative agreement, NHGRI participated in the study design, data collection and analysis, and preparation of the manuscript. NR 54 TC 6 Z9 6 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 MAR 3 PY 2014 VL 9 IS 3 AR e86931 DI 10.1371/journal.pone.0086931 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC4CT UT WOS:000332468900001 PM 24595071 ER PT J AU Fliedner, S Engel, T Lendvai, N Shankavaram, U Nolting, S Wesley, R Elkalouhn, A Ungefroren, H Lehnert, H Timmers, H Pacak, K AF Fliedner, S. Engel, T. Lendvai, N. Shankavaram, U. Noelting, S. Wesley, R. Elkalouhn, A. Ungefroren, H. Lehnert, H. Timmers, H. Pacak, K. TI Anti-cancer potential of MAPK pathway inhibition in paragangliomas - effect of different statins on mouse pheochromocytoma cells SO EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES LA English DT Meeting Abstract C1 [Fliedner, S.; Engel, T.; Lendvai, N.; Noelting, S.; Pacak, K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, Bethesda, MD USA. [Fliedner, S.; Ungefroren, H.; Lehnert, H.] Univ Med Ctr Schleswig Holstein, Dept Med 1, Lubeck, Germany. [Engel, T.; Timmers, H.] Radboud Univ Nijmegen, Med Ctr, Dept Endocrinol, NL-6525 ED Nijmegen, Netherlands. [Shankavaram, U.] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Noelting, S.] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med, Dept Endocrinol, London, England. [Noelting, S.] Queen Mary Univ London, Barts Canc Inst, Barts & London Sch Med, Dept Endocrinol, London, England. [Wesley, R.] NIH, Warren G Magnuseon Clin Ctr, Bethesda, MD 20892 USA. [Elkalouhn, A.] NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHANN AMBROSIUS BARTH VERLAG MEDIZINVERLAGE HEIDELBERG GMBH PI STUTTGART PA RUEDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0947-7349 EI 1439-3646 J9 EXP CLIN ENDOCR DIAB JI Exp. Clin. Endocrinol. Diabet. PD MAR PY 2014 VL 122 IS 3 MA OP6_29 DI 10.1055/s-0034-1372004 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AY2FF UT WOS:000347403300051 ER PT J AU Richter, S Peitzsch, M Rapizzi, E Lenders, JW Qin, N de Cubas, AA Schiavi, F Rao, JU Beuschlein, F Quinkler, M Timmers, HJ Opocher, G Mannelli, M Pacak, K Robledo, M Eisenhofer, G AF Richter, S. Peitzsch, M. Rapizzi, E. Lenders, J. W. Qin, N. de Cubas, A. A. Schiavi, F. Rao, J. U. Beuschlein, F. Quinkler, M. Timmers, H. J. Opocher, G. Mannelli, M. Pacak, K. Robledo, M. Eisenhofer, G. TI Identification and stratification of pheochromocytomas/paragangliomas with SDHx mutations using the succinate to fumarate ratio SO EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES LA English DT Meeting Abstract C1 [Richter, S.; Peitzsch, M.; Qin, N.; Eisenhofer, G.] Tech Univ Dresden, Univ Hosp Dresden, Dept Clin Chem & Lab Med, Dresden, Germany. [Rapizzi, E.; Mannelli, M.] Univ Florence, Ist Toscano Tumori, Dept Clin Pathophysiol, Florence, Italy. [Lenders, J. W.; Rao, J. U.; Timmers, H. J.] Radboud Univ Nijmegen, Med Ctr, Dept Med, NL-6525 ED Nijmegen, Netherlands. [Lenders, J. W.; Eisenhofer, G.] Tech Univ Dresden, Univ Hosp Dresden, Dept Med 3, Dresden, Germany. [de Cubas, A. A.; Robledo, M.] CNIO Madrid, Hereditary Endocrine Canc Grp, Madrid, Spain. [Schiavi, F.; Opocher, G.] Veneto Inst Oncol IRCCS Padova, Padua, Italy. [Beuschlein, F.] Univ Munich, Med Klin & Poliklin 4, Munich, Germany. [Quinkler, M.] Univ Hosp Charite Berlin, Berlin, Germany. [Pacak, K.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHANN AMBROSIUS BARTH VERLAG MEDIZINVERLAGE HEIDELBERG GMBH PI STUTTGART PA RUEDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0947-7349 EI 1439-3646 J9 EXP CLIN ENDOCR DIAB JI Exp. Clin. Endocrinol. Diabet. PD MAR PY 2014 VL 122 IS 3 MA OP6_30 DI 10.1055/s-0034-1372005 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AY2FF UT WOS:000347403300052 ER PT J AU Sue, M Martucci, V Frey, F Lenders, JWM Timmers, H Peczkowska, M Robledo, M Pacak, K Eisenhofer, G AF Sue, M. Martucci, V. Frey, F. Lenders, J. W. M. Timmers, H. Peczkowska, M. Robledo, M. Pacak, K. Eisenhofer, G. TI SDHB mutation testing in metastatic pheochromocytoma and paraganglioma: Is this required in patients with adrenaline-producing tumors? SO EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES LA English DT Meeting Abstract C1 [Sue, M.; Eisenhofer, G.] Univ Dresden, Dept Med 3, Dresden, Germany. [Martucci, V.; Pacak, K.] NIH, Bethesda, MD 20892 USA. [Frey, F.; Eisenhofer, G.] Univ Dresden, Inst Clin Chem & Lab Med, Dresden, Germany. [Lenders, J. W. M.; Timmers, H.] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 ED Nijmegen, Netherlands. [Peczkowska, M.] Inst Cardiol, Dept Hypertent, Warsaw, Poland. [Robledo, M.] Spanish Natl Canc Res Ctr Med, Hereditary Endocrine Canc Grp, Madrid, Spain. RI Lenders, J.W.M./L-4487-2015 NR 0 TC 0 Z9 0 U1 0 U2 2 PU JOHANN AMBROSIUS BARTH VERLAG MEDIZINVERLAGE HEIDELBERG GMBH PI STUTTGART PA RUEDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0947-7349 EI 1439-3646 J9 EXP CLIN ENDOCR DIAB JI Exp. Clin. Endocrinol. Diabet. PD MAR PY 2014 VL 122 IS 3 MA P111 DI 10.1055/s-0034-1372128 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AY2FF UT WOS:000347403300172 ER PT J AU Parisiadou, L Yu, J Sgobio, C Xie, CS Liu, GX Sun, LX Gu, XL Lin, X Crowley, NA Lovinger, DM Cai, HB AF Parisiadou, Loukia Yu, Jia Sgobio, Carmelo Xie, Chengsong Liu, Guoxiang Sun, Lixin Gu, Xing-Long Lin, Xian Crowley, Nicole A. Lovinger, David M. Cai, Huaibin TI LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity SO NATURE NEUROSCIENCE LA English DT Article ID PROTEIN-KINASE-A; DENDRITIC SPINE MORPHOGENESIS; AKAP SIGNALING COMPLEXES; PARKINSONS-DISEASE; SYNAPTIC PLASTICITY; POSTSYNAPTIC DENSITY; ROC DOMAIN; CYCLIC-AMP; PHOSPHORYLATION; MICE AB Leucine-rich repeat kinase 2 (LRRK2) is enriched in the striatal projection neurons (SPNs). We found that LRRK2 negatively regulates protein kinase A (PKA) activity in the SPNs during synaptogenesis and in response to dopamine receptor Drd1 activation. LRRK2 interacted with PKA regulatory subunit II beta (PKARII beta). A lack of LRRK2 promoted the synaptic translocation of PKA and increased PKA-mediated phosphorylation of actin-disassembling enzyme cofilin and glutamate receptor GluR1, resulting in abnormal synaptogenesis and transmission in the developing SPNs. Furthermore, PKA-dependent phosphorylation of GluR1 was also aberrantly enhanced in the striatum of young and aged Lrrk2(-/-) mice after treatment with a Drd1 agonist. Notably, a Parkinson's disease-related Lrrk2 R1441C missense mutation that impaired the interaction of LRRK2 with PKARIIb also induced excessive PKA activity in the SPNs. Our findings reveal a previously unknown regulatory role for LRRK2 in PKA signaling and suggest a pathogenic mechanism of SPN dysfunction in Parkinson's disease. C1 [Parisiadou, Loukia; Yu, Jia; Sgobio, Carmelo; Xie, Chengsong; Liu, Guoxiang; Sun, Lixin; Gu, Xing-Long; Lin, Xian; Cai, Huaibin] NIA, Transgen Sect, Neurogenet Lab, US NIH, Bethesda, MD 20892 USA. [Parisiadou, Loukia; Liu, Guoxiang] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Yu, Jia] Beijing Geriatr Hosp, Dept Geriatr, Beijing, Peoples R China. [Crowley, Nicole A.; Lovinger, David M.] NIAAA, Lab Integrat Neurosci, US NIH, Rockville, MD 20852 USA. RP Cai, HB (reprint author), NIA, Transgen Sect, Neurogenet Lab, US NIH, Bethesda, MD 20892 USA. EM loukia.parisiadou@northwestern.edu; caih@mail.nih.gov RI Yu, Jia/J-2792-2014; gu, xinglong/A-3054-2011 OI gu, xinglong/0000-0002-0437-5606 FU National Institute on Aging [AG000944, AG000928]; National Institute of Alcohol Abuse and Alcoholism FX We thank H. Zhong (Vollum Institute) for providing PKA expression vectors, M. Cookson (National Institute on Aging) for providing human Lrrk2 expression vector, J. Shen and Y. Tong (Harvard University) for providing Lrrk2 R1441C knock-in mice, P. Lewis (University College London) for providing LRRK2 wild-type and R1441C recombinant proteins, and V. Alvarez (National Institute of Alcohol Abuse and Alcoholism), B. Ma (National Institute on Aging) and Z. Li, J.-M. Jia and S. Jiao (National Institute of Mental Health) for their advice and technical support. We also thank L. Donahue and N. Sastry for their assistance in editing the manuscript. This work was supported by the intramural research programs of National Institute on Aging (AG000944 and AG000928 to H. C.) and National Institute of Alcohol Abuse and Alcoholism (D.L.). NR 59 TC 45 Z9 46 U1 0 U2 8 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 MAR PY 2014 VL 17 IS 3 BP 367 EP 376 DI 10.1038/nn.3636 PG 10 WC Neurosciences SC Neurosciences & Neurology GA AB8CA UT WOS:000332016500009 PM 24464040 ER PT J AU Jin, X Tecuapetla, F Costa, RM AF Jin, Xin Tecuapetla, Fatuel Costa, Rui M. TI Basal ganglia subcircuits distinctively encode the parsing and concatenation of action sequences SO NATURE NEUROSCIENCE LA English DT Article ID DIFFERENTIAL ROLES; FOREBRAIN CIRCUIT; SUBSTANTIA-NIGRA; GLOBUS-PALLIDUS; EYE-MOVEMENTS; NEURONS; INFORMATION; CHUNKING; DISEASE; SPEECH AB Chunking allows the brain to efficiently organize memories and actions. Although basal ganglia circuits have been implicated in action chunking, little is known about how individual elements are concatenated into a behavioral sequence at the neural level. Using a task in which mice learned rapid action sequences, we uncovered neuronal activity encoding entire sequences as single actions in basal ganglia circuits. In addition to neurons with activity related to the start/stop activity signaling sequence parsing, we found neurons displaying inhibited or sustained activity throughout the execution of an entire sequence. This sustained activity covaried with the rate of execution of individual sequence elements, consistent with motor concatenation. Direct and indirect pathways of basal ganglia were concomitantly active during sequence initiation, but behaved differently during sequence performance, revealing a more complex functional organization of these circuits than previously postulated. These results have important implications for understanding the functional organization of basal ganglia during the learning and execution of action sequences. C1 [Jin, Xin; Costa, Rui M.] NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. [Jin, Xin] Salk Inst Biol Studies, Mol Neurobiol Lab, La Jolla, CA 92037 USA. [Tecuapetla, Fatuel; Costa, Rui M.] Inst Gulbenkian Ciencias, Champalimaud Neurosci Programme, Lisbon, Portugal. [Tecuapetla, Fatuel; Costa, Rui M.] Champalimaud Ctr Unknown, Lisbon, Portugal. RP Jin, X (reprint author), NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. EM xjin@salk.edu; rui.costa@neuro.fchampalimaud.org OI Tecuapetla, Fatuel/0000-0002-9191-6553; Costa, Rui/0000-0003-0495-8374 FU National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research; Champalimaud Neuroscience Programme, European Research Council [243393]; Howard Hughes Medical Institute International Early Careers Scientist Grant; Whitehall Foundation; US National Institutes of Health [NS083815] FX We thank C. Gerfen for the D1-Cre and D2-Cre mice (US National Institutes of Health), Y. Li for the Rgs9-cre mice (University of Florida), K. Nakazawa for the Grin1loxP/loxP mice (US National Institutes of Health), G. Luo and A. Vaz for genotyping, and G. Cui for comments on the manuscript. This research was supported by the National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, the Champalimaud Neuroscience Programme, European Research Council grant 243393 and Howard Hughes Medical Institute International Early Careers Scientist Grant to R. M. C., the Whitehall Foundation, and US National Institutes of Health grant NS083815 to X.J. NR 50 TC 80 Z9 80 U1 5 U2 24 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 MAR PY 2014 VL 17 IS 3 BP 423 EP 430 DI 10.1038/nn.3632 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AB8CA UT WOS:000332016500016 PM 24464039 ER PT J AU Raj, P Hohenadel, K Demers, PA Zahm, SH Blair, A AF Raj, Priyanka Hohenadel, Karin Demers, Paul A. Zahm, Shelia Hoar Blair, Aaron TI Recent Trends in Published Occupational Cancer Epidemiology Research: Results from a Comprehensive Review of the Literature SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Review DE occupational; epidemiology; literature review; dose-response; cancer ID EXPOSURE; COUNTRIES; WORKERS AB Objective To assess trends in occupational cancer epidemiology research through a literature review of occupational health and epidemiology journals. Methods Fifteen journals were reviewed from 1991 to 2009, and characteristics of articles that assessed the risk of cancer associated with an occupation, industry, or occupational exposure, were incorporated into a database. Results The number of occupational cancer epidemiology articles published annually declined in recent years (2003 onwards) in the journals reviewed. The number of articles presenting dose-response analyses increased over the review period, from 29% in the first 4 years of review to 49% in the last 4 years. Conclusion There has been a decrease in the number of occupational cancer epidemiology articles published annually during the review period. The results of these articles help determine the carcinogenicity of workplace exposures and permissible exposure limits, both of which may be hindered with a decline in research. (C) 2013 Wiley Periodicals, Inc. C1 [Raj, Priyanka; Hohenadel, Karin; Demers, Paul A.; Blair, Aaron] Occupat Canc Res Ctr, Toronto, ON, Canada. [Demers, Paul A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Zahm, Shelia Hoar] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Raj, P (reprint author), 505 Univ Ave,Seventeenth Floor, Toronto, ON M5G 1X3, Canada. EM priyanka.raj@occupationalcancer.ca RI Zahm, Shelia/B-5025-2015 NR 17 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0271-3586 EI 1097-0274 J9 AM J IND MED JI Am. J. Ind. Med. PD MAR PY 2014 VL 57 IS 3 BP 259 EP 264 DI 10.1002/ajim.22280 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AX0SE UT WOS:000346661300001 PM 24488816 ER PT J AU Gupta, S Tatouli, IP Rosen, LB Hasni, S Siegel, RM Holland, SM Moutsopopoulos, HM Browne, SK AF Gupta, Sarthak Tatouli, Ioanna P. Rosen, Lindsey B. Hasni, Sarfaraz Siegel, Richard M. Holland, Steven M. Moutsopopoulos, Haralampos M. Browne, Sarah K. TI RHEUMATOID ARTHRITIS, SJOGREN'S SYNDROME AND SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS HAVE A DISTINCT SPECTRUM OF SERUM ANTICYTOKINE AUTOANTIBODIES SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT European Workshop for Rheumatology Research CY FEB 20-22, 2014 CL Lisbon, PORTUGAL C1 [Gupta, Sarthak; Hasni, Sarfaraz; Siegel, Richard M.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Gupta, Sarthak; Rosen, Lindsey B.; Holland, Steven M.; Browne, Sarah K.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Tatouli, Ioanna P.; Moutsopopoulos, Haralampos M.] Natl Tech Univ Athens, Sch Med, GR-10682 Athens, Greece. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD MAR PY 2014 VL 73 SU 1 MA A3.31 BP A54 EP A55 DI 10.1136/annrheumdis-2013-205124.124 PG 6 WC Rheumatology SC Rheumatology GA AW4JW UT WOS:000346248400125 ER PT J AU Roth, JC Cassady, KA Cody, JJ Parker, JN Price, KH Coleman, JM Peggins, JO Noker, PE Powers, NW Grimes, SD Carroll, SL Gillespie, GY Whitley, RJ Markert, JM AF Roth, Justin C. Cassady, Kevin A. Cody, James J. Parker, Jackie N. Price, Kathleen H. Coleman, Jennifer M. Peggins, James O. Noker, Patricia E. Powers, Nicholas W. Grimes, Sheila D. Carroll, Steven L. Gillespie, G. Yancey Whitley, Richard J. Markert, James M. TI Evaluation of the Safety and Biodistribution of M032, an Attenuated Herpes Simplex Virus Type 1 Expressing hIL-12, After Intracerebral Administration to Aotus Nonhuman Primates SO HUMAN GENE THERAPY CLINICAL DEVELOPMENT LA English DT Article ID HUMAN-MALIGNANT GLIOMA; BRAIN-TUMORS; GAMMA(1)34.5 PROTEIN; EXPERIMENTAL-THERAPY; CYTOSINE DEAMINASE; ONCOLYTIC VIRUS; OWL MONKEY; IFN-GAMMA; IN-VIVO; MUTANT AB Herpes simplex virus type 1 (HSV-1) mutants lacking the gamma(1)34.5 neurovirulence loci are promising agents for treating malignant glioma. Arming oncolytic HSV-1 to express immunostimulatory genes may potentiate therapeutic efficacy. We have previously demonstrated improved preclinical efficacy, biodistribution, and safety of M002, a gamma(1)34.5-deleted HSV-1 engineered to express murine IL-12. Herein, we describe the safety and biodistribution of M032, a gamma(1)34.5-deleted HSV-1 virus that expresses human IL-12 after intracerebral administration to nonhuman primates, Aotus nancymae. Cohorts were administered vehicle, 10(6), or 10(8) pfu of M032 on day 1 and subjected to detailed clinical observations performed serially over a 92-day trial. Animals were sacrificed on days 3, 31, and 91 for detailed histopathologic assessments of all organs and to isolate and quantify virus in all organs. With the possible exception of one animal euthanized on day 16, neither adverse clinical signs nor sex- or dose-related differences were attributed to M032. Elevated white blood cell and neutrophil counts were observed in virus-injected groups on day 3, but no other significant changes were noted in clinical chemistry or coagulation parameters. Minimal to mild inflammation and fibrosis detected, primarily in meningeal tissues, in M032-injected animals on days 3 and 31 had mostly resolved by day 91. The highest viral DNA levels were detected at the injection site and motor cortex on day 3 but decreased in central nervous system tissues over time. These data demonstrate the requisite safety of intracerebral M032 administration for consideration as a therapeutic for treating malignant brain tumors. C1 [Roth, Justin C.; Cassady, Kevin A.; Cody, James J.; Parker, Jackie N.; Price, Kathleen H.; Whitley, Richard J.; Markert, James M.] Univ Alabama Birmingham, Dept Pediat, Div Infect Dis, Birmingham, AL 35294 USA. [Coleman, Jennifer M.; Gillespie, G. Yancey; Whitley, Richard J.; Markert, James M.] Univ Alabama Birmingham, Dept Neurosurg, Birmingham, AL 35294 USA. [Carroll, Steven L.] Univ Alabama Birmingham, Dept Pathol, Div Neuropathol, Birmingham, AL 35294 USA. [Gillespie, G. Yancey; Whitley, Richard J.; Markert, James M.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Gillespie, G. Yancey] Univ Alabama Birmingham, Dept Cell Biol, Birmingham, AL 35294 USA. [Whitley, Richard J.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Markert, James M.] Univ Alabama Birmingham, Dept Physiol & Biophys, Birmingham, AL 35294 USA. [Peggins, James O.] NCI, Bethesda, MD 20892 USA. [Noker, Patricia E.; Powers, Nicholas W.; Grimes, Sheila D.] So Res Inst, Birmingham, AL 35205 USA. RP Markert, JM (reprint author), Univ Alabama Birmingham, Dept Neurosurg FOT 1050, 1530,3rd Ave South, Birmingham, AL 35294 USA. EM markert@uab.edu FU National Institutes of Health, National Cancer Institute [P01 CA71933, P20 CA151129]; Department of Defense [W81XWH-11-1-0498]; RAID program of the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX This work was supported by the National Institutes of Health, National Cancer Institute Grants P01 CA71933 (J.M.M., J.C.R., K. A. C., G.Y.G., and R.J.W.) and P20 CA151129 (J.M.M., G.Y.G., K. A. C.), as well as Department of Defense Grant W81XWH-11-1-0498 (J.M.M, G.Y.G., K. A. C.). This research was also supported in part by the RAID program of the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. (J.M.M.). We would also like to posthumously acknowledge Dr. Ronna Fulton, from Fulton Veterinary Clinical Pathology Consulting, for her clinical assessment of the NHP study samples. NR 61 TC 10 Z9 11 U1 2 U2 7 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2324-8637 EI 2324-8645 J9 HUM GENE THER CL DEV JI Hum. Gene Ther. Clin. Dev. PD MAR 1 PY 2014 VL 25 IS 1 BP 16 EP 27 DI 10.1089/humc.2013.201 PG 12 WC Biotechnology & Applied Microbiology; Critical Care Medicine; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; General & Internal Medicine; Research & Experimental Medicine GA AS8BT UT WOS:000344476100003 PM 24649838 ER PT J AU Xie, QQ Ding, LP Wei, Y Ito, Y AF Xie, Qianqian Ding, Liping Wei, Yun Ito, Yoichiro TI Determination of Major Components and Fingerprint Analysis of Flaveria bidentis (L.) Kuntze SO JOURNAL OF CHROMATOGRAPHIC SCIENCE LA English DT Article ID SULFATED FLAVONOIDS; COMPOSITAE AB A sensitive high-performance liquid chromatography method coupled with photodiode array detection was developed for the simultaneous determination of six major constituents in Flaveria bidentis (L.) Kuntze: hyperoside, patuletin-3-O-glucoside, isorhamnetin 3-sulfate, astragalin, 6-methoxykaempferol-3-O-galactoside and alpha-terthienyl. The chemical fingerprint of Flaveria bidentis (L.) Kuntze leaves was established using raw materials of 12 batches in China. The chromatographic separations were obtained by using an Eclipse XDB-C18 reserved-phase column (150 x 4.6 mm i.d., 5 mu m) using gradient elution with water (0.0125% trifluoroacetic acid, v/v) and acetonitrile at a flow rate of 1.0 mL/min, an operating temperature of 30 degrees C and a detection wavelength of 360 nm. The new method was validated by linearity, limits of detection and quantification, precision, reproducibility, stability and recovery, and was also successfully applied to the simultaneous determination of components in Flaveria bidentis (L.) Kuntze. The results indicate that this multi-component determination method in combination with chromatographic fingerprint analysis is suitable for the quantitative analysis and identification of Flaveria bidentis (L.) Kuntze. C1 [Xie, Qianqian; Ding, Liping; Wei, Yun] Beijing Univ Chem Technol, State Key Lab Chem Resource Engn, Beijing 100029, Peoples R China. [Ito, Yoichiro] NHLBI, NIH, Bethesda, MD 20892 USA. RP Wei, Y (reprint author), Beijing Univ Chem Technol, State Key Lab Chem Resource Engn, Beijing 100029, Peoples R China. EM weiyun@mail.buct.edu.cn FU Special Fund for Agro-scientific Research in the Public Interest [200803022, 201103027]; Program for New Century Excellent Talents in University [NCET-11-0563]; National Natural Science Foundation of China [21075007] FX Financial support by Special Fund for Agro-scientific Research in the Public Interest (projects 200803022 and 201103027), Program for New Century Excellent Talents in University (NCET-11-0563) and the National Natural Science Foundation of China (Project 21075007) are gratefully acknowledged. NR 20 TC 1 Z9 2 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0021-9665 EI 1945-239X J9 J CHROMATOGR SCI JI J. Chromatogr. Sci. PD MAR PY 2014 VL 52 IS 3 BP 252 EP 257 DI 10.1093/chromsci/bmt020 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AQ4AG UT WOS:000342734000010 PM 23515193 ER PT J AU Clements, N Sarkar, SK Zhao, ZG Kim, DY AF Clements, Nicolle Sarkar, Sanat K. Zhao, Zhigen Kim, Dong-Yun TI APPLYING MULTIPLE TESTING PROCEDURES TO DETECT CHANGE IN EAST AFRICAN VEGETATION SO ANNALS OF APPLIED STATISTICS LA English DT Article DE False discovery rate; directional false discovery rate; NDVI; East Africa vegetation ID FALSE DISCOVERY RATE; TIME-SERIES; GROWTH; RATES AB The study of vegetation fluctuations gives valuable information toward effective land use and development. We consider this problem for the East African region based on the Normalized Difference Vegetation Index (NDVI) series from satellite remote sensing data collected between 1982 and 2006 over 8-kilometer grid points. We detect areas with significant increasing or decreasing monotonic vegetation changes using a multiple testing procedure controlling the mixed directional false discovery rate (mdFDR). Specifically, we use a three-stage directional Benjamini-Hochberg (BH) procedure with proven mdFDR control under independence and a suitable adaptive version of it. The performance of these procedures is studied through simulations before applying them to the vegetation data. Our analysis shows increasing vegetation in the Northern hemisphere as well as coastal Tanzania and generally decreasing Southern hemisphere vegetation trends, which are consistent with historical evidence. C1 [Clements, Nicolle] St Josephs Univ, Philadelphia, PA 19131 USA. [Sarkar, Sanat K.; Zhao, Zhigen] Temple Univ, Philadelphia, PA 19122 USA. [Kim, Dong-Yun] NIH, Off Biostat Res, Bethesda, MD 20892 USA. RP Clements, N (reprint author), St Josephs Univ, Mandeville 349,5600 City Ave, Philadelphia, PA 19131 USA. EM nclement@sju.edu; sanat@temple.edu; zhaozhg@temple.edu; kimd10@nhlbi.nih.gov FU NSF [DMS-10-06344, DMS-12-08735]; National Science Foundation Biocomplexity of Coupled Human and Natural Systems Program [BCS/CNH 0709671] FX The NDVI data set was collected as part of a Michigan State University research project, namely, the "Dynamic Interactions among People, Livestock, and Savanna Ecosystems under Climate Change" project (funded by the National Science Foundation Biocomplexity of Coupled Human and Natural Systems Program, Award No. BCS/CNH 0709671). We thank the anonymous referees for their constructive comments which have helped to improve the quality of the paper. NR 24 TC 2 Z9 2 U1 1 U2 4 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 1932-6157 J9 ANN APPL STAT JI Ann. Appl. Stat. PD MAR PY 2014 VL 8 IS 1 BP 286 EP 308 DI 10.1214/13-AOAS686 PG 23 WC Statistics & Probability SC Mathematics GA AP9KT UT WOS:000342399400012 ER PT J AU Park, Y Wang, S Kitahara, CM Moore, SC de Gonzalez, AB Bernstein, L Chang, ET Flint, AJ Freedman, DM Gaziano, JM Hoover, RN Linet, MS Purdue, M Robien, K Schairer, C Sesso, HD White, E Willcox, BJ Thun, MJ Hartge, P Willett, WC AF Park, Yikyung Wang, Sophia Kitahara, Cari M. Moore, Steven C. de Gonzalez, Amy Berrington Bernstein, Leslie Chang, Ellen T. Flint, Alan J. Freedman, D. Michal Gaziano, J. Michael Hoover, Robert N. Linet, Martha S. Purdue, Mark Robien, Kim Schairer, Catherine Sesso, Howard D. White, Emily Willcox, Bradley J. Thun, Michael J. Hartge, Patricia Willett, Walter C. TI Body Mass Index and Risk of Death in Asian Americans SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID CAUSE-SPECIFIC MORTALITY; PROSPECTIVE COHORT; UNITED-STATES; ALL-CAUSE; OBESITY; WOMEN; WEIGHT; ASSOCIATION; OVERWEIGHT; ADULTS AB Objectives. We investigated the association between body mass index (BMI) and mortality among Asian Americans. Methods. We pooled data from prospective cohort studies with 20 672 Asian American adults with no baseline cancer or heart disease history. We estimated hazard ratios and 95% confidence intervals (CIs) with Cox proportional hazards models. Results. A high, but not low, BMI was associated with increased risk of total mortality among individuals aged 35 to 69 years. The BMI was not related to total mortality among individuals aged 70 years and older. With a BMI 22.5 to < 25 as the reference category among never-smokers aged 35 to 69 years, the hazard ratios for total mortality were 0.83 (95% CI = 0.47, 1.47) for BMI 15 to < 18.5; 0.91 (95% CI = 0.62, 1.32) for BMI 18.5 to < 20; 1.08 (95% CI = 0.86, 1.36) for BMI 20 to < 22.5; 1.14 (95% CI = 0.90, 1.44) for BMI 25 to < 27.5; 1.13 (95% CI = 0.79, 1.62) for BMI 27.5 to < 30; 1.82 (95% CI = 1.25, 2.64) for BMI 30 to < 35; and 2.09 (95% CI = 1.06, 4.11) for BMI 35 to 50. Higher BMI was also related to increased cardiovascular disease and cancer mortality. Conclusions. High BMI is associated with increased mortality risk among Asian Americans. C1 [Park, Yikyung; Kitahara, Cari M.; Moore, Steven C.; de Gonzalez, Amy Berrington; Freedman, D. Michal; Hoover, Robert N.; Linet, Martha S.; Purdue, Mark; Schairer, Catherine; Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Wang, Sophia; Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Div Canc Etiol, Dept Populat Sci, Duarte, CA 91010 USA. [Wang, Sophia; Bernstein, Leslie] City Hope Natl Med Ctr, Duarte, CA USA. [Chang, Ellen T.] Exponent Inc, Menlo Pk, CA USA. [Flint, Alan J.; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Gaziano, J. Michael; Sesso, Howard D.; Willett, Walter C.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, Boston, MA 02115 USA. [Robien, Kim] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Epidemiol & Biostat, Washington, DC USA. [Robien, Kim] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Exercise Sci, Washington, DC USA. [White, Emily] Univ Washington, Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Dept Epidemiol, Seattle, WA 98195 USA. [Willcox, Bradley J.] Pacific Hlth Res & Educ Inst, Honolulu, HI USA. [Willcox, Bradley J.] Queens Med Ctr, Honolulu, HI USA. [Thun, Michael J.] Amer Canc Soc, Dept Epidemiol Epidemiol & Surveillance Res, Atlanta, GA 30329 USA. RP Park, Y (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM parkyik@mail.nih.gov RI Moore, Steven/D-8760-2016; Kitahara, Cari/R-8267-2016; OI Moore, Steven/0000-0002-8169-1661; Robien, Kim/0000-0002-2120-2280; Park, Yikyung/0000-0002-6281-489X FU National Institutes of Health [UM1CA167752, CA 097193, CA 34944, CA 40360, HL 26490, HL 34595]; National Cancer Institute at the National Institutes of Health [R03 CA135687, R01 CA77398, K05 CA136967]; California Breast Cancer Research fund [97-10500]; California Breast Cancer Act FX This study was supported by the Intramural Research Program of the National Institutes of Health. The California Teachers Study was supported by the National Cancer Institute at the National Institutes of Health (grants R03 CA135687, R01 CA77398, and K05 CA136967), the California Breast Cancer Research fund (contract 97-10500), and the California Breast Cancer Act of 1993. The Health Professionals Follow-up Study is supported by the National Institutes of Health (grant UM1CA167752). The Physicians' Health Study was supported by the National Institutes of Health (grants CA 097193, CA 34944, CA 40360, HL 26490, and HL 34595). NR 35 TC 12 Z9 12 U1 0 U2 3 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAR PY 2014 VL 104 IS 3 BP 520 EP 525 DI 10.2105/AJPH.2013.301573 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AP0LP UT WOS:000341753300046 PM 24432919 ER PT J AU Mallon, BS Hamilton, RS Kozhich, OA Johnson, KR Fann, YC Rao, MS Robey, PG AF Mallon, Barbara S. Hamilton, Rebecca S. Kozhich, Olga A. Johnson, Kory R. Fann, Yang C. Rao, Mahendra S. Robey, Pamela G. TI Comparison of the molecular profiles of human embryonic and induced pluripotent stem cells of isogenic origin SO STEM CELL RESEARCH LA English DT Article ID GENE-EXPRESSION SIGNATURES; ALLELIC VARIATION; COPY NUMBER; HUMAN ES; METHYLATION; PATIENT; MEMORY AB Many studies have compared the genetic and epigenetic profiles of human induced pluripotent stem cells (hiPSCs) to human embryonic stem cells (hESCs) and yet the picture remains unclear. To address this, we derived a population of neural precursor cells (NPCs) from the H1 (WA01) hESC line and generated isogenic iPSC lines by reprogramming. The gene expression and methylation profile of three lines were compared to the parental line and intermediate NPC population. We found no gene probe with expression that differed significantly between hESC and iPSC samples under undifferentiated or differentiated conditions. Analysis of the global methylation pattern also showed no significant difference between the two PSC populations. Both undifferentiated populations were distinctly different from the intermediate NPC population in both gene expression and methylation profiles. One point to note is that H1 is a male line and so extrapolation to female lines should be cautioned. However, these data confirm our previous findings that there are no significant differences between hESCs and hiPSCs at the gene expression or methylation level. (C) 2013 The Authors. Published by Elsevier B. V. All rights reserved. C1 [Mallon, Barbara S.; Hamilton, Rebecca S.; Robey, Pamela G.] NINDS, NIH, Stem Cell Unit, Bethesda, MD 20892 USA. [Kozhich, Olga A.] NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Johnson, Kory R.; Fann, Yang C.] NINDS, Bioinformat Sect, Intramural IT & Bioinformat Program, NIH, Bethesda, MD 20892 USA. [Rao, Mahendra S.] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. [Robey, Pamela G.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Mallon, BS (reprint author), NINDS, NIH, Stem Cell Unit, Bethesda, MD 20892 USA. EM mallonb@mail.nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU Intramural Research Program of the NIH, NINDS FX This research was supported by the Intramural Research Program of the NIH, NINDS. NR 28 TC 18 Z9 19 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1873-5061 EI 1876-7753 J9 STEM CELL RES JI Stem Cell Res. PD MAR PY 2014 VL 12 IS 2 BP 376 EP 386 DI 10.1016/j.scr.2013.11.010 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AP7VU UT WOS:000342286600005 PM 24374290 ER PT J AU Kerever, A Mercier, F Nonaka, R de Vega, S Oda, Y Zalc, B Okada, Y Hattori, N Yamada, Y Arikawa-Hirasawa, E AF Kerever, Aurelien Mercier, Frederic Nonaka, Risa de Vega, Susana Oda, Yuka Zalc, Bernard Okada, Yohei Hattori, Nobutaka Yamada, Yoshihiko Arikawa-Hirasawa, Eri TI Perlecan is required for FGF-2 signaling in the neural stem cell niche SO STEM CELL RESEARCH LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; ADULT SUBVENTRICULAR ZONE; MAMMALIAN BRAIN; OLFACTORY-BULB; VASCULAR NICHE; CYCLIN D2; PROLIFERATION; NEUROGENESIS; BINDING; PROTEOGLYCAN AB In the adult subventricular zone (neurogenic niche), neural stem cells double-positive for two markers of subsets of neural stem cells in the adult central nervous system, glial fibrillary acidic protein and CD133, lie in proximity to fractones and to blood vessel basement membranes, which contain the heparan sulfate proteoglycan perlecan. Here, we demonstrate that perlecan deficiency reduces the number of both GFAP/CD133-positive neural stem cells in the subventricular zone and new neurons integrating into the olfactory bulb. We also show that FGF-2 treatment induces the expression of cyclin D2 through the activation of the Akt and Erk1/2 pathways and promotes neurosphere formation in vitro. However, in the absence of perlecan, FGF-2 fails to promote neurosphere formation. These results suggest that perlecan is a component of the neurogenic niche that regulates FGF-2 signaling and acts by promoting neural stem cell self-renewal and neurogenesis. (C) 2013 The Authors. Published by Elsevier B. V. All rights reserved. C1 [Kerever, Aurelien; Nonaka, Risa; de Vega, Susana; Oda, Yuka; Arikawa-Hirasawa, Eri] Juntendo Univ, Grad Sch Med, Res Inst Dis Old Age, Tokyo 1138421, Japan. [Mercier, Frederic] Univ Hawaii, John A Burns Sch Med, Dept Trop Med & Infect Dis, Honolulu, HI 96822 USA. [Zalc, Bernard] Univ Paris 06, Ctr Rech, Inst Cerveau & Moelle Epiniere CRICM, UMRS 975, F-75013 Paris, France. [Zalc, Bernard] Univ Paris 06, INSERM, U975, F-75013 Paris, France. [Zalc, Bernard] CNRS, UMR 7225, F-75013 Paris, France. [Okada, Yohei] Keio Univ, Sch Med, Dept Physiol, Shinjuku Ku, Tokyo 160, Japan. [Okada, Yohei] Keio Univ, Sch Med, Kanrinmaru Project, Tokyo, Japan. [Hattori, Nobutaka; Arikawa-Hirasawa, Eri] Juntendo Univ, Sch Med, Dept Neurol, Tokyo 113, Japan. [Yamada, Yoshihiko] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Arikawa-Hirasawa, E (reprint author), Juntendo Univ, Grad Sch Med, Res Inst Dis Old Age, Bunkyo Ku, Bldg 10,Room 606,2-1-1 Hongo, Tokyo 1138421, Japan. EM ehirasaw@juntendo.ac.jp FU MEXT; Ministry of Education, Culture, Sports Science, and Technology of Japan [17082008, 2230023]; Intramural Program of the NIDCR, National Institutes of Health; program "Investissements d'avenir" [ANR-10-IAIHU-06] FX This work was supported by grants from MEXT-Supported Program for the Strategic Research Foundation at Private Universities (2011-2015) and the Ministry of Education, Culture, Sports Science, and Technology of Japan (17082008 and 2230023 to E. A-H.) and the Intramural Program of the NIDCR, National Institutes of Health (Y.Y.). Bernard Zalc has received funding from the program "Investissements d'avenir" ANR-10-IAIHU-06. NR 53 TC 15 Z9 15 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1873-5061 EI 1876-7753 J9 STEM CELL RES JI Stem Cell Res. PD MAR PY 2014 VL 12 IS 2 BP 492 EP 505 DI 10.1016/j.scr.2013.12.009 PG 14 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AP7VU UT WOS:000342286600014 PM 24434631 ER PT J AU Lea, CS Efird, JT Toland, AE Lewis, DR Phillips, CJ AF Lea, C. Suzanne Efird, Jimmy T. Toland, Amanda E. Lewis, Denise R. Phillips, Christopher J. TI Melanoma Incidence Rates in Active Duty Military Personnel Compared With a Population-Based Registry in the United States, 2000-2007 SO MILITARY MEDICINE LA English DT Article ID CANCER INCIDENCE; SUN EXPOSURE; MALIGNANT-MELANOMA; CUTANEOUS MELANOMA; SKIN CANCERS; AIR-FORCE; RISK; METAANALYSIS; WOMEN AB Objectives: This study was conducted to investigate whether incidence rates of malignant cutaneous melanoma in U.S. Department of Defense active duty military personnel differed from rates in the U.S. general population between 2000 and 2007. Methods: The study population included active duty military personnel and the general population aged 18 to 56 years. Data were obtained from the U.S. Department of Defense medical data systems and from the Surveillance Epidemiology and End Results program. Melanoma risk was estimated by incidence rate ratios (IRRs). Results: Melanoma risk was higher among active duty personnel than the general population (IRR = 1.62, 95% confidence interval = 1.40-1.86). Incidence rates were higher for white military personnel than for white rates in general population (36.89 and 23.05 per 100,000 person-years, respectively). Rates were also increased for military men and women compared with SEER (men, 25.32 and 16.53 per 100,000; women, 30.00 and 17.55 per 100,000). Air Force service personnel had the highest rates and Army had the lowest. Conclusion: Melanoma rates were marginally higher among active duty military personnel than the general population between 2000 and 2007. C1 [Lea, C. Suzanne; Efird, Jimmy T.] E Carolina Univ, Brody Sch Med, Dept Publ Hlth, Greenville, NC 27834 USA. [Toland, Amanda E.] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Lewis, Denise R.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Phillips, Christopher J.] Naval Hlth Res Ctr, Deployment Hlth Res Dept, San Diego, CA 92152 USA. RP Lea, CS (reprint author), E Carolina Univ, Brody Sch Med, Dept Publ Hlth, Greenville, NC 27834 USA. FU Deployment Health Research Department [60002] FX We thank Zhuoqiao Wang, MS, with IMS, Inc., an NCI contractor, for reviewing programming code and appreciate helpful comments from Dr. Nancy Crum-Cianflone, Chair, Deployment Health Research Department, Naval Health Research Center. This work represents report 12-60, supported by the Deployment Health Research Department, under work unit number 60002. NR 31 TC 3 Z9 3 U1 4 U2 5 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD MAR PY 2014 VL 179 IS 3 BP 247 EP 253 DI 10.7205/MILMED-D-13-00356 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA AN7UJ UT WOS:000340806200007 PM 24594457 ER PT J AU Neta, G Hatch, M Kitahara, CM Ostroumova, E Bolshova, EV Tereschenko, VP Tronko, MD Brenner, AV AF Neta, Gila Hatch, Maureen Kitahara, Cari M. Ostroumova, Evgenia Bolshova, Elena V. Tereschenko, Valery P. Tronko, Mykola D. Brenner, Alina V. TI In Utero Exposure to Iodine-131 from Chernobyl Fallout and Anthropometric Characteristics in Adolescence SO RADIATION RESEARCH LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHILDHOOD-CANCER SURVIVOR; ATOMIC-BOMB SURVIVORS; BODY-MASS-INDEX; THYROID-CANCER; ADULT SURVIVORS; RADIATION; RADIOIODINE; HIROSHIMA; NAGASAKI AB Prenatal exposure to external radiation has been linked to growth retardation among atomic bomb survivors in adolescence. It is unclear from previous studies whether in utero exposure to internal radiation such as iodine-131 (I-131), which concentrates in the thyroid gland, has an effect on physical growth. We examined the associations between estimated thyroid gland dose from prenatal exposure to I-131 and self-reported height and weight in a cohort of 2,460 individuals exposed to radioactive fallout from the 1986 Chernobyl nuclear accident [mean I-131 dose 72 (mGy)] and screened for thyroid diseases in adolescence. Using multivariable linear regression models, we estimated the mean differences in height, weight and body mass index (BMI) per unit increase in dose (100 mGy) in models adjusted for gender, age at examination, type of residence (rural/urban) and presence of thyroid disease diagnosed at screening. All of the adjustment factors as well as the trimester of exposure were evaluated as potential modifiers of the dose response. Overall, no significant dose response was found for height (P = 0.29), weight (P = 0.14) or BMI (P = 0.16). We found significant modification of the dose response for weight and BMI by presence/absence of thyroid disease (P = 0.02 and P = 0.03, respectively), but not for other factors. In individuals without thyroid disease (n = 1,856), there was a weak, significant association between I-131 thyroid dose and higher weight (210 g per 100 mGy, P = 0.02) or BMI (70 g/m(2) per 100 mGy, P 0.02) that depended on individuals (n 52) exposed to >= 500 mGy. In individuals with thyroid disease (n = 579, 67.4% with simple diffuse goiter) no significant association with I-131 for weight (P = 0.14) or BMI (P = 0.14) was found. These results do not support the hypothesis that in utero exposure to I-131 at levels experienced by a majority of study subjects may be associated with meaningful differences in adolescent anthropometry. However, additional studies are needed to clarify whether in utero exposure to I-131 at levels > = 500 mGy may be associated with increases in weight/BMI and to evaluate the confounding or modifying role of thyroid disease, past iodine deficiency, maternal and prenatal/postnatal factors. (C) 2014 by Radiation Research Society C1 [Neta, Gila; Hatch, Maureen; Kitahara, Cari M.; Ostroumova, Evgenia; Brenner, Alina V.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20852 USA. [Bolshova, Elena V.; Tereschenko, Valery P.; Tronko, Mykola D.] Inst Endocrinol & Metab, Kiev, Ukraine. RP Neta, G (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv,EPS, Room 7092,6120 Execut Blvd, Bethesda, MD 20852 USA. EM netagil@mail.nih.gov RI Kitahara, Cari/R-8267-2016 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute at the National Institutes of Health FX We would like to acknowledge the contributions to this study of Drs. Galina A. Zamotaeva, Ihor P. Paster, Ludmila V. Chaykovskaya, Victor I. Kravchenko, Oleksandr V. Zvinchuk and Victor M. Shpak, all of the Institute of Endocrinology and Metabolism in Kiev, Ukraine. This research was supported, in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute at the National Institutes of Health. NR 38 TC 1 Z9 1 U1 1 U2 7 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD MAR PY 2014 VL 181 IS 3 BP 293 EP 301 DI 10.1667/RR13304.1 PG 9 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA AO4KR UT WOS:000341307200007 PM 24611659 ER PT J AU Zhao, XN Usdin, K AF Zhao, Xiao-Nan Usdin, Karen TI Gender and Cell-Type-Specific Effects of the Transcription-Coupled Repair Protein, ERCC6/CSB, on Repeat Expansion in a Mouse Model of the Fragile X-Related Disorders SO HUMAN MUTATION LA English DT Article DE CSB; ERCC6; repeat expansion; Fragile X-related; ataxia; primary ovarian insufficiency; transcription-coupled repair ID NUCLEOTIDE EXCISION-REPAIR; ESTROGEN-RECEPTOR-ALPHA; RNA-POLYMERASE-II; CAG REPEAT; CGG-REPEAT; DNA-REPAIR; TRANSGENIC MICE; TREMOR/ATAXIA SYNDROME; GENETIC INSTABILITY; PREMUTATION MICE AB The repeat expansion diseases are human genetic disorders that arise from the expansion of a tandem-repeat tract. The Fragile X-related disorders are members of this disease group in which the repeat unit is CGG/CCG and is located in the 5 ' untranslated region of the FMR1 gene. Affected individuals often show mosaicism with respect to repeat number resulting from both expansion and contraction of the repeat tract; however, the mechanism responsible for these changes in repeat number is unknown. The work from a variety of model systems suggests that transcription-coupled repair (TCR) may contribute to repeat instability in diseases resulting from CAG/CTG-repeat expansion. To test whether TCR could contribute to repeat instability in the Fragile X-related disorders, we tested the effect of mutations in Csb (Cockayne syndrome group B), a gene essential for TCR, in a knock-in mouse model of these disorders. We found that the loss of CSB affects expansions in a gender and cell-type-specific manner. Our data also show an unanticipated gender difference in instability even in Csb(+/+) animals that may have implications for our understanding of the mechanism of repeat expansion in the FX mouse model and perhaps for humans as well. Hum Mutat 35:341-349, 2014. Published 2013 Wiley Periodicals, Inc. C1 [Zhao, Xiao-Nan; Usdin, Karen] NIDDK, Sect Gene Struct & Dis, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Usdin, K (reprint author), NIH, Bldg 8,Room 2A19,8 Ctr DR MSC 0830, Bethesda, MD 20892 USA. EM ku@helix.nih.gov RI Zhao, Xiaonan/S-3139-2016 FU Intramural Program of the NIDDK, National Institutes of Health [DK057808-05] FX Contract grant sponsor: Intramural Program of the NIDDK, National Institutes of Health (DK057808-05). NR 58 TC 10 Z9 10 U1 1 U2 6 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 MAR PY 2014 VL 35 IS 3 BP 341 EP 349 DI 10.1002/humu.22495 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA AB6OP UT WOS:000331909600011 PM 24352881 ER PT J AU Kleinman, S Busch, MP Murphy, EL Shan, H Ness, P Glynn, SA AF Kleinman, Steven Busch, Michael P. Murphy, Edward L. Shan, Hua Ness, Paul Glynn, Simone A. CA Natl Heart Lung Blood Inst Recipie TI The National Heart, Lung, and Blood Institute Recipient Epidemiology and Donor Evaluation Study (REDS-III): a research program striving to improve blood donor and transfusion recipient outcomes SO TRANSFUSION LA English DT Article ID SICKLE-CELL-DISEASE; IMMUNODEFICIENCY-VIRUS-INFECTION; RISK-FACTORS; IRON-DEFICIENCY; UNITED-STATES; BRAZIL; TRANSMISSION; MORTALITY; DENGUE; ALLOIMMUNIZATION AB BACKGROUND: The Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) is a 7-year multi-center transfusion safety research initiative launched in 2011 by the National Heart, Lung, and Blood Institute. STUDY DESIGN AND METHODS: The domestic component involves four blood centers, 12 hospitals, a data coordinating center, and a central laboratory. The international component consists of distinct programs in Brazil, China, and South Africa, which involve US and in-country investigators. RESULTS: REDS-III is using two major methods to address key research priorities in blood banking and transfusion medicine. First, there will be numerous analyses of large "core" databases; the international programs have each constructed a donor and donation database while the domestic program has established a detailed research database that links data from blood donors and their donations, the components made from these donations, and data extracts from the electronic medical records of the recipients of these components. Second, there are more than 25 focused research protocols involving transfusion recipients, blood donors, or both that either are in progress or are scheduled to begin within the next 3 years. Areas of study include transfusion epidemiology and blood utilization, transfusion outcomes, noninfectious transfusion risks, human immunodeficiency virus-related safety issues (particularly in the international programs), emerging infectious agents, blood component quality, donor health and safety, and other donor issues. CONCLUSIONS: It is intended that REDS-III serve as an impetus for more widespread recipient and linked donor-recipient research in the United States as well as to help assure a safe and available blood supply in the United States and in international locations. C1 [Kleinman, Steven] Univ British Columbia, Dept Pathol, Victoria, BC, Canada. [Busch, Michael P.; Murphy, Edward L.] Blood Syst Res Inst, San Francisco, CA USA. [Busch, Michael P.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [Murphy, Edward L.] Univ Calif San Francisco, Dept Lab Med & Epidemiol Biostat, San Francisco, CA 94143 USA. [Shan, Hua] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. [Ness, Paul] Johns Hopkins Univ, Dept Pathol & Med, Baltimore, MD USA. [Ness, Paul] Johns Hopkins Med Inst, Dept Transfus Med, Baltimore, MD 21205 USA. [Glynn, Simone A.] NHLBI, Dept Transfus Med, NIH, Bethesda, MD 20892 USA. [Glynn, Simone A.] NHLBI, Cellular Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Kleinman, S (reprint author), 1281 Rockcrest Ave, Victoria, BC V9A 4W4, Canada. EM skleinman@shaw.ca FU NHLBI [NHLBI HHSN2682011-00001I, NHLBI HHSN2682011-00002I, NHLBI HHSN2682011-00003I, NHLBI HHSN2682011-00004I, NHLBI HHSN2682011-00005I, NHLBI HHSN2682011-00006I, NHLBI HHSN2682011-00007I, NHLBI HHSN2682011-00008I, NHLBI HHSN2682011-00009I] FX REDS-III is supported by NHLBI contracts NHLBI HHSN2682011-00001I, -00002I, -00003I, -00004I, -00005I, -00006I, -00007I, -00008I, and -00009I. NR 70 TC 23 Z9 23 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD MAR PY 2014 VL 54 IS 3 SI SI BP 942 EP 955 DI 10.1111/trf.12468 PN 2 PG 14 WC Hematology SC Hematology GA AM9GI UT WOS:000340188500027 PM 24188564 ER PT J AU Ochi, F Fujiwara, H Tanimoto, K Asai, H Miyazaki, Y Okamoto, S Mineno, J Kuzushima, K Shiku, H Barrett, J Ishii, E Yasukawa, M AF Ochi, Fumihiro Fujiwara, Hiroshi Tanimoto, Kazushi Asai, Hiroaki Miyazaki, Yukihiro Okamoto, Sachiko Mineno, Junichi Kuzushima, Kiyotaka Shiku, Hiroshi Barrett, John Ishii, Eiichi Yasukawa, Masaki TI Gene-Modified Human alpha/beta-T Cells Expressing a Chimeric CD16-CD3 zeta Receptor as Adoptively Transferable Effector Cells for Anticancer Monoclonal Antibody Therapy SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID FC-GAMMA-RIIIA; DEPENDENT CELLULAR CYTOTOXICITY; ANTILEUKEMIA REACTIVITY; CANCER-IMMUNOTHERAPY; BREAST-CANCER; LEUKEMIA; LYMPHOMA; POLYMORPHISM; LYMPHOCYTES; RITUXIMAB AB The central tumoricidal activity of anticancer monoclonal antibodies (mAb) is exerted by Fc gamma R IIIa (CD16)-expressing effector cells in vivo via antibody-dependent cell-mediated cytotoxicity (ADCC), as observed for natural killer (NK) cells. In practice, chemotherapy-induced leukopenia and exhaustion of NK cells resulting from ADCC often hamper the clinical efficacy of cancer treatment. To circumvent this drawback, we examined in vivo the feasibility of T cells, gene-modified to express a newly generated affinity-matured (158V/V) chimeric CD16-CD3 zeta receptor (cCD16 zeta-T cells), as a transferable alternative effector for cancer mAb therapy. cCD16 zeta-T cells were readily expandable in ex vivo culture using anti-CD2/CD3/CD28 beads and recombinant human interleukin-2 (rhIL-2), and they successfully displayed ADCC-mediated tumoricidal activity in vitro. During ADCC, ligation of opsonized cancer cells to the introduced cCD16 zeta-T cells stimulated the effector cells to produce proinflammatory cytokines and release toxic granules through the activation of the Nuclear factor of activated T cells (NFAT) pathway after phosphorylation of the CD3 zeta chain. In parallel, these stimulated cCD16 zeta-T cells transiently proliferated and differentiated into effector memory T cells. In contrast, NK cells activated by rhIL-2 displayed similar ADCC activity, but failed to proliferate. Human cCD16 zeta-T cells infused concomitantly with anti-CD20 mAb synergistically inhibited the growth of disseminated Raji cells, a CD20(+) lymphoma cell line, in immunodeficient mice, whereas similarly infused rhIL-2-treated NK cells survived for a shorter time and displayed less effective tumor suppression. Our findings strongly suggest the clinical feasibility of cCD16 zeta-T cells as adoptively transferable ADCC effector cells that could potentially enhance the clinical responses mediated by currently available anticancer mAbs. (C) 2014 AACR. C1 [Ochi, Fumihiro; Fujiwara, Hiroshi; Tanimoto, Kazushi; Asai, Hiroaki; Miyazaki, Yukihiro; Yasukawa, Masaki] Ehime Univ, Dept Hematol Clin Immunol & Infect Dis, Grad Sch Med, Toon, Ehime 7910295, Japan. [Ochi, Fumihiro; Ishii, Eiichi] Ehime Univ, Dept Pediat, Grad Sch Med, Toon, Ehime 7910295, Japan. [Okamoto, Sachiko; Mineno, Junichi] Takara Bio Inc, Ctr Cell & Gene Therapy, Shiga, Japan. [Kuzushima, Kiyotaka] Aichi Canc Ctr, Div Immunol, Aichi, Japan. [Shiku, Hiroshi] Mie Univ, Grad Sch Med, Dept Canc Vaccine & Immuno Gene Therapy, Tsu, Mie, Japan. [Tanimoto, Kazushi; Barrett, John] NHLBI, Hematol Branch, NIH, Bethesda, MD USA. RP Fujiwara, H (reprint author), Ehime Univ, Dept Hematol Clin Immunol & Infect Dis, Grad Sch Med, Toon, Ehime 7910295, Japan. EM yunarief@m.ehime-u.ac.jp; yasukawa@m.ehime-u.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan; Ministry of Health, Labor and Welfare FX This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan to H. Fujiwara and M. Yasukawa, and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare to M. Yasukawa. NR 41 TC 2 Z9 2 U1 3 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD MAR PY 2014 VL 2 IS 3 BP 249 EP 262 DI 10.1158/2326-6066.CIR-13-0099-T PG 14 WC Oncology; Immunology SC Oncology; Immunology GA AM7GH UT WOS:000340032800008 PM 24778321 ER PT J AU Shankar, A Kumar, S Iskander, A Varma, NRS Janic, B deCarvalho, A Mikkelsen, T Frank, JA Ali, MM Knight, RA Brown, S Arbab, AS AF Shankar, Adarsh Kumar, Sanath Iskander, Asm Varma, Nadimpalli R. S. Janic, Branislava deCarvalho, Ana Mikkelsen, Tom Frank, Joseph A. Ali, Meser M. Knight, Robert A. Brown, Stephen Arbab, Ali S. TI Subcurative radiation significantly increases cell proliferation, invasion, and migration of primary glioblastoma multiforme in vivo SO CHINESE JOURNAL OF CANCER LA English DT Article DE Glioblastoma multiforme; radiation; treatment resistance; invasion ID ENDOTHELIAL GROWTH-FACTOR; PANCREATIC-CANCER CELLS; MALIGNANT GLIOMAS; ANTIANGIOGENIC THERAPIES; IONIZING-RADIATION; TUMOR ANGIOGENESIS; SIGNALING PATHWAY; BRAIN; RADIOTHERAPY; IRRADIATION AB Tumor cell proliferation, infiltration, migration, and neovascularization are known causes of treatment resistance in glioblastoma multiforme (GBM). The purpose of this study was to determine the effect of radiation on the growth characteristics of primary human GBM developed in a nude rat. Primary GBM cells grown from explanted GBM tissues were implanted orthotopically in nude rats. Tumor growth was confirmed by magnetic resonance imaging on day 77 (baseline) after implantation. The rats underwent irradiation to a dose of 50 Gy delivered subcuratively on day 84 postimplantation (n = 8), or underwent no radiation (n = 8). Brain tissues were obtained on day 112 (nonirradiated) or day 133 (irradiated). Immunohistochemistry was performed to determine tumor cell proliferation (Ki-67) and to assess the expression of infiltration marker (matrix metalloproteinase-2, MMP-2) and cell migration marker (CD44). Tumor neovascularization was assessed by microvessel density using von-Willebrand factor (vWF) staining. Magnetic resonance imaging showed well-developed, infiltrative tumors in 11 weeks postimplantation. The proportion of Ki-67-positive cells in tumors undergoing radiation was (71 +/- 15)% compared with (25 +/- 12)% in the nonirradiated group (P = 0.02). The number of MMP-2-positive areas and proportion of CD44-positive cells were also high in tumors receiving radiation, indicating great invasion and infiltration. Microvessel density analysis did not show a significant difference between nonirradiated and irradiated tumors. Taken together, we found that subcurative radiation significantly increased proliferation, invasion, and migration of primary GBM. Our study provides insights into possible mechanisms of treatment resistance following radiation therapy for GBM. C1 [Shankar, Adarsh; Iskander, Asm; Varma, Nadimpalli R. S.; Janic, Branislava; Ali, Meser M.; Arbab, Ali S.] Henry Ford Hosp, Dept Radiol, Detroit, MI 48202 USA. [Kumar, Sanath; Brown, Stephen] Henry Ford Hosp, Dept Radiat Oncol, Detroit, MI 48202 USA. [deCarvalho, Ana; Mikkelsen, Tom] Henry Ford Hosp, Dept Neurosurg, Detroit, MI 48202 USA. [Frank, Joseph A.; Knight, Robert A.] NIH, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. Henry Ford Hosp, Dept Neurol, Detroit, MI 48202 USA. [Brown, Stephen] Wayne State Univ, Dept Radiat Oncol, Sch Med, Detroit, MI 48202 USA. [Arbab, Ali S.] Wayne State Univ, Dept Radiol, Sch Med, Detroit, MI 48202 USA. RP Kumar, S (reprint author), Henry Ford Hosp, Dept Radiat Oncol, Detroit, MI 48202 USA. EM skumar4@hfhs.org OI deCarvalho, Ana C/0000-0003-1183-4548 FU National Institutes of Health (NIH) [K25CA129173, R01CA122031, 1R01CA160216] FX We thank Thaiz Borin for her assistance during immunohistochemistry analysis. This work was supported by grants from the National Institutes of Health (NIH) [No. K25CA129173 (MMA), R01CA122031 (ASA), and 1R01CA160216 (ASA)]. NR 48 TC 4 Z9 4 U1 0 U2 5 PU SUN YAT SEN UNIV MED SCI WHO PI GUANGZHOU PA 651 DONGFENG RD E, GUANGZHOU, GUANGDONG 510060, PEOPLES R CHINA SN 1000-467X EI 1944-446X J9 CHIN J CANCER JI Chin. J. Cancer PD MAR PY 2014 VL 33 IS 3 BP 148 EP 158 DI 10.5732/cjc.013.10095 PG 11 WC Oncology SC Oncology GA AM2BB UT WOS:000339652000004 PM 24016393 ER PT J AU Damiano, DL AF Damiano, Diane L. TI Progressive resistance exercise increases strength but does not improve objective measures of mobility in young people with cerebral palsy SO JOURNAL OF PHYSIOTHERAPY LA English DT Editorial Material ID CHILDREN; ADOLESCENTS C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Damiano, DL (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CL999999] NR 7 TC 6 Z9 6 U1 0 U2 9 PU AUSTRALIAN PHYSIOTHERAPY ASSOC PI ST KILDA PA LEVEL 3, 201 FITZROY ST, ST KILDA, 3182, AUSTRALIA SN 1836-9553 EI 1836-9561 J9 J PHYSIOTHER JI J. Physiother. PD MAR PY 2014 VL 60 IS 1 BP 58 EP 58 DI 10.1016/j.jphys.2013.12.010 PG 1 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA AL9GV UT WOS:000339449500011 PM 24856945 ER PT J AU Gorelic, LS AF Gorelic, Lester S. TI DEPICTING the CREATION of a NATION The story Behind the murals About our Founding Documents SO PROLOGUE-QUARTERLY OF THE NATIONAL ARCHIVES AND RECORDS ADMINISTRATION LA English DT Article C1 [Gorelic, Lester S.] NCI, Rockville, MD 20850 USA. RP Gorelic, LS (reprint author), Natl Arch Bldg, Washington, DC 20408 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU NATL ARCHIVES RECORDS ADMINISTRATION PI WASHINGTON PA TRUST FUND BOARD, WASHINGTON, DC 20408 USA SN 0033-1031 J9 PROLOGUE JI Prologue PD SPR PY 2014 VL 46 IS 1 BP 44 EP 54 PG 11 WC History SC History GA AK4SV UT WOS:000338415300007 ER PT J AU Tan, Y Lam, TTY Wu, CW Lee, SS Viboud, C Zhang, RL Weinberger, DM AF Tan, Yi Lam, Tommy Tsan-Yuk Wu, Chunli Lee, Shui-shan Viboud, Cecile Zhang, Renli Weinberger, Daniel M. TI Increasing similarity in the dynamics of influenza in two adjacent subtropical Chinese cities following the relaxation of border restrictions SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID EPIDEMIOLOGIC DYNAMICS; SPATIAL HIERARCHIES; HONG-KONG; SEASONALITY; VIRUS; SYNCHRONY; EPIDEMICS; PATTERNS; WAVES AB The drivers of influenza seasonality remain heavily debated, especially in tropical/subtropical regions where influenza activity can peak in winter, during the rainy season, or remain constant throughout the year. We compared the epidemiological and evolutionary patterns of seasonal influenza epidemics in Hong Kong and Shenzhen, two adjacent cities in subtropical southern China. This comparison represents a unique natural experiment, as connectivity between these two cities has increased over the past decade. We found that, whilst summer influenza epidemics in Shenzhen used to peak 1-3 months later than those in Hong Kong, the difference decreased after 2005 (P<0.0001). Phylogenetic analysis revealed that influenza isolates from Shenzhen have become genetically closer to those circulating in Hong Kong over time (P=0.045). Furthermore, although Shenzhen isolates used to be more distant from the global putative source of influenza viruses than isolates from Hong Kong (P<0.001), this difference has narrowed (P=0.02). Overall, our study reveals that influenza activities show remarkably distinct epidemiological and evolutionary patterns in adjacent subtropical cities and suggests that human mobility patterns can play a major role in influenza dynamics in the subtropics. C1 [Tan, Yi; Viboud, Cecile; Weinberger, Daniel M.] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Tan, Yi; Lee, Shui-shan] Chinese Univ Hong Kong, Stanley Ho Ctr Emerging Infect Dis, Sch Publ Hlth & Primary Care, Fac Med, Hong Kong, Hong Kong, Peoples R China. [Lam, Tommy Tsan-Yuk] Univ Hong Kong, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China. [Wu, Chunli; Zhang, Renli] Shenzhen Ctr Dis Control & Prevent, Shenzhen 518055, Guangdong, Peoples R China. [Weinberger, Daniel M.] Yale Univ, Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT 06520 USA. RP Tan, Y (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM yiyity@gmail.com RI Lee, Shui Shan/B-9374-2008; Lam, Tommy Tsan-Yuk/D-4837-2012; OI Lee, Shui Shan/0000-0003-1448-765X; Weinberger, Daniel/0000-0003-1178-8086 FU International Influenza Unit, Office of Global Affairs, US Department of Health and Human Services FX This research was conducted in the context of the MISMS Study, an ongoing international collaborative effort to understand influenza epidemiological and evolutionary patterns, led by the Fogarty International Center, National Institutes of Health (http://www.origem.info/misms/index.php). The MISMS study is funded by the International Influenza Unit, Office of Global Affairs, US Department of Health and Human Services. The Department of Health, Hong Kong, is acknowledged for access to the laboratory surveillance data from Hong Kong. The authors declare no conflicts of interest. NR 35 TC 2 Z9 2 U1 0 U2 2 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 EI 1465-2099 J9 J GEN VIROL JI J. Gen. Virol. PD MAR PY 2014 VL 95 BP 531 EP 538 DI 10.1099/vir.0.059998-0 PN 3 PG 8 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA AK1LV UT WOS:000338177500002 PM 24310518 ER PT J AU Hart, BJ Dyall, J Postnikova, E Zhou, HY Kindrachuk, J Johnson, RF Olinger, GG Frieman, MB Holbrook, MR Jahrling, PB Hensley, L AF Hart, Brit J. Dyall, Julie Postnikova, Elena Zhou, Huanying Kindrachuk, Jason Johnson, Reed F. Olinger, Gene G., Jr. Frieman, Matthew B. Holbrook, Michael R. Jahrling, Peter B. Hensley, Lisa TI Interferon-beta and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID IN-VITRO; C VIRUS; ANTIVIRAL ACTIVITY; IMP DEHYDROGENASE; CYCLOSPORINE-A; RIBAVIRIN; COV; REPLICATION; ALPHA; VIVO AB The Middle East respiratory syndrome coronavirus (MERS-CoV) presents a novel emerging threat to public health worldwide. Several treatments for infected individuals have been suggested including IFN, ribavirin and passive immunotherapy with convalescent plasma. Administration of IFN-alpha 2b and ribavirin has improved outcomes of MERS-CoV infection in rhesus macaques when administered within 8 h post-challenge. However, detailed and systematic evidence on the activity of other clinically available drugs is limited. Here we compared the susceptibility of MERS-CoV with different IFN products (IFN-alpha 2b, IFN-gamma, IFN-universal, IFN-alpha 2a and IFN-beta), as well as with two antivirals, ribavirin and mycophenolic acid (MPA), against MERS-CoV (Hu/Jordan-N3/2012) in vitro. Of all the IFNs tested, IFN-beta showed the strongst inhibition of MERS-CoV in vitro, with an IC50 of 1.37 U ml(-1), 41 times lower than the previously reported IC50 (56.08 U ml(-1)) of IFN-alpha 2b. IFN-beta inhibition was confirmed in the virus yield reduction assay, with an IC90 of 38.8 U ml(-1). Ribavirin did not inhibit viral replication in vitro at a dose that would be applicable to current treatment protocols in humans. In contrast, MPA showed strong inhibition, with an IC50 of 2.87 mu M. This drug has not been previously tested against MERS-CoV and may provide an alternative to ribavirin for treatment of MERS-CoV. In conclusion, IFN-beta, MPA or a combination of the two may be beneficial in the treatment of MERS-CoV or as a post-exposure intervention in high-risk patients with known exposures to MERS-CoV. C1 [Hart, Brit J.; Dyall, Julie; Postnikova, Elena; Zhou, Huanying; Kindrachuk, Jason; Olinger, Gene G., Jr.; Holbrook, Michael R.; Jahrling, Peter B.; Hensley, Lisa] NIAID, Integrated Res Facil, NIH, Frederick, MD 21703 USA. [Johnson, Reed F.; Jahrling, Peter B.] NIAID, Emerging Viral Pathogens Sect, NIH, Frederick, MD USA. [Frieman, Matthew B.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. RP Jahrling, PB (reprint author), NIAID, Integrated Res Facil, NIH, Frederick, MD 21703 USA. EM jahrlingp@niaid.nih.gov RI Hart, Brit/G-6205-2015 OI Hart, Brit/0000-0002-9389-2786 FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID); Integrated Research Facility (NIAID, Division of Clinical Research); Battelle Memorial Institute; NIAID [HHSN272200700016I] FX We thank Calli Lear, Yingyun Cai and Cindy Allan for outstanding assistance in development of the drug screen protocol and Cindy Allan for implementation of protocols in the biocontainment suite. We thank cell culture staff in preparing the cells used in this study. In addition, we acknowledge Laura Bollinger for technical writing services in preparation of this manuscript and Jiro Wada for figure preparation. This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID), Integrated Research Facility (NIAID, Division of Clinical Research) and Battelle Memorial Institute's prime contract with NIAID (contract no. HHSN272200700016I). The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services or of the institutions and companies affiliated with the authors. B. J. H., J. D. and E. P. performed this work as employees of Tunnell Consulting, Inc., a subcontractor to Battelle Memorial Institute; H. Z. performed this work as an employee of Loveless Commercial Contracting, Inc., a subcontractor to Battelle Memorial Institute; G. G. O., Jr performed this work as an employee of Midwest Research Institute, a subcontractor to Battelle Memorial Institute; and J. K. and M. R. H. performed this work as employees of Battelle Memorial Institute, all under its prime contract with NIAID, under contract no. HHSN272200700016I. NR 21 TC 29 Z9 31 U1 0 U2 3 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 EI 1465-2099 J9 J GEN VIROL JI J. Gen. Virol. PD MAR PY 2014 VL 95 BP 571 EP 577 DI 10.1099/vir.0.061911-0 PN 3 PG 7 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA AK1LV UT WOS:000338177500006 PM 24323636 ER PT J AU Nair, SC Pattaradilokrat, S Zilversmit, MM Dommer, J Nagarajan, V Stephens, MT Xiao, WM Tan, JC Su, XZ AF Nair, Sethu C. Pattaradilokrat, Sittiporn Zilversmit, Martine M. Dommer, Jennifer Nagarajan, Vijayaraj Stephens, Melissa T. Xiao, Wenming Tan, John C. Su, Xin-zhuan TI Genome-wide polymorphisms and development of a microarray platform to detect genetic variations in Plasmodium yoelii SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Malaria; Rodent; High-throughput genotyping; Single nucleotide polymorphism; Genome sequencing ID RODENT MALARIA PARASITE; DRUG-RESISTANCE; IMMUNE-RESPONSES; FALCIPARUM; PHENOTYPE; PATHOLOGY; SELECTION; MODELS; MOUSE; MICE AB The rodent malaria parasite Plasmodium yoelii is an important model for studying malaria immunity and pathogenesis. One approach for studying malaria disease phenotypes is genetic mapping, which requires typing a large number of genetic markers from multiple parasite strains and/or progeny from genetic crosses. Hundreds of microsatellite (MS) markers have been developed to genotype the P. yoelii genome; however, typing a large number of MS markers can be labor intensive, time consuming, and expensive. Thus, development of high-throughput genotyping tools such as DNA microarrays that enable rapid and accurate large-scale genotyping of the malaria parasite will be highly desirable. In this study, we sequenced the genomes of two P. yoelii strains (33X and N67) and obtained a large number of single nucleotide polymorphisms (SNPs). Based on the SNPs obtained, we designed sets of oligonucleotide probes to develop a microarray that could interrogate 11,000 SNPs across the 14 chromosomes of the parasite in a single hybridization. Results from hybridizations of DNA samples of five P. yoelii strains or cloned lines (17XNL, YM, 33X, N67 and N67C) and two progeny from a genetic cross (N67 x 17XNL) to the microarray showed that the array had a high call rate (similar to 97%) and accuracy (99.9%) in calling SNPs, providing a simple and reliable tool for typing the P. yoelii genome. Our data show that the P. yoelii genome is highly polymorphic, although isogenic pairs of parasites were also detected. Additionally, our results indicate that the 33X parasite is a progeny of 17XNL (or YM) and an unknown parasite. The highly accurate and reliable microarray developed in this study will greatly facilitate our ability to study the genetic basis of important traits and the disease it causes. Published by Elsevier B.V. C1 [Nair, Sethu C.; Pattaradilokrat, Sittiporn; Zilversmit, Martine M.; Su, Xin-zhuan] NIAID, Laboratoty Malaria & Vector Researnh, NIH, Bethesda, MD 20892 USA. [Pattaradilokrat, Sittiporn] Chulalongkorn Univ, Fac Sci, Dept Biol, Bangkok 10330, Thailand. [Dommer, Jennifer; Nagarajan, Vijayaraj] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. [Stephens, Melissa T.; Tan, John C.] Univ Notre Dame, Eck Inst Global Hlth, Dept Biol Sci, Notre Dame, IN 46556 USA. [Xiao, Wenming] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Su, XZ (reprint author), NIAID, Laboratoty Malaria & Vector Researnh, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM xsu@niaid.nih.gov OI Pattaradilokrat, Sittiporn/0000-0001-8090-6301; Su, Xinzhuan/0000-0003-3246-3248 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. We thank Brenda Rae Marshall, DPSS, NIAID, for editing. Because SCN, SP, MZ, JD, VN, WX, and X-zS are government employees and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. You can establish rights outside of the U.S. subject to a government use license. NR 31 TC 2 Z9 2 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 EI 1872-9428 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD MAR-APR PY 2014 VL 194 IS 1-2 BP 9 EP 15 DI 10.1016/j.molbiopara.2014.03.006 PG 7 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA AJ9AR UT WOS:000337999700002 PM 24685548 ER PT J AU Ford, N Mofenson, L Shubber, Z Calmy, A Andrieux-Meyer, I Vitoria, M Shaffer, N Renaud, F AF Ford, Nathan Mofenson, Lynne Shubber, Zara Calmy, Alexandra Andrieux-Meyer, Isabelle Vitoria, Marco Shaffer, Nathan Renaud, Francoise TI Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis SO AIDS LA English DT Article DE birth defects; congenital anomalies; efavirenz; HIV; AIDS; pregnancy; systematic review; WHO ID ACTIVE ANTIRETROVIRAL THERAPY; HIV ASSOCIATION GUIDELINES; CONGENITAL-ABNORMALITIES; INFECTED WOMEN; BIRTH-DEFECTS; EXPOSURE; RISK; RECOMMENDATIONS; OUTCOMES; INFANTS AB Introduction:Primate studies and some observational human data have raised concern regarding an association of first-trimester efavirenz exposure with central nervous system congenital anomalies. The objective of this review is to update evidence on efavirenz safety in HIV-infected pregnant women to inform revision of the 2013 WHO guidelines for antiretroviral therapy in low and middle-income countries.Design:A systematic review and meta-analysis.Methods:We searched for studies reporting birth outcomes among women exposed to efavirenz during the first trimester of pregnancy up to 10 January 2014. Relative risks of congenital anomalies comparing women exposed to efavirenz and nonefavirenz-based antiretroviral regimens were pooled using random effects meta-analysis.Results:Twenty-three studies were included in this review, among which 21 reported the birth outcomes of 2026 live births among women exposed to efavirenz during the first trimester of pregnancy. Forty-four congenital anomalies were reported, giving a pooled proportion of 1.63% [95% confidence interval (95% CI) 0.78-2.48], with only one neural tube defect. Twelve studies reported birth outcomes of women exposed to efavirenz or nonefavirenz-containing regimens during the first trimester of pregnancy. Pooled analysis found no differences in overall risks congenital anomalies between these two groups (relative risk 0.78, 95% CI 0.56-1.08). The incidence of neural tube defects was low, 0.05% (95% CI <0.01-0.28), and similar to incidence in the general population.Discussion:This updated analysis found no evidence of an increased risk of overall or central nervous system congenital anomalies associated with first-trimester exposure to efavirenz, similar to previous systematic reviews. This review contributed to the evidence base for the revised 2013 WHO guidelines on antiretroviral therapy, which recommend that efavirenz can be included as part of first-line therapy in adults regardless of sex, and that it can be used throughout pregnancy, including during the first trimester. However, because of the low incidence of central nervous system anomalies in the overall population and relatively small number of exposures in the current literature, continued birth outcomes prospective surveillance is warranted. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Ford, Nathan; Vitoria, Marco; Shaffer, Nathan; Renaud, Francoise] WHO, HIV Dept, CH-1211 Geneva 27, Switzerland. [Mofenson, Lynne] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Rockville, MD USA. [Shubber, Zara] Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis Epidemiol, London, England. [Calmy, Alexandra] Univ Hosp Geneva, HIV AIDS Unit, Infect Dis Serv, Geneva, Switzerland. [Calmy, Alexandra; Andrieux-Meyer, Isabelle] Med Sans Frontieres, Geneva, Switzerland. RP Ford, N (reprint author), WHO, HIV Dept, 20 Ave Appia, CH-1211 Geneva 27, Switzerland. EM fordn@who.int FU Bill and Melinda Gates Foundation FX We would like to thank Martina Penazatto for comments on an earlier draft, and Heather Watts for assisting with access to data from the Antiretroviral Pregnancy Registry. The review was supported by funds from the Bill and Melinda Gates Foundation. This manuscript represents the views of the authors and does not necessarily represent the view of the National Institutes of Health or Department of Health and Human Services. NR 51 TC 24 Z9 25 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD MAR PY 2014 VL 28 SU 2 BP S123 EP S131 DI 10.1097/QAD.0000000000000231 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AJ4XO UT WOS:000337683200005 PM 24849471 ER PT J AU Siberry, G Tindyebwa, D AF Siberry, George Tindyebwa, Denis TI Commentary: When to start and what to use in children - recommendations and rationale SO AIDS LA English DT Article ID HIV-INFECTED CHILDREN; ANTIRETROVIRAL THERAPY; NEVIRAPINE; TRIAL C1 [Siberry, George] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis MPID Branch, NIH, Bethesda, MD 20892 USA. [Tindyebwa, Denis] ANECCA, Kampala, Uganda. RP Siberry, G (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis MPID Branch, NIH, 6100 Execut Blvd,Room 4B11H, Bethesda, MD 20892 USA. EM siberryg@mail.nih.gov NR 10 TC 2 Z9 2 U1 0 U2 0 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 MAR PY 2014 VL 28 SU 2 BP S133 EP S135 DI 10.1097/QAD.0000000000000241 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AJ4XO UT WOS:000337683200006 PM 24849472 ER PT J AU Parsons, HM Harlan, LC Stevens, JL Ullmann, CD AF Parsons, Helen M. Harlan, Linda C. Stevens, Jennifer L. Ullmann, Claudio Dansky TI Treatment of Small Cell Lung Cancer in Academic and Community Settings Factors Associated With Receiving Standard Therapy and Survival SO CANCER JOURNAL LA English DT Article DE small cell; lung cancer; treatment patterns; survival ID PROPHYLACTIC CRANIAL IRRADIATION; END RESULTS DATABASE; MEDICARE BENEFICIARIES; UNITED-STATES; OUTCOMES; EPIDEMIOLOGY; SURVEILLANCE; CHEMOTHERAPY; CARCINOMA; CISPLATIN AB Purpose: Small cell lung cancer (SCLC) historically has had poor prognosis. Clinical trials have demonstrated improved survival among patients receiving standard platinum-/etoposide-based chemotherapy. Whereas treatment patterns and outcomes have been evaluated for patients with SCLC in clinical trials, population-based practice patterns are not well known. Methods: The National Cancer Institute's Patterns of Care study was used to evaluate patient and provider factors associated with standard treatment, clinical trial enrollment, and 12-month relative hazard of death. Results: Among 931 patients with SCLC diagnosed in 2007 in academic and community settings, 72.2% of patients with limited-stage (LS) disease received chemoradiation and 42.2% of patients with extensive-stage (ES) disease received chemotherapy only; the expected treatment scenarios by stage. Less than 1% of the patients enrolled in clinical trials and 2.1% of the patients with LS disease and 3.4% of the patients with ES disease refused any type of treatment. Patients 80 years or older at diagnosis and those with pneumonia/lung collapse were less likely to receive chemoradiation for LS disease. Patients treated in hospitals with residency programs were more likely to receive chemotherapy for ES disease, and patients 80 years or older were less likely to receive chemotherapy for ES disease. Finally, female patients with LS disease, black patients with ES disease, and all patients who received chemotherapy compared to receiving radiation alone or no therapy experienced significantly lower mortality. Discussion: Despite the demonstrated lower mortality, a relatively large proportion of patients with SCLC are not treated with a standard treatment regimen. Future studies should evaluate efforts to promote use of appropriate treatment regimens and encourage clinical trial participation. C1 [Parsons, Helen M.; Harlan, Linda C.] NCI, Appl Res Program, Bethesda, MD 20892 USA. [Stevens, Jennifer L.] Informat Management Serv Inc, Calverton, MD USA. [Ullmann, Claudio Dansky] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Parsons, HM (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Sch Med, Dept Epidemiol & Biostat, 7703 Floyd Curl Dr,Mail Code 7933, San Antonio, TX 78229 USA. EM parsonsh@uthscsa.edu FU National Cancer Institute [HHSN261201000024C, HHSN261201000025C, HHSN261201000032C, HHSN261201000027C]; National Cancer Institute. [HHSN261201000026C, HHSN261201000140C, HHSN261201000037C, HHSN261201000033C, HHSN261201000034C, HHSN261201000035C, HHSN261201000029C, HHSN261201000031C, HHSN261201000028C, HHSN261201000030C, K07CA175063] FX Dr. Parsons receives support from the National Cancer Institute (K07CA175063).; This work was supported by National Cancer Institute contracts HHSN261201000024C, HHSN261201000025C, HHSN261201000032C, HHSN261201000027C, HHSN261201000026C, HHSN261201000140C, HHSN261201000037C, HHSN261201000033C, HHSN261201000034C, HHSN261201000035C, HHSN261201000029C, HHSN261201000031C, HHSN261201000028C, HHSN261201000030C. NR 30 TC 4 Z9 4 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 EI 1540-336X J9 CANCER J JI Cancer J. PD MAR-APR PY 2014 VL 20 IS 2 BP 97 EP 104 PG 8 WC Oncology SC Oncology GA AJ4ZD UT WOS:000337688200001 PM 24667952 ER PT J AU Wassmann, C AF Wassmann, Claudia TI "PICTURESQUE INCISIVENESS": EXPLAINING THE CELEBRITY OF JAMES'S THEORY OF EMOTION SO JOURNAL OF THE HISTORY OF THE BEHAVIORAL SCIENCES LA English DT Article ID LANGE THEORY; FEELINGS AB William James is the name that comes to mind when asked about scientific explanations of emotion in the nineteenth century. However, strictly speaking James's theory of emotion does not explain emotions and never did. Indeed, James contemporaries pointed this out already more than a hundred years ago. Why could "James' theory" nevertheless become a landmark that psychologists, neuroscientists, and historians alike refer to today? The strong focus on James and Anglo-American sources in historiography has overshadowed all other answers given to the question of emotion at the time of James. For that reason, the article returns to the primary sources and places James's work back into the context of nineteenth century brain research in which it developed. (C) 2014 Wiley Periodicals, Inc. C1 [Wassmann, Claudia] Max Planck Inst Human Dev, Ctr Hist Emot, Berlin, Germany. [Wassmann, Claudia] NIH, Bethesda, MD USA. RP Wassmann, C (reprint author), Univ Navarra, Inst Culture & Soc, E-31080 Pamplona, Spain. NR 85 TC 2 Z9 2 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-5061 EI 1520-6696 J9 J HIST BEHAV SCI JI J. Hist. Behav. Sci. PD SPR PY 2014 VL 50 IS 2 BP 166 EP 188 DI 10.1002/jhbs.21651 PG 23 WC History Of Social Sciences SC Social Sciences - Other Topics GA AI9TL UT WOS:000337280100003 PM 24615670 ER PT J AU Moyes, CL Henry, AJ Golding, N Huang, Z Singh, B Baird, JK Newton, PN Huffman, M Duda, KA Drakeley, CJ Elyazar, IRF Anstey, NM Chen, QJ Zommers, Z Bhatt, S Gething, PW Hay, SI AF Moyes, Catherine L. Henry, Andrew J. Golding, Nick Huang, Zhi Singh, Balbir Baird, J. Kevin Newton, Paul N. Huffman, Michael Duda, Kirsten A. Drakeley, Chris J. Elyazar, Iqbal R. F. Anstey, Nicholas M. Chen, Qijun Zommers, Zinta Bhatt, Samir Gething, Peter W. Hay, Simon I. TI Defining the Geographical Range of the Plasmodium knowlesi Reservoir SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID ANOPHELES-BALABACENSIS-BALABACENSIS; LONG-TAILED MACAQUE; MACACA-FASCICULARIS; SIMIAN-MALARIA; HUMAN INFECTIONS; MALAYSIAN-BORNEO; MONKEY MALARIA; VIVAX MALARIA; P. FALCIPARUM; M-MULATTA AB Background: The simian malaria parasite, Plasmodium knowlesi, can cause severe and fatal disease in humans yet it is rarely included in routine public health reporting systems for malaria and its geographical range is largely unknown. Because malaria caused by P. knowlesi is a truly neglected tropical disease, there are substantial obstacles to defining the geographical extent and risk of this disease. Information is required on the occurrence of human cases in different locations, on which non-human primates host this parasite and on which vectors are able to transmit it to humans. We undertook a systematic review and ranked the existing evidence, at a subnational spatial scale, to investigate the potential geographical range of the parasite reservoir capable of infecting humans. Methodology/Principal Findings: After reviewing the published literature we identified potential host and vector species and ranked these based on how informative they are for the presence of an infectious parasite reservoir, based on current evidence. We collated spatial data on parasite occurrence and the ranges of the identified host and vector species. The ranked spatial data allowed us to assign an evidence score to 475 subnational areas in 19 countries and we present the results on a map of the Southeast and South Asia region. Conclusions/Significance: We have ranked subnational areas within the potential disease range according to evidence for presence of a disease risk to humans, providing geographical evidence to support decisions on prevention, management and prophylaxis. This work also highlights the unknown risk status of large parts of the region. Within this unknown category, our map identifies which areas have most evidence for the potential to support an infectious reservoir and are therefore a priority for further investigation. Furthermore we identify geographical areas where further investigation of putative host and vector species would be highly informative for the region-wide assessment. C1 [Moyes, Catherine L.; Henry, Andrew J.; Golding, Nick; Huang, Zhi; Duda, Kirsten A.; Bhatt, Samir; Gething, Peter W.; Hay, Simon I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. [Singh, Balbir] Univ Malaysia Sarawak, Malaria Res Ctr, Kuching, Sarawak, Malaysia. [Baird, J. Kevin; Elyazar, Iqbal R. F.] Eijkman Oxford Clin Res Unit, Jakarta, Indonesia. [Baird, J. Kevin; Newton, Paul N.] Univ Oxford, Ctr Trop Med, Oxford, England. [Newton, Paul N.] Mahosot Hosp, Microbiol Lab, Wellcome Trust Res Unit, Lao Oxford Mahosot Hosp, Viangchan, Laos. [Huffman, Michael] Kyoto Univ, Primate Res Inst, Inuyama, Aichi 484, Japan. [Drakeley, Chris J.] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Immunol & Infect, London WC1, England. [Anstey, Nicholas M.] Menzies Sch Hlth Res, Global & Trop Hlth Div, Darwin, NT, Australia. [Chen, Qijun] Chinese Acad Med Sci, Inst Pathogen Biol, Beijing 100730, Peoples R China. [Chen, Qijun] Jilin Univ, Key Lab Zoonosis, Changchun 130023, Peoples R China. [Zommers, Zinta] United Nations Environm Programme, Div Early Warning & Assessment, Nairobi, Kenya. [Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Moyes, CL (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, S Parks Rd, Oxford OX1 3PS, England. EM catherine.moyes@zoo.ox.ac.uk RI Hay, Simon/F-8967-2015; OI Hay, Simon/0000-0002-0611-7272; Singh, Balbir/0000-0002-9143-3965; Golding, Nick/0000-0001-8916-5570; Gething, Peter/0000-0001-6759-5449; Moyes, Catherine/0000-0002-8028-4079 FU Wellcome Trust [091835, B9RZGS0, 095066]; Bill & Melinda Gates Foundation [OPP1053338, OPP1068048]; Vector-Borne Disease Network; Wellcome Trust of Great Britain; Asia Africa Science Platform Program of the Japan Society for the Promotion of Science; Japanese Ministry of Education Science; ESEI/UKRC programme grant on Plasmodium knowlesi [G1100796]; National Health and Medical Research Council Practitioner Fellowship; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX CLM and AJH are supported by the Wellcome Trust [091835]. NG is funded by a Bill & Melinda Gates Foundation grant [OPP1053338]. ZH is funded by the Vector-Borne Disease Network. PNN is funded by the Wellcome Trust of Great Britain. MH is funded by the Asia Africa Science Platform Program of the Japan Society for the Promotion of Science and Grants-In-Aid for Overseas Research, Japanese Ministry of Education Science awarded to Shusuke Nakazawa. CJD is funded by a ESEI/UKRC programme grant on Plasmodium knowlesi [G1100796]. IRFE is supported by a Wellcome Trust Research Training Fellowship [B9RZGS0]. NMA is supported by a National Health and Medical Research Council Practitioner Fellowship. PWG is a Medical Research Council Career Development Fellow [K00669X] and receives support from the Bill and Melinda Gates Foundation [OPP1068048] that also supports SB. SIH is funded by a Senior Research Fellowship from the Wellcome Trust that also supports KAD [095066]. SIH also acknowledges support from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health (http://www.fic.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 91 TC 23 Z9 23 U1 6 U2 28 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD MAR PY 2014 VL 8 IS 3 AR e2780 DI 10.1371/journal.pntd.0002780 PG 13 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AJ0MU UT WOS:000337348800043 PM 24676231 ER PT J AU Zahedifard, F Gholami, E Taheri, T Taslimi, Y Doustdari, F Seyed, N Torkashvand, F Meneses, C Papadopoulou, B Kamhawi, S Valenzuela, JG Rafati, S AF Zahedifard, Farnaz Gholami, Elham Taheri, Tahereh Taslimi, Yasaman Doustdari, Fatemeh Seyed, Negar Torkashvand, Fatemeh Meneses, Claudio Papadopoulou, Barbara Kamhawi, Shaden Valenzuela, Jesus G. Rafati, Sima TI Enhanced Protective Efficacy of Nonpathogenic Recombinant Leishmania tarentolae Expressing Cysteine Proteinases Combined with a Sand Fly Salivary Antigen SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID VISCERAL LEISHMANIASIS; VACCINE CANDIDATES; MICE; GENE; CHALLENGE; IMMUNITY; VECTOR; CELLS; STAGE AB Background: Novel vaccination approaches are needed to prevent leishmaniasis. Live attenuated vaccines are the gold standard for protection against intracellular pathogens such as Leishmania and there have been new developments in this field. The nonpathogenic to humans lizard protozoan parasite, Leishmania (L) tarentolae, has been used effectively as a vaccine platform against visceral leishmaniasis in experimental animal models. Correspondingly, pre-exposure to sand fly saliva or immunization with a salivary protein has been shown to protect mice against cutaneous leishmaniasis. Methodology/Principal Findings: Here, we tested the efficacy of a novel combination of established protective parasite antigens expressed by L. tarentolae together with a sand fly salivary antigen as a vaccine strategy against L. major infection. The immunogenicity and protective efficacy of different DNA/Live and Live/Live prime-boost vaccination modalities with live recombinant L. tarentolae stably expressing cysteine proteinases (type I and II, CPA/CPB) and PpSP15, an immunogenic salivary protein from Phlebotomus papatasi, a natural vector of L. major, were tested both in susceptible BALB/c and resistant C57BL/6 mice. Both humoral and cellular immune responses were assessed before challenge and at 3 and 10 weeks after Leishmania infection. In both strains of mice, the strongest protective effect was observed when priming with PpSP15 DNA and boosting with PpSP15 DNA and live recombinant L. tarentolae stably expressing cysteine proteinase genes. Conclusion/Significance: The present study is the first to use a combination of recombinant L. tarentolae with a sand fly salivary antigen (PpSP15) and represents a novel promising vaccination approach against leishmaniasis. C1 [Zahedifard, Farnaz; Gholami, Elham; Taheri, Tahereh; Taslimi, Yasaman; Doustdari, Fatemeh; Seyed, Negar; Rafati, Sima] Pasteur Inst Iran, Mol Immunol & Vaccine Res Lab, Tehran, Iran. [Torkashvand, Fatemeh] Pasteur Inst Iran, Biotechnol Res Ctr, Tehran, Iran. [Meneses, Claudio; Kamhawi, Shaden; Valenzuela, Jesus G.] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Papadopoulou, Barbara] Univ Laval, CHUL Res Ctr, CHU Quebec Res Ctr, Res Ctr Infect Dis, Quebec City, PQ, Canada. [Papadopoulou, Barbara] Univ Laval, Dept Microbiol Infect Dis & Immunol, Quebec City, PQ, Canada. RP Zahedifard, F (reprint author), Pasteur Inst Iran, Mol Immunol & Vaccine Res Lab, Tehran, Iran. EM s_rafati@yahoo.com FU CRDF [INB2-7015-TN-10]; Pasteur Institute of Iran; Intramural Research Program, NIAID, NIH FX This project received financial support from CRDF (award number INB2-7015-TN-10) and Pasteur Institute of Iran. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work (JGV, SK) was supported in part by the Intramural Research Program, NIAID, NIH. NR 36 TC 19 Z9 19 U1 2 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD MAR PY 2014 VL 8 IS 3 AR e2751 DI 10.1371/journal.pntd.0002751 PG 14 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AJ0MU UT WOS:000337348800033 PM 24675711 ER PT J AU Chiu, C McCausland, M Sidney, J Duh, FM Rouphael, N Mehta, A Mulligan, M Carrington, M Wieland, A Sullivan, NL Weinberg, A Levin, MJ Pulendran, B Peters, B Sette, A Ahmed, R AF Chiu, Christopher McCausland, Megan Sidney, John Duh, Fuh-Mei Rouphael, Nadine Mehta, Aneesh Mulligan, Mark Carrington, Mary Wieland, Andreas Sullivan, Nicole L. Weinberg, Adriana Levin, Myron J. Pulendran, Bali Peters, Bjoern Sette, Alessandro Ahmed, Rafi TI Broadly Reactive Human CD8 T Cells that Recognize an Epitope Conserved between VZV, HSV and EBV SO PLOS PATHOGENS LA English DT Article ID VARICELLA-ZOSTER-VIRUS; HERPES-SIMPLEX VIRUSES; EPSTEIN-BARR-VIRUS; IMMUNE EVASION; VACCINE; INFECTION; RESPONSES; ANTIGENS; DELETION AB Human herpesviruses are important causes of potentially severe chronic infections for which T cells are believed to be necessary for control. In order to examine the role of virus-specific CD8 T cells against Varicella Zoster Virus (VZV), we generated a comprehensive panel of potential epitopes predicted in silico and screened for T cell responses in healthy VZV seropositive donors. We identified a dominant HLA-A*0201-restricted epitope in the VZV ribonucleotide reductase subunit 2 and used a tetramer to analyze the phenotype and function of epitope-specific CD8 T cells. Interestingly, CD8 T cells responding to this VZV epitope also recognized homologous epitopes, not only in the other alpha-herpesviruses, HSV-1 and HSV-2, but also the gamma-herpesvirus, EBV. Responses against these epitopes did not depend on previous infection with the originating virus, thus indicating the cross-reactive nature of this T cell population. Between individuals, the cells demonstrated marked phenotypic heterogeneity. This was associated with differences in functional capacity related to increased inhibitory receptor expression (including PD-1) along with decreased expression of co-stimulatory molecules that potentially reflected their stimulation history. Vaccination with the live attenuated Zostavax vaccine did not efficiently stimulate a proliferative response in this epitope-specific population. Thus, we identified a human CD8 T cell epitope that is conserved in four clinically important herpesviruses but that was poorly boosted by the current adult VZV vaccine. We discuss the concept of a "pan-herpesvirus" vaccine that this discovery raises and the hurdles that may need to be overcome in order to achieve this. C1 [Chiu, Christopher; McCausland, Megan; Wieland, Andreas; Sullivan, Nicole L.; Pulendran, Bali; Ahmed, Rafi] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Chiu, Christopher; McCausland, Megan; Wieland, Andreas; Sullivan, Nicole L.; Ahmed, Rafi] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Chiu, Christopher] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Ctr Resp Infect, London, England. [Sidney, John; Peters, Bjoern; Sette, Alessandro] La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA USA. [Duh, Fuh-Mei; Carrington, Mary] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD USA. [Duh, Fuh-Mei; Carrington, Mary] MIT & Harvard, Ragon Inst MGH, Cambridge, MA USA. [Rouphael, Nadine; Mulligan, Mark] Emory Univ, Sch Med, Emory Vaccine Ctr, Hope Clin, Atlanta, GA USA. [Rouphael, Nadine; Mehta, Aneesh; Mulligan, Mark] Emory Univ, Sch Med, Div Infect Dis, Atlanta, GA USA. [Weinberg, Adriana; Levin, Myron J.] Univ Colorado, Dept Pediat, Aurora, CO USA. [Weinberg, Adriana; Levin, Myron J.] Univ Colorado, Dept Med, Aurora, CO USA. [Weinberg, Adriana; Levin, Myron J.] Univ Colorado, Dept Pathol, Aurora, CO USA. RP Chiu, C (reprint author), Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. EM c.chiu@imperial.ac.uk; rahmed@emory.edu RI Mehta, Aneesh/B-8054-2012 OI Mehta, Aneesh/0000-0002-6552-9162 FU NIH/NIAID [U19-A1057266, U19-A1090023-01]; Cooperative Centers for Translational Research on Human Immunology and Biodefense (CCHI) grant [U19-AI05726]; Frederick National Laboratory for Cancer Research [HHSN261200800001E]; Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research; Medical Research Council, UK [G0902266]; Irvington Institute Fellowship Program of the Cancer Research Institute FX This work was in part funded by NIH/NIAID U19-A1057266, NIH/NIAID U19-A1090023-01 (RA), Cooperative Centers for Translational Research on Human Immunology and Biodefense (CCHI) grant U19-AI05726, with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E, and by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. CC is funded by the Medical Research Council, UK (G0902266). NLS was supported by the Irvington Institute Fellowship Program of the Cancer Research Institute. 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 11 Z9 11 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD MAR PY 2014 VL 10 IS 3 AR e1004008 DI 10.1371/journal.ppat.1004008 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AJ2FF UT WOS:000337470300050 PM 24675761 ER PT J AU Cirelli, KM Gorfu, G Hassan, MA Printz, M Crown, D Leppla, SH Grigg, ME Saeij, JPJ Moayeri, M AF Cirelli, Kimberly M. Gorfu, Gezahegn Hassan, Musa A. Printz, Morton Crown, Devorah Leppla, Stephen H. Grigg, Michael E. Saeij, Jeroen P. J. Moayeri, Mahtab TI Inflammasome Sensor NLRP1 Controls Rat Macrophage Susceptibility to Toxoplasma gondii SO PLOS PATHOGENS LA English DT Article ID RECOMBINANT INBRED STRAINS; HOST-CELL SUBVERSION; CASPASE-1 ACTIVATION; MURINE MACROPHAGES; PROTEASES; PARASITE; ANTHRAX; EXPRESSION; RECEPTORS; INFECTION AB Toxoplasma gondii is an intracellular parasite that infects a wide range of warm-blooded species. Rats vary in their susceptibility to this parasite. The Toxo1 locus conferring Toxoplasma resistance in rats was previously mapped to a region of chromosome 10 containing Nlrp1. This gene encodes an inflammasome sensor controlling macrophage sensitivity to anthrax lethal toxin (LT) induced rapid cell death (pyroptosis). We show here that rat strain differences in Toxoplasma infected macrophage sensitivity to pyroptosis, IL-1 beta/IL-18 processing, and inhibition of parasite proliferation are perfectly correlated with NLRP1 sequence, while inversely correlated with sensitivity to anthrax LT-induced cell death. Using recombinant inbred rats, SNP analyses and whole transcriptome gene expression studies, we narrowed the candidate genes for control of Toxoplasma-mediated rat macrophage pyroptosis to four genes, one of which was Nlrp1. Knockdown of Nlrp1 in pyroptosis-sensitive macrophages resulted in higher parasite replication and protection from cell death. Reciprocally, overexpression of the NLRP1 variant from Toxoplasma-sensitive macrophages in pyroptosis-resistant cells led to sensitization of these resistant macrophages. Our findings reveal Toxoplasma as a novel activator of the NLRP1 inflammasome in rat macrophages. C1 [Cirelli, Kimberly M.; Hassan, Musa A.; Saeij, Jeroen P. J.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Gorfu, Gezahegn; Grigg, Michael E.] NIAID, Mol Parasitol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Printz, Morton] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. [Crown, Devorah; Leppla, Stephen H.; Moayeri, Mahtab] NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Cirelli, KM (reprint author), MIT, Dept Biol, Cambridge, MA 02139 USA. EM griggm@niaid.nih.gov; jsaeij@mit.edu; mmoayeri@niaid.nih.gov RI Hassan, Musa/E-8324-2016; OI Hassan, Musa/0000-0002-0371-3300; Saeij, Jeroen/0000-0003-0289-7109 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases; National Institutes of Health [F31-AI104170, R01-AI080621]; Wellcome Trust-MIT postdoctoral fellowship FX This research was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. KMC was supported by National Institutes of Health (F31-AI104170), MAH by a Wellcome Trust-MIT postdoctoral fellowship, and JPJS by National Institutes of Health (R01-AI080621. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 25 Z9 26 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD MAR PY 2014 VL 10 IS 3 AR e1003927 DI 10.1371/journal.ppat.1003927 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AJ2FF UT WOS:000337470300008 PM 24626226 ER PT J AU de Wit, E Prescott, J Falzarano, D Bushmaker, T Scott, D Feldmann, H Munster, VJ AF de Wit, Emmie Prescott, Joseph Falzarano, Darryl Bushmaker, Trenton Scott, Dana Feldmann, Heinz Munster, Vincent J. TI Foodborne Transmission of Nipah Virus in Syrian Hamsters SO PLOS PATHOGENS LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; FLYING-FOXES; BANGLADESH; PARAMYXOVIRUS; INFECTION; MALAYSIA; ROUTE; MODEL; BATS AB Since 2001, outbreaks of Nipah virus have occurred almost every year in Bangladesh with high case-fatality rates. Epidemiological data suggest that in Bangladesh, Nipah virus is transmitted from the natural reservoir, fruit bats, to humans via consumption of date palm sap contaminated by bats, with subsequent human-to-human transmission. To experimentally investigate this epidemiological association between drinking of date palm sap and human cases of Nipah virus infection, we determined the viability of Nipah virus (strain Bangladesh/200401066) in artificial palm sap. At 22 degrees C virus titers remained stable for at least 7 days, thus potentially allowing food-borne transmission. Next, we modeled food-borne Nipah virus infection by supplying Syrian hamsters with artificial palm sap containing Nipah virus. Drinking of 5 x 10(8) TCID50 of Nipah virus resulted in neurological disease in 5 out of 8 hamsters, indicating that food-borne transmission of Nipah virus can indeed occur. In comparison, intranasal (i.n.) inoculation with the same dose of Nipah virus resulted in lethal respiratory disease in all animals. In animals infected with Nipah virus via drinking, virus was detected in respiratory tissues rather than in the intestinal tract. Using fluorescently labeled Nipah virus particles, we showed that during drinking, a substantial amount of virus is deposited in the lungs, explaining the replication of Nipah virus in the respiratory tract of these hamsters. Besides the ability of Nipah virus to infect hamsters via the drinking route, Syrian hamsters infected via that route transmitted the virus through direct contact with naive hamsters in 2 out of 24 transmission pairs. Although these findings do not directly prove that date palm sap contaminated with Nipah virus by bats is the origin of Nipah virus outbreaks in Bangladesh, they provide the first experimental support for this hypothesis. Understanding the Nipah virus transmission cycle is essential for preventing and mitigating future outbreaks. C1 [de Wit, Emmie; Prescott, Joseph; Falzarano, Darryl; Bushmaker, Trenton; Feldmann, Heinz; Munster, Vincent J.] NIAID, Virol Lab, NIH, Hamilton, MT 59840 USA. [Feldmann, Heinz] NIAID, Rocky Mt Vet Branch, NIH, Hamilton, MT USA. [Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. RP de Wit, E (reprint author), NIAID, Virol Lab, NIH, Hamilton, MT 59840 USA. EM emmie.dewit@nih.gov; vincent.munster@nih.gov OI de Wit, Emmie/0000-0002-9763-7758; Munster, Vincent/0000-0002-2288-3196 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 13 Z9 13 U1 0 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD MAR PY 2014 VL 10 IS 3 AR e1004001 DI 10.1371/journal.ppat.1004001 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AJ2FF UT WOS:000337470300044 PM 24626480 ER PT J AU Kearney, MF Spindler, J Shao, W Yu, S Anderson, EM O'Shea, A Rehm, C Poethke, C Kovacs, N Mellors, JW Coffin, JM Maldarelli, F AF Kearney, Mary F. Spindler, Jonathan Shao, Wei Yu, Sloane Anderson, Elizabeth M. O'Shea, Angeline Rehm, Catherine Poethke, Carry Kovacs, Nicholas Mellors, John W. Coffin, John M. Maldarelli, Frank TI Lack of Detectable HIV-1 Molecular Evolution during Suppressive Antiretroviral Therapy SO PLOS PATHOGENS LA English DT Article ID VIRUS TYPE-1 VIREMIA; LOW-LEVEL VIREMIA; CD4(+) T-CELLS; RALTEGRAVIR INTENSIFICATION; DRUG-RESISTANCE; LYMPHOID-TISSUE; INFECTED INDIVIDUALS; RESIDUAL VIREMIA; PLASMA VIREMIA; REPLICATION AB A better understanding of changes in HIV-1 population genetics with combination antiretroviral therapy (cART) is critical for designing eradication strategies. We therefore analyzed HIV-1 genetic variation and divergence in patients' plasma before cART, during suppression on cART, and after viral rebound. Single-genome sequences of plasma HIV-1 RNA were obtained from HIV-1 infected patients prior to cART (N = 14), during suppression on cART (N = 14) and/or after viral rebound following interruption of cART (N = 5). Intra-patient population diversity was measured by average pairwise difference (APD). Population structure was assessed by phylogenetic analyses and a test for panmixia. Measurements of intra-population diversity revealed no significant loss of overall genetic variation in patients treated for up to 15 years with cART. A test for panmixia, however, showed significant changes in population structure in 2/10 patients after short-term cART (<1 year) and in 7/10 patients after long-term cART (1-15 years). The changes consisted of diverse sets of viral variants prior to cART shifting to populations containing one or more genetically uniform subpopulations during cART. Despite these significant changes in population structure, rebound virus after long-term cART had little divergence from pretherapy virus, implicating long-lived cells infected before cART as the source for rebound virus. The appearance of genetically uniform virus populations and the lack of divergence after prolonged cART and cART interruption provide strong evidence that HIV-1 persists in long-lived cells infected before cART was initiated, that some of these infected cells may be capable of proliferation, and that on-going cycles of viral replication are not evident. C1 [Kearney, Mary F.; Spindler, Jonathan; Yu, Sloane; Anderson, Elizabeth M.; Poethke, Carry; Kovacs, Nicholas; Maldarelli, Frank] NCI, HIV Drug Resistance Program 1, Ctr Canc Res, Frederick, MD 21701 USA. [Shao, Wei] SAIC, Adv Biomed Comp Ctr, Frederick, MD USA. [O'Shea, Angeline; Rehm, Catherine] NIAID, Immunoregulat Lab, NIH Bethesda, Bethesda, MD USA. [Mellors, John W.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Kearney, MF (reprint author), NCI, HIV Drug Resistance Program 1, Ctr Canc Res, Frederick, MD 21701 USA. EM kearneym@ncifcrf.gov FU Federal funds from the National Cancer Institute, NIH; FM Kirby Foundation; National Cancer Institute (SAIC) [25XS119] FX Funding for this research was provided with Federal funds from the National Cancer Institute, NIH. JMC was a Research Professor of the American Cancer Society, with support from the FM Kirby Foundation. Supported in part (JWM) by funding from the National Cancer Institute (SAIC contract 25XS119). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 50 Z9 51 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD MAR PY 2014 VL 10 IS 3 AR e1004010 DI 10.1371/journal.ppat.1004010 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AJ2FF UT WOS:000337470300051 PM 24651464 ER PT J AU Klase, Z Yedavalli, VSRK Houzet, L Perkins, M Maldarelli, F Brenchley, J Strebel, K Liu, P Jeang, KT AF Klase, Zachary Yedavalli, Venkat S. R. K. Houzet, Laurent Perkins, Molly Maldarelli, Frank Brenchley, Jason Strebel, Klaus Liu, Paul Jeang, Kuan-Teh TI Activation of HIV-1 from Latent Infection via Synergy of RUNX1 Inhibitor Ro5-3335 and SAHA SO PLOS PATHOGENS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL DIFFERENTIATION; TAT ANTAGONIST; TRANSCRIPTION INITIATION; MOLECULAR-BASIS; CBF-BETA; GENE; EXPRESSION; PROTEINS; PHOSPHORYLATION AB A major barrier to the elimination of HIV-1 infection is the presence of a pool of long-lived, latently infected CD4+ memory T-cells. The search for treatments to re-activate latent HIV to aid in clearance is hindered by the incomplete understanding of the mechanisms that lead to transcriptional silencing of viral gene expression in host cells. Here we identify a previously unknown role for RUNX1 in HIV-1 transcriptional latency. The RUNX proteins, in combination with the co-factor CBF-beta, are critical transcriptional regulators in T-cells. RUNX1 strongly modulates CD4 expression and contributes to CD4+ T-cell function. We show that RUNX1 can bind DNA sequences within the HIV-1 LTR and that this binding represses transcription. Using patient samples we show a negative correlation between RUNX1 expression and viral load. Furthermore, we find that pharmacologic inhibition of RUNX1 by a small molecule inhibitor, Ro5-3335, synergizes with the histone deacetylase (HDAC) inhibitor SAHA (Vorinostat) to enhance the activation of latent HIV-1 in both cell lines and PBMCs from patients. Our findings indicate that RUNX1 and CBF-beta cooperate in cells to modulate HIV-1 replication, identifying for the first time RUNX1 as a cellular factor involved in HIV-1 latency. This work highlights the therapeutic potential of inhibitors of RUNX1 to reactivate virus and aid in clearance of HIV-1. C1 [Klase, Zachary; Yedavalli, Venkat S. R. K.; Houzet, Laurent; Perkins, Molly; Brenchley, Jason; Strebel, Klaus; Jeang, Kuan-Teh] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Maldarelli, Frank] NCI, Host Virus Interact Branch, NIH, Bethesda, MD 20892 USA. [Liu, Paul] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Klase, Z (reprint author), NIAID, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM klaseza@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, NIH; National Human Genome Research Institute, NIH; Intramural AIDS Targeted Antiviral Program from the Office of the Director, NIH; Office of AIDS Research, NIH FX This work was supported by the intramural research programs of National Institute of Allergy and Infectious Diseases and National Human Genome Research Institute, NIH, and by the Intramural AIDS Targeted Antiviral Program from the Office of the Director, NIH. ZK was supported by a fellowship from the Office of AIDS Research, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 12 Z9 12 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD MAR PY 2014 VL 10 IS 3 AR e1003997 DI 10.1371/journal.ppat.1003997 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AJ2FF UT WOS:000337470300040 PM 24651404 ER PT J AU Labo, N Miley, W Marshall, V Gillette, W Esposito, D Bess, M Turano, A Uldrick, T Polizzotto, MN Wyvill, KM Bagni, R Yarchoan, R Whitby, D AF Labo, Nazzarena Miley, Wendell Marshall, Vickie Gillette, William Esposito, Dominic Bess, Matthew Turano, Alexandra Uldrick, Thomas Polizzotto, Mark N. Wyvill, Kathleen M. Bagni, Rachel Yarchoan, Robert Whitby, Denise TI Heterogeneity and Breadth of Host Antibody Response to KSHV Infection Demonstrated by Systematic Analysis of the KSHV Proteome SO PLOS PATHOGENS LA English DT Article ID SARCOMA-ASSOCIATED HERPESVIRUS; MULTICENTRIC CASTLEMAN DISEASE; HUMAN-IMMUNODEFICIENCY-VIRUS; EPSTEIN-BARR-VIRUS; KAPOSIS-SARCOMA; HUMAN-HERPESVIRUS-8 INFECTION; RISK-FACTORS; SEROLOGIC ASSAYS; ORF59 PROTEIN; DNA-SEQUENCES AB The Kaposi sarcoma associated herpesvirus (KSHV) genome encodes more than 85 open reading frames (ORFs). Serological evaluation of KSHV infection now generally relies on reactivity to just one latent and/or one lytic protein (commonly ORF73 and K8.1). Most of the other polypeptides encoded by the virus have unknown antigenic profiles. We have systematically expressed and purified products from 72 KSHV ORFs in recombinant systems and analyzed seroreactivity in US patients with KSHV-associated malignancies, and US blood donors (low KSHV seroprevalence population). We identified several KSHV proteins (ORF38, ORF61, ORF59 and K5) that elicited significant responses in individuals with KSHV-associated diseases. In these patients, patterns of reactivity were heterogeneous; however, HIV infection appeared to be associated with breadth and intensity of serological responses. Improved antigenic characterization of additional ORFs may increase the sensitivity of serologic assays, lead to more rapid progresses in understanding immune responses to KSHV, and allow for better comprehension of the natural history of KSHV infection. To this end, we have developed a bead-based multiplex assay detecting antibodies to six KSHV antigens. C1 [Labo, Nazzarena; Miley, Wendell; Marshall, Vickie; Whitby, Denise] Frederick Natl Lab Canc Res, Viral Oncol Sect, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Labo, Nazzarena] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Gillette, William; Esposito, Dominic; Bess, Matthew; Turano, Alexandra; Bagni, Rachel] Frederick Natl Lab Canc Res, Prot Express Lab, Adv Technol Program, Frederick, MD USA. [Uldrick, Thomas; Polizzotto, Mark N.; Wyvill, Kathleen M.; Yarchoan, Robert] NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. RP Labo, N (reprint author), Frederick Natl Lab Canc Res, Viral Oncol Sect, AIDS & Canc Virus Program, Frederick, MD 21702 USA. EM whitbyd@mail.nih.gov RI Labo, Nazzarena/H-8655-2012 OI Labo, Nazzarena/0000-0001-5953-4064 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E and the Intramural Research Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 8 Z9 8 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD MAR PY 2014 VL 10 IS 3 AR e1004046 DI 10.1371/journal.ppat.1004046 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AJ2FF UT WOS:000337470300068 PM 24675986 ER PT J AU Lakdawala, SS Wu, YC Wawrzusin, P Kabat, J Broadbent, AJ Lamirande, EW Fodor, E Altan-Bonnet, N Shroff, H Subbarao, K AF Lakdawala, Seema S. Wu, Yicong Wawrzusin, Peter Kabat, Juraj Broadbent, Andrew J. Lamirande, Elaine W. Fodor, Ervin Altan-Bonnet, Nihal Shroff, Hari Subbarao, Kanta TI Influenza A Virus Assembly Intermediates Fuse in the Cytoplasm SO PLOS PATHOGENS LA English DT Article ID PROTEIN-PROTEIN INTERACTIONS; GENOMIC RNA SEGMENTS; SINGLE AMINO-ACID; PA SUBUNIT; HOST-RANGE; RIBONUCLEOPROTEIN COMPLEXES; NUCLEAR EXPORT; IN-VIVO; VISUALIZATION; TRANSMISSION AB Reassortment of influenza viral RNA (vRNA) segments in co-infected cells can lead to the emergence of viruses with pandemic potential. Replication of influenza vRNA occurs in the nucleus of infected cells, while progeny virions bud from the plasma membrane. However, the intracellular mechanics of vRNA assembly into progeny virions is not well understood. Here we used recent advances in microscopy to explore vRNA assembly and transport during a productive infection. We visualized four distinct vRNA segments within a single cell using fluorescent in situ hybridization (FISH) and observed that foci containing more than one vRNA segment were found at the external nuclear periphery, suggesting that vRNA segments are not exported to the cytoplasm individually. Although many cytoplasmic foci contain multiple vRNA segments, not all vRNA species are present in every focus, indicating that assembly of all eight vRNA segments does not occur prior to export from the nucleus. To extend the observations made in fixed cells, we used a virus that encodes GFP fused to the viral polymerase acidic (PA) protein (WSN PA-GFP) to explore the dynamics of vRNA assembly in live cells during a productive infection. Since WSN PA-GFP colocalizes with viral nucleoprotein and influenza vRNA segments, we used it as a surrogate for visualizing vRNA transport in 3D and at high speed by inverted selective-plane illumination microscopy. We observed cytoplasmic PA-GFP foci colocalizing and traveling together en route to the plasma membrane. Our data strongly support a model in which vRNA segments are exported from the nucleus as complexes that assemble en route to the plasma membrane through dynamic colocalization events in the cytoplasm. C1 [Lakdawala, Seema S.; Broadbent, Andrew J.; Lamirande, Elaine W.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Wu, Yicong; Wawrzusin, Peter; Shroff, Hari] Natl Inst Biomed Imaging & Bioengn, Sect High Resolut Opt Imaging, NIH, Bethesda, MD USA. [Kabat, Juraj] NIAID, Res Technol Branch, NIH, Bethesda, MD 20892 USA. [Fodor, Ervin] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. [Altan-Bonnet, Nihal] NHLBI, Lab Host Pathogen Dynam, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Lakdawala, SS (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM Seema.Lakdawala@nih.gov; Hari.Shroff@nih.gov RI Shroff, Hari/E-7247-2016; OI Shroff, Hari/0000-0003-3613-8215; Broadbent, Andrew/0000-0002-4716-1835 FU Division of Intramural Research of NIAID, NIH; Intramural Research Program of the NIH National Institute of Biomedical Imaging and Bioengineering FX This research was supported in part by the Division of Intramural Research of NIAID, NIH, and the Intramural Research Program of the NIH National Institute of Biomedical Imaging and Bioengineering. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 24 Z9 25 U1 3 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD MAR PY 2014 VL 10 IS 3 AR e1003971 DI 10.1371/journal.ppat.1003971 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AJ2FF UT WOS:000337470300025 PM 24603687 ER PT J AU Le Saout, C Hasley, RB Imamichi, H Tcheung, L Hu, ZH Luckey, MA Park, JH Durum, SK Smith, M Rupert, AW Sneller, MC Lane, HC Catalfamo, M AF Le Saout, Cecile Hasley, Rebecca B. Imamichi, Hiromi Tcheung, Lueng Hu, Zonghui Luckey, Megan A. Park, Jung-Hyun Durum, Scott K. Smith, Mindy Rupert, Adam W. Sneller, Michael C. Lane, H. Clifford Catalfamo, Marta TI Chronic Exposure to Type-I IFN under Lymphopenic Conditions Alters CD4 T Cell Homeostasis SO PLOS PATHOGENS LA English DT Article ID HEMATOPOIETIC STEM-CELLS; HIV-INFECTED PATIENTS; IMMUNE ACTIVATION; INTERFERON-ALPHA; DENDRITIC CELLS; POTENTIAL ROLE; SIV INFECTION; HUMAN NAIVE; IL-7; PROLIFERATION AB HIV infection and the associated chronic immune activation alter T cell homeostasis leading to CD4 T cell depletion and CD8 T cell expansion. The mechanisms behind these outcomes are not totally defined and only partially explained by the direct cytopathic effect of the virus. In this manuscript, we addressed the impact of lymphopenia and chronic exposure to IFN-alpha on T cell homeostasis. In a lymphopenic murine model, this interaction led to decreased CD4 counts and CD8 T cell expansion in association with an increase in the Signal Transducer and Activator of Transcription 1 (STAT1) levels resulting in enhanced CD4 T cell responsiveness to IFN-alpha. Thus, in the setting of HIV infection, chronic stimulation of this pathway could be detrimental for CD4 T cell homeostasis. C1 [Le Saout, Cecile; Hasley, Rebecca B.; Imamichi, Hiromi; Tcheung, Lueng; Smith, Mindy; Sneller, Michael C.; Lane, H. Clifford; Catalfamo, Marta] NIAID, CMRS, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Hu, Zonghui] NIAID, Biostat Res Branch, DCR, NIH, Bethesda, MD 20892 USA. [Luckey, Megan A.; Park, Jung-Hyun] NCI, Expt Immunol Branch, CCR, NIH, Bethesda, MD 20892 USA. [Durum, Scott K.] NCI, Immunoregulat Lab, CCR, NIH, Frederick, MD 21701 USA. [Rupert, Adam W.] Leidos Biomed Res Inc, AIDS Monitoring Labs, Frederick, MD USA. RP Le Saout, C (reprint author), NIAID, CMRS, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM catalfam@mail.nih.gov RI Park, Jung Hyun /B-5712-2015; Davis, Megan/F-5339-2015 OI Park, Jung Hyun /0000-0002-9547-9055; FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] 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. 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 3 Z9 3 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD MAR PY 2014 VL 10 IS 3 AR e1003976 DI 10.1371/journal.ppat.1003976 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AJ2FF UT WOS:000337470300026 PM 24603698 ER PT J AU Kuller, LH Mackey, RH Walitt, BT Deane, KD Holers, VM Robinson, WH Sokolove, J Chang, YF Liu, SM Parks, CG Wright, NC Moreland, LW AF Kuller, Lewis H. Mackey, Rachel H. Walitt, Brian T. Deane, Kevin D. Holers, V. Michael Robinson, William H. Sokolove, Jeremy Chang, Yuefang Liu, Simin Parks, Christine G. Wright, Nicole C. Moreland, Larry W. TI Determinants of Mortality Among Postmenopausal Women in the Women's Health Initiative Who Report Rheumatoid Arthritis SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID CYCLIC CITRULLINATED PEPTIDE; PULMONARY-FIBROSIS; REVISED CRITERIA; EXCESS MORTALITY; PREDICTIVE-VALUE; DISEASE; RISK; ASSOCIATION; POPULATION; ANTIBODIES AB Objective. Rheumatoid arthritis (RA) patients have an increased risk of cardiovascular disease (CVD) and mortality. We measured anti-cyclic citrullinated peptide (anti-CCP) antibody levels and determined use of disease-modifying antirheumatic drugs (DMARDs) among women in the Women's Health Initiative (WHI). Using these data, we undertook this study to assess total mortality over 10 years of followup among white, black, or Hispanic women with self-reported RA in the WHI. Methods. Using stored baseline serum, we measured anti-CCP, rheumatoid factor (RF), and antinuclear antibodies (ANAs) in 9,988 women who reported having RA. Based on a previous chart review study, probable RA was defined as either self-reported RA and anti-CCP positivity, or anti-CCP negativity and DMARD use. Cox proportional hazards regression was used to model the relationship of self-reported RA, DMARD exposure, and anti-CCP positivity to total mortality, using followup data through April 2009. Results. At baseline, the mean age was 62.8 years; 24.5% of subjects were black and 10% were Hispanic. Prevalence of anti-CCP positivity was 8.1% (n = 812), and 217 women were anti-CCP negative but had reported use of DMARDs; therefore, 1,029 women (of 9,988) were classified as having probable RA, and 8,958 were classified as unlikely to have RA (with data on DMARD use missing for 1 subject). Age-adjusted mortality rates were similar to 2-fold higher for anti-CCP-positive women, with 20.2 deaths per 1,000 person-years, as compared to 11.4 deaths per 1,000 person-years among anti-CCP-negative women with self-reported RA who never used DMARDs. Among women who did not report any arthritis at baseline, we found 8.3 deaths per 1,000 person-years. The increased risk among anti-CCP-positive women with RA was not explained by age, RF positivity, ANA positivity, or DMARD use. Conclusion. Anti-CCP-positive RA was associated with substantial excess mortality among postmenopausal women in the WHI. This result was not explained by the risk factors we measured. C1 [Kuller, Lewis H.; Mackey, Rachel H.; Chang, Yuefang; Moreland, Larry W.] Univ Pittsburgh, Pittsburgh, PA 15261 USA. [Walitt, Brian T.] Washington Hosp Ctr, Washington, DC 20010 USA. [Deane, Kevin D.; Holers, V. Michael] Univ Colorado, Denver, CO 80202 USA. [Robinson, William H.; Sokolove, Jeremy] Stanford Univ, Stanford, CA 94305 USA. [Liu, Simin] Brown Univ, Providence, RI 02912 USA. [Parks, Christine G.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Wright, Nicole C.] Univ Alabama Birmingham, Birmingham, AL 35205 USA. RP Kuller, LH (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, 130 North Bellefield Ave,Room 550, Pittsburgh, PA 15261 USA. EM kullerl@edc.pitt.edu RI Liu, Simin/I-3689-2014; OI Liu, Simin/0000-0003-2098-3844; Mackey, Rachel/0000-0001-6088-2664; Parks, Christine/0000-0002-5734-3456 FU NIH (National Heart, Lung, and Blood Institute [NHLBI]) [BAA-WH-09-01, HHSN268200960006C]; NIH (NHLBI) [N01-WH-22110, N01-WH-24152, N01-WH-32100-2, N01-WH-32105-6, N01-WH-32108-9, N01-WH-32111-13, N01-WH-32115, N01-WH-32118-32119, N01-WH-32122, N01-WH-42107-26, N01-WH-42129-32, N01-WH-44221] FX Supported by the NIH (National Heart, Lung, and Blood Institute [NHLBI] BAA-WH-09-01 contract HHSN268200960006C). The Women's Health Initiative program is funded by the NIH (NHLBI contracts N01-WH-22110, N01-WH-24152, N01-WH-32100-2, N01-WH-32105-6, N01-WH-32108-9, N01-WH-32111-13, N01-WH-32115, N01-WH-32118-32119, N01-WH-32122, N01-WH-42107-26, N01-WH-42129-32, and N01-WH-44221). NR 53 TC 8 Z9 9 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD MAR PY 2014 VL 66 IS 3 BP 497 EP 507 DI 10.1002/art.38268 PG 11 WC Rheumatology SC Rheumatology GA AJ0QD UT WOS:000337359400004 PM 24574208 ER PT J AU Aggarwal, R Bandos, A Reed, AM Ascherman, DP Barohn, RJ Feldman, BM Miller, FW Rider, LG Harris-Love, MO Levesque, MC Oddis, CV AF Aggarwal, Rohit Bandos, Andriy Reed, Ann M. Ascherman, Dana P. Barohn, Richard J. Feldman, Brian M. Miller, Frederick W. Rider, Lisa G. Harris-Love, Michael O. Levesque, Marc C. Oddis, Chester V. CA Rim Study Grp TI Predictors of Clinical Improvement in Rituximab-Treated Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID IDIOPATHIC INFLAMMATORY MYOPATHIES; TRANSFER-RNA-SYNTHETASE; MYOSITIS-SPECIFIC AUTOANTIBODIES; PROGNOSTIC-FACTORS; JAPANESE PATIENTS; DISEASE-ACTIVITY; TERM; SURVIVAL; ANTIBODY; TRIAL AB Objective. To identify the clinical and laboratory predictors of clinical improvement in a cohort of myositis patients treated with rituximab. Methods. We analyzed data for 195 patients with myositis (75 with adult polymyositis [PM], 72 with adult dermatomyositis [DM], and 48 with juvenile DM) in the Rituximab in Myositis trial. Clinical improvement was defined as 20% improvement in at least 3 of the following 6 core set measures of disease activity: physician's and patient's/parent's global assessment of disease activity, manual muscle testing, physical function, muscle enzymes, and extramuscular disease activity. We analyzed the association of the following baseline variables with improvement: myositis clinical subgroup, demographics, myositis damage, clinical and laboratory parameters, core set measures, rituximab treatment, and myositis autoantibodies (antisynthetase, anti-Mi-2, anti-signal recognition particle, anti-transcription intermediary factor 1 gamma [TIF-1 gamma], anti-MJ, other autoantibodies, and no autoantibodies). All measures were univariately assessed for association with improvement using time-to-event analyses. A multivariable time-dependent proportional hazards model was used to evaluate the association of individual predictive factors with improvement. Results. In the final multivariable model, the presence of an antisynthetase, primarily anti-Jo-1 (hazard ratio [HR] 3.08, P < 0.01), anti-Mi-2 (HR 2.5, P < 0.01), or other autoantibody (HR 1.4, P = 0.14) predicted a shorter time to improvement compared to the absence of autoantibodies. A lower physician's global assessment of damage (HR 2.32, P = 0.02) and juvenile DM (versus adult myositis) (HR 2.45, P = 0.01) also predicted improvement. Unlike autoantibody status, the predictive effect of physician's global assessment of damage and juvenile DM diminished by week 20. Rituximab treatment did not affect these associations. Conclusion. Our findings indicate that the presence of antisynthetase and anti-Mi-2 autoantibodies, juvenile DM subset, and lower disease damage strongly predict clinical improvement in patients with refractory myositis. C1 [Aggarwal, Rohit; Bandos, Andriy; Levesque, Marc C.; Oddis, Chester V.] Univ Pittsburgh, Pittsburgh, PA 15261 USA. [Reed, Ann M.] Mayo Clin, Rochester, MN USA. [Ascherman, Dana P.] Univ Miami, Miami, FL USA. [Barohn, Richard J.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Feldman, Brian M.] Hosp Sick Children, Toronto, ON, Canada. [Feldman, Brian M.] Univ Toronto, Toronto, ON, Canada. [Miller, Frederick W.; Rider, Lisa G.] Natl Inst Environm Hlth Sci, NIH, Bethesda, MD USA. [Harris-Love, Michael O.] Washington DC VA Med Ctr, Washington, DC USA. RP Aggarwal, R (reprint author), Univ Pittsburgh, BST S705A,3500 Terrace St, Pittsburgh, PA 15261 USA. EM aggarwalr@upmc.edu RI Harris-Love, Michael/J-1359-2014; OI Harris-Love, Michael/0000-0002-1842-3269; Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 FU NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases) [N01-AR-4-2273]; NIH (National Institute of Environmental Health Sciences) [M01-RR-023940/UL1-RR-033179]; Genentech Inc.; Questcor; aTyr Pharma; Genentech; Novartis; Grifols FX Supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases contract N01-AR-4-2273), the Intramural Program of the NIH (National Institute of Environmental Health Sciences), a General Clinical Research Center/Clinical and Translational Science Award (M01-RR-023940/UL1-RR-033179) to the University of Kansas Medical Center, and by Genentech Inc.; Dr. Aggarwal has received consulting fees and/or honoraria from Questcor and aTyr Pharma for service on the Advisory Boards of the companies (less than $10,000 each). Dr. Reed has received consulting fees and/or honoraria from Genentech for service on the Genentech Advisory Board (less than $10,000). Dr. Barohn has received consulting fees from Novartis (more than $10,000) and speaking fees from Grifols (more than $10,000). Dr. Feldman has received consulting fees, speaking fees, and/or honoraria from Novartis (less than $10,000). Dr. Levesque has received consulting fees, speaking fees, and/or honoraria from Genentech (less than $10,000) and has received research support from Genentech. Dr. Oddis has received consulting fees from Questcor (less than $10,000) and has served as an expert witness concerning appropriateness of rituximab therapy in a patient with myositis. NR 42 TC 44 Z9 45 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD MAR PY 2014 VL 66 IS 3 BP 740 EP 749 DI 10.1002/art.38270 PG 10 WC Rheumatology SC Rheumatology GA AJ0QD UT WOS:000337359400031 PM 24574235 ER PT J AU Blanchet, EM Millo, C Martucci, V Maass-Moreno, R Bluemke, DA Pacak, K AF Blanchet, Elise M. Millo, Corina Martucci, Victoria Maass-Moreno, Roberto Bluemke, David A. Pacak, Karel TI Integrated Whole-Body PET/MRI With F-18-FDG, F-18-FDOPA, and F-18-FDA in Paragangliomas in Comparison With PET/CT NIH First Clinical Experience With a Single-Injection, Dual-Modality Imaging Protocol SO CLINICAL NUCLEAR MEDICINE LA English DT Article DE pheochromocytoma; paraganglioma; PET/MRI; F-18-FDG; F-18-fluorodopamine; F-18-fluorodihydroxyphenylalanine ID EMISSION TOMOGRAPHY/COMPUTED TOMOGRAPHY; ATTENUATION CORRECTION; FUNCTIONAL-CHARACTERIZATION; NEUROENDOCRINE TUMORS; INITIAL-EXPERIENCE; PHEOCHROMOCYTOMA; MR; CT; PERFORMANCE; SCANNER AB Purpose: Paragangliomas (PGLs) are tumors that can metastasize and recur; therefore, lifelong imaging follow-up is required. Hybrid PET/CT is an essential tool to image PGLs. Novel hybrid PET/MRI scanners are currently being studied in clinical oncology. We studied the feasibility of simultaneous whole-body PET/MRI to evaluate patients with PGLs. Methods: Fifty-three PGLs or PGL-related lesions from 8 patients were evaluated. All patients underwent a single-injection, dual-modality imaging protocol consisting of a PET/CT and a subsequent PET/MRI scan. Four patients were evaluated with F-18-FDG, 2 with F-18-fluorodihydroxyphenylalanine, and 2 with F-18-fluorodopamine. PET/MRI data were acquired using a hybrid whole-body 3-tesla integrated PET/MRI scanner. PET and MRI data (Dixon sequence for attenuation correction and T2-weighted sequences for anatomic allocation) were acquired simultaneously. Imaging workflow and imaging times were documented. PET/MRI and PET/CT data were visually assessed (blindly) in regards to image quality, lesion detection, and anatomic allocation and delineation of the PET findings. Results: With hybrid PET/MRI, we obtained high-quality images in an acceptable acquisition time (median, 31 minutes; range, 25-40 minutes) with good patient compliance. A total of 53 lesions, located in the head and neck area (6 lesions), mediastinum (2 lesions), abdomen and pelvis (13 lesions), lungs (2 lesions), liver (4 lesions), and bones (26 lesions), were evaluated. Fifty-one lesions were detected with PET/MRI and confirmed by PET/CT. Two bone lesions (L4 body, 8 mm, and sacrum, 6 mm) were not detectable on an F-18-FDA scan PET/MRI, likely because F-18-FDA was washed out between PET/CT and PET/MRI acquisitions. Coregistered MRI tended to be superior to coregistered CT for head and neck, abdomen, pelvis, and liver lesions for anatomic allocation and delineation. Conclusions: Clinical PGL evaluation with hybrid PET/MRI is feasible with high-quality image and can be obtained in a reasonable time. It could be particularly beneficial for the pediatric population and for precise lesion definition in the head and neck, abdomen, pelvis, and liver. C1 [Blanchet, Elise M.; Martucci, Victoria; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. [Millo, Corina] NIH, Dept PET, Warren Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Maass-Moreno, Roberto] NIH, Dept Nucl Med, Warren Magnuson Clin Ctr, Bethesda, MD USA. [Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Warren Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Blanchet, EM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bldg 10,CRC 1 E,Rm 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM elise.blanchet@gmail.com OI Bluemke, David/0000-0002-8323-8086 NR 41 TC 4 Z9 5 U1 1 U2 8 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 MAR PY 2014 VL 39 IS 3 BP 243 EP 250 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AI9YP UT WOS:000337304400018 PM 24152658 ER PT J AU Likhtarov, I Kovgan, L Masiuk, S Talerko, M Chepurny, M Ivanova, O Gerasymenko, V Boyko, Z Voilleque, P Drozdovitch, V Bouville, A AF Likhtarov, Ilya Kovgan, Lina Masiuk, Sergii Talerko, Mykola Chepurny, Mykola Ivanova, Olga Gerasymenko, Valentina Boyko, Zulfira Voilleque, Paul Drozdovitch, Vladimir Bouville, Andre TI THYROID CANCER STUDY AMONG UKRAINIAN CHILDREN EXPOSED TO RADIATION AFTER THE CHORNOBYL ACCIDENT: IMPROVED ESTIMATES OF THE THYROID DOSES TO THE COHORT MEMBERS SO HEALTH PHYSICS LA English DT Article DE I-131; Chernobyl; dose assessment; thyroid ID RADIOACTIVE CONTAMINATION; RECONSTRUCTION; I-131; POPULATION; UNCERTAINTIES; MILK AB In collaboration with the Ukrainian Research Center for Radiation Medicine, the U. S. National Cancer Institute initiated a cohort study of children and adolescents exposed to Chornobyl fallout in Ukraine to better understand the long-term health effects of exposure to radioactive iodines. All 13,204 cohort members were subjected to at least one direct thyroid measurement between 30 April and 30 June 1986 and resided at the time of the accident in the northern parts of Kyiv, Zhytomyr, or Chernihiv Oblasts, which were the most contaminated territories of Ukraine as a result of radioactive fallout from the Chornobyl accident. Thyroid doses for the cohort members, which had been estimated following the first round of interviews, were re-evaluated following the second round of interviews. The revised thyroid doses range from 0.35 mGy to 42 Gy, with 95% of the doses between 1 mGy and 4.2 Gy, an arithmetic mean of 0.65 Gy, and a geometric mean of 0.19 Gy. These means are 70% of the previous estimates, mainly because of the use of country-specific thyroid masses. Many of the individual thyroid dose estimates show substantial differences because of the use of an improved questionnaire for the second round of interviews. Limitations of the current set of thyroid dose estimates are discussed. For the epidemiologic study, the most notable improvement is a revised assessment of the uncertainties, as shared and unshared uncertainties in the parameter values were considered in the calculation of the 1,000 stochastic estimates of thyroid dose for each cohort member. This procedure makes it possible to perform a more realistic risk analysis. C1 [Likhtarov, Ilya; Kovgan, Lina; Masiuk, Sergii; Chepurny, Mykola; Ivanova, Olga; Gerasymenko, Valentina; Boyko, Zulfira] Natl Acad Med Sci Ukraine, Natl Res Ctr Radiat Med, State Inst, UA-04050 Kiev, Ukraine. [Talerko, Mykola] Natl Acad Sci Ukraine, Inst Safety Problems Nucl Power Plants, UA-03028 Kiev, Ukraine. [Voilleque, Paul] MJP Risk Assessment Inc, Denver, CO 80220 USA. [Drozdovitch, Vladimir] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Bouville, Andre] US Natl Canc Inst, Bethesda, MD USA. RP Drozdovitch, V (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 9609 Med Ctr Dr,7E548, Bethesda, MD 20892 USA. EM drozdovv@mail.nih.gov FU U.S. National Cancer Institute, National Institutes of Health FX The authors are grateful to all of the subjects who participated in the study. Special thanks are to the staff of V.P. Komisarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Sciences of Ukraine (Kyiv, Ukraine), who conducted personal interviews. The authors thank Cindy Clark, NIH Library Writing Center, for manuscript editing assistance. The research was supported by the Intramural Research Program of the U.S. National Cancer Institute, National Institutes of Health, within the framework of the Ukraine-U.S. Study of Thyroid Cancer and Other Diseases Following the Chornobyl Accident. NR 58 TC 10 Z9 10 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD MAR PY 2014 VL 106 IS 3 BP 370 EP 396 DI 10.1097/HP.0b013e31829f3096 PG 27 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA AJ2TC UT WOS:000337514800004 PM 25208014 ER PT J AU Bashirova, AA Martin-Gayo, E Jones, DC Qi, Y Apps, R Gao, XJ Burke, PS Taylor, CJ Rogich, J Wolinsky, S Bream, JH Duggal, P Hussain, S Martinson, J Weintrob, A Kirk, GD Fellay, J Buchbinder, SP Goedert, JJ Deeks, SG Pereyra, F Trowsdale, J Lichterfeld, M Telenti, A Walker, BD Allen, RL Carrington, M Yu, XG AF Bashirova, Arman A. Martin-Gayo, Enrique Jones, Des C. Qi, Ying Apps, Richard Gao, Xiaojiang Burke, Patrick S. Taylor, Craig J. Rogich, Jerome Wolinsky, Steven Bream, Jay H. Duggal, Priya Hussain, Shehnaz Martinson, Jeremy Weintrob, Amy Kirk, Gregory D. Fellay, Jacques Buchbinder, Susan P. Goedert, James J. Deeks, Steven G. Pereyra, Florencia Trowsdale, John Lichterfeld, Mathias Telenti, Amalio Walker, Bruce D. Allen, Rachel L. Carrington, Mary Yu, Xu G. TI LILRB2 Interaction with HLA Class I Correlates with Control of HIV-1 Infection SO PLOS GENETICS LA English DT Article ID MHC CLASS-I; INHIBITORY RECEPTOR; DENDRITIC CELLS; MYELOMONOCYTIC CELLS; HOST CONTROL; MOLECULES; AIDS; COMPLEX; BINDING; ILT4 AB Natural progression of HIV-1 infection depends on genetic variation in the human major histocompatibility complex (MHC) class I locus, and the CD8(+) T cell response is thought to be a primary mechanism of this effect. However, polymorphism within the MHC may also alter innate immune activity against human immunodeficiency virus type 1 (HIV-1) by changing interactions of human leukocyte antigen (HLA) class I molecules with leukocyte immunoglobulin-like receptors (LILR), a group of immunoregulatory receptors mainly expressed on myelomonocytic cells including dendritic cells (DCs). We used previously characterized HLA allotype-specific binding capacities of LILRB1 and LILRB2 as well as data from a large cohort of HIV-1-infected individuals (N = 5126) to test whether LILR-HLA class I interactions influence viral load in HIV-1 infection. Our analyses in persons of European descent, the largest ethnic group examined, show that the effect of HLA-B alleles on HIV-1 control correlates with the binding strength between corresponding HLA-B allotypes and LILRB2 (p = 10(-2)). Moreover, overall binding strength of LILRB2 to classical HLA class I allotypes, defined by the HLA-A/B/C genotypes in each patient, positively associates with viral replication in the absence of therapy in patients of both European (p = 10(-11)-10(-9)) and African (p = 10(-5)-10(-3)) descent. This effect appears to be driven by variations in LILRB2 binding affinities to HLA-B and is independent of individual class I allelic effects that are not related to the LILRB2 function. Correspondingly, in vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of DCs. Thus, we propose an impact of LILRB2 on HIV-1 disease outcomes through altered regulation of DCs by LILRB2-HLA engagement. C1 [Bashirova, Arman A.; Qi, Ying; Apps, Richard; Gao, Xiaojiang; Carrington, Mary] Leidos Biomed Res Inc, Canc & Inflammat Program, Expt Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Bashirova, Arman A.; Martin-Gayo, Enrique; Burke, Patrick S.; Rogich, Jerome; Pereyra, Florencia; Walker, Bruce D.; Carrington, Mary; Yu, Xu G.] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Jones, Des C.; Trowsdale, John] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Taylor, Craig J.] Addenbrookes Hosp, Tissue Typing Labs, Cambridge, England. [Wolinsky, Steven] Northwestern Univ, Sch Med, Chicago, IL USA. [Bream, Jay H.; Duggal, Priya] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Hussain, Shehnaz] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Los Angeles, CA USA. [Martinson, Jeremy] Univ Pittsburgh, Pittsburgh, PA USA. [Weintrob, Amy] USU Infect Dis Clin Res Program, Bethesda, MD USA. [Kirk, Gregory D.] Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD USA. [Fellay, Jacques] Ecole Polytech Fed Lausanne, Sch Life Sci, Lausanne, Switzerland. [Buchbinder, Susan P.] San Francisco Dept Publ Hlth, San Francisco, CA USA. [Goedert, James J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Deeks, Steven G.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Pereyra, Florencia] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Lichterfeld, Mathias] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Telenti, Amalio] Univ Lausanne Hosp, Inst Microbiol, Lausanne, Switzerland. [Telenti, Amalio] Univ Lausanne, Lausanne, Switzerland. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Allen, Rachel L.] Univ London, St Georges Med Sch, London, England. RP Bashirova, AA (reprint author), Leidos Biomed Res Inc, Canc & Inflammat Program, Expt Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM xyu@partners.org RI SHCS, int. coll. A/G-4083-2011; Fellay, Jacques/A-6681-2009; SHCS, all/G-4072-2011; OI Fellay, Jacques/0000-0002-8240-939X; Martinson, Jeremy/0000-0003-4673-7238; Wolinsky, Steven/0000-0002-9625-6697 FU Frederick National Laboratory for Cancer Research [HHSN261200800001E]; NIH, Frederick National Lab, Center for Cancer Research; NIAID [R01 AI087145, K24 AI069994, R24 AI067039]; UCSF/Gladstone CFAR [P30 AI027763]; UCSF CTSI [UL1 RR024131]; Center for AIDS Prevention Studies [P30 MH62246]; Bill and Melinda Gates Foundation; AIDS Healthcare Foundation; Harvard University Center for AIDS Research (CFAR), an NIH [P30 AI060354]; NIAID, NIH; NCI, NIH; NICHD, NIH; NHLBI, NIH; NIDA, NIH; NIMH, NIH; NIA, NIH; FIC, NIH; OAR, NIH; Swiss National Science Foundation; NIH/NIAID [R01 AI078799, R56 AI098484, R01 AI087452, R01 AI089339]; MRC; Wellcome Trust; AICR; NIHR Cambridge BRC; National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Heart, Lung, and Blood Institute [U01-AI-35042, UL1-RR025005, U01-AI-35043, U01-AI-35039, U01-AI-35040, U01-AI-35041] FX 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 U.S. Government. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. The SCOPE cohort was supported in part by the NIAID (R01 AI087145, K24 AI069994, R24 AI067039), UCSF/Gladstone CFAR (P30 AI027763), the UCSF CTSI (UL1 RR024131), and the Center for AIDS Prevention Studies (P30 MH62246). The International HIV Controllers Study (IHCS), was funded by the Bill and Melinda Gates Foundation, the AIDS Healthcare Foundation and the Harvard University Center for AIDS Research (CFAR), an NIH funded program(P30 AI060354), which is supported by the following NIH Co-Funding and Participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC and OAR. Members of the International HIV Controllers Study can be found at www.hivcontrollers.org. The Swiss HIV Cohort study (www.shcs.ch) is funded by the Swiss National Science Foundation. XGY was supported by NIH/NIAID R01 AI078799, R56 AI098484, R01 AI087452 and R01 AI089339. JT and DCJ were supported by the MRC, Wellcome Trust and AICR, with partial funding from the NIHR Cambridge BRC. We thank Randy Johnson and George Nelson for helpful discussions. We are grateful to the USU Infectious Disease Clinical Research Program HIV Working Group for collecting and providing clinical data. The MACS clinical data used in this manuscript were collected at: The Johns Hopkins Bloomberg School of Public Health (Joseph Margolick); Howard Brown Health Center and Northwestern University Medical School (John Phair, Steven Wolinsky); University of California, Los Angeles (Roger Detels, Oto Martinez-Maza); University of Pittsburgh (Charles Rinaldo); and Data Analysis Center (Lisa Jacobson). The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute; and the National Heart, Lung, and Blood Institute: U01-AI-35042, UL1-RR025005 (GCRC), U01-AI-35043, U01-AI-35039, U01-AI-35040, and U01-AI-35041. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 20 Z9 20 U1 3 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2014 VL 10 IS 3 AR e1004196 DI 10.1371/journal.pgen.1004196 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA AI8FM UT WOS:000337144700026 PM 24603468 ER PT J AU Bentley, AR Chen, GJ Shriner, D Doumatey, AP Zhou, J Huang, HX Mullikin, JC Blakesley, RW Hansen, NF Bouffard, GG Cherukuri, PF Maskeri, B Young, AC Adeyemo, A Rotimi, CN AF Bentley, Amy R. Chen, Guanjie Shriner, Daniel Doumatey, Ayo P. Zhou, Jie Huang, Hanxia Mullikin, James C. Blakesley, Robert W. Hansen, Nancy F. Bouffard, Gerard G. Cherukuri, Praveen F. Maskeri, Baishali Young, Alice C. Adeyemo, Adebowale Rotimi, Charles N. TI Gene-Based Sequencing Identifies Lipid-Influencing Variants with Ethnicity-Specific Effects in African Americans SO PLOS GENETICS LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; METABOLIC SYNDROME; HDL-CHOLESTEROL; BLOOD-LIPIDS; ADMIXED POPULATIONS; LINKAGE ANALYSIS; CANDIDATE GENES; ASSOCIATION; LIPASE; POLYMORPHISMS AB Although a considerable proportion of serum lipids loci identified in European ancestry individuals (EA) replicate in African Americans (AA), interethnic differences in the distribution of serum lipids suggest that some genetic determinants differ by ethnicity. We conducted a comprehensive evaluation of five lipid candidate genes to identify variants with ethnicity-specific effects. We sequenced ABCA1, LCAT, LPL, PON1, and SERPINE1 in 48 AA individuals with extreme serum lipid concentrations (high HDLC/low TG or low HDLC/high TG). Identified variants were genotyped in the full population-based sample of AA (n = 1694) and tested for an association with serum lipids. rs328 (LPL) and correlated variants were associated with higher HDLC and lower TG. Interestingly, a stronger effect was observed on a "European'' vs. "African'' genetic background at this locus. To investigate this effect, we evaluated the region among West Africans (WA). For TG, the effect size among WA was the same in AA with only African local ancestry (2-3% lower TG), while the larger association among AA with local European ancestry matched previous reports in EA (10%). For HDLC, there was no association with rs328 in AA with only African local ancestry or in WA, while the association among AA with European local ancestry was much greater than what has been observed for EA (15 vs. similar to 5 mg/dl), suggesting an interaction with an environmental or genetic factor that differs by ethnicity. Beyond this ancestry effect, the importance of African ancestry-focused, sequence-based work was also highlighted by serum lipid associations of variants that were in higher frequency (or present only) among those of African ancestry. By beginning our study with the sequence variation present in AA individuals, investigating local ancestry effects, and seeking replication in WA, we were able to comprehensively evaluate the role of a set of candidate genes in serum lipids in AA. C1 [Bentley, Amy R.; Chen, Guanjie; Shriner, Daniel; Doumatey, Ayo P.; Zhou, Jie; Huang, Hanxia; Adeyemo, Adebowale; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Mullikin, James C.; Blakesley, Robert W.; Bouffard, Gerard G.; Maskeri, Baishali; Young, Alice C.] NHGRI, NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. [Hansen, Nancy F.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Cherukuri, Praveen F.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Bentley, AR (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. EM amy.bentley@mail.nih.gov; rotimic@mail.nih.gov OI Adeyemo, Adebowale/0000-0002-3105-3231 FU NIGMS/MBRS/SCORE Program [S06GM008016-320107, S06GM008016-380111]; National Center for Research Resources, a component of the NIH [2M01RR010284]; National Human Genome Research Institute in the Center for Research in Genomics and Global Health [CRGGH-Z01HG200362]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Center for Information Technology; Office of the Director at the NIH; National Institute on Minority Health and Health Disparities; NIDDK; NHGRI FX The study was supported by grants S06GM008016-320107 to CNR and S06GM008016-380111 to AA, both from the NIGMS/MBRS/SCORE Program. Participant enrollment was carried out at the Howard University General Clinical Research Center, which is supported by grant 2M01RR010284 from the National Center for Research Resources, a component of the NIH. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute in the Center for Research in Genomics and Global Health (CRGGH-Z01HG200362). CRGGH is also supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Center for Information Technology, and the Office of the Director at the NIH. Support for the Africa America Diabetes Mellitus (AADM) study is provided by the National Institute on Minority Health and Health Disparities, NIDDK, and NHGRI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 9 Z9 11 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2014 VL 10 IS 3 AR e1004190 DI 10.1371/journal.pgen.1004190 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA AI8FM UT WOS:000337144700022 PM 24603370 ER PT J AU Haeusser, DP Hoashi, M Weaver, A Brown, N Pan, J Sawitzke, JA Thomason, LC Court, DL Margolin, W AF Haeusser, Daniel P. Hoashi, Marina Weaver, Anna Brown, Nathan Pan, James Sawitzke, James A. Thomason, Lynn C. Court, Donald L. Margolin, William TI The Kil Peptide of Bacteriophage lambda Blocks Escherichia coli Cytokinesis via ZipA-Dependent Inhibition of FtsZ Assembly SO PLOS GENETICS LA English DT Article ID BACTERIAL-CELL-DIVISION; CYTOSKELETAL PROTEIN FTSZ; HIGH-LEVEL EXPRESSION; Z-RING; BACILLUS-SUBTILIS; GENE-PRODUCT; IMAGE-ANALYSIS; CROSS-LINKING; MECHANISM; SULA AB Assembly of the essential, tubulin-like FtsZ protein into a ring-shaped structure at the nascent division site determines the timing and position of cytokinesis in most bacteria and serves as a scaffold for recruitment of the cell division machinery. Here we report that expression of bacteriophage lambda kil, either from a resident phage or from a plasmid, induces filamentation of Escherichia coli cells by rapid inhibition of FtsZ ring formation. Mutant alleles of ftsZ resistant to the Kil protein map to the FtsZ polymer subunit interface, stabilize FtsZ ring assembly, and confer increased resistance to endogenous FtsZ inhibitors, consistent with Kil inhibiting FtsZ assembly. Cells with the normally essential cell division gene zipA deleted (in a modified background) display normal FtsZ rings after kil expression, suggesting that ZipA is required for Kil-mediated inhibition of FtsZ rings in vivo. In support of this model, point mutations in the C-terminal FtsZ-interaction domain of ZipA abrogate Kil activity without discernibly altering FtsZ-ZipA interactions. An affinity-tagged-Kil derivative interacts with both FtsZ and ZipA, and inhibits sedimentation of FtsZ filament bundles in vitro. Together, these data inspire a model in which Kil interacts with FtsZ and ZipA in the cell to prevent FtsZ assembly into a coherent, division-competent ring structure. Phage growth assays show that kil(+) phage lyse similar to 30% later than kil mutant phage, suggesting that Kil delays lysis, perhaps via its interaction with FtsZ and ZipA. C1 [Haeusser, Daniel P.; Margolin, William] Univ Texas Med Sch Houston, Dept Microbiol & Mol Genet, Houston, TX 77030 USA. [Hoashi, Marina; Weaver, Anna; Brown, Nathan; Pan, James; Sawitzke, James A.; Court, Donald L.] NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21701 USA. [Thomason, Lynn C.] Leidos Biomed Inc, Frederick Natl Lab Canc Res, Gene Regulat & Chromosome Biol Lab, Frederick, MD USA. RP Haeusser, DP (reprint author), Univ Texas Med Sch Houston, Dept Microbiol & Mol Genet, Houston, TX 77030 USA. EM courtd@mail.nih.gov; William.Margolin@uth.tmc.edu FU NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIGMS [R01-GM61074] FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and in part with federal funds from the National Cancer Institute, National Institutes of Health, 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 U.S. Government. This work was also funded through NIGMS grant R01-GM61074 to WM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 99 TC 12 Z9 12 U1 1 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2014 VL 10 IS 3 AR e1004217 DI 10.1371/journal.pgen.1004217 PG 25 WC Genetics & Heredity SC Genetics & Heredity GA AI8FM UT WOS:000337144700042 PM 24651041 ER PT J AU Weinberg, CR Shi, M DeRoo, LA Taylor, JA Sandler, DP Umbach, DM AF Weinberg, Clarice R. Shi, Min DeRoo, Lisa A. Taylor, Jack A. Sandler, Dale P. Umbach, David M. TI Asymmetry in Family History Implicates Nonstandard Genetic Mechanisms: Application to the Genetics of Breast Cancer SO PLOS GENETICS LA English DT Article ID CASE-PARENT-TRIAD; RISK; VARIANTS; COHORT AB Genome-wide association studies typically target inherited autosomal variants, but less studied genetic mechanisms can play a role in complex disease. Sex-linked variants aside, three genetic phenomena can induce differential risk in maternal versus paternal lineages of affected individuals: 1. maternal effects, reflecting the maternal genome's influence on prenatal development; 2. mitochondrial variants, which are inherited maternally; 3. autosomal genes, whose effects depend on parent of origin. We algebraically show that small asymmetries in family histories of affected individuals may reflect much larger genetic risks acting via those mechanisms. We apply these ideas to a study of sisters of women with breast cancer. Among 5,091 distinct families of women reporting that exactly one grandmother had breast cancer, risk was skewed toward maternal grandmothers (p<0.0001), especially if the granddaughter was diagnosed between age 45 and 54. Maternal genetic effects, mitochondrial variants, or variant genes with parent-of-origin effects may influence risk of perimenopausal breast cancer. C1 [Weinberg, Clarice R.; Shi, Min; Umbach, David M.] NIEHS, Biostat Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [DeRoo, Lisa A.; Taylor, Jack A.; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Weinberg, CR (reprint author), NIEHS, Biostat Branch, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM weinber2@niehs.nih.gov OI taylor, jack/0000-0001-5303-6398; Sandler, Dale/0000-0002-6776-0018 FU NIH, National Institute of Environmental Health Sciences [Z01-ES040007, Z01-ES45002] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES040007; Z01-ES45002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 4 Z9 4 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2014 VL 10 IS 3 AR e1004174 DI 10.1371/journal.pgen.1004174 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA AI8FM UT WOS:000337144700013 PM 24651610 ER PT J AU Williams, SR Yang, Q Chen, F Liu, X Keene, KL Jacques, P Chen, WM Weinstein, G Hsu, FC Beiser, A Wang, LW Bookman, E Doheny, KF Wolf, PA Zilka, M Selhub, J Nelson, S Gogarten, SM Worrall, BB Seshadri, S Sale, MM AF Williams, Stephen R. Yang, Qiong Chen, Fang Liu, Xuan Keene, Keith L. Jacques, Paul Chen, Wei-Min Weinstein, Galit Hsu, Fang-Chi Beiser, Alexa Wang, Liewei Bookman, Ebony Doheny, Kimberly F. Wolf, Philip A. Zilka, Michelle Selhub, Jacob Nelson, Sarah Gogarten, Stephanie M. Worrall, Bradford B. Seshadri, Sudha Sale, Michele M. CA Genomics Randomized Trials Network Framingham Heart Study TI Genome-Wide Meta-Analysis of Homocysteine and Methionine Metabolism Identifies Five One Carbon Metabolism Loci and a Novel Association of ALDH1L1 with Ischemic Stroke SO PLOS GENETICS LA English DT Article ID INDEPENDENT RISK-FACTOR; CYSTATHIONINE BETA-SYNTHASE; GLYCINE N-METHYLTRANSFERASE; VASCULAR-DISEASE; PLASMA HOMOCYSTEINE; DNA METHYLATION; GENETIC POLYMORPHISMS; VITAMIN INTERVENTION; MOLECULAR-BASIS; POTENTIAL ROLE AB Circulating homocysteine levels (tHcy), a product of the folate one carbon metabolism pathway (FOCM) through the demethylation of methionine, are heritable and are associated with an increased risk of common diseases such as stroke, cardiovascular disease (CVD), cancer and dementia. The FOCM is the sole source of de novo methyl group synthesis, impacting many biological and epigenetic pathways. However, the genetic determinants of elevated tHcy (hyperhomocysteinemia), dysregulation of methionine metabolism and the underlying biological processes remain unclear. We conducted independent genome-wide association studies and a meta-analysis of methionine metabolism, characterized by post-methionine load test tHcy, in 2,710 participants from the Framingham Heart Study (FHS) and 2,100 participants from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, and then examined the association of the identified loci with incident stroke in FHS. Five genes in the FOCM pathway (GNMT [p = 1.60 x 10(-63)], CBS [p = 3.15 x 10(-26)], CPS1 [p = 9.10 x 10(-13)], ALDH1L1 [p = 7.3 x 10(-13)] and PSPH [p = 1.17 x 10(-16)]) were strongly associated with the difference between pre- and post-methionine load test tHcy levels (Delta POST). Of these, one variant in the ALDH1L1 locus, rs2364368, was associated with incident ischemic stroke. Promoter analyses reveal genetic and epigenetic differences that may explain a direct effect on GNMT transcription and a downstream affect on methionine metabolism. Additionally, a genetic-score consisting of the five significant loci explains 13% of the variance of DPOST in FHS and 6% of the variance in VISP. Association between variants in FOCM genes with Delta POST suggest novel mechanisms that lead to differences in methionine metabolism, and possibly the epigenome, impacting disease risk. These data emphasize the importance of a concerted effort to understand regulators of one carbon metabolism as potential therapeutic targets. C1 [Williams, Stephen R.; Chen, Fang; Keene, Keith L.; Chen, Wei-Min; Sale, Michele M.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22903 USA. [Williams, Stephen R.] Univ Virginia, Cardiovasc Res Ctr, Charlottesville, VA USA. [Yang, Qiong; Liu, Xuan; Beiser, Alexa] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Yang, Qiong] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Keene, Keith L.; Worrall, Bradford B.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Keene, Keith L.] E Carolina Univ, Dept Biol, Greenville, NC USA. [Keene, Keith L.] E Carolina Univ, Ctr Hlth Dispar Res, Greenville, NC USA. [Jacques, Paul; Selhub, Jacob] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Jacques, Paul; Selhub, Jacob] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Weinstein, Galit; Wolf, Philip A.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Hsu, Fang-Chi] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Wang, Liewei] Mayo Clin, Coll Med, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN USA. [Bookman, Ebony] NHGRI, Bethesda, MD 20892 USA. [Doheny, Kimberly F.; Zilka, Michelle] Johns Hopkins Univ, Ctr Inherited Dis Res, Baltimore, MD USA. [Nelson, Sarah; Gogarten, Stephanie M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Worrall, Bradford B.] Univ Virginia, Dept Neurol, Charlottesville, VA USA. [Sale, Michele M.] Univ Virginia, Dept Med, Charlottesville, VA USA. [Sale, Michele M.] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA USA. RP Williams, SR (reprint author), Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22903 USA. EM ms5fe@eservices.virginia.edu OI Seshadri, Sudha/0000-0001-6135-2622; Williams, Stephen/0000-0003-2108-2757; Gogarten, Stephanie/0000-0002-7231-9745; Beiser, Alexa/0000-0001-8551-7778 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; National Institute of Neurological Disorders and Stroke [NS17950]; National Heart, Lung and Blood Association [U01HL 096917]; National Institute of Aging [AG08122, AG033193]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; National Human Genome Research institute; Genomics and Randomized Trials Network [U01HG00516-03] FX This work was supported by the dedication of the Framingham Heart Study participants, the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195, http://www.framinghamheartstudy.org/) and by grants from the National Institute of Neurological Disorders and Stroke (NS17950, www.ninds.nih.gov/), the National Heart, Lung and Blood Association (U01HL 096917, www.nhlbi.nih.gov) and the National Institute of Aging (AG08122, AG033193, www.nia.nih.gov). A portion of FHS computations were using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Additionally, VISP is supported by the National Human Genome Research institute and the Genomics and Randomized Trials Network (U01HG00516-03, http://www.genome.gov/27541119). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 19 Z9 20 U1 1 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2014 VL 10 IS 3 AR e1004214 DI 10.1371/journal.pgen.1004214 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA AI8FM UT WOS:000337144700039 PM 24651765 ER PT J AU Berlett, BS Levine, RL AF Berlett, Barbara S. Levine, Rodney L. TI Designing antioxidant peptides SO REDOX REPORT LA English DT Article DE Ionizing radiation; Radioprotection; Amino acid oxidation; Methionine; Histidine ID BACTERIUM DEINOCOCCUS-RADIODURANS; METHIONINE SULFOXIDE REDUCTASE; ESCHERICHIA-COLI; GLUTAMINE-SYNTHETASE; AMINO-ACIDS; RADIATION-RESISTANCE; IONIZING-RADIATION; HYDROGEN-PEROXIDE; PROTEIN OXIDATION; GAMMA-RADIATION AB Background: Ionizing radiation causes the generation of damaging reactive oxygen species that lead to cellular damage and death. Organisms such as Deinococcus radiodurans have evolved mechanisms for extreme resistance to ionizing radiation, and resistance has been shown to be a consequence of protection of critical proteins from oxidative inactivation. Objectives: D. radiodurans accumulates high levels of manganese and of small peptides that together are protective. Our aim was to rationally design antioxidant peptides. Methods: Amino acid analysis was utilized to determine the rates of loss of the 20 amino acids exposed to varying doses of irradiation. The activity of glutamine synthetase and methionine sulfoxide reductase was assayed to follow their inactivation by irradiation. Results: The ability of an amino acid to protect enzymes from inactivation by ionizing radiation paralleled its sensitivity to ionizing radiation. Based on this observation and the ability of histidine to confer water solubility, we synthesized the hexapeptide His-Met-His-Met-His-Met and found that it provided markedly increased protection against irradiation. Discussion: Small peptides containing histidine and methionine were readily soluble and provided enzymes with remarkable protection from inactivation by ionizing radiation. C1 [Berlett, Barbara S.; Levine, Rodney L.] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Levine, RL (reprint author), NHLBI, Biochem Lab, NIH, Bldg 50,Room 2351, Bethesda, MD 20892 USA. EM rlevine@nih.gov RI Levine, Rodney/D-9885-2011 FU Intramural Research Program of the National Heart, Lung, and Blood Institute FX This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute. NR 39 TC 5 Z9 5 U1 2 U2 11 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1351-0002 EI 1743-2928 J9 REDOX REP JI Redox Rep. PD MAR PY 2014 VL 19 IS 2 BP 80 EP 86 DI 10.1179/1351000213Y.0000000078 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AI8BQ UT WOS:000337129800005 PM 24520968 ER PT J AU Miyagishima, KJ Grunert, U Li, W AF Miyagishima, Kiyoharu J. Gruenert, Ulrike Li, Wei TI Processing of S-cone signals in the inner plexiform layer of the mammalian retina SO VISUAL NEUROSCIENCE LA English DT Review DE Color vision; Primate and nonprimate retina; Amacrine cell; Blue-ON pathway; Blue-OFF pathway ID NEW-WORLD MONKEY; MARMOSET CALLITHRIX-JACCHUS; LATERAL GENICULATE-NUCLEUS; MIDGET GANGLION-CELLS; PRIMATE COLOR-VISION; RECEPTIVE-FIELD STRUCTURE; DIFFUSE BIPOLAR CELLS; MACAQUE RETINA; RABBIT RETINA; MOUSE RETINA AB Color information is encoded by two parallel pathways in the mammalian retina. One pathway compares signals from long- and middle-wavelength sensitive cones and generates red-green opponency. The other compares signals from short- and middle-/long-wavelength sensitive cones and generates blue-green (yellow) opponency. Whereas both pathways operate in trichromatic primates (including humans), the fundamental, phylogenetically ancient color mechanism shared among most mammals is blue-green opponency. In this review, we summarize the current understanding of how signals from short-wavelength sensitive cones are processed in the primate and nonprimate mammalian retina, with a focus on the inner plexiform layer where bipolar, amacrine, and ganglion cell processes interact to facilitate the generation of blue-green opponency. C1 [Miyagishima, Kiyoharu J.; Li, Wei] NEI, NIH, Bethesda, MD 20892 USA. [Gruenert, Ulrike] Univ Sydney, Dept Ophthalmol, Sydney, NSW 2006, Australia. [Gruenert, Ulrike] Univ Sydney, Save Sight Inst, Sydney, NSW 2006, Australia. [Gruenert, Ulrike] Univ Sydney, Australian Res Council, Ctr Excellence Vis Sci, Sydney, NSW 2006, Australia. RP Grunert, U (reprint author), Save Sight Inst, Sydney Eye Hosp Campus,GPO Box 4337, Bethesda, MD 20014 USA. EM ugrunert@sydney.edu.au; liwei2@nei.nih.gov RI Grunert, Ulrike/A-5194-2012 OI Grunert, Ulrike/0000-0002-9595-8152 FU National Health & Medical Research Council of Australia [632640, 1022609]; National Eye Institute (USA) FX We would like to thank our colleagues and co-authors for their help. For this review T. Chan, K. Ghosh, S. Lee, P. Martin, I. Telkes and H. Wassle made important contributions. We would like to thank Heinz Wassle, Paul Martin, Alexander Sher, and Steven DeVries for providing images and Paul Martin for critically reading an earlier version of this manuscript. This work was supported by Project Grants from the National Health & Medical Research Council of Australia 632640 and 1022609 to UG, and the National Eye Institute (USA) intramural research program to KJM & WL. NR 101 TC 10 Z9 10 U1 2 U2 9 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0952-5238 EI 1469-8714 J9 VISUAL NEUROSCI JI Visual Neurosci. PD MAR PY 2014 VL 31 IS 2 SI SI BP 153 EP 163 DI 10.1017/S0952523813000308 PG 11 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA AI9YJ UT WOS:000337303800004 PM 24016424 ER PT J AU Nieman, L AF Nieman, Lynette TI Pitfalls in the diagnosis and differential diagnosis of Cushing's syndrome SO CLINICAL ENDOCRINOLOGY LA English DT Editorial Material ID MULTICENTER; DISEASE C1 NICHD, NIH, RBMB, Bethesda, MD 20817 USA. RP Nieman, L (reprint author), NICHD, NIH, RBMB, 8220 Hamilton Spring Ct, Bethesda, MD 20817 USA. EM niemanl@nih.gov FU Intramural NIH HHS [Z01 HD000638-14] NR 8 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD MAR PY 2014 VL 80 IS 3 BP 333 EP 334 DI 10.1111/cen.12362 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AI8RW UT WOS:000337193000004 PM 24303816 ER PT J AU Cappelle, J Zhao, DL Gilbert, M Nelson, MI Newman, SH Takekawa, JY Gaidet, N Prosser, DJ Liu, Y Li, P Shu, YL Xiao, XM AF Cappelle, Julien Zhao, Delong Gilbert, Marius Nelson, Martha I. Newman, Scott H. Takekawa, John Y. Gaidet, Nicolas Prosser, Diann J. Liu, Ying Li, Peng Shu, Yuelong Xiao, Xiangming TI Risks of Avian Influenza Transmission in Areas of Intensive Free-Ranging Duck Production with Wild Waterfowl SO ECOHEALTH LA English DT Article DE avian influenza virus; wild birds; migration; interface; contact; ecology; epidemiology; China; Poyang; telemetry; remote sensing; GPS ID DOMESTIC DUCKS; H5N1 OUTBREAKS; POYANG LAKE; CLADE 2.3.2; VIRUS H5N1; A VIRUSES; HONG-KONG; EXPERIMENTAL-INFECTION; SOUTHERN CHINA; BIRDS AB For decades, southern China has been considered to be an important source for emerging influenza viruses since key hosts live together in high densities in areas with intensive agriculture. However, the underlying conditions of emergence and spread of avian influenza viruses (AIV) have not been studied in detail, particularly the complex spatiotemporal interplay of viral transmission between wild and domestic ducks, two major actors of AIV epidemiology. In this synthesis, we examine the risks of avian influenza spread in Poyang Lake, an area of intensive free-ranging duck production and large numbers of wild waterfowl. Our synthesis shows that farming of free-grazing domestic ducks is intensive in this area and synchronized with wild duck migration. The presence of juvenile domestic ducks in harvested paddy fields prior to the arrival and departure of migrant ducks in the same fields may amplify the risk of AIV circulation and facilitate the transmission between wild and domestic populations. We provide evidence associating wild ducks migration with the spread of H5N1 in the spring of 2008 from southern China to South Korea, Russia, and Japan, supported by documented wild duck movements and phylogenetic analyses of highly pathogenic avian influenza H5N1 sequences. We suggest that prevention measures based on a modification of agricultural practices may be implemented in these areas to reduce the intensity of AIV transmission between wild and domestic ducks. This would require involving all local stakeholders to discuss feasible and acceptable solutions. C1 [Cappelle, Julien; Gaidet, Nicolas] CIRAD ES, UR AGIRs, F-34398 Montpellier 5, France. [Cappelle, Julien; Zhao, Delong; Xiao, Xiangming] Univ Oklahoma, Ctr Spatial Anal, Dept Bot & Microbiol, Norman, OK 73019 USA. [Cappelle, Julien] Inst Pasteur Cambodge, Epidemiol & Publ Hlth Unit, Phnom Penh, Cambodia. [Gilbert, Marius] Univ Libre Brussels, B-1050 Brussels, Belgium. [Gilbert, Marius] Fonds Natl Rech Sci, B-1000 Brussels, Belgium. [Nelson, Martha I.] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Newman, Scott H.] Vietnam Food & Agr Org United Nations FAO, Emergency Ctr Transboundary Anim Dis ECTAD Progra, Hanoi, Vietnam. [Takekawa, John Y.] US Geol Survey, Western Ecol Res Ctr, San Francisco Bay Estuary Field Stn, Vallejo, CA USA. [Prosser, Diann J.] US Geol Survey, Patuxent Wildlife Res Ctr, Beltsville, MD USA. [Liu, Ying; Li, Peng] Jiangxi Normal Univ, Sch Geog & Environm, Nanchang, Peoples R China. [Li, Peng] Chinese Acad Sci, Inst Geog Sci & Nat Resources Res, Beijing, Peoples R China. [Shu, Yuelong] China CDC, Natl Inst Viral Dis Control & Prevent, Beijing, Peoples R China. RP Cappelle, J (reprint author), CIRAD ES, UR AGIRs, TA C 22-E,Campus Int Baillarguet, F-34398 Montpellier 5, France. EM julien.cappelle@cirad.fr RI Gaidet, Niccolas/H-8122-2013; OI Gilbert, Marius/0000-0003-3708-3359; Prosser, Diann/0000-0002-5251-1799 FU National Institutes of Health [NIH 1R01AI101028-01A1]; NIH Fogarty International Center through the NSF/NIH Ecology of Infectious Diseases program [R01-TW007869]; Food and Agriculture Organization of the United Nations; U.S. Geological Survey; National Aeronautics and Space Administration (NASA) Public Health Program [NNX11AF66G]; Gripavi project - French Ministry of Foreign Affairs FX This study was supported by a grant from the National Institutes of Health (NIH 1R01AI101028-01A1), a grant from the NIH Fogarty International Center (R01-TW007869) through the NSF/NIH Ecology of Infectious Diseases program, the Food and Agriculture Organization of the United Nations, the U.S. Geological Survey, and a grant from National Aeronautics and Space Administration (NASA) Public Health Program (NNX11AF66G). Julien Cappelle was supported by the Gripavi project funded by the French Ministry of Foreign Affairs. We thank Martine Duportal for her help in designing the figures and Isa Woo with editorial assistance. The 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 45 TC 9 Z9 9 U1 5 U2 40 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1612-9202 EI 1612-9210 J9 ECOHEALTH JI EcoHealth PD MAR PY 2014 VL 11 IS 1 BP 109 EP 119 DI 10.1007/s10393-014-0914-2 PG 11 WC Biodiversity Conservation; Ecology; Environmental Sciences SC Biodiversity & Conservation; Environmental Sciences & Ecology GA AI7MP UT WOS:000337076000013 PM 24652313 ER PT J AU Gharwan, H Sci, D AF Gharwan, Helen Groninger, Hunter TI Targeted Cancer Therapies, Part 2 #277 SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Editorial Material ID ADVERSE-REACTIONS; ANTIBODIES; THERAPEUTICS; MANAGEMENT; TOXICITY C1 [Groninger, Hunter] NIH, Pain & Palliat Care Serv, Clin Res Ctr, Bethesda, MD 20892 USA. RP Sci, D (reprint author), NIH, Pain & Palliat Care Serv, Clin Res Ctr, Bldg 10,Room 2-1733,10 Ctr Dr, Bethesda, MD 20892 USA. EM hunter.groninger@nih.gov NR 10 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 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD MAR PY 2014 VL 17 IS 3 BP 358 EP 360 DI 10.1089/jpm.2014.9444 PG 3 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AI6ZL UT WOS:000337027700021 PM 24528156 ER PT J AU Glinskii, OV Li, F Wilson, LS Barnes, S Rittenhouse-Olson, K Barchi, JJ Pienta, KJ Glinsky, VV AF Glinskii, Olga V. Li, Feng Wilson, Landon S. Barnes, Stephen Rittenhouse-Olson, Kate Barchi, Joseph J., Jr. Pienta, Kenneth J. Glinsky, Vladislav V. TI Endothelial integrin alpha 3 beta 1 stabilizes carbohydrate-mediated tumor/endothelial cell adhesion and induces macromolecular signaling complex formation at the endothelial cell membrane SO ONCOTARGET LA English DT Article DE tumor metastasis; adhesion; Thomsen-Friedenreich antigen; galectin; integrin ID THOMSEN-FRIEDENREICH DISACCHARIDE; PROSTATE-CANCER METASTASIS; TUMOR-CELL; MONOCLONAL-ANTIBODY; BONE METASTASIS; HUMAN BREAST; IN-VITRO; GALECTIN-3; ANTIGEN; INHIBITOR AB Blood borne metastatic tumor cell adhesion to endothelial cells constitutes a critical rate-limiting step in hematogenous cancer metastasis. Interactions between cancer associated carbohydrate Thomsen-Friedenreich antigen (TF-Ag) and endothelium-expressed galectin-3 (Gal-3) have been identified as the leading molecular mechanism initiating tumor/endothelial cell adhesion in several types of cancer. However, it is unknown how these rather weak and transient carbohydrate/lectin mediated interactions are stabilized. Here, using Western blot and LC tandem mass spectrometry analyses of pull-downs utilizing TF-Ag loaded gold nanoparticles, we identified Gal-3, endothelial integrin alpha 3 beta 1, Src kinase, as well as 5 additional molecules mapping onto focal adhesion pathway as parts of the macromolecular complexes formed at the endothelial cell membranes downstream of TF-Ag/Gal-3 interactions. In a modified parallel flow chamber assay, inhibiting a3 beta 1 integrin greatly reduced the strength of tumor/endothelial cell interactions without affecting the initial cancer cell adhesion. Further, the macromolecular complex induced by TF-Ag/Gal-3/alpha 3 beta 1 interactions activates Src kinase, p38, and ERK1/2, pathways in endothelial cells in a time- and alpha 3 beta 1-dependent manner. We conclude that, following the initial metastatic cell attachment to endothelial cells mediated by TF-Ag/Gal-3 interactions, endothelial integrin alpha 3 beta 1 stabilizes tumor/endothelial cell adhesion and induces the formation of macromolecular signaling complex activating several major signaling pathways in endothelial cells. C1 [Glinskii, Olga V.; Li, Feng; Glinsky, Vladislav V.] Harry S Truman Mem Vet Hosp, Res Serv, Columbia, MO 65201 USA. [Glinskii, Olga V.; Li, Feng; Glinsky, Vladislav V.] Univ Missouri, Sch Med, Dept Pathol & Anat Sci, Columbia, MO USA. [Glinskii, Olga V.; Li, Feng; Glinsky, Vladislav V.] Univ Missouri, Sch Med, Dept Med Pharmacol & Physiol, Columbia, MO USA. [Wilson, Landon S.; Barnes, Stephen] Univ Alabama Birmingham, Dept Pharmacol & Toxicol, Birmingham, AL USA. [Wilson, Landon S.; Barnes, Stephen] Univ Alabama Birmingham, Targeted Metabol & Prote Lab, Birmingham, AL USA. [Rittenhouse-Olson, Kate] SUNY Buffalo, Dept Biotech & Clin Lab Sci, Buffalo, NY 14260 USA. [Rittenhouse-Olson, Kate] SUNY Buffalo, Dept Microbiol, Buffalo, NY 14260 USA. [Barchi, Joseph J., Jr.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Pienta, Kenneth J.] Johns Hopkins Sch Med, James Buchanan Brady Urol Inst, Dept Urol, Dept Oncol, Baltimore, MD USA. [Pienta, Kenneth J.] Johns Hopkins Sch Med, James Buchanan Brady Urol Inst, Dept Urol, Dept Pharmacol & Mol Sci, Baltimore, MD USA. RP Glinsky, VV (reprint author), Harry S Truman Mem Vet Hosp, Res Serv, Columbia, MO 65201 USA. EM glinskiivl@health.missouri.edu RI Barchi Jr., Joseph/N-3784-2014 FU Biomedical Laboratory Research & Development Service of the VA Office of Research and Development [1I01BX000609]; National Cancer Institute of the National Institutes of Health [R01CA160461] FX This research was supported in parts by the Award Number 1I01BX000609 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (VVG) and the National Cancer Institute of the National Institutes of Health Award R01CA160461 (VVG). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, or VA Office of Research and Development. NR 36 TC 9 Z9 9 U1 1 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR PY 2014 VL 5 IS 5 BP 1382 EP 1389 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AI6EI UT WOS:000336963200023 PM 24675526 ER PT J AU Mamessier, E Song, JY Eberle, FC Pack, S Drevet, C Chetaille, B Abdullaev, Z Adelaide, J Birnbaum, D Chaffanet, M Pittaluga, S Roulland, S Chott, A Jaffe, ES Nadel, B AF Mamessier, Emilie Song, Joo Y. Eberle, Franziska C. Pack, Svetlana Drevet, Charlotte Chetaille, Bruno Abdullaev, Ziedulla Adelaide, Jose Birnbaum, Daniel Chaffanet, Max Pittaluga, Stefania Roulland, Sandrine Chott, Andreas Jaffe, Elaine S. Nadel, Bertrand TI Early lesions of follicular lymphoma: a genetic perspective SO HAEMATOLOGICA LA English DT Article ID B-CELL LYMPHOMA; ACUTE LYMPHOBLASTIC-LEUKEMIA; IN-SITU LOCALIZATION; SOMATIC MUTATIONS; CLONAL EVOLUTION; HODGKIN-LYMPHOMA; FUSION; EXPRESSION; BLOOD; TRANSPLANTATION AB The pathogenesis of follicular lymphoma is a multi-hit process progressing over many years through the accumulation of numerous genetic alterations. Besides the hallmark t(14;18), it is still unclear which other oncogenic hits contribute to the early steps of transformation and in which precursor stages these occur. To address this issue, we performed high-resolution comparative genomic hybridization microarrays on laser-capture micro-dissected cases of follicular lymphoma in situ (n=4), partial involvement by follicular lymphoma (n=4), and duodenal follicular lymphoma (n=4), assumed to represent, potentially, the earliest stages in the evolution of follicular lymphoma. Cases of reactive follicular hyperplasia (n=2), uninvolved areas from follicular lymphoma in situ lymph nodes, follicular lymphoma grade 1-2 (n=5) and follicular lymphoma grade 3A (n=5) were used as controls. Surprisingly, alterations involving several relevant (onco)genes were found in all entities, but at significantly lower proportions than in overt follicular lymphoma. While the number of alterations clearly assigns all these entities as precursors, the pattern of partial involvement by follicular lymphoma alterations was quantitatively and qualitatively closer to that of follicular lymphoma, indicating significant selective pressure in line with its faster rate of progression. Among the most notable alterations, we observed and validated deletions of 1p36 and gains of the 7p and 12q chromosomes and related oncogenes, which include some of the most recurrent oncogenic alterations in overt follicular lymphoma (TNFRSF14, EZH2, MLL2). By further delineating distinctive and hierarchical molecular and genetic features of early follicular lymphoma entities, our analysis underlines the importance of applying appropriate criteria for the differential diagnosis. It also provides a first set of candidates likely to be involved in the cascade of hits that pave the path of the various progression phases to follicular lymphoma development. C1 [Mamessier, Emilie; Drevet, Charlotte; Roulland, Sandrine; Nadel, Bertrand] CIML, Marseille, France. [Song, Joo Y.; Eberle, Franziska C.; Pack, Svetlana; Abdullaev, Ziedulla; Pittaluga, Stefania; Jaffe, Elaine S.] NIH, Pathol Lab, Bethesda, MD 20892 USA. [Chetaille, Bruno] IPC, Pathol Lab, Marseille, France. [Adelaide, Jose; Birnbaum, Daniel; Chaffanet, Max] IPC, Marseille, France. [Chott, Andreas] Wilhelminenspital Stadt Wien, Inst Pathol & Microbiol, Vienna, Austria. RP Jaffe, ES (reprint author), NIH, Pathol Lab, Bethesda, MD 20892 USA. EM elainejaffe@nih.gov; nadel@ciml.univ-mrs.fr RI Pack, Svetlana/C-2020-2014; Nadel, Bertrand/J-2197-2014; OI Jaffe, Elaine/0000-0003-4632-0301 FU Institut National du Cancer (INCa); Association pour la Recherche sur le Cancer (ARC); MedImmune's Strategic Collaboration to Fund; Conduct Medical Science Research program, Canceropole PACA; Institut National de la Sante et de la Recherche Medicale (INSERM); Centre National de la Recherche Scientifique (CNRS); Center for Cancer Research, National Cancer Institute, National Institutes of Health; Canceropole PACA FX This work was funded by grants from the Institut National du Cancer (INCa), the Association pour la Recherche sur le Cancer (ARC), a MedImmune's Strategic Collaboration to Fund and Conduct Medical Science Research program, Canceropole PACA, and institutional grants from the Institut National de la Sante et de la Recherche Medicale (INSERM), the Centre National de la Recherche Scientifique (CNRS) and Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. EM and CD were recipients of fellowships from the Institut National du Cancer (INCa), Canceropole PACA, and MedImmune's Strategic Collaboration to Fund and Conduct Medical Science Research program. We thank Shelley Hoover and Dr. Mark Simpson for their support. NR 49 TC 22 Z9 22 U1 0 U2 6 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD MAR PY 2014 VL 99 IS 3 BP 481 EP 488 DI 10.3324/haematol.2013.094474 PG 8 WC Hematology SC Hematology GA AH6QF UT WOS:000336255000018 PM 24162788 ER PT J AU Amable, L Gavin, E Kudo, K Meng, E Rocconi, RP Shevde, LA Reed, E AF Amable, Lauren Gavin, Elaine Kudo, Kenji Meng, Erhong Rocconi, Rodney P. Shevde, Lalita A. Reed, Eddie TI GLI1 upregulates C-JUN through a specific 130-kDa isoform SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE Hedgehog; GLI1; AP1; C-JUN; cisplatin resistance ID HEDGEHOG SIGNALING PATHWAY; MESSENGER-RNA EXPRESSION; OVARIAN-CANCER CELLS; DNA-DAMAGE; STEM-CELL; REPAIR; ACTIVATION; GENES; TRANSCRIPTION; INHIBITION AB The Hedgehog pathway is molecularly linked to increased resistance to cisplatin and increased repair of platinum-DNA damage, through C-JUN. GLI1, which has five known isoforms, is a positive transcriptional regulator in Hedgehog. Southwestern blot assay, EMSA and ChIP assays indicate that only one of five isoforms of GLI1 may be responsible for the Hedgehog link with C-JUN and thus, increased platinum-DNA adduct repair. Cancer tissues express this 130-kDa isoform at levels 6-fold higher than non-malignant tissues; and this isoform exists in abundance in six of seven ovarian cancer cell lines examined. C1 [Amable, Lauren; Reed, Eddie] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD 20892 USA. [Gavin, Elaine; Kudo, Kenji; Meng, Erhong; Rocconi, Rodney P.] Univ S Alabama, Mitchell Canc Inst, Mobile, AL 36604 USA. [Shevde, Lalita A.] Univ Alabama Birmingham, Dept Pathol, Ctr Comprehens Canc, Birmingham, AL 35233 USA. RP Reed, E (reprint author), Natl Inst Minor Hlth & Hlth Dispar, NIH, 3 Ctr Dr, Bethesda, MD 20892 USA. EM eddie.reed@nih.gov FU NIH, National Institute on Minority Health and Health Disparities FX This study was supported by Intramural Research Program of the NIH, National Institute on Minority Health and Health Disparities. We thank Wesley Denny for his helpful discussions and technical assistance. NR 26 TC 3 Z9 3 U1 0 U2 2 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 EI 1791-2423 J9 INT J ONCOL JI Int. J. Oncol. PD MAR PY 2014 VL 44 IS 3 BP 655 EP 661 DI 10.3892/ijo.2013.2222 PG 7 WC Oncology SC Oncology GA AI5GZ UT WOS:000336894900003 PM 24366538 ER PT J AU Logan, JK Walton-Diaz, A Rais-Bahrami, S Merino, MJ Turkbey, B Choyke, PL Pinto, PA AF Logan, Jennifer K. Walton-Diaz, Annerleim Rais-Bahrami, Soroush Merino, Maria J. Turkbey, Baris Choyke, Peter L. Pinto, Peter A. TI Changes Observed in Multiparametric Prostate Magnetic Resonance Imaging Characteristics Correlate With Histopathological Development of Chronic Granulomatous Prostatitis After Intravesical Bacillus Calmette-Guerin Therapy SO JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY LA English DT Article DE granulomatous prostatitis; intravesical BCG; prostate neoplasms; magnetic resonance imaging; ultrasound ID NEEDLE-ASPIRATION-CYTOLOGY; BLADDER-CANCER; IMMUNOTHERAPY; APPEARANCE AB Administration of Bacillus Calmette-Guerin (BCG) has been shown to cause granulomatous prostatitis, a rare inflammatory process that can be mistaken for prostate cancer. We present a case of a 78-year-old man on active surveillance for prostate cancer with a subsequent diagnosis of high-grade urothelial carcinoma. After intravesical BCG therapy, he developed chronic granulomatous prostatitis. We present serial magnetic resonance imaging and biopsy data demonstrating the time interval between BCG administration and the manifestation of chronic granulomatous prostatitis. C1 [Logan, Jennifer K.; Walton-Diaz, Annerleim; Rais-Bahrami, Soroush; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Pinto, Peter A.] NCI, Ctr Intervent Oncol, NIH, Bethesda, MD 20892 USA. RP Logan, JK (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,MSC 1210,Bldg 10,CRC Room 2W-5940, Bethesda, MD 20892 USA. EM jklogan@gmail.com OI Rais-Bahrami, Soroush/0000-0001-9466-9925 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; Center for Interventional Oncology; National Institutes of Health FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the Center for Interventional Oncology. National Institutes of Health and Philips Healthcare have a cooperative research and development agreement. National Institutes of Health and Philips share intellectual property in the field. This research was also made possible through the National Institutes of Health Medical Research Scholars Program, a public-private partnership supported jointly by the National Institutes of Health and generous contributions to the Foundation for the National Institutes of Health from Pfizer Inc, The Leona M. and Harry B. Helmsley Charitable Trust, and the Howard Hughes Medical Institute as well as other private donors. For a complete list, please visit the Foundation website at http://www.fnih.org/work/programs-development/medical-research-scholars- program. NR 10 TC 3 Z9 4 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-8715 EI 1532-3145 J9 J COMPUT ASSIST TOMO JI J. Comput. Assist. Tomogr. PD MAR-APR PY 2014 VL 38 IS 2 BP 274 EP 276 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AI2YZ UT WOS:000336726400021 PM 24637671 ER PT J AU Soliman, SE Kovac, P AF Soliman, Sameh E. Kovac, Pavol TI Practical Synthesis of Building Blocks for Oligosaccharides Containing the beta-D-Galp-(1 -> 3)-beta-D-GlcpNAc Motif SO SYNTHESIS-STUTTGART LA English DT Article DE carbohydrates; oligosaccharides; synthetic methods; thioglycosides; protecting groups ID DISACCHARIDE; POLYSACCHARIDE; CONJUGATION; FRAGMENTS AB An efficient, new pathway for the synthesis of the title sequence has been developed. The sequence has been obtained as a glycosyl donor, beta-D-Galp-(1 -> 3)-beta-D-GlcpNAc-1-SEt, or equipped with a linker (spacer) suitable for conjugation to other molecules, beta-D-Galp-(1 -> 3)-beta-D-GlcpNAc-1-(OCH2CH2)(3)N-3. Both disaccharides have been obtained in crystalline condition for the first time and fully characterized. The existing synthesis of the intermediate disaccharide glycosyl donor was improved by conducting the silver triflate mediated glycosylation under base-deficient conditions in the presence of 1,1,3,3-tetramethylurea and in the absence of molecular sieves. C1 [Soliman, Sameh E.] Univ Alexandria, Fac Sci, Dept Chem, Alexandria 21321, Egypt. [Soliman, Sameh E.; Kovac, Pavol] NIDDK, LBC, NIH, Bethesda, MD 20892 USA. RP Kovac, P (reprint author), NIDDK, LBC, NIH, Bethesda, MD 20892 USA. EM kpn@helix.nih.gov RI Kovac, Pavol/B-8813-2008 OI Kovac, Pavol/0000-0001-5044-3449 FU NIH, NIDDK FX This research was supported by the Intramural Research Program of the NIH, NIDDK. NR 12 TC 4 Z9 4 U1 1 U2 7 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0039-7881 EI 1437-210X J9 SYNTHESIS-STUTTGART JI Synthesis PD MAR PY 2014 VL 46 IS 6 BP 748 EP 751 DI 10.1055/s-0033-1340620 PG 4 WC Chemistry, Organic SC Chemistry GA AI4MD UT WOS:000336838600004 ER PT J AU Kaiser, E Wess, J Tian, Q Schroder, L Kaestner, L Lipp, P AF Kaiser, E. Wess, J. Tian, Q. Schroeder, L. Kaestner, L. Lipp, P. TI Conditional and selective activation of the Gq pathway in the heart and its impact on cardiac function in vivo SO ACTA PHYSIOLOGICA LA English DT Meeting Abstract C1 [Kaiser, E.; Tian, Q.; Schroeder, L.; Kaestner, L.; Lipp, P.] Univ Saarland, Fac Med, Homburg, Germany. [Wess, J.] Natl Inst Diabet & Digest & Kidney Dis, Lab Bioorgan Chem, Bethesda, MD USA. RI Kaestner, Lars/P-6988-2016 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 1748-1708 EI 1748-1716 J9 ACTA PHYSIOL JI Acta Physiol. PD MAR PY 2014 VL 210 SU 695 BP 94 EP 96 PG 2 WC Physiology SC Physiology GA AC1MP UT WOS:000332259900239 ER PT J AU Evans, JD Aizenstein, H Petrides, G Gunning, F AF Evans, Jovier D. Aizenstein, Howard Petrides, Georgios Gunning, Faith TI INTEGRATING NEUROIMAGING INTO CLINICAL TRIALS: OPPORTUNITIES & CHALLENGES SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) CY MAR, 2014 CL Orlando, FL SP Amer Assoc Geriatr Psychiat C1 [Evans, Jovier D.] NIMH, Bethesda, MD 20892 USA. [Aizenstein, Howard] Univ Pittsburgh, Pttsburgh, PA USA. [Petrides, Georgios] Northsore LIJ Hlth Syst, Zucker Hillside Hosp, Glen Oaks, NY USA. [Gunning, Faith] Weill Cornell Med Coll, White Plains, 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2014 VL 22 IS 3 SU S BP S20 EP S21 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AH4FE UT WOS:000336081800023 ER PT J AU Lavretsky, H Wagster, MV Evans, JD Niederehe, G AF Lavretsky, Helen Wagster, Molly V. Evans, Jovier D. Niederehe, George TI SENIOR INVESTIGATOR WORKSHOP ON THE NEW NIH POLICIES FOR RESEARCH FUNDING AND PROGRAM OPPORTUNITIES SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) CY MAR, 2014 CL Orlando, FL SP Amer Assoc Geriatr Psychiat C1 [Lavretsky, Helen] Univ Calif Los Angeles, Los Angeles, CA USA. [Wagster, Molly V.; Evans, Jovier D.; Niederehe, George] NIH, Bethesda, MD 20892 USA. RI Lavretsky, Helen/M-5711-2015 OI Lavretsky, Helen/0000-0001-9990-5085 NR 0 TC 0 Z9 0 U1 0 U2 2 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 MAR PY 2014 VL 22 IS 3 SU S BP S30 EP S30 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AH4FE UT WOS:000336081800037 ER PT J AU Niederehe, G Yaffe, K Bogner, HR Bromberger, JT AF Niederehe, George Yaffe, Kristine Bogner, Hillary R. Bromberger, Joyce T. TI TRAJECTORIES OF RISK AND SYMPTOM EXPRESSION IN LATE LIFE DEPRESSION SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) CY MAR, 2014 CL Orlando, FL SP Amer Assoc Geriatr Psychiat C1 [Niederehe, George] NIMH, Bethesda, MD 20892 USA. [Bogner, Hillary R.] Univ Penn, Philadelphia, PA 19104 USA. [Yaffe, Kristine] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Bromberger, Joyce T.] Univ Pittsburgh, Pittsburgh, PA 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2014 VL 22 IS 3 SU S BP S35 EP S35 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AH4FE UT WOS:000336081800045 ER PT J AU Widemann, BC Acosta, MT Ammoun, S Belzberg, AJ Bernards, A Blakeley, J Bretscher, A Cichowski, K Clapp, DW Dombi, E Evans, GD Ferner, R Fernandez-Valle, C Fisher, MJ Giovannini, M Gutmann, DH Hanemann, CO Hennigan, R Huson, S Ingram, D Kissil, J Korf, BR Legius, E Packer, RJ McClatchey, AI McCormick, F North, K Pehrsson, M Plotkin, SR Ramesh, V Ratner, N Schirmer, S Sherman, L Schorry, E Stevenson, D Stewart, DR Ullrich, N Bakker, AC Morrison, H AF Widemann, Brigitte C. Acosta, Maria T. Ammoun, Sylvia Belzberg, Allan J. Bernards, Andre Blakeley, Jaishri Bretscher, Antony Cichowski, Karen Clapp, D. Wade Dombi, Eva Evans, Gareth D. Ferner, Rosalie Fernandez-Valle, Cristina Fisher, Michael J. Giovannini, Marco Gutmann, David H. Hanemann, C. Oliver Hennigan, Robert Huson, Susan Ingram, David Kissil, Joe Korf, Bruce R. Legius, Eric Packer, Roger J. McClatchey, Andrea I. McCormick, Frank North, Kathryn Pehrsson, Minja Plotkin, Scott R. Ramesh, Vijaya Ratner, Nancy Schirmer, Susann Sherman, Larry Schorry, Elizabeth Stevenson, David Stewart, Douglas R. Ullrich, Nicole Bakker, Annette C. Morrison, Helen TI CTF Meeting 2012: Translation of the Basic Understanding of the Biology and Genetics of NF1, NF2, and Schwannomatosis Toward the Development of Effective Therapies SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE neurofibromatosis type 1; neurofibromatosis type 2; NF1; NF2; schwannomatosis; tumor suppressor; SMARCB1; merlin neurofibromin; preclinical models ID HISTONE DEACETYLASE INHIBITOR; NEUROFIBROMATOSIS TYPE-2; VESTIBULAR SCHWANNOMAS; FAMILIAL SCHWANNOMATOSIS; SPORADIC SCHWANNOMATOSIS; RETROSPECTIVE ANALYSIS; MULTIPLE MENINGIOMAS; DIAGNOSTIC-CRITERIA; SMARCB1 MUTATIONS; CLINICAL ARTICLE AB The neurofibromatoses (NF) are autosomal dominant genetic disorders that encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect more people worldwide than Duchenne muscular dystrophy and Huntington's disease combined. NF1 and NF2 are caused by mutations of known tumor suppressor genes (NF1 and NF2, respectively). For schwannomatosis, although mutations in SMARCB1 were identified in a subpopulation of schwannomatosis patients, additional causative gene mutations are still to be discovered. Individuals with NF1 may demonstrate manifestations in multiple organ systems, including tumors of the nervous system, learning disabilities, and physical disfigurement. NF2 ultimately can cause deafness, cranial nerve deficits, and additional severe morbidities caused by tumors of the nervous system. Unmanageable pain is a key finding in patients with schwannomatosis. Although today there is no marketed treatment for NF-related tumors, a significant number of clinical trials have become available. In addition, significant preclinical efforts have led to a more rational selection of potential drug candidates for NF trials. An important element in fueling this progress is the sharing of knowledge. For over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share novel findings, ideas, and build collaborations. The 2012 NF Conference held in New Orleans hosted over 350 NF researchers and clinicians. This article provides a synthesis of the highlights presented at the conference and as such, is a state-of-the-field for NF research in 2012. (c) 2014 Wiley Periodicals, Inc. C1 [Widemann, Brigitte C.; Dombi, Eva] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Acosta, Maria T.; Packer, Roger J.] Gilbert NF Inst, Washington, DC USA. [Ammoun, Sylvia; Hanemann, C. Oliver] Univ Plymouth, Peninsula Sch Med, Plymouth PL4 8AA, Devon, England. [Ammoun, Sylvia; Hanemann, C. Oliver] Univ Plymouth, Peninsula Sch Dent, Plymouth PL4 8AA, Devon, England. [Belzberg, Allan J.; Blakeley, Jaishri] Johns Hopkins Univ, Baltimore, MD USA. [Bernards, Andre; McClatchey, Andrea I.; Plotkin, Scott R.; Ramesh, Vijaya] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. [Bernards, Andre; McClatchey, Andrea I.; Plotkin, Scott R.; Ramesh, Vijaya] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA USA. [Bretscher, Antony] Cornell Univ, New York, NY 10021 USA. [Cichowski, Karen] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Clapp, D. Wade; Ingram, David] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Evans, Gareth D.; Huson, Susan] Univ Manchester, St Marys Hosp, Manchester M13 0JH, Lancs, England. [Ferner, Rosalie] Guys & St Thomas NHS Fdn Trust, London, England. [Ferner, Rosalie] Kings Coll London, Dept Clin Neurosci, London, England. [Fernandez-Valle, Cristina] Univ Cent Florida, Orlando, FL 32816 USA. [Fisher, Michael J.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Giovannini, Marco] Univ So Calif, House Res Inst, Los Angeles, CA USA. [Gutmann, David H.] Washington Univ, Sch Med, St Louis, MO USA. [Hennigan, Robert; Ratner, Nancy; Schorry, Elizabeth] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Kissil, Joe] Scripps Res Inst Florida, Jupiter, FL USA. [Korf, Bruce R.] Univ Alabama Birmingham, Birmingham, AL USA. [Legius, Eric] Catholic Univ Louvain, B-3000 Louvain, Belgium. [McCormick, Frank] Univ Calif San Francisco, San Francisco, CA 94143 USA. [North, Kathryn] Childrens Hosp, Westmead, NSW, Australia. [Pehrsson, Minja] Biomed Helsinki, Helsinki, Finland. [Schirmer, Susann; Morrison, Helen] Leibniz Inst Age Res, Jena, Germany. [Sherman, Larry] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Stevenson, David] Univ Utah, Salt Lake City, UT USA. [Stewart, Douglas R.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Ullrich, Nicole] Childrens Hosp, Boston, MA 02115 USA. [Bakker, Annette C.] Childrens Tumor Fdn, New York, NY 10005 USA. RP Bakker, AC (reprint author), Childrens Tumor Fdn, 95 Pine St, New York, NY 10005 USA. EM widemanb@mail.nih.gov; abakker@ctf.org RI North, Kathryn/K-6476-2012; Morrison, Helen/B-3984-2017; OI North, Kathryn/0000-0003-0841-8009; Morrison, Helen/0000-0003-4938-1409; Hanemann, Clemens Oliver/0000-0002-1951-1025; Evans, Gareth/0000-0002-8482-5784 FU National Institutes of Health Grant Award [1R13NS070505-01]; Center for Cancer Research; National Cancer Institute FX Grant sponsor: National Institutes of Health Grant Award; Grant number: 1R13NS070505-01; Grant sponsor: Center for Cancer Research; Grant sponsor: National Cancer Institute. NR 70 TC 4 Z9 4 U1 0 U2 15 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 MAR PY 2014 VL 164 IS 3 BP 563 EP 578 DI 10.1002/ajmg.a.36312 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA AB7NZ UT WOS:000331978700001 PM 24443315 ER PT J AU Vanderver, A Tonduti, D Kahn, I Schmidt, J Medne, L Vento, J Chapman, KA Lanpher, B Pearl, P Gropman, A Lourenco, C Bamforth, JS Sharpe, C Pineda, M Schallner, J Bodamer, O Orcesi, S Oberstein, SAJL Sistermans, EA Yntema, HG Bonnemann, C Waldman, AT van der Knaap, MS AF Vanderver, Adeline Tonduti, Davide Kahn, Ilana Schmidt, Johanna Medne, Livija Vento, Jodie Chapman, Kimberly A. Lanpher, Brendan Pearl, Phillip Gropman, Andrea Lourenco, Charles Bamforth, John-Steven Sharpe, Cynthia Pineda, Mercedes Schallner, Jens Bodamer, Olaf Orcesi, Simona Oberstein, Saskia A. J. Lesnik Sistermans, Erik A. Yntema, Helger G. Bonnemann, Carsten Waldman, Amy T. van der Knaap, Marjo S. TI Characteristic Brain Magnetic Resonance Imaging Pattern in Patients With Macrocephaly and PTEN Mutations SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE macrocephaly; perivascular; autism spectrum disorder; magnetic resonance imaging; genetics; PTEN; hamartoma; leukoencephalopathy ID RILEY-RUVALCABA-SYNDROME; AUTISM SPECTRUM DISORDERS; LHERMITTE-DUCLOS-DISEASE; COWDEN-SYNDROME; PROTEUS SYNDROME; GERMLINE; TUMOR; GENE; HYPOMELANOSIS; PREVALENCE AB We describe an MRI phenotype seen in a series of patients with mutations in PTEN who have clinical features consistent with PTEN hamartoma tumor syndrome (PHTS). Retrospective review of clinical data and MRI was performed in 23 subjects evaluated in four different tertiary care centers with clinical programs in inherited disorders of the white matter. Patients were referred due to abnormal MRI features and abnormal PTEN sequencing was identified. All subjects had significant macrocephaly (on average >4 SD above the mean), developmental delay with or without autism spectrum disorder and uniform MRI features of enlarged perivascular spaces and multifocal periventricular white matter abnormalities. The phenotype of PHTS may include MRI abnormalities such as multifocal periventricular white matter abnormalities and enlarged perivascular spaces. These neuroimaging findings, in association with macrocephaly and developmental delay, should prompt consideration of PTEN as a diagnostic possibility. (c) 2013 Wiley Periodicals, Inc. C1 [Vanderver, Adeline; Schmidt, Johanna; Pearl, Phillip; Gropman, Andrea] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Tonduti, Davide] Univ Pavia, Dept Brain & Behav Sci, Child Neuropsychiat Unit, I-27100 Pavia, Italy. [Kahn, Ilana] Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. [Medne, Livija; Waldman, Amy T.] Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA. [Vento, Jodie] Childrens Hosp Pittsburgh, UPMC, Div Child Neurol, Pittsburgh, PA 15213 USA. [Chapman, Kimberly A.; Lanpher, Brendan] Childrens Natl Med Ctr, Dept Genet, Washington, DC 20010 USA. [Lourenco, Charles] Univ Sao Paulo, Clin Hosp Ribeirao Preto, Neurogenet Unit, Sao Paulo, Brazil. [Bamforth, John-Steven] Univ Alberta Hosp, Med Genet Clin, Edmonton, AB T6G 2B7, Canada. [Sharpe, Cynthia] Starship Childrens Hosp, Paediat Neurol, Auckland, New Zealand. [Pineda, Mercedes] Hosp San Juan Dios, Barcelona, Spain. [Schallner, Jens] Uniklin Dresden, Klin & Poliklin Kinder & Jugendmed, Dresden, Germany. [Bodamer, Olaf] Univ Miami, Miller Sch Med, Dept Human Genet, Miami, FL 33136 USA. [Orcesi, Simona] C Mondino Natl Neurol Inst, Child Neurol & Psychiat Unit, Pavia, Italy. [Oberstein, Saskia A. J. Lesnik] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands. [Sistermans, Erik A.] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. [Yntema, Helger G.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Bonnemann, Carsten] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [van der Knaap, Marjo S.] Vrije Univ Amsterdam, Med Ctr, Dept Child Neurol, Amsterdam, Netherlands. RP Vanderver, A (reprint author), Childrens Natl Med Ctr, 111 Michigan Ave,NW, Washington, DC 20010 USA. EM avanderv@childrensnational.org RI Yntema, H.G./L-4771-2015; Lesnik Oberstein, Saskia/C-3643-2016; tonduti, davide/K-1673-2016; OI tonduti, davide/0000-0001-9371-7454; Sistermans, Erik/0000-0001-7187-4563 FU Myelin Disorders Bioregistry Project FX Grant sponsor: Myelin Disorders Bioregistry Project. NR 32 TC 12 Z9 12 U1 3 U2 10 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 MAR PY 2014 VL 164 IS 3 BP 627 EP 633 DI 10.1002/ajmg.a.36309 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA AB7NZ UT WOS:000331978700008 PM 24375884 ER PT J AU Beaulieu, LM Lin, E Mick, E Koupenova, M Weinberg, EO Kramer, CD Genco, CA Tanriverdi, K Larson, MG Benjamin, EJ Freedman, JE AF Beaulieu, Lea M. Lin, Elaine Mick, Eric Koupenova, Milka Weinberg, Ellen O. Kramer, Carolyn D. Genco, Caroline A. Tanriverdi, Kahraman Larson, Martin G. Benjamin, Emelia J. Freedman, Jane E. TI Interleukin 1 Receptor 1 and Interleukin 1 beta Regulate Megakaryocyte Maturation, Platelet Activation, and Transcript Profile During Inflammation in Mice and Humans SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE blood platelets; diet; high-fat; IL1R1 protein; human; infection; megakaryocytes ID HIGH-FAT DIET; CYTOKINE PRODUCTION; CELLS; EXPRESSION; ATHEROSCLEROSIS; IL-1-BETA; THROMBOPOIESIS; CANAKINUMAB; INHIBITION; ARTERIES AB Objective Interleukin 1 Receptor 1 (IL1R1) and its ligand, IL1, are upregulated in cardiovascular disease, obesity, and infection. Previously, we reported a higher level of IL1R1 transcripts in platelets from obese individuals of the Framingham Heart Study (FHS), but its functional effect in platelets has never been described. Additionally, IL1 levels are increased in atherosclerotic plaques and in bacterial infections. The aim of this work is to determine whether IL1, through IL1R1, can activate platelets and megakaryocytes to promote atherothrombosis. Approach and Results We found that IL1-related genes from platelets, as measured in 1819 FHS participants, were associated with increased body mass index, and a direct relationship was shown in wild-type mice fed a high-fat diet. Mechanistically, IL1 activated nuclear factor-B and mitogen-activated protein kinase signaling pathways in megakaryocytes. IL1, through IL1R1, increased ploidy of megakaryocytes to 64+ N by 2-fold over control. IL1 increased agonist-induced platelet aggregation by 1.2-fold with thrombin and 4.2-fold with collagen. IL1 increased adhesion to both collagen and fibrinogen, and heterotypic aggregation by 1.9-fold over resting. High fat diet-enhanced platelet adhesion was absent in IL1R1(-/-) mice. Wild-type mice infected with Porphyromonas gingivalis had circulating heterotypic aggregates (1.5-fold more than control at 24 hours and 6.2-fold more at 6 weeks) that were absent in infected IL1R1(-/-) and IL1(-/-) mice. Conclusions In summary, IL1R1- and IL1-related transcripts are elevated in the setting of obesity. IL1R1/IL1 augment both megakaryocyte and platelet functions, thereby promoting a prothrombotic environment during infection and obesity; potentially contributing to the development of atherothrombotic disease. C1 [Beaulieu, Lea M.; Koupenova, Milka; Tanriverdi, Kahraman; Freedman, Jane E.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01605 USA. [Mick, Eric] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. [Lin, Elaine; Koupenova, Milka; Weinberg, Ellen O.; Kramer, Carolyn D.; Genco, Caroline A.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Framingham, MA USA. [Genco, Caroline A.] Boston Univ, Sch Med, Infect Dis Sect, Framingham, MA USA. [Genco, Caroline A.] Boston Univ, Sch Med, Dept Microbiol, Framingham, MA USA. [Larson, Martin G.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Larson, Martin G.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Inst, Framingham, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Framingham, MA USA. RP Beaulieu, LM (reprint author), Univ Massachusetts, Sch Med, 368 Plantat St,ACS7-1012, Worcester, MA 01605 USA. EM lea.beaulieu@umassmed.edu FU National Institute of Allergy and Infectious Disease [P01 AI078894]; National Heart, Lung, and Blood Institute [HL087201, RFA-HL-12-008, N01-HC 25195, 1R01AG028321, T32 HL07224]; National Institutes of Health FX This work was supported by grants from the National Institutes of Health, including the National Institute of Allergy and Infectious Disease (P01 AI078894 to L. M. Beaulieu, E.O. Weinberg, C. D. Kramer, C. A. Genco, and J.E. Freedman) and the National Heart, Lung, and Blood Institute (HL087201 and RFA-HL-12-008 to J.E. Freedman, N01-HC 25195 and 1R01AG028321 to E.J. Benjamin, and T32 HL07224 to L. M. Beaulieu, M. Koupenova, and C. D. Kramer). NR 42 TC 23 Z9 25 U1 2 U2 8 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 MAR PY 2014 VL 34 IS 3 BP 552 EP 564 DI 10.1161/ATVBAHA.113.302700 PG 13 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AD1LX UT WOS:000332996600012 PM 24458711 ER PT J AU Shao, Z Fu, ZJ Stahl, A Joyal, JS Hatton, C Juan, A Hurst, C Evans, L Cui, ZH Pei, D Gong, Y Xu, D Tian, K Bogardus, H Edin, ML Lih, F Sapieha, P Chen, J Panigrahy, D Hellstrom, A Zeldin, DC Smith, LEH AF Shao, Zhuo Fu, Zhongjie Stahl, Andreas Joyal, Jean-Sebastien Hatton, Colman Juan, Aimee Hurst, Christian Evans, Lucy Cui, Zhenghao Pei, Dorothy Gong, Yan Xu, Dan Tian, Katherine Bogardus, Hannah Edin, Matthew L. Lih, Fred Sapieha, Przemyslaw Chen, Jing Panigrahy, Dipak Hellstrom, Ann Zeldin, Darryl C. Smith, Lois E. H. TI Cytochrome P450 2C8 omega 3-Long-Chain Polyunsaturated Fatty Acid Metabolites Increase Mouse Retinal Pathologic Neovascularization-Brief Report SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE angiogenesis factor; cytochrome P450 CYP2C8 (human); pathologic neovascularization ID OXYGEN-INDUCED RETINOPATHY; SOLUBLE EPOXIDE HYDROLASE; ENDOTHELIAL EXPRESSION; UNITED-STATES; ANGIOGENESIS; METASTASIS; GROWTH; MODEL; MICE; PREVALENCE AB Objective Regulation of angiogenesis is critical for many diseases. Specifically, pathological retinal neovascularization, a major cause of blindness, is suppressed with dietary 3-long-chain polyunsaturated fatty acids (3LCPUFAs) through antiangiogenic metabolites of cyclooxygenase and lipoxygenase. Cytochrome P450 epoxygenases (CYP2C8) also metabolize LCPUFAs, producing bioactive epoxides, which are inactivated by soluble epoxide hydrolase (sEH) to transdihydrodiols. The effect of these enzymes and their metabolites on neovascularization is unknown. Approach and Results The mouse model of oxygen-induced retinopathy was used to investigate retinal neovascularization. We found that CYP2C (localized in wild-type monocytes/macrophages) is upregulated in oxygen-induced retinopathy, whereas sEH is suppressed, resulting in an increased retinal epoxide:diol ratio. With a 3LCPUFA-enriched diet, retinal neovascularization increases in Tie2-driven human-CYP2C8-overexpressing mice (Tie2-CYP2C8-Tg), associated with increased plasma 19,20-epoxydocosapentaenoic acid and retinal epoxide:diol ratio. 19,20-Epoxydocosapentaenoic acids and the epoxide:diol ratio are decreased with overexpression of sEH (Tie2-sEH-Tg). Overexpression of CYP2C8 or sEH in mice does not change normal retinal vascular development compared with their wild-type littermate controls. The proangiogenic role in retina of CYP2C8 with both 3LCPUFA and 6LCPUFA and antiangiogenic role of sEH in 3LCPUFA metabolism were corroborated in aortic ring assays. Conclusions Our results suggest that CYP2C 3LCPUFA metabolites promote retinal pathological angiogenesis. CYP2C8 is part of a novel lipid metabolic pathway influencing retinal neovascularization. C1 [Shao, Zhuo; Fu, Zhongjie; Joyal, Jean-Sebastien; Hatton, Colman; Juan, Aimee; Hurst, Christian; Evans, Lucy; Cui, Zhenghao; Pei, Dorothy; Gong, Yan; Xu, Dan; Tian, Katherine; Bogardus, Hannah; Chen, Jing; Smith, Lois E. H.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston Childrens Hosp, Boston, MA USA. [Pei, Dorothy] Harvard Univ, Sch Med, Dept Pathol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Stahl, Andreas] Univ Eye Hosp Freiburg, Freiburg, Germany. [Edin, Matthew L.; Lih, Fred; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Sapieha, Przemyslaw] Univ Montreal, Dept Ophthalmol, Hop Maisonneuve Rosemont, Montreal, PQ, Canada. [Hellstrom, Ann] Univ Gothenburg, Dept Ophthalmol, Sahlgrenska Acad, Gothenburg, Sweden. RP Smith, LEH (reprint author), Boston Childrens Hosp, Dept Ophthalmol, 300 Longwood Ave, Boston, MA 02115 USA. EM Lois.Smith@childrens.harvard.edu FU National Institutes of Health (NIH)/National Eye Institute [EY022275, EY017017, P01HD18655]; RPB Senior Investigator Award; Lowy Medical Foundation; European Commission [305485]; Canadian Institute of Health Research; BrightFocus Foundation; BCH Faculty Career Development Award; Canada Research Chair tier II; Deutsche Ophthalmologische Gesellschaft; Freifrau von Nauendorff Foundation; NCI [RO1CA148633-01A4]; NIH, National Institute of Environmental Health Sciences [Z01025034] FX This work was supported by the National Institutes of Health (NIH)/National Eye Institute (EY022275, EY017017, and P01HD18655), RPB Senior Investigator Award, Lowy Medical Foundation, European Commission FP7 project 305485 PREVENT-ROP (LEHS), Canadian Institute of Health Research (Z. Shao), BrightFocus Foundation and BCH Faculty Career Development Award (J. Chen), Canada Research Chair tier II. (P. Sapieha), Deutsche Ophthalmologische Gesellschaft and Freifrau von Nauendorff Foundation (A. Stahl), NCI RO1CA148633-01A4 (D. Panigrahy) and supported, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01025034; D. C. Zeldin). NR 28 TC 14 Z9 14 U1 0 U2 5 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 MAR PY 2014 VL 34 IS 3 BP 581 EP 586 DI 10.1161/ATVBAHA.113.302927 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AD1LX UT WOS:000332996600015 PM 24458713 ER PT J AU Albert, PS Liu, AY Nansel, T AF Albert, Paul S. Liu, Aiyi Nansel, Tonja TI Efficient Logistic Regression Designs under an Imperfect Population Identifier SO BIOMETRICS LA English DT Article DE Case-control designs; Diagnostic accuracy; Epidemiologic designs; Misclassification; Measurement error ID MISCLASSIFICATION; INTERVENTION; ACCURACY; 2-PHASE; TRIAL AB Motivated by actual study designs, this article considers efficient logistic regression designs where the population is identified with a binary test that is subject to diagnostic error. We consider the case where the imperfect test is obtained on all participants, while the gold standard test is measured on a small chosen subsample. Under maximum-likelihood estimation, we evaluate the optimal design in terms of sample selection as well as verification. We show that there may be substantial efficiency gains by choosing a small percentage of individuals who test negative on the imperfect test for inclusion in the sample (e.g., verifying 90% test-positive cases). We also show that a two-stage design may be a good practical alternative to a fixed design in some situations. Under optimal and nearly optimal designs, we compare maximum-likelihood and semi-parametric efficient estimators under correct and misspecified models with simulations. The methodology is illustrated with an analysis from a diabetes behavioral intervention trial. C1 [Albert, Paul S.; Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. [Nansel, Tonja] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. RP Albert, PS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, 6100 Execut Blvd,Room 7B05, Bethesda, MD 20892 USA. EM albertp@mail.nih.gov OI Nansel, Tonja/0000-0002-8298-7595; Liu, Aiyi/0000-0002-6618-5082 FU National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We thank the Editor, Associate Editor, and Referee for constructive comments that led to an improved paper. We thank the Center for Information Technology, National Institutes of Health, for providing access to the high-performance computational capabilities of the Biowulf cluster computing system. This research was supported by the Intramural Research Program of the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 23 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD MAR PY 2014 VL 70 IS 1 BP 175 EP 184 DI 10.1111/biom.12106 PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA AC4BS UT WOS:000332466200019 PM 24261471 ER PT J AU Mitchell, EM Lyles, RH Manatunga, AK Danaher, M Perkins, NJ Schisterman, EF AF Mitchell, Emily M. Lyles, Robert H. Manatunga, Amita K. Danaher, Michelle Perkins, Neil J. Schisterman, Enrique F. TI Regression for Skewed Biomarker Outcomes Subject to Pooling SO BIOMETRICS LA English DT Article ID LOGNORMAL SUM DISTRIBUTIONS; CARLO EM ALGORITHM; EXPOSURE; APPROXIMATION; MISCARRIAGE; PREVALENCE; LIKELIHOOD; DESIGN; LIMIT; MODEL C1 [Mitchell, Emily M.; Lyles, Robert H.; Manatunga, Amita K.] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. [Danaher, Michelle; Perkins, Neil J.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. RP Mitchell, EM (reprint author), Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. EM emitch8@emory.edu OI Perkins, Neil/0000-0002-6802-4733; Schisterman, Enrique/0000-0003-3757-641X FU National Institute of Nursing Research [1RC4NR012527-01]; National Institute of Environmental Health Sciences [5R01ES012458-07]; National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR-000454] FX This research was supported by grants from the National Institute of Nursing Research (1RC4NR012527-01) and from the National Institute of Environmental Health Sciences (5R01ES012458-07). Additional partial support from the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR-000454 is also acknowledged. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 29 TC 7 Z9 7 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD MAR PY 2014 VL 70 IS 1 BP 202 EP 211 PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA AC4BS UT WOS:000332466200007 PM 24521420 ER PT J AU Hirko, KA Soliman, AS Banerjee, M Ruterbusch, J Harford, JB Merajver, SD Schwartz, K AF Hirko, Kelly A. Soliman, Amr S. Banerjee, Mousumi Ruterbusch, Julie Harford, Joe B. Merajver, Sofia D. Schwartz, Kendra TI A Comparison of Criteria to Identify Inflammatory Breast Cancer Cases from Medical Records and the Surveillance, Epidemiology and End Results Data base, 2007-2009 SO BREAST JOURNAL LA English DT Article DE diagnostic criteria; inflammatory breast cancer; SEER ID CARCINOMA INCIDENCE; RESULTS PROGRAM; INSTITUTE; SURVIVAL; FEATURES; REGISTRY; TUNISIA AB Inflammatory breast cancer (IBC) is a relatively rare and extremely aggressive form of breast cancer that is diagnosed clinically. Standardization of clinical diagnoses is challenging, both nationally and internationally; moreover, IBC coding definitions used by registries have changed over time. This study aimed to compare diagnostic factors of IBC reported in a U.S. Surveillance, Epidemiology, and End Results (SEER) registry to clinical criteria found in the medical records of all invasive breast cancer cases at a single institution. We conducted a medical record review of all female invasive breast cancers (n=915) seen at an NCI-designated comprehensive cancer center in Detroit from 2007 to 2009. IBC cases were identified based on the presence of the main clinical characteristics of the disease (erythema, edema, peau d'orange). We compared the proportion of IBC out of all breast cancers, using these clinical criteria and the standard SEER IBC codes. In the reviewed cases, the clinical criteria identified significantly more IBC cases (n=74, 8.1%) than the standard IBC SEER definition (n=19, 2.1%; p<0.0001). No IBC cases were identified in the cancer center records using the SEER pathologic coding, which requires the diagnosis of inflammatory carcinoma on the pathology report, a notation that is rarely made. Emphasis must be placed on the documentation of clinical and pathologic characteristics of IBC in the medical record, so that analysis of putative IBC subtypes will be possible. Our results indicate the need for a consensus on the definition of IBC to be utilized in future research. C1 [Hirko, Kelly A.; Merajver, Sofia D.] Univ Michigan, Dept Epidemiol, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Soliman, Amr S.] Univ Nebraska Med Ctr, Coll Publ Hlth, Dept Epidemiol, Omaha, NE USA. [Banerjee, Mousumi] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Ruterbusch, Julie] Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI USA. [Harford, Joe B.] NCI, Dept Hlth & Human Serv, Ctr Global Hlth, NIH, Bethesda, MD 20892 USA. [Merajver, Sofia D.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. [Schwartz, Kendra] Wayne State Univ, Sch Med, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. RP Hirko, KA (reprint author), Univ Michigan, Dept Epidemiol, 109 Observ St, Ann Arbor, MI 48109 USA. EM kalamb@umich.edu FU University of Michigan Center for Global Health Predoctoral Fellowship; Cancer Epidemiology Education in Special Populations Program of the University of Michigan [CA R25 112383]; Avon Foundation; Breast Cancer Research Foundation FX The authors would like to thank Dr. William Anderson and Dr. Catherine Schairer at the Division of Cancer Epidemiology and Genetics, National Cancer Institute, for providing expertise on defining IBC from the SEER data base. We would also like to express gratitude to Kari Borden at the Detroit SEER registry for providing training on the electronic medical record system and to Denise Cadwell for her assistance in pulling paper medical records for this study. Finally, we would like to thank Dr. Kirsten Herold for her help with editing this manuscript. This research was supported by the University of Michigan Center for Global Health Predoctoral Fellowship (K. A. Hirko) and the Cancer Epidemiology Education in Special Populations Program of the University of Michigan (CA R25 112383). Additional funding was received from the Avon Foundation (ASS and SDM) and the Breast Cancer Research Foundation (SDM). NR 28 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1075-122X EI 1524-4741 J9 BREAST J JI Breast J. PD MAR PY 2014 VL 20 IS 2 BP 185 EP 191 DI 10.1111/tbj.12234 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AC5ZS UT WOS:000332600200011 PM 24372839 ER PT J AU Louie, GH Ward, MM AF Louie, Grant H. Ward, Michael M. TI Measurement and treatment of radiographic progression in ankylosing spondylitis: lessons learned from observational studies and clinical trials SO CURRENT OPINION IN RHEUMATOLOGY LA English DT Review DE ankylosing spondylitis; measurement; radiographic progression; treatment ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; RESONANCE-IMAGING EXAMINATIONS; SACROILIAC JOINT INFLAMMATION; SCORING SYSTEM; SPINE; THERAPY; SYNDESMOPHYTES; ETANERCEPT; INFLIXIMAB; ADALIMUMAB AB Purpose of reviewOne of the major goals of treatment of ankylosing spondylitis is to prevent or slow the development of spinal new bone formation. Recent observational studies are compared with the results from clinical trials for the effects of tumor necrosis factor-alpha inhibitors (TNFi) and NSAIDs on radiographic measures of spinal damage.Recent findingsData from clinical trials indicate that treatment up to 2 years with TNFi was not associated with a difference in rates of progression of spinal damage, compared with historical controls. These studies were based on open-label extensions, and analyzed as cohort studies. Recent observational studies have suggested that TNFi may reduce radiographic progression. The different conclusions may be related to the longer treatment and observation period of these observational studies, which may have permitted detection of changes in this slowly evolving process. There is emerging evidence from a clinical trial and retrospective studies that continuous NSAID use may slow radiographic progression.SummaryLack of evidence that TNFi slows radiographic progression in ankylosing spondylitis in data from clinical trials may be because of the design of these studies, and possibly not a true null treatment effect. C1 [Louie, Grant H.] Johns Hopkins Univ, Sch Med, Div Rheumatol, Baltimore, MD USA. [Ward, Michael M.] NIAMSD, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMS NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health FX Disclosures: GHL: AbbVie (advisory board); MMW: none. This work was supported in part by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. NR 29 TC 3 Z9 3 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8711 EI 1531-6963 J9 CURR OPIN RHEUMATOL JI Curr. Opin. Rheumatol. PD MAR PY 2014 VL 26 IS 2 BP 145 EP 150 DI 10.1097/BOR.0000000000000025 PG 6 WC Rheumatology SC Rheumatology GA AC9BU UT WOS:000332829900007 PM 24389865 ER PT J AU Dorner, T Lipsky, PE AF Doerner, Thomas Lipsky, Peter E. TI B cells: depletion or functional modulation in rheumatic diseases SO CURRENT OPINION IN RHEUMATOLOGY LA English DT Review DE B cells; belimumab; biological therapy; CD20; CD22; rituximab ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; TUMOR-NECROSIS-FACTOR; HELPER T-CELLS; PERIPHERAL-BLOOD; GERMINAL-CENTERS; PLASMA-CELLS; INADEQUATE RESPONSE; REGISTRY GRAID; CUTTING EDGE; MURINE LUPUS AB Purpose of reviewThe availability of drugs directly and indirectly targeting the B cells has refocussed attention on the role of B lymphocytes in rheumatic autoimmune/inflammatory diseases (RAIDs), but their distinct therapeutic potential for certain diseases remains to be further assessed.Recent findingsAlthough additional drugs are currently in clinical development targeting surface molecules (CD19, CD20, CD22, etc.) and cytokines (IL-6, IL-21, BAFF and APRIL) with key effects on B cell/plasma cell survival and differentiation, respectively, recent studies have also provided further insights into the effects of currently available drugs on protective immunity and mechanisms of the initiation and progression of RAIDs (i.e. rituximab, belimumab, mycophenolate and azathioprine). A key aspect of B-cell-directed drugs is their impact on continuous immune activation and chronic maintenance which may differ between individual RAIDs.SummaryThe translational advances in the area of B-cell-depleting therapies and more sophisticated approaches to modulate key B-cell functions, such as blocking B-cell receptor downstream effects, interfering with the differentiation and survival of antigen-experienced memory B and plasma cells are of central interest. Differences in the efficacy and safety profiles of B-cell depletion compared with B-cell-modulating therapies (including antigen-specific tolerance induction) need to be further delineated. C1 [Doerner, Thomas] Charite, Dept Rheumatol & Clin Immunol, Dept Med CC12, Deutsch Rheuma Forschungszentrum Berlin, D-10117 Berlin, Germany. [Lipsky, Peter E.] NIAMS, NIH, Bethesda, MD USA. RP Dorner, T (reprint author), Charite, Dept Med Rheumatol & Clin Immunol Berlin, Charitepl 1, D-10117 Berlin, Germany. EM thomas.doerner@charite.de FU DFG [Do491/7-2, Do491/7-3, Do491/5-4]; SFB programs [633/A14, 650/TP14]; Immunobone SPP; Roche/Chugai; Sanofi; Eli Lilly; NovoNordisk; UCB Pharma FX T.D. received grant support by DFG grants Do491/7-2 and 7-3, 5-4, SFB programs 633/A14 and 650/TP14 as well as the Immunobone SPP. T. D. received study support and honoraria for consultancy by Roche/Chugai, Sanofi, Eli Lilly, NovoNordisk and UCB Pharma. NR 61 TC 12 Z9 12 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8711 EI 1531-6963 J9 CURR OPIN RHEUMATOL JI Curr. Opin. Rheumatol. PD MAR PY 2014 VL 26 IS 2 BP 228 EP 236 DI 10.1097/BOR.0000000000000000 PG 9 WC Rheumatology SC Rheumatology GA AC9BU UT WOS:000332829900014 PM 24126901 ER PT J AU Gadina, M AF Gadina, Massimo TI Advances in kinase inhibition: treating rheumatic diseases and beyond SO CURRENT OPINION IN RHEUMATOLOGY LA English DT Review DE cytokines; jak; kinase; therapy ID STAT1 TRANSACTIVATION DOMAIN; TYROSINE KINASE; SERINE PHOSPHORYLATION; SELECTIVE INHIBITOR; IMMUNE-RESPONSES; IN-VIVO; AUTOIMMUNE; MICE; ARTHRITIS; JAK3 AB Purpose of reviewKinases inhibitors are now used for the treatment of autoimmune diseases. Here, the most recent findings related to their mechanism of action and some of the newest molecules and targets which are being investigated for autoimmune and inflammatory disorders are reviewed.Recent findingsSimilarly to p38 inhibitors, current spleen tyrosine kinase inhibitors have not fulfilled the expectations of researchers and clinicians, and will likely not be used therapeutically in autoimmunity. Bruton's tyrosine kinase inhibitors remain in the preclinical phase. Studies on the mechanism of action of successful Janus kinase (Jak) inhibitors have revealed that, apart from T and B cells, bone cells such as osteoclasts and innate immunity cells such as dendritic cells are positively affected. More specific, novel Jak inhibitors are now in clinical trials and newer Jak inhibitors are being developed. Other kinases are emerging from basic studies as potentially druggable and will surely be investigated.SummaryFirst-generation pan-Jak inhibitors can be useful for a wide variety of diseases. They act on adaptive as well as innate immune cells and can promote tolerance. More specific inhibitors will soon be available and these may be used in a disease-specific manner. C1 NIAMSD, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. RP Gadina, M (reprint author), NIAMSD, Off Sci & Technol, NIH, Bldg 10,Room 10C101-C, Bethesda, MD 20892 USA. EM gadinama@mail.nih.gov FU NIAMS Intramural Research Program; Pfizer FX The work was supported by the by the NIAMS Intramural Research Program.; The US National Institutes of Health holds a patent related to Janus family kinases and identification of immune modulators, and has a Collaborative Research Agreement and Development Award with Pfizer. NR 47 TC 2 Z9 2 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8711 EI 1531-6963 J9 CURR OPIN RHEUMATOL JI Curr. Opin. Rheumatol. PD MAR PY 2014 VL 26 IS 2 BP 237 EP 243 DI 10.1097/BOR.0000000000000023 PG 7 WC Rheumatology SC Rheumatology GA AC9BU UT WOS:000332829900016 PM 24419749 ER PT J AU Chowdhuri, SR Fetsch, P Squires, J Kohn, E Filie, AC AF Chowdhuri, Sinchita Roy Fetsch, Patricia Squires, Jennifer Kohn, Elise Filie, Armando C. TI Adenocarcinoma cells in effusion cytology as a diagnostic pitfall with potential impact on clinical management: A case report with brief review of immunomarkers SO DIAGNOSTIC CYTOPATHOLOGY LA English DT Review DE effusion; immunostaining; cytology; reactive mesothelial cells; adenocarcinoma cells ID REACTIVE MESOTHELIAL CELLS; CARCINOEMBRYONIC ANTIGEN CEA; EPITHELIAL OVARIAN-CARCINOMA; SEROUS EFFUSIONS; MALIGNANT MESOTHELIOMA; MONOCLONAL-ANTIBODIES; IMMUNOHISTOCHEMICAL DIAGNOSIS; METASTATIC ADENOCARCINOMA; PERITONEAL MESOTHELIOMAS; DIFFERENTIAL-DIAGNOSIS AB Distinguishing metastatic carcinoma cells from reactive mesothelial cells in effusion samples is often challenging based on morphology alone. Metastatic carcinoma cells in fluid samples may mimic reactive mesothelial cells due to overlapping cytological features. We report a case of a pleural effusion in a 51-year-old female patient with a medical history significant for bilateral ovarian tumors and peritoneal implants diagnosed as serous tumor of borderline malignant potential. The effusion was composed almost entirely of adenocarcinoma cells that morphologically mimicked reactive mesothelial cells. The diagnosis of metastatic adenocarcinoma was made after a wide immunostaining panel of antibodies. Recognizing metastatic adenocarcinoma cells in effusion samples can be challenging and an accurate diagnosis may have significant impact on clinical management as demonstrated by this case. Diagn. Cytopathol. 2012;42:253-258. (c) 2012 Wiley Periodicals, Inc. C1 [Chowdhuri, Sinchita Roy; Fetsch, Patricia; Filie, Armando C.] NCI, Cytopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Squires, Jennifer; Kohn, Elise] NCI, Mol Signaling Sect, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Filie, AC (reprint author), NCI, Cytopathol Sect, Pathol Lab, Ctr Canc Res, 10 Ctr Dr,Bldg 10,Room 2A19, Bethesda, MD 20892 USA. EM afilie@mail.nih.gov FU Intramural Research Program of the NIH (in part), National Cancer Institute FX Contract grant sponsor: Intramural Research Program of the NIH (in part), National Cancer Institute. NR 57 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8755-1039 EI 1097-0339 J9 DIAGN CYTOPATHOL JI Diagn. Cytopathol. PD MAR PY 2014 VL 42 IS 3 BP 253 EP 258 DI 10.1002/dc.22915 PG 6 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA AD8QN UT WOS:000333530800012 PM 23161830 ER PT J AU Losada, L Pakala, SB Fedorova, ND Joardar, V Shabalina, SA Hostetler, J Pakala, SM Zafar, N Thomas, E Rodriguez-Carres, M Dean, R Vilgalys, R Nierman, WC Cubeta, MA AF Losada, Liliana Pakala, Suman B. Fedorova, Natalie D. Joardar, Vinita Shabalina, Svetlana A. Hostetler, Jessica Pakala, Suchitra M. Zafar, Nikhat Thomas, Elizabeth Rodriguez-Carres, Marianela Dean, Ralph Vilgalys, Rytas Nierman, William C. Cubeta, Marc A. TI Mobile elements and mitochondrial genome expansion in the soil fungus and potato pathogen Rhizoctonia solani AG-3 SO FEMS MICROBIOLOGY LETTERS LA English DT Article DE Basidiomycota; homing endonucleases; repetitive elements ID DOUBLE-STRANDED-RNA; NATURAL-POPULATION; AGARICUS-BISPORUS; GROUP-I; SEQUENCE; DNA; INHERITANCE; EVOLUTION; RECOMBINATION; INTRONS AB The soil fungus Rhizoctonia solani is an economically important pathogen of agricultural and forestry crops. Here, we present the complete sequence and analysis of the mitochondrial genome of R.solani, field isolate Rhs1AP. The genome (235849bp) is the largest mitochondrial genome of a filamentous fungus sequenced to date and exhibits a rich accumulation of introns, novel repeat sequences, homing endonuclease genes, and hypothetical genes. Stable secondary structures exhibited by repeat sequences suggest that they comprise functional, possibly catalytic RNA elements. RNA-Seq expression profiling confirmed that the majority of homing endonuclease genes and hypothetical genes are transcriptionally active. Comparative analysis suggests that the mitochondrial genome of R.solani is an example of a dynamic history of expansion in filamentous fungi. C1 [Losada, Liliana; Pakala, Suman B.; Fedorova, Natalie D.; Joardar, Vinita; Hostetler, Jessica; Pakala, Suchitra M.; Zafar, Nikhat; Nierman, William C.] J Craig Venter Inst, Rockville, MD USA. [Fedorova, Natalie D.; Shabalina, Svetlana A.; Hostetler, Jessica] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Thomas, Elizabeth; Rodriguez-Carres, Marianela; Dean, Ralph; Cubeta, Marc A.] N Carolina State Univ, Raleigh, NC 27606 USA. [Vilgalys, Rytas] Duke Univ, Durham, NC USA. RP Cubeta, MA (reprint author), N Carolina State Univ, Dept Plant Pathol, 851 Main Campus Dr, Raleigh, NC 27606 USA. EM macubeta@ncsu.edu RI Abrams, Natalie/F-4845-2011; OI Abrams, Natalie/0000-0001-9698-2819; Vilgalys, Rytas/0000-0001-8299-3605 FU NSF/USDA-CSREES Microbial Genome Sequencing Program [2007-35600-18550] FX We thank Dana Busam, Karen Beeson, Sana Scherbakova, and Lakshmi Viswanathan from JCVI for assistance with sample processing, library construction, and sequencing. We are also grateful to Paul Paukstelis from the University of Maryland for helpful suggestions regarding the analysis of the RSOL-mtRPT secondary structure. We thank JoAnne Crouch, Frank Martin, and Stellos Tavantizis for presubmission review of this manuscript. Funding for this study has been provided by a grant from NSF/USDA-CSREES Microbial Genome Sequencing Program #2007-35600-18550 to W.N., R.D., and M.C. NR 59 TC 11 Z9 11 U1 2 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0378-1097 EI 1574-6968 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD MAR PY 2014 VL 352 IS 2 BP 165 EP 173 DI 10.1111/1574-6968.12387 PG 9 WC Microbiology SC Microbiology GA AD5UA UT WOS:000333317500005 PM 24461055 ER PT J AU Kumar, N Gaur, D Masison, DC Sharma, D AF Kumar, Navinder Gaur, Deepika Masison, Daniel C. Sharma, Deepak TI The BAG Homology Domain of Snl1 Cures Yeast Prion [URE3] Through Regulation of Hsp70 Chaperones SO G3-GENES GENOMES GENETICS LA English DT Article DE Snl1; Hsp70; yeast prion; nucleotide exchange factor; BAG domain ID NUCLEOTIDE EXCHANGE FACTORS; BETA-SHEET STRUCTURE; HEAT-SHOCK-PROTEIN; SACCHAROMYCES-CEREVISIAE; CELL-SURVIVAL; PROPAGATION; HSP104; STRESS; HSC70; SUBFAMILY AB The BAG family of proteins is evolutionarily conserved from yeast to humans and plants. In animals and plants, the BAG family possesses multiple members with overlapping and distinct functions that regulate many cellular processes, such as signaling, protein degradation, and stress response. The only BAG domain protein in Saccharomyces cerevisiae is Snl1, which is anchored to the endoplasmic reticulum through an amino-terminal transmembrane region. Snl1 is the only known membrane-associated nucleotide exchange factor for 70-kilodalton heat shock protein (Hsp70), and thus its role in regulating cytosolic Hsp70 functions is not clear. Here, we examine whether Snl1 regulates Hsp70 activity in the propagation of stable prion-like protein aggregates. We show that unlike other nucleotide exchange factors, Snl1 is not required for propagation of yeast prions [URE3] and [PSI+]. Overexpressing Snl1 derivative consisting of only the BAG domain (Snl1-S) cures [URE3]; however, elevated levels of the entire cytosolic domain of Snl1 (Snl1-M), which has nine additional amino-terminal residues, has no effect. Substituting the three lysine residues in this region of Snl1-M with alanine restores ability to cure [URE3]. [PSI+] is unaffected by overproduction of either Snl1-S or Snl1-M. The Snl1-S mutant engineered with weaker affinity to Hsp70 does not cure [URE3], indicating that curing of [URE3] by Snl1-S requires Hsp70. Our data suggest that Snl1 anchoring to endoplasmic reticulum or nuclear membrane restricts its ability to modulate cytosolic activities of Hsp70 proteins. Furthermore, the short amino-terminal extension of the BAG domain profoundly affects its function. C1 [Kumar, Navinder; Gaur, Deepika; Sharma, Deepak] Inst Microbial Technol, Council Sci & Ind Res, Chandigarh, India. [Masison, Daniel C.] Natl Inst Diabet & Digest & Kidney Dis, Lab Biochem & Genet, Bethesda, MD USA. RP Sharma, D (reprint author), Inst Microbial Technol, Sect 39A, Chandigarh, India. EM deepaks@imtech.res.in FU Council of Scientific and Industrial Research (CSIR), India; Ramalingaswami Re-entry Fellowship, Department of Biotechnology (DBT), India FX We thank Dr. Susan R. Wente for providing us strain SWY027 and plasmids pSW171 and pSW534. The work is supported by Council of Scientific and Industrial Research (CSIR), India, and the Ramalingaswami Re-entry Fellowship, Department of Biotechnology (DBT), India. NR 43 TC 5 Z9 5 U1 0 U2 3 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD MAR PY 2014 VL 4 IS 3 BP 461 EP 470 DI 10.1534/g3.113.009993 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA AG9PM UT WOS:000335751700008 PM 24408033 ER PT J AU Brielmaier, J Senerth, JM Silverman, JL Matteson, PG Millonig, JH DiCicco-Bloom, E Crawley, JN AF Brielmaier, J. Senerth, J. M. Silverman, J. L. Matteson, P. G. Millonig, J. H. DiCicco-Bloom, E. Crawley, J. N. TI Chronic desipramine treatment rescues depression-related, social and cognitive deficits in Engrailed-2 knockout mice SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Autism; depression; desipramine; knockout mouse; norepinephrine; social behavior ID OBJECT RECOGNITION MEMORY; AUTISM SPECTRUM DISORDER; TAIL SUSPENSION TEST; ANTIDEPRESSANT TREATMENTS; HIPPOCAMPAL NEUROGENESIS; CHRONIC FLUOXETINE; CELL LOSS; CEREBELLAR; NOREPINEPHRINE; MOUSE AB Engrailed-2 (En2) is a homeobox transcription factor that regulates neurodevelopmental processes including neuronal connectivity and elaboration of monoaminergic neurons in the ventral hindbrain. We previously reported abnormalities in brain noradrenergic concentrations in En2 null mutant mice that were accompanied by increased immobility in the forced swim test, relevant to depression. An EN2 genetic polymorphism has been associated with autism spectrum disorders, and mice with a deletion in En2 display social abnormalities and cognitive deficits that may be relevant to multiple neuropsychiatric conditions. This study evaluated the ability of chronic treatment with desipramine (DMI), a selective norepinephrine (NE) reuptake inhibitor and classical antidepressant, to reverse behavioral abnormalities in En2-/- mice. Desipramine treatment significantly reduced immobility in the tail suspension and forced swim tests, restored sociability in the three-chambered social approach task and reversed impairments in contextual fear conditioning in En2-/- mice. Our findings indicate that modulation of brain noradrenergic systems rescues the depression-related phenotype in En2-/- mice and suggest new roles for NE in the pathophysiology of the social and cognitive deficits seen in neuropsychiatric disorders such as autism or schizophrenia. C1 [Brielmaier, J.; Senerth, J. M.; Silverman, J. L.; Crawley, J. N.] NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA. [Matteson, P. G.; Millonig, J. H.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Ctr Adv Biotechnol & Med, New Brunswick, NJ USA. [Millonig, J. H.; DiCicco-Bloom, E.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, New Brunswick, NJ USA. [DiCicco-Bloom, E.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pediat, New Brunswick, NJ USA. RP Brielmaier, J (reprint author), George Mason Univ, Dept Psychol, MS 3F5,4400 Univ Dr, Fairfax, VA 22030 USA. EM jbrielma@gmu.edu FU National Institute of Mental Health Intramural Research Program; NIH [R01 MH076624]; NJ Governor's Council for Medical Research and Treatment of Autism FX This research was supported by the National Institute of Mental Health Intramural Research Program (J.B., J.L.S., J.M.S. and J.N.C.), NIH R01 MH076624 (J.H.M. and E.D.B.) and the NJ Governor's Council for Medical Research and Treatment of Autism (E.D.B.). The authors declare no conflicts of interest. NR 45 TC 12 Z9 12 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 EI 1601-183X J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD MAR PY 2014 VL 13 IS 3 BP 286 EP 298 DI 10.1111/gbb.12115 PG 13 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA AB8ND UT WOS:000332046400004 PM 24730055 ER PT J AU Pike, ER Rothenberg, KH Berkman, BE AF Pike, Elizabeth R. Rothenberg, Karen H. Berkman, Benjamin E. TI Finding Fault? Exploring Legal Duties to Return Incidental Findings in Genomic Research SO GEORGETOWN LAW JOURNAL LA English DT Article ID RESEARCH PARTICIPANTS; CARE RESPONSIBILITIES; MEDICAL RESEARCHERS; CLINICAL CARE; RECOMMENDATIONS; FUTURE; DISCLOSURE; AUTONOMY; OWE AB The use of whole-genome sequencing in biomedical research is expected to produce dramatic advances in human health. The increasing use of this powerful, data-rich new technology in research, however; will inevitably give rise to incidental findings (IFs)-findings with individual health or reproductive significance that are beyond the aims of the particular research-and the related questions of whether and to what extent researchers have an ethical obligation to return IFs. Many have concluded that researchers have an ethical obligation to return some findings in some circumstances but have provided vague or context-dependent approaches to determining which IFs must be returned and when. As a result, researchers have started returning IFs inconsistently, giving rise to concerns about legal liability in circumstances in which notification could have potentially prevented injury. Although it is clear that ethical guidance should not be automatically codified as law and that crafting ethical obligations around legal duties can be inappropriate, the ethical debate should not proceed unaware of the potential legal ramifications of advancing and implementing an ethical obligation to return IFs. This Article assesses the legal claims that could be brought for a researcher's failure to return IFs. The potential for researchers to be held liable in tort is still uncertain and turns largely on a number of factors-including customary practice and guidance documents-that are still in flux. Unlike medical care, which has a well-defined duty into which evolving scientific knowledge about genetics and genomics can readily be incorporated, a researcher's duty to return IFs is less well defined, making it difficult to determine at the outset whether and when legal liability will attach. This Article advocates for a clearer; ethically sound standard of requiring that researchers disclose in the informed consent document which approach to offering IFs will be taken. This approach enables participants to know at the outset which findings, if any, will be returned, allows researchers to ascertain when their failure to appropriately return incidental findings will give rise to liability, and enables courts to make determinations that will produce more consistent legal guidance. C1 [Pike, Elizabeth R.] Natl Inst Hlth, Dept Bioeth, Bethesda, MD USA. [Rothenberg, Karen H.] Univ Maryland, Sch Law, Law & Hlth Care Program, College Pk, MD 20742 USA. [Rothenberg, Karen H.] Natl Human Genome Res Inst, Bethesda, MD USA. [Berkman, Benjamin E.] Natl Human Genome Res Inst, Bioeth Core, Bethesda, MD USA. FU Intramural NIH HHS [Z99 HG999999] NR 95 TC 8 Z9 8 U1 0 U2 4 PU GEORGETOWN LAW JOURNAL ASSOC PI WASHINGTON PA 600 NEW JERSEY AVE N W, WASHINGTON, DC 20001 USA SN 0016-8092 J9 GEORGETOWN LAW J JI Georget. Law J. PD MAR PY 2014 VL 102 IS 3 BP 795 EP 843 PG 49 WC Law SC Government & Law GA AH2FY UT WOS:000335938100004 PM 25346543 ER PT J AU Marks, KM Kitch, D Chung, RT Hadigan, C Andersen, J Tien, P Luetkemeyer, A Alston-Smith, B Glesby, MJ AF Marks, Kristen M. Kitch, Douglas Chung, Raymond T. Hadigan, Colleen Andersen, Janet Tien, Phyllis Luetkemeyer, Annie Alston-Smith, Beverly Glesby, Marshall J. CA A5239 Team TI Pilot Study of Pioglitazone Before HCV Retreatment in HIV/HCV Genotype 1-Infected Subjects With Insulin Resistance and Previous Nonresponse to Peginterferon and Ribavirin Therapy: A5239 SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE metabolic; hepatitis C; nonresponder; pegylated interferon; insulin resistance; HIV ID HEPATITIS-C VIRUS; ALPHA-2A PLUS RIBAVIRIN; VIROLOGICAL RESPONSE; COINFECTED PATIENTS; NONALCOHOLIC STEATOHEPATITIS; ANTIRETROVIRAL THERAPY; INFECTED PATIENTS; HIV; STEATOSIS; METFORMIN AB Insulin resistance is associated with nonresponse to hepatitis C virus (HCV) treatment. In this multicenter, single-arm pilot study, adult, HIV/HCV genotype 1-coinfected previous nonresponders to peginterferon/ribavirin (PegIFN/RBV) with homeostatic model assessment of insulin resistance >2.5 were treated with pioglitazone (PIO) for 24 weeks followed by PegIFN/RBV/PIO. Three of 19 subjects (15.8%) achieved undetectable HCV RNA at week 24 of PegIFN/RBV/PIO, which was not significantly different than the historical null rate of 10% (P = 0.29, lower limit of the exact 1-sided 90% confidence interval 5.9%). Over the 24 weeks of PIO monotherapy, alanine aminotransferase and aspartate aminotransferase declined significantly and correlated with improved metabolic parameters. C1 [Marks, Kristen M.; Glesby, Marshall J.] Weill Cornell Med Coll, Div Infect Dis, New York, NY 10065 USA. [Kitch, Douglas; Andersen, Janet] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Chung, Raymond T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Div, Boston, MA USA. [Hadigan, Colleen; Alston-Smith, Beverly] NIAID, NIH, Bethesda, MD 20892 USA. [Tien, Phyllis] Univ Calif San Francisco, Sch Med, Div Infect Dis, San Francisco, CA USA. [Tien, Phyllis] Dept Vet Affairs, Med Serv, San Francisco, CA USA. [Luetkemeyer, Annie] Univ Calif San Francisco, San Francisco Gen Hosp, Div HIV AIDS, San Francisco, CA USA. RP Marks, KM (reprint author), Weill Cornell Med Coll, Div Infect Dis, 525 East 68th St,F24, New York, NY 10065 USA. EM markskr@med.cornell.edu FU National Institute of Allergy and Infectious Diseases [UM1AI068636]; National Institute of Mental Health, National Institute of Dental and Craniofacial Research; Roche (Genentech); Takeda Pharmaceuticals, USA, Inc.; AACTG/ACTG Statistical and Data Management Center [1 UM1 AI068634, 5 U01 AI38855]; Intramural National Institute of Allergy and Infectious Diseases support [NIH DK078772, K24 AI078884, U01 AI069502]; Roche Laboratories; Bristol-Myers Squibb; Gilead; Vertex Pharmaceuticals; Pfizer; Gilead Sciences; SIGA Technologies; Boehringer Ingelheim; CTU [U01 AI69419, 5UO1 AI069502-07, UM1AI069532, UM1 AI069511, AI69501, AI 069471, UM1-AI069503, IU0IAI69472]; CTSCs from the National Center for Advancing Translational Sciences component of the National Institutes of Health (NIH) [UL1 TR000457, UL1TR000439]; National Center for Advancing Translational Sciences (Virginia Commonwealth University) [UL1TR000058] FX Supported by Award Number UM1AI068636 from the National Institute of Allergy and Infectious Diseases and supported by National Institute of Mental Health, National Institute of Dental and Craniofacial Research. This research was also supported by Roche (Genentech) and Takeda Pharmaceuticals, USA, Inc. Other grant support included 1 UM1 AI068634 and 5 U01 AI38855 to AACTG/ACTG Statistical and Data Management Center; Intramural National Institute of Allergy and Infectious Diseases support (C. H.); NIH DK078772 (R. T. C.); K24 AI078884 (M. G.), U01 AI069502 (A. L.). R. T. C. received research funding from Roche Laboratories. A. L. has received research grant support to University of California San Francisco from Bristol-Myers Squibb, Gilead, and Vertex Pharmaceuticals. M.J.G. has received research support from Pfizer to Weill Cornell Medical College and has served as a consultant to Gilead Sciences, SIGA Technologies, and Pfizer. K. M. M. has received research support to Weill Cornell Medical College from Bristol-Myers Squibb, Vertex Pharmaceuticals, Janssen Pharmaceuticals, Boehringer Ingelheim, and Gilead and has received honoraria for lectures from Boehringer Ingelheim and Bristol-Myers Squibb. Also supported in part by CTU grants, including U01 AI69419 [Cornell (Site 7804)], 5UO1 AI069502-07 [University of California San Francisco AIDS CRS (Site 801)], UM1AI069532 [New York University/NYC HHC at Bellevue Hospital Center (Site 401)], UM1 AI069511 [University of Rochester (Site 1101)], AI69501 [MetroHealth Medical Center (Site 2503)], AI 069471 [Northwestern University (A2701)], UM1-AI069503 [Virginia Commonwealth University (Site 31475)], and Massachusetts General Hospital (Site 101) CTU Grant IU0IAI69472. Also supported in part by grants funded by site CTSCs, including UL1 TR000457 (Cornell CTSC), UL1TR000439 from the National Center for Advancing Translational Sciences component of the National Institutes of Health (NIH) and NIH roadmap for Medical Research (Clinical and Translational Science Collaborative of Cleveland), UL1TR000058 from the National Center for Advancing Translational Sciences (Virginia Commonwealth University). NR 19 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD MAR 1 PY 2014 VL 65 IS 3 BP 345 EP 349 DI 10.1097/QAI.0000000000000073 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AH0DL UT WOS:000335789200025 PM 24525470 ER PT J AU Fowler, MG Coovadia, H Herron, CM Maldonado, Y Chipato, T Moodley, D Musoke, P Aizire, J Manji, K Stranix-Chibanda, L Fawzi, W Chetty, V Msweli, L Kisenge, R Brown, E Mwatha, A Eshleman, SH Richardson, P Allen, M George, K Andrew, P Zwerski, S Mofenson, LM Jackson, JB AF Fowler, Mary Glenn Coovadia, Hoosen Herron, Casey M. Maldonado, Yvonne Chipato, Tsungai Moodley, Dhayendre Musoke, Philippa Aizire, Jim Manji, Karim Stranix-Chibanda, Lynda Fawzi, Wafaie Chetty, Vani Msweli, Lindiwe Kisenge, Rodrick Brown, Elizabeth Mwatha, Anthony Eshleman, Susan H. Richardson, Paul Allen, Melissa George, Kathleen Andrew, Philip Zwerski, Sheryl Mofenson, Lynne M. Jackson, J. Brooks CA HPTN 046 Protocol Team TI Efficacy and Safety of an Extended Nevirapine Regimen in Infants of Breastfeeding Mothers With HIV-1 Infection for Prevention of HIV-1 Transmission (HPTN 046): 18-Month Results of a Randomized, Double-Blind, Placebo-Controlled Trial SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE PMTCT; nevirapine; infant HIV prophylaxis ID ANTIRETROVIRAL REGIMENS; CHILDREN AB Background: HPTN 046 compared the efficacy and safety of infant nevirapine (NVP) among HIV-exposed breastfed infants randomized at 6 weeks to 6 months to t NVP or placebo to prevent postnatal infection: we report final 18-month outcomes. Methods: Randomized, placebo-controlled trial in 4 African countries. Infant diagnostic HIV testing was performed regularly from birth through 18 months. Kaplan-Meier analysis was used to assess 18-month cumulative infant HIV infection, HIV infection/or death, and mortality rates. Results: Between 6 weeks and 6 months, postnatal HIV infection rates were significantly lower among infants receiving daily NVP from 6 weeks to 6 months 1.1% [95% confidence interval (CI): 0.2% to 1.8%], compared with placebo 2.4% (95% CI: 1.3% to 2.6%), P = 0.049, but not significantly lower thereafter. Eighteen-month postnatal infection rates were low: 2.2% (95% CI: 1.1% to 3.3%) versus 3.1% (95% CI: 1.9% to 4.4%), respectively, P = 0.28. Mortality and HIV infection/death did not differ between arms at any age. Infants of women receiving antiretroviral therapy (ART) for their own health had the lowest 18-month postnatal infection rates (0.5%, 95% CI: 0.0% to 1.1%). However, HIV infection/death rates at 18 months were not significantly different for infants of mothers on ART (3.7%, 95% CI: 1.9% to 5.5%), and infants of mothers with CD4 counts of >= 350 cells per cubic millimeter not receiving ART (4.8%, 95% CI: 2.7% to 6.8%; P = 0.46). There were no differences in adverse events between study arms. Conclusions: This trial demonstrated early but not late differences in postnatal HIV transmission among infants randomized at age 6 weeks to extended NVP or placebo, underscoring the importance of continued prophylaxis throughout breastfeeding. C1 [Fowler, Mary Glenn; Eshleman, Susan H.; Richardson, Paul; Jackson, J. Brooks] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Coovadia, Hoosen] Univ Witwatersrand, ZA-2050 Johannesburg, South Africa. [Herron, Casey M.; Brown, Elizabeth; Mwatha, Anthony] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Maldonado, Yvonne] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA. [Chipato, Tsungai] Univ Zimbabwe, Dept Obstet & Gynecol, Coll Hlth Sci, Harare, Zimbabwe. [Moodley, Dhayendre; Chetty, Vani; Msweli, Lindiwe] Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa CAPRISA, Nelson R Mandela Sch Med, Durban, South Africa. [Musoke, Philippa; Aizire, Jim; Allen, Melissa] Johns Hopkins Univ, Makerere Univ, Res Collaborat, Kampala, Uganda. [Manji, Karim; Kisenge, Rodrick] Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania. [Stranix-Chibanda, Lynda] Univ Zimbabwe, Dept Pediat, Coll Hlth Sci, Harare, Zimbabwe. [Fawzi, Wafaie; George, Kathleen] Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. [Andrew, Philip] Family Hlth Int, Res Triangle Pk, NC 27709 USA. [Zwerski, Sheryl] NIAID, Div HIV AIDS, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, Rockville, MD USA. RP Fowler, MG (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. EM mgfowler@mujhu.org OI Mofenson, Lynne/0000-0002-2818-9808 FU National Institutes of Health (National Institute of Allergy and Infectious Diseases) [U01 AI068632]; National Institutes of Health (Eunice Kennedy Shriver National Institute of Child Health and Human Development) [U01 AI068632]; US National Institutes of Health through the HPTN; US National Institutes of Health through International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) group; National Institute of Allergy and Infectious Diseases (NIAID); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Drug Abuse; National Institute of Mental Health (NIMH); NIAID [U01AI068632]; NICHD; NIMH; Boehringer Ingelheim Pharmaceuticals FX Supported by the National Institutes of Health (National Institute of Allergy and Infectious Diseases, and Eunice Kennedy Shriver National Institute of Child Health and Human Development) Grant U01 AI068632. HIV Prevention Trials Network (HPTN) 046 (ClinicalTrials.gov Identifier: NCT00074412) was funded by the US National Institutes of Health, initially through the HPTN and later through the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) group. The HPTN (U01AI46749) has been funded by the National Institute of Allergy and Infectious Diseases (NIAID), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Drug Abuse, and National Institute of Mental Health (NIMH). The IMPAACT Group (U01AI068632) has been funded by NIAID, NICHD, and NIMH. The study products were provided free of charge by Boehringer Ingelheim Pharmaceuticals. NR 22 TC 8 Z9 8 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD MAR 1 PY 2014 VL 65 IS 3 BP 366 EP 374 DI 10.1097/QAI.0000000000000052 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AH0DL UT WOS:000335789200028 PM 24189151 ER PT J AU Spinner, JL Winfree, S Starr, T Shannon, JG Nair, V Steele-Mortimer, O Hinnebusch, BJ AF Spinner, Justin L. Winfree, Seth Starr, Tregei Shannon, Jeffrey G. Nair, Vinod Steele-Mortimer, Olivia Hinnebusch, B. Joseph TI Yersinia pestis survival and replication within human neutrophil phagosomes and uptake of infected neutrophils by macrophages SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE polymorphonuclear leukocytes; phagocytosis; intracellular; apoptosis; efferocytosis ID PRIMARY PNEUMONIC PLAGUE; MOUSE PERITONEAL-MACROPHAGES; III SECRETION SYSTEM; POLYMORPHONUCLEAR LEUKOCYTES; PASTEURELLA-PESTIS; CELL-DEATH; SPONTANEOUS APOPTOSIS; RECEPTOR ANTAGONIST; LEISHMANIA-MAJOR; LYMPH-NODE AB Yersinia pestis survives and replicates within PMNs, which are taken up by macrophages in vitro. Yersinia pestis, the bacterial agent of plague, is transmitted by fleas. The bite of an infected flea deposits Y. pestis into the dermis and triggers recruitment of innate immune cells, including phagocytic PMNs. Y. pestis can subvert this PMN response and survive at the flea-bite site, disseminate, and persist in the host. Although its genome encodes a number of antiphagocytic virulence factors, phagocytosis of Y. pestis by PMNs has been observed. This study tests the hypotheses that Y. pestis, grown at the ambient temperature of the flea vector (21 degrees C), where the major antiphagocytic virulence factors are not produced, can survive and replicate within human PMNs and can use PMNs as a route to infect macrophages subsequently. We show that Y. pestis is localized within PMN phagosomes, predominately as individual bacteria, and that intracellular bacteria can survive and replicate. Within 12 h of infection, approximate to 70% of infected PMNs had PS on their surface and were plausibly competent for efferocytosis. With the use of live cell confocal imaging, we show that autologous HMDMs recognize and internalize infected PMNs and that Y. pestis survives and replicates within these HMDMs following efferocytosis. Addition of HMDMs to infected PMNs resulted in decreased secretion of inflammatory cytokines (compared with HMDMs incubated directly with pCD1(-) Y. pestis) and increased secretion of the anti-inflammatory cytokine IL-1ra. Thus, Y. pestis can survive and replicate within PMNs, and infected PMNs may be a route for noninflammatory infection of macrophages. C1 [Spinner, Justin L.; Shannon, Jeffrey G.; Hinnebusch, B. Joseph] NIAID, Lab Zoonot Pathogens, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Winfree, Seth; Starr, Tregei; Steele-Mortimer, Olivia] NIAID, Labs Intracellular Parasites, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Nair, Vinod] NIAID, Electron Microscopy Unit, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Spinner, JL (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, 903 South 4th St, Hamilton, MT 59840 USA. EM justin.spinner@nih.gov FU Division of Intramural Research, NIAID, U.S. National Institutes of Health FX This research was supported by the Division of Intramural Research, NIAID, U.S. National Institutes of Health. We thank Frank DeLeo, Addie Porter, Kevin Braughton, and Brett Freedman for providing isolated human PMNs and blood samples. We thank Yi-Cheng Sun for providing the plasmid pCD1 Delta yadA::kan. We thank Chris Bosio, Iman Chouikha, Clayton Jarrett, Aaron Hasenkrug, and Scott Kobayashi for critical review of the manuscript. NR 56 TC 9 Z9 9 U1 0 U2 8 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAR PY 2014 VL 95 IS 3 BP 389 EP 398 DI 10.1189/jlb.1112551 PG 10 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA AG3MU UT WOS:000335324400003 PM 24227798 ER PT J AU Siddoway, B Hou, HL Yang, HT Petralia, R Xia, HH AF Siddoway, Benjamin Hou, Hailong Yang, Hongtian Petralia, Ronald Xia, Houhui TI Synaptic activity bidirectionally regulates a novel sequence-specific S-Q phosphoproteome in neurons SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE L-type calcium channels; Phosphoproteomics; phosphorylation; SQ motif; synaptic activity ID ATM PROTEIN; DNA-DAMAGE; EMBRYONIC LETHALITY; SIGNALING PATHWAYS; PLASTICITY; KINASES; MICE; PHOSPHORYLATION; ACTIVATION; MEMORY AB Protein phosphorylation plays a critical role in neuronal transcription, translation, cell viability, and synaptic plasticity. In neurons, phospho-enzymes and specific substrates directly link glutamate release and post-synaptic depolarization to these cellular functions; however, many of these enzymes and their protein substrates remain uncharacterized or unidentified. In this article, we identify a novel, synaptically driven neuronal phosphoproteome characterized by a specific motif of serine/threonine-glutamine ([S/T]-Q, abbreviated as SQ). These SQ-containing substrates are predominantly localized to dendrites, synapses, the soma; and activation of this SQ phosphoproteome by bicuculline application is induced via calcium influx through L-type calcium channels. On the other hand, acute application of NMDA can inactivate this SQ phosphoproteome. We demonstrate that the SQ motif kinase Ataxia-telangiectasia mutated can also localize to dendrites and dendritic spines, in addition to other subcellular compartments, and is activated by bicuculline application. Pharmacology studies indicate that Ataxia-telangiectasia mutated and its sister kinase ataxia telangiectasia mutated and Rad3-related up-regulate these neuronal SQ substrates. Phosphoproteomics identified over 150 SQ-containing substrates whose phosphorylation is bidirectionally regulated by synaptic activity. C1 [Siddoway, Benjamin; Hou, Hailong; Yang, Hongtian; Xia, Houhui] Louisiana State Univ, Ctr Neurosci, Hlth Sci Ctr, New Orleans, LA 70112 USA. [Petralia, Ronald] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. RP Xia, HH (reprint author), Louisiana State Univ, Ctr Excellence, Hlth Sci Ctr, New Orleans, LA 70112 USA. EM hxia@lsuhsc.edu FU NIH [R01NS060879]; NSF [IOS-0824393]; NARSAD [2006YI]; LSU REF (Research Enhancement Fund); NIDCD Intramural Research Program; Ataxia-Telangiectasia Children's Project (ATCP) FX This work is supported by NIH R01NS060879, NSF IOS-0824393, NARSAD (2006YI), and LSU REF (Research Enhancement Fund) to HX, the NIDCD Intramural Research Program to RSP, and the Ataxia-Telangiectasia Children's Project (ATCP) to BS. We thank Dr Ya-Xian Wang for help with the immunogold study. The authors declare no competing financial interests. NR 34 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2014 VL 128 IS 6 BP 841 EP 851 DI 10.1111/jnc.12487 PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AC2PV UT WOS:000332347300007 PM 24117848 ER PT J AU Hicks, R Koroshetz, W AF Hicks, Ramona Koroshetz, Walter TI NIH PARTICIPATION IN THE INTERNATIONAL TRAUMATIC BRAIN INJURY RESEARCH (INTBIR) INITIATIVE SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 11th Symposium of the International-Neurotrauma-Society CY MAR 19-23, 2014 CL Budapest, HUNGARY SP Int Neurotrauma Soc C1 [Hicks, Ramona; Koroshetz, Walter] NINDS, NIH, Bethesda, MD 20892 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 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD MAR 1 PY 2014 VL 31 IS 5 MA 204 BP A63 EP A63 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AB4ZV UT WOS:000331799600205 ER PT J AU Forde, PM Hooker, CM Boikos, SA Petrini, I Giaccone, G Rudin, CM Yang, SC Illei, PB Hann, CL Ettinger, DS Brahmer, JR Kelly, RJ AF Forde, Patrick M. Hooker, Craig M. Boikos, Sosipatros A. Petrini, Iacope Giaccone, Giuseppe Rudin, Charles M. Yang, Stephen C. Illei, Peter B. Hann, Christine L. Ettinger, David S. Brahmer, Julie R. Kelly, Ronan J. TI Systemic Therapy, Clinical Outcomes, and Overall Survival in Locally Advanced or Metastatic Pulmonary Carcinoid SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Pulmonary carcinoid; Metastatic carcinoid; Chemotherapy pulmonary carcinoid; Chemotherapy bronchial carcinoid; Therapy carcinoid; Atypical carcinoid; Typical carcinoid ID NEUROENDOCRINE TUMORS; EXPERIENCE; RADIANT-2; PHASE-3 AB Background: Data to guide the management of advanced pulmonary carcinoid (APC) come from retrospective reports and subgroup analyses of trials that included mainly extrapulmonary carcinoid tumors. We report the largest series to date of 49 patients with locally advanced or metastatic pulmonary carcinoid. Methods: The Johns Hopkins Pathology Database was reviewed for APC patients treated between January 1992 and December 2012. Data on time to recurrence, progression-free survival, and overall survival were estimated by using the Kaplan-Meier method. Results: Forty-nine patients were treated for APC in the specified time period. Median time to recurrence after surgical resection was 2.5 years (atypical carcinoid [AC] versus typical carcinoid [TC], 2.5 versus 6.3 years; p = 0.063). Median survival with advanced disease was 7.1 years and significantly longer for TC compared with AC (10.2 versus 4 years; p = 0.009). Among the diverse systemic therapies used, responses occurred in four of 17 patients (23.5%) who received platinum/etoposide with a median progression-free survival of 7 months. Conclusion: Although systemic chemotherapy has moderate activity for APC, novel approaches are required. TC and AC, although both classified as pulmonary carcinoid, are clearly different clinical and molecular entities and require separate treatment paradigms in the advanced/metastatic setting. C1 [Forde, Patrick M.; Boikos, Sosipatros A.; Rudin, Charles M.; Hann, Christine L.; Ettinger, David S.; Brahmer, Julie R.; Kelly, Ronan J.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Dept Med Oncol, Baltimore, MD USA. [Hooker, Craig M.; Yang, Stephen C.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Dept Surg, Baltimore, MD USA. [Illei, Peter B.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Dept Pathol, Baltimore, MD USA. [Petrini, Iacope; Giaccone, Giuseppe] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Kelly, RJ (reprint author), Johns Hopkins Univ, Canc Res Bldg 1,1650 Orleans St,Room G93, Baltimore, MD 21287 USA. EM rkelly25@jhmi.edu RI Petrini, Iacopo/K-7316-2016; Giaccone, Giuseppe/E-8297-2017 OI Petrini, Iacopo/0000-0002-7752-6866; Giaccone, Giuseppe/0000-0002-5023-7562 FU NCI NIH HHS [P30 CA006973] NR 14 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD MAR PY 2014 VL 9 IS 3 BP 414 EP 418 DI 10.1097/JTO.0000000000000065 PG 5 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AB1EO UT WOS:000331534500024 PM 24518093 ER PT J AU Modi, MN Palmer, S Armstrong, A AF Modi, Monica N. Palmer, Sheallah Armstrong, Alicia TI The Role of Violence Against Women Act in Addressing Intimate Partner Violence: A Public Health Issue SO JOURNAL OF WOMENS HEALTH LA English DT Article ID DOMESTIC VIOLENCE; SUICIDAL-BEHAVIOR; PREVALENCE; CARE; PREGNANCY; HISTORY AB Intimate partner violence (IPV) is defined as violence committed by a current or former boyfriend or girlfriend, spouse or ex-spouse. Each year, 1.3 to 5.3 million women in the United States experience IPV. The large number of individuals affected, the enormous healthcare costs, and the need for a multidisciplinary approach make IPV an important healthcare issue. The Violence Against Women Act (VAWA) addresses domestic violence, dating violence, sexual assault, and stalking. It emphasizes development of coordinated community care among law enforcement, prosecutors, victim services, and attorneys. VAWA was not reauthorized in 2012 because it lacked bipartisan support. VAWA 2013 contains much needed new provisions for Native Americans; lesbian, gay, bisexual, transgender, gay, and queer (LGBTQ) individuals; and victims of human trafficking but does not address the large amount of intimate partner violence in America's immigrant population. There are important remaining issues regarding intimate partner violence that need to be addressed by future legislation. This review examines the role of legislation and addresses proposals for helping victims of IPV. C1 [Modi, Monica N.; Armstrong, Alicia] NICHHD, Program Reprod & Adult Endocrinol, NIH, Rockville, MD 20852 USA. [Palmer, Sheallah] Florida State Univ, Coll Med, Tallahassee, FL 32306 USA. RP Armstrong, A (reprint author), NICHHD, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. EM armstroa@mail.nih.gov NR 53 TC 8 Z9 8 U1 8 U2 53 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 MAR 1 PY 2014 VL 23 IS 3 BP 253 EP 259 DI 10.1089/jwh.2013.4387 PG 7 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 AC4BQ UT WOS:000332466000011 PM 24299159 ER PT J AU Jonsson, E Salmon, A Warren, KR AF Jonsson, Egon Salmon, Amy Warren, Kenneth R. TI The international charter on prevention of fetal alcohol spectrum disorder SO LANCET GLOBAL HEALTH LA English DT Editorial Material ID PERSPECTIVE; PREVALENCE C1 [Jonsson, Egon; Salmon, Amy] Inst Hlth Econ, Edmonton, AB T5J 3N4, Canada. [Warren, Kenneth R.] NIAAA, NIH, US Dept HHS, Bethesda, MD USA. RP Jonsson, E (reprint author), Inst Hlth Econ, Edmonton, AB T5J 3N4, Canada. EM ejonsson@ihe.ca OI Salmon, Amy/0000-0002-1337-7582 NR 10 TC 14 Z9 14 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-109X J9 LANCET GLOB HEALTH JI Lancet Glob. Health PD MAR PY 2014 VL 2 IS 3 BP E135 EP E137 DI 10.1016/S2214-109X(13)70173-6 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AH8YR UT WOS:000336424600010 PM 25102841 ER PT J AU Sly, PD Neira, M Collman, G Carpenter, DO Landrigan, PJ Van Den Berg, M Barriga, FD Ruchirawat, M Laborde, A Pascale, A Heacock, M Dalmau, MT Suk, WA AF Sly, Peter D. Neira, Maria Collman, Gwen Carpenter, David O. Landrigan, Philip J. Van Den Berg, Martin Diaz Barriga, Fernando Ruchirawat, Mathuros Laborde, Amalia Pascale, Antonio Heacock, Michelle Dalmau, Marguerite T. Suk, William A. TI Networking to advance progress in children's environmental health SO LANCET GLOBAL HEALTH LA English DT Editorial Material ID SYSTEMATIC ANALYSIS; GLOBAL BURDEN; DISEASES C1 [Sly, Peter D.; Dalmau, Marguerite T.] Univ Queensland, WHO Collaborating Ctr Childrens Hlth & Environm, Childrens Hlth & Environm Program, Brisbane, Qld 4029, Australia. [Neira, Maria] WHO, Publ Hlth & Environm, CH-1211 Geneva, Switzerland. [Collman, Gwen; Heacock, Michelle; Suk, William A.] NIEHS, WHO Collaborating Ctr Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. [Carpenter, David O.] SUNY Albany, WHO Collaborating Ctr Environm Hlth, Inst Hlth & Environm, Albany, NY 12222 USA. [Landrigan, Philip J.] Mt Sinai Sch Med, WHO Collaborating Ctr Childrens Environm Hlth, New York, NY USA. [Van Den Berg, Martin] Univ Utrecht, Inst Risk Assessment Sci, WHO Collaborating Ctr Res Environm Hlth Risk Asse, Utrecht, Netherlands. [Diaz Barriga, Fernando] Univ Autonoma San Luis Potosi, WHO Collaborating Ctr Childrens Environm Hlth & H, San Luis Potosi, Mexico. [Ruchirawat, Mathuros] Chulabhorn Res Inst, WHO Collaborating Ctr Capac Bldg & Res Environm H, Bangkok, Thailand. [Laborde, Amalia; Pascale, Antonio] Univ Republ Oriental Uruguay, WHO Collaborating Ctr Human Environm Toxicol, Dept Toxicol, Montevideo, Uruguay. RP Sly, PD (reprint author), Univ Queensland, WHO Collaborating Ctr Childrens Hlth & Environm, Childrens Hlth & Environm Program, Brisbane, Qld 4029, Australia. EM p.sly@uq.edu.au RI Sly, Peter/F-1486-2010 OI Sly, Peter/0000-0001-6305-2201 NR 10 TC 7 Z9 8 U1 1 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-109X J9 LANCET GLOB HEALTH JI Lancet Glob. Health PD MAR PY 2014 VL 2 IS 3 BP E129 EP E130 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AH8YR UT WOS:000336424600007 PM 25102838 ER PT J AU Turkbey, B Kobayashi, H Hoyt, RF Choyke, PL Nakajima, T Griffiths, GL Bernardo, M Rialon, K Fishman, SJ Sena, LM AF Turkbey, Baris Kobayashi, Hisataka Hoyt, Robert F., Jr. Choyke, Peter L. Nakajima, Takahito Griffiths, Gary L. Bernardo, Marcelino Rialon, Kristy Fishman, Steven J. Sena, Laureen M. TI Magnetic Resonance Lymphography of the Thoracic Duct after Interstitial Injection of Gadofosveset Trisodium: A Pilot Dosing Study in a Porcine Model SO LYMPHATIC RESEARCH AND BIOLOGY LA English DT Article ID POSTOPERATIVE CHYLOTHORAX; MR LYMPHOGRAPHY; LYMPHANGIOGRAPHY; DENDRIMER; MS-325; MANAGEMENT; MOLECULES; AGENTS AB Background-rationale: To investigate whether interstitial injection of gadofosveset trisodium (Ablavar (R), Lantheus Medical, North Billerica, MA) would be suitable for thoracic duct (TD) imaging in a pig model. Methods and Results: Gadofosveset trisodium alone or premixed with 10% human serum albumin (HSA) was administered intradermally in the extremities of pigs at varying doses to visualize the TD by MRI. Two blinded readers evaluated MRIs for TD visibility. The inter-observer variability for all MR imaging sessions was assessed using the Spearman rank correlation test. MR lymphography using gadofosveset trisodium premixed with HSA yielded superior visualization of the TD compared to gadofosveset trisodium alone, with a high inter-observer agreement (correlation coefficient of 0.88 (p=0.00000115)). Conclusions: We demonstrate that gadofosveset trisodium (premixed with 10%HSA) can be injected intradermally in order to perform MR lymphography of the thoracic duct. Since this agent is already FDA approved for MR imaging, the off-label use of it for imaging of the thoracic duct in humans is feasible, and the approach may prove to be beneficial for patients with TD abnormalities. C1 [Turkbey, Baris; Kobayashi, Hisataka; Choyke, Peter L.; Nakajima, Takahito] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Hoyt, Robert F., Jr.] NHLBI, Lab Anim Med & Surg, NIH, Bethesda, MD 20892 USA. [Griffiths, Gary L.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Clin Res Directorate CMRP, Frederick, MD USA. [Bernardo, Marcelino] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Res Technol Program, Frederick, MD USA. [Rialon, Kristy; Fishman, Steven J.; Sena, Laureen M.] Boston Children s Hosp, Boston, MA USA. RP Turkbey, B (reprint author), NCI, Mol Imaging Program, 10 Ctr Dr MSC 1182 Bldg 10,Room B3B85, Bethesda, MD 20892 USA. EM turkbeyi@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Laura Marie Fazio and Taylor Robert Gladd PLE Fund; Stuart and Jane Weitzman Vascular Anomalies Fund 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. 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.; Additional funding was provided by the Laura Marie Fazio and Taylor Robert Gladd PLE Fund and the Stuart and Jane Weitzman Vascular Anomalies Fund. NR 14 TC 3 Z9 3 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1539-6851 EI 1557-8585 J9 LYMPHAT RES BIOL JI Lymphat. Res. Biol. PD MAR 1 PY 2014 VL 12 IS 1 BP 32 EP 36 DI 10.1089/lrb.2013.0029 PG 5 WC Medicine, Research & Experimental; Physiology SC Research & Experimental Medicine; Physiology GA AE6JT UT WOS:000334098600005 PM 24502282 ER PT J AU Townsend, SSM Eliezer, D Major, B Mendes, WB AF Townsend, Sarah S. M. Eliezer, Dina Major, Brenda Mendes, Wendy Berry TI Influencing the World Versus Adjusting to Constraints: Social Class Moderates Responses to Discrimination SO SOCIAL PSYCHOLOGICAL AND PERSONALITY SCIENCE LA English DT Article DE socioeconomic status; prejudice; stress reactions; neuroendocrinology ID SELF-ESTEEM; SOCIOECONOMIC-STATUS; HEALTH; STRESS; ATTRIBUTIONS; PREJUDICE; AMERICAN; PATTERNS; CHOICE; ALWAYS AB Although higher social class carries mental and physical health benefits, these advantages are less robust among members of racial and ethnic minority groups than among European Americans. We explore whether differential reactions to discrimination may be a factor in explaining why. Working-class and middle-class Latino American women engaged in an evaluative interaction with a European American woman who rejected them and held either prejudiced or unprejudiced attitudes. We examined how participants responded to this rejection by measuring neuroendocrine reactivity, executive functioning, and the affective content of their verbal responses during the interaction. Among middle-class Latinas, rejection from a prejudiced, compared to unprejudiced, out-group member was associated with less adaptive stress responses, greater cognitive depletion, and more feelings of uncertainty. In contrast, among working-class Latinas, neuroendocrine, cognitive, and affective responses were similar across the two sources of rejection. Results suggest that social class is an important moderator of responses to discrimination. C1 [Townsend, Sarah S. M.] Northwestern Univ, Kellogg Sch Management, Evanston, IL 60208 USA. [Eliezer, Dina] NIH, Bethesda, MD 20892 USA. [Major, Brenda] Univ Calif Santa Barbara, Dept Psychol & Brain Sci, Santa Barbara, CA 93106 USA. [Mendes, Wendy Berry] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Townsend, SSM (reprint author), Northwestern Univ, Kellogg Sch Management, Dept Management & Org, Evanston, IL 60208 USA. EM s-townsend@kellogg.northwestern.edu NR 44 TC 4 Z9 4 U1 4 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1948-5506 EI 1948-5514 J9 SOC PSYCHOL PERS SCI JI Soc. Psychol. Personal Sci. PD MAR PY 2014 VL 5 IS 2 BP 226 EP 234 DI 10.1177/1948550613490968 PG 9 WC Psychology, Social SC Psychology GA AH9CI UT WOS:000336437600012 ER PT J AU Austin, SK Dowd, KA AF Austin, S. Kyle Dowd, Kimberly A. TI B Cell Response and Mechanisms of Antibody Protection to West Nile Virus SO VIRUSES-BASEL LA English DT Review DE West Nile virus; flavivirus; humoral immunity; neutralizing antibody; epitopes; therapeutics ID FC-GAMMA-RECEPTOR; HUMANIZED MONOCLONAL-ANTIBODY; BORNE ENCEPHALITIS-VIRUS; FUSION-LOOP ANTIBODY; ENVELOPE PROTEIN; DENGUE VIRUS; CRYSTAL-STRUCTURE; NEUTRALIZING ANTIBODIES; MEDIATED NEUTRALIZATION; FLAVIVIRUS INFECTION AB West Nile virus (WNV) has become the principal cause of viral encephalitis in North America since its introduction in New York in 1999. This emerging virus is transmitted to humans via the bite of an infected mosquito. While there have been several candidates in clinical trials, there are no approved vaccines or WNV-specific therapies for the treatment of WNV disease in humans. From studies with small animal models and convalescent human patients, a great deal has been learned concerning the immune response to infection with WNV. Here, we provide an overview of a subset of that information regarding the humoral and antibody response generated during WNV infection. C1 [Austin, S. Kyle] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Dowd, Kimberly A.] NIAID, NIH, Bethesda, MD 20892 USA. RP Austin, SK (reprint author), Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. EM skaustin@DOM.wustl.edu; dowdka@mail.nih.gov FU NIH [5R01AI098723] FX This work was supported by the NIH intramural program and NIH Grant 5R01AI098723. NR 109 TC 2 Z9 4 U1 1 U2 4 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD MAR PY 2014 VL 6 IS 3 BP 1015 EP 1036 DI 10.3390/v6031015 PG 22 WC Virology SC Virology GA AG9RC UT WOS:000335756100005 PM 24594676 ER PT J AU Schountz, T Prescott, J AF Schountz, Tony Prescott, Joseph TI Hantavirus Immunology of Rodent Reservoirs: Current Status and Future Directions SO VIRUSES-BASEL LA English DT Review DE hantavirus; rodent; immune response; ecoimmunology; zoonosis; systems biology ID SIN-NOMBRE-VIRUS; REGULATORY T-CELLS; MOUSE PEROMYSCUS-MANICULATUS; CREEK-CANAL-VIRUS; VOLES CLETHRIONOMYS-GLAREOLUS; ALPHA-INDUCED ACTIVATION; G1 CYTOPLASMIC TAIL; MALE NORWAY RATS; NF-KAPPA-B; SEOUL-VIRUS AB Hantaviruses are hosted by rodents, insectivores and bats. Several rodent-borne hantaviruses cause two diseases that share many features in humans, hemorrhagic fever with renal syndrome in Eurasia or hantavirus cardiopulmonary syndrome in the Americas. It is thought that the immune response plays a significant contributory role in these diseases. However, in reservoir hosts that have been closely examined, little or no pathology occurs and infection is persistent despite evidence of adaptive immune responses. Because most hantavirus reservoirs are not model organisms, it is difficult to conduct meaningful experiments that might shed light on how the viruses evade sterilizing immune responses and why immunopathology does not occur. Despite these limitations, recent advances in instrumentation and bioinformatics will have a dramatic impact on understanding reservoir host responses to hantaviruses by employing a systems biology approach to identify important pathways that mediate virus/reservoir relationships. C1 [Schountz, Tony] Colorado State Univ, Coll Vet Med, Dept Microbiol Immunol & Pathol, Arthropod Borne & Infect Dis Lab, Ft Collins, CO 80524 USA. [Prescott, Joseph] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. RP Schountz, T (reprint author), Colorado State Univ, Coll Vet Med, Dept Microbiol Immunol & Pathol, Arthropod Borne & Infect Dis Lab, Ft Collins, CO 80524 USA. EM tony.schountz@colostate.edu; prescottjb@niaid.nih.gov FU Department of Microbiology, Immunology and Pathology, Colorado State University; NIH [AI054461]; Intramural Program of NIAID, NIH FX The authors thank Brian Hjelle, Charles H. Calisher, Rushika Perera and Heinz Feldmann for helpful comments, support and advice leading to the preparation of this manuscript. Support for this work was provided by the Department of Microbiology, Immunology and Pathology, Colorado State University (TS), NIH grant AI054461 (TS), and Intramural Program of NIAID, NIH (JP). NR 114 TC 7 Z9 7 U1 2 U2 24 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD MAR PY 2014 VL 6 IS 3 BP 1317 EP 1335 DI 10.3390/v6031317 PG 19 WC Virology SC Virology GA AG9RC UT WOS:000335756100020 PM 24638205 ER PT J AU Das, S Chigurupat, S Mattson, MP Self, WT Seal, S AF Das, S. Chigurupat, S. Mattson, M. P. Self, W. T. Seal, S. TI NOVEL RARE EARTH OXIDE ACCELERATES ANGIOGENESIS AND WOUND HEALING BY DECREASING OXIDATIVE STRESS AND CONTROLLING LOCAL OXYGEN ENVIRONMENT SO WOUND REPAIR AND REGENERATION LA English DT Meeting Abstract C1 [Das, S.; Self, W. T.; Seal, S.] Univ Cent Florida, Orlando, FL 32816 USA. [Chigurupat, S.; Mattson, M. P.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. RI Self, William/A-6704-2008 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 1067-1927 EI 1524-475X J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD MAR PY 2014 VL 22 IS 2 BP A37 EP A37 PG 1 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA AC9DV UT WOS:000332835400041 ER PT J AU Wynn, TA AF Wynn, T. A. TI IMMUNOLOGICAL MECHANISMS OF FIBROSIS SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Meeting Abstract C1 [Wynn, T. A.] NIAID, Program Tissue Immun & Repair, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD MAR-APR PY 2014 VL 32 IS 2 SU 81 BP S11 EP S11 PG 1 WC Rheumatology SC Rheumatology GA AH2FH UT WOS:000335936400017 ER PT J AU Csoka, B Koscso, B Toro, G Kokai, E Virag, L Nemeth, ZH Pacher, P Bai, P Hasko, G AF Csoka, Balazs Koscso, Balazs Toero, Gabor Kokai, Endre Virag, Laszlo Nemeth, Zoltan H. Pacher, Pal Bai, Peter Hasko, Gyoergy TI A2B Adenosine Receptors Prevent Insulin Resistance by Inhibiting Adipose Tissue Inflammation via Maintaining Alternative Macrophage Activation SO DIABETES LA English DT Article ID NECROSIS-FACTOR-ALPHA; BODY-MASS INDEX; A(2B) RECEPTORS; MEDIATED INFLAMMATION; OXIDATIVE-METABOLISM; GLUCOSE-HOMEOSTASIS; IL-10 PRODUCTION; INNATE IMMUNITY; OBESITY; CELLS C1 [Csoka, Balazs; Koscso, Balazs; Nemeth, Zoltan H.; Hasko, Gyoergy] Rutgers New Jersey Med Sch, Dept Surg, Newark, NJ USA. [Toero, Gabor; Kokai, Endre; Virag, Laszlo; Bai, Peter; Hasko, Gyoergy] Univ Debrecen, Dept Med Chem, Med & Hlth Sci Ctr, H-4012 Debrecen, Hungary. [Virag, Laszlo; Bai, Peter] Hungarian Acad Sci, Cell Biol & Signalling Res Grp, Debrecen, Hungary. [Nemeth, Zoltan H.] Morristown Med Ctr, Dept Surg, Morristown, NJ USA. [Pacher, Pal] NIAAA, Bethesda, MD USA. RP Csoka, B (reprint author), Rutgers New Jersey Med Sch, Dept Surg, Newark, NJ USA. EM csokaba@njms.rutgers.edu; haskoge@njms.rutgers.edu RI Pacher, Pal/B-6378-2008; OI Pacher, Pal/0000-0001-7036-8108; Csoka, Balazs/0000-0002-7562-1130 FU National Institutes of Health [R01GM66189]; U.S. Army Medical Research and Materiel Command grant [09065004/W81XWH-10-1-1015]; Hungarian Scientific Research Fund Grants (OTKA) [PD83473, K108308, CK 78275, K109178, MB08-1-2011-0015 84685]; National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism; Bolyai fellowship; National Innovation Office [TeT_09-2010-0023, TaMOP-4.2.2/A-11/1/KONV-2012-0025, TaMOP-4.2.1/B-09/KONV-2010-0007, TaMOP-4.2.2/B-10/1-2010-0024]; Medical and Health Science Center [Mecenatura Mec-8/2011] FX This work was supported by National Institutes of Health grant R01GM66189 (G.H.); U.S. Army Medical Research and Materiel Command grant 09065004/W81XWH-10-1-1015 (G.H.); Hungarian Scientific Research Fund Grants (OTKA) PD83473 and K108308 (P.B.), CK 78275 and K109178 (G.H.), and Human MB08-1-2011-0015 84685 (E.K.); the Intramural Research Program of the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism (P.P.); a Bolyai fellowship (P.B.); National Innovation Office (Baross program Seahorse grant, TeT_09-2010-0023) grants TaMOP-4.2.2/A-11/1/KONV-2012-0025, TaMOP-4.2.1/B-09/KONV-2010-0007, and TaMOP-4.2.2/B-10/1-2010-0024; and a grant from the Medical and Health Science Center (Mecenatura Mec-8/2011). NR 58 TC 14 Z9 15 U1 0 U2 4 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 MAR PY 2014 VL 63 IS 3 BP 850 EP 866 PG 17 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB2HQ UT WOS:000331614200008 PM 24194503 ER PT J AU Walters, DM White, KM Patel, U Davis, MJ Veluci-Marlow, RM Sunkesula, SRB Bonner, JC Martin, JR Gladwell, W Kleeberger, SR AF Walters, Dianne M. White, Kevin M. Patel, Ushma Davis, Martin J. Veluci-Marlow, Roberta M. Sunkesula, Solomon Raju Bhupanapadu Bonner, James C. Martin, Jessica R. Gladwell, Wes Kleeberger, Steven R. TI Genetic susceptibility to interstitial pulmonary fibrosis in mice induced by vanadium pentoxide (V2O5) SO FASEB JOURNAL LA English DT Article DE lung injury; inflammation; collagen; haplotype; mapping ID HUMAN LUNG FIBROBLASTS; FUEL-OIL ASH; MESSENGER-RNA EXPRESSION; BRONCHOALVEOLAR LAVAGE; ALVEOLAR MACROPHAGES; EOSINOPHIL ACTIVATION; GROWTH-FACTOR; ANIMAL-MODEL; INFLAMMATION; BETA AB Interstitial lung diseases (ILDs) are characterized by injury, inflammation, and scarring of alveoli, leading to impaired function. The etiology of idiopathic forms of ILD is not understood, making them particularly difficult to study due to the lack of appropriate animal models. Consequently, few effective therapies have emerged. We developed an inbred mouse model of ILD using vanadium pentoxide (V2O5), the most common form of a transition metal found in cigarette smoke, fuel ash, mineral ores, and steel alloys. Pulmonary responses to V2O5, including dose-dependent increases in lung permeability, inflammation, collagen content, and dysfunction, were significantly greater in DBA/2J mice compared to C57BL/6J mice. Inflammatory and fibrotic responses persisted for 4 mo in DBA/2J mice, while limited responses in C57BL/6J mice resolved. We investigated the genetic basis for differential responses through genetic mapping of V2O5-induced lung collagen content in BXD recombinant inbred (RI) strains and identified significant linkage on chromosome 4 with candidate genes that associate with V2O5-induced collagen content across the RI strains. Results suggest that V2O5 may induce pulmonary fibrosis through mechanisms distinct from those in other models of pulmonary fibrosis. These findings should further advance our understanding of mechanisms involved in ILD and thereby aid in identification of new therapeutic targets.Walters, D. M., White, K. M., Patel, U., Davis, M. J., Veluci-Marlow, R. M., Bhupanapadu Sunkesula, S. R., Bonner, J. C., Martin, J. R., Gladwell, W., Kleeberger, S. R. Genetic susceptibility to interstitial pulmonary fibrosis in mice induced by vanadium pentoxide (V2O5). C1 [Walters, Dianne M.; White, Kevin M.; Patel, Ushma; Davis, Martin J.; Veluci-Marlow, Roberta M.; Sunkesula, Solomon Raju Bhupanapadu] E Carolina Univ, Dept Physiol, Greenville, NC 27834 USA. [Bonner, James C.] N Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA. [Martin, Jessica R.; Gladwell, Wes; Kleeberger, Steven R.] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. RP Walters, DM (reprint author), E Carolina Univ, Brody Sch Med, Dept Physiol, 6N-98,600 Moye Blvd, Greenville, NC 27834 USA. EM waltersd@ecu.edu FU Intramural Research Program of the U.S. National Institutes of Health; NIEHS; East Carolina University FX The authors gratefully acknowledge the U.S. National Institute of Environmental Health Sciences (NIEHS) Histology Core facility and Joani Zary Oswald (Brody School of Medicine Histology Core, East Carolina University) for histological services, and Dr. Paul Strausbauch for pathology advice. The authors also thank Dr. Jared M. Brown for use of laboratory equipment and technical advice, and M. Anthony Phipps for technical assistance. This research was supported (in part) by the Intramural Research Program of the U.S. National Institutes of Health, NIEHS, and East Carolina University. The authors declare no conflicts of interest. NR 72 TC 2 Z9 2 U1 2 U2 6 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD MAR PY 2014 VL 28 IS 3 BP 1098 EP 1112 DI 10.1096/fj.13-235044 PG 15 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AG3MY UT WOS:000335324800007 PM 24285090 ER PT J AU Suzuki, N Numakawa, T Chou, J Vega, S Mizuniwa, C Sekimoto, K Adachi, N Kunugi, H Arikawa-Hirasawa, E Yamada, Y Akazawa, C AF Suzuki, Nobuharu Numakawa, Tadahiro Chou, Joshua de Vega, Susana Mizuniwa, Chihiro Sekimoto, Kaori Adachi, Naoki Kunugi, Hiroshi Arikawa-Hirasawa, Eri Yamada, Yoshihiko Akazawa, Chihiro TI Teneurin-4 promotes cellular protrusion formation and neurite outgrowth through focal adhesion kinase signaling SO FASEB JOURNAL LA English DT Article DE neuronal differentiation; cytoskeleton ID PAIR-RULE GENE; BIPOLAR DISORDER; GROWTH CONE; FILOPODIA; CDC42; PROTEINS; REGULATOR; NEURONS; FAMILY; CELLS AB Teneurin-4 (Ten-4), a transmembrane protein, is highly expressed in the central nervous system; however, its cellular and molecular function in neuronal differentiation remains unknown. In this study, we aimed to elucidate the function of Ten-4 in neurite outgrowth. Ten-4 expression was induced during neurite outgrowth of the neuroblastoma cell line Neuro-2a. Ten-4 protein was localized at the neurite growth cones. Knockdown of Ten-4 expression in Neuro-2a cells decreased the formation of the filopodia-like protrusions and the length of individual neurites. Conversely, overexpression of Ten-4 promoted filopodia-like protrusion formation. In addition, knockdown and overexpression of Ten-4 reduced and elevated the activation of focal adhesion kinase (FAK) and Rho-family small GTPases, Cdc42 and Rac1, key molecules for the membranous protrusion formation downstream of FAK, respectively. Inhibition of the activation of FAK and neural Wiskott-Aldrich syndrome protein (N-WASP), which is a downstream regulator of FAK and Cdc42, blocked protrusion formation by Ten-4 overexpression. Further, Ten-4 colocalized with phosphorylated FAK in the filopodia-like protrusion regions. Together, our findings show that Ten-4 is a novel positive regulator of cellular protrusion formation and neurite outgrowth through the FAK signaling pathway.Suzuki, N., Numakawa, T., Chou, J., de Vega, S., Mizuniwa, C., Sekimoto, K., Adachi, N., Kunugi, H., Arikawa-Hirasawa, E., Yamada, Y., Akazawa, C. Teneurin-4 promotes cellular protrusion formation and neurite outgrowth through focal adhesion kinase signaling. C1 [Suzuki, Nobuharu; Mizuniwa, Chihiro; Sekimoto, Kaori; Akazawa, Chihiro] Tokyo Med & Dent Univ, Grad Sch Hlth Care Sci, Dept Biochem & Biophys, Tokyo 1138510, Japan. [Suzuki, Nobuharu; Chou, Joshua; de Vega, Susana; Yamada, Yoshihiko] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. [Numakawa, Tadahiro; Adachi, Naoki; Kunugi, Hiroshi] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Mental Disorder Res, Tokyo, Japan. [de Vega, Susana; Arikawa-Hirasawa, Eri] Juntendo Univ, Res Inst Dis Old Age, Fac Med, Tokyo, Japan. [de Vega, Susana; Arikawa-Hirasawa, Eri] Juntendo Univ, Dept Neurol, Fac Med, Tokyo, Japan. RP Akazawa, C (reprint author), Tokyo Med & Dent Univ, Grad Sch Hlth Care Sci, Dept Biochem & Biophys, Bunkyo Ku, 1-5-45 Yushima,Bldg 3, Tokyo 1138510, Japan. EM c.akazawa.bb@tmd.ac.jp FU Intramural Research Program of the National Institute of Dental and Craniofacial Research, U.S. National Institutes of Health; Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan [24300139]; MEXT Program for Strategic Research Foundation at Private Universities; MEXT [25860701]; Ministry of Health, Labor, and Welfare of Japan [23040101] FX The authors thank Dr. Yukiko Goda (RIKEN BSI, Wako, Japan) for her valuable suggestion. This work was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, U.S. National Institutes of Health (Y.Y.), a Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan (24300139; T.N.), the MEXT Program for Strategic Research Foundation at Private Universities 2011-2015 (S. V. and E. A-H.), a Grant-in-Aid for Young Scientists from MEXT (25860701; N.S.), and a Grant-in-Aid from the Ministry of Health, Labor, and Welfare of Japan (23040101; C. A.). NR 33 TC 7 Z9 7 U1 0 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD MAR PY 2014 VL 28 IS 3 BP 1386 EP 1397 DI 10.1096/fj.13-241034 PG 12 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AG3MY UT WOS:000335324800030 PM 24344332 ER PT J AU Di Michele, DM Gibb, C Lefkowitz, JM Ni, Q Gerber, LM Ganguly, A AF Di Michele, D. M. Gibb, C. Lefkowitz, J. M. Ni, Q. Gerber, L. M. Ganguly, A. TI Severe and moderate haemophilia A and B in US females SO HAEMOPHILIA LA English DT Article ID X-CHROMOSOME INACTIVATION; QUALITY-OF-LIFE; INHERITED BLEEDING DISORDERS; FACTOR-IX DEFICIENCY; FACTOR-VIII; MUTATION; GENE; PATTERNS; CARRIERS; MANIFESTATIONS C1 [Di Michele, D. M.; Gibb, C.] Weill Cornell Med Coll, Dept Pediat, New York, NY USA. [Lefkowitz, J. M.] New York Presbyterian Hosp, Weill Cornell Med Ctr, Dept Social Work, New York, NY USA. [Ni, Q.; Gerber, L. M.] Weill Cornell Med Coll, Dept Publ Hlth, New York, NY USA. [Ganguly, A.] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. RP Di Michele, DM (reprint author), NHLBI, Div Blood Dis & Resources, NIH, 6701 Rockledge Dr,Room 9132, Bethesda, MD 20892 USA. EM dimicheledm@nhlbi.nih.gov FU CSL-Behring(R); National Hemophilia Foundation Social Work Excellence Fellowship award FX This study was funded by an unrestricted grant from CSL-Behring (R) and by a National Hemophilia Foundation Social Work Excellence Fellowship award. The authors thank the participating centre directors and their staff: Thomas Abshire; Lisa Boggio; Alice Cohen; Nadia P. Ewing; Ralph Gruppo; Keith Hoots; Jeffrey Hord; Barbara Konkle; Peter Kouides; Philip Kuriakose; Richard Lipton; Marilyn Manco-Johnson; Ellis Neufeld; Idith Ortiz; Mary Jane Petruzzi; Edward Romond; Charles Sexauer. We also thank Andra James for her thoughtful review of this manuscript. NR 42 TC 8 Z9 8 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-8216 EI 1365-2516 J9 HAEMOPHILIA JI Haemophilia PD MAR PY 2014 VL 20 IS 2 BP E136 EP E143 PG 8 WC Hematology SC Hematology GA AB0CO UT WOS:000331459600004 PM 24533955 ER PT J AU Lozier, JN Nghiem, K Lee, M Hodsdon, B Joe, G Weitzel, RP Tisdale, JF Hsieh, M AF Lozier, J. N. Nghiem, K. Lee, M. Hodsdon, B. Joe, g. Weitzel, R. P. Tisdale, J. F. Hsieh, M. TI Acquired haemophilia A after stem cell transplant for sickle cell disease: treatment with recombinant porcine factor VIII (OBI-1) and tolerance induction with rituximab/prednisone SO HAEMOPHILIA LA English DT Letter ID ANTIBODIES; INHIBITORS C1 [Lozier, J. N.; Nghiem, K.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Lee, M.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Hodsdon, B.; Joe, g.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Weitzel, R. P.; Tisdale, J. F.; Hsieh, M.] NHLBI, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Lozier, JN (reprint author), Bldg 10,Room 2C306,MSC 1508,10 Ctr Dr, Bethesda, MD 20892 USA. EM lozierjn@cc.nih.gov FU Intramural NIH HHS NR 8 TC 6 Z9 6 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-8216 EI 1365-2516 J9 HAEMOPHILIA JI Haemophilia PD MAR PY 2014 VL 20 IS 2 BP E185 EP E188 PG 4 WC Hematology SC Hematology GA AB0CO UT WOS:000331459600020 PM 24533959 ER PT J AU Cheng, J Fang, ZZ Kim, JH Krausz, KW Tanaka, N Chiang, JYL Gonzalez, FJ AF Cheng, Jie Fang, Zhong-Ze Kim, Jung-Hwan Krausz, Kristopher W. Tanaka, Naoki Chiang, John Y. L. Gonzalez, Frank J. TI Intestinal CYP3A4 protects against lithocholic acid-induced hepatotoxicity in intestine-specific VDR-deficient mice SO JOURNAL OF LIPID RESEARCH LA English DT Article DE bile acids; vitamin D receptor; metabolomics ID VITAMIN-D-RECEPTOR; BILE-ACID; 1,25-DIHYDROXYVITAMIN D-3; CYTOCHROME-P450 3A4; PERMEABILITY; DISEASE; ABSORPTION; EXPRESSION AB Vitamin D receptor (VDR) mediates vitamin D signaling involved in bone metabolism, cellular growth and differentiation, cardiovascular function, and bile acid regulation. Mice with an intestine-specific disruption of VDR (Vdr(Delta IEpC)) have abnormal body size, colon structure, and imbalance of bile acid metabolism. Lithocholic acid (LCA), a secondary bile acid that activates VDR, is among the most toxic of the bile acids that when overaccumulated in the liver causes hepatotoxicity. Because cytochrome P450 3A4 (CYP3A4) is a target gene of VDR-involved bile acid metabolism, the role of CYP3A4 in VDR biology and bile acid metabolism was investigated. The CYP3A4 gene was inserted into Vdr(Delta IEpC) mice to produce the Vdr(Delta IEpC)/3A4 line. LCA was administered to control, transgenic-CYP3A4, Vdr(Delta IEpC), and Vdr(Delta IEpC)/3A4 mice, and hepatic toxicity and bile acid levels in the liver, intestine, bile, and urine were measured. VDR deficiency in the intestine of the Vdr(Delta IEpC) mice exacerbates LCA-induced hepatotoxicity manifested by increased necrosis and inflammation, due in part to over-accumulation of hepatic bile acids including taurocholic acid and taurodeoxycholic acid. Intestinal expression of CYP3A4 in the Vdr(Delta IEpC)/3A4 mouse line reduces LCA-induced hepatotoxicity through elevation of LCA metabolism and detoxification, and suppression of bile acid transporter expression in the small intestine.(jlr) This study reveals that intestinal CYP3A4 protects against LCA hepatotoxicity. C1 [Cheng, Jie; Fang, Zhong-Ze; Kim, Jung-Hwan; Krausz, Kristopher W.; Tanaka, Naoki; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Cheng, Jie; Chiang, John Y. L.] Northeast Ohio Med Univ, Dept Integrat Med Sci, Rootstown, OH 44272 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov OI Chiang, John/0000-0001-9360-7650 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [R37DK058379, R01DK044442]; National Cancer Institute FX This work was funded by the National Cancer Institute Intramural Research Program, and by grants R37DK058379 and R01DK044442 to J.Y.L.C. from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 32 TC 15 Z9 15 U1 1 U2 19 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 MAR PY 2014 VL 55 IS 3 BP 455 EP 465 DI 10.1194/jlr.M044420 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AH8YX UT WOS:000336425300010 PM 24343899 ER PT J AU Wakabayashi, KT Kiyatkin, EA AF Wakabayashi, Ken T. Kiyatkin, Eugene A. TI Critical role of peripheral drug actions in experience-dependent changes in nucleus accumbens glutamate release induced by intravenous cocaine SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE electrochemistry; enzyme-based glutamate biosensors; experience-dependent neuroplasticity of glutamate neurotransmission; glutamate release; peripheral actions of cocaine ID VENTRAL TEGMENTAL AREA; ACID TRANSPORTER FAMILY; HIGH-AFFINITY GLUTAMATE; DOPAMINE UPTAKE; IN-VIVO; EXTRACELLULAR GLUTAMATE; ADDICTION; RATS; SENSITIZATION; TRANSMISSION AB Recent studies reveal that cocaine experience results in persistent neuroadaptive changes within glutamate (Glu) synapses in brain areas associated with drug reward. However, it remains unclear whether cocaine affects Glu release in drug-naive animals and how it is altered by drug experience. Using high-speed amperometry with enzyme-based and enzyme-free biosensors in freely moving rats, we show that an initial intravenous cocaine injection at a low self-administering dose (1mg/kg) induces rapid, small and transient Glu release in the nucleus accumbens shell (NAc), which with subsequent injections rapidly becomes a much stronger, two-component increase. Using cocaine-methiodide, cocaine's analog that does not cross the blood-brain barrier, we confirm that the initial cocaine-induced Glu release in the NAc has a peripheral neural origin. Unlike cocaine, Glu responses induced by cocaine-methiodide rapidly habituate following repeated exposure. However, after cocaine experience this drug induces cocaine-like Glu responses. Hence, the interoceptive actions of cocaine, which essentially precede its direct actions in the brain, play a critical role in experience-dependent alterations in Glu release, cocaine-induced neural sensitization and may contribute to cocaine addiction. Using high-speed amperometry with enzyme-based biosensors in freely moving rats, we show that initial intravenous cocaine induces rapid, transient glutamate (Glu) release in the Nac (Nucleus accumbens), rapidly becoming a stronger, two-component increase with subsequent injections. We show that the peripheral actions of cocaine, which precedes its direct central actions, play a critical role in experience-dependent alterations in Glu release, possibly contributing to cocaine addiction. C1 [Wakabayashi, Ken T.; Kiyatkin, Eugene A.] NIDA, In Vivo Electrophysiol Unit, Behav Neurosci Branch, Intramural Res Program,NIH,DHHS, Baltimore, MD 21224 USA. RP Kiyatkin, EA (reprint author), NIDA, In Vivo Electrophysiol Unit, Behav Neurosci Branch, Intramural Res Program,NIH,DHHS, 333 Cassell Dr, Baltimore, MD 21224 USA. EM ekiyatki@intra.nida.nih.gov FU Intramural Research Program of NIDA-IRP FX We thank Drs A. Bonci, C. Lupica, and T. Robinson for helpful suggestions regarding this manuscript. We also appreciate editorial assistance of Ms. Stephanie Myal. This study was supported by the Intramural Research Program of NIDA-IRP. The Authors declare no competitive interests in relation to the work described. EAK supervised the project. KTW and EAK performed experiments, wrote the manuscript and both have approved the submission of this version. NR 60 TC 10 Z9 10 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2014 VL 128 IS 5 BP 672 EP 685 DI 10.1111/jnc.12472 PG 14 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AB1KX UT WOS:000331551600007 PM 24111505 ER PT J AU Alagaili, AN Briese, T Mishra, N Kapoor, V Sameroff, SC de Wit, E Munster, VJ Hensley, LE Zalmout, IS Kapoor, A Epstein, JH Karesh, WB Daszak, P Mohammed, OB Lipkin, WI AF Alagaili, Abdulaziz N. Briese, Thomas Mishra, Nischay Kapoor, Vishal Sameroff, Stephen C. de Wit, Emmie Munster, Vincent J. Hensley, Lisa E. Zalmout, Iyad S. Kapoor, Amit Epstein, Jonathan H. Karesh, William B. Daszak, Peter Mohammed, Osama B. Lipkin, W. Ian TI Middle East Respiratory Syndrome Coronavirus Infection in Dromedary Camels in Saudi Arabia SO MBIO LA English DT Article ID BATS AB The Middle East respiratory syndrome (MERS) is proposed to be a zoonotic disease; however, the reservoir and mechanism for transmission of the causative agent, the MERS coronavirus, are unknown. Dromedary camels have been implicated through reports that some victims have been exposed to camels, camels in areas where the disease has emerged have antibodies to the virus, and viral sequences have been recovered from camels in association with outbreaks of the disease among humans. Nonetheless, whether camels mediate transmission to humans is unresolved. Here we provide evidence from a geographic and temporal survey of camels in the Kingdom of Saudi Arabia that MERS coronaviruses have been circulating in camels since at least 1992, are distributed countrywide, and can be phylogenetically classified into clades that correlate with outbreaks of the disease among humans. We found no evidence of infection in domestic sheep or domestic goats. IMPORTANCE This study was undertaken to determine the historical and current prevalence of Middle East respiratory syndrome (MERS) coronavirus infection in dromedary camels and other livestock in the Kingdom of Saudi Arabia, where the index case and the majority of cases of MERS have been reported. C1 [Alagaili, Abdulaziz N.; Zalmout, Iyad S.; Mohammed, Osama B.] King Saud Univ, Coll Med, Dept Zool, KSU Mammals Res Chair, Riyadh 11461, Saudi Arabia. [Alagaili, Abdulaziz N.] Saudi Wildlife Author, Riyadh, Saudi Arabia. [Briese, Thomas; Mishra, Nischay; Kapoor, Vishal; Sameroff, Stephen C.; Kapoor, Amit; Lipkin, W. Ian] Columbia Univ, Mailman Sch Publ Hlth, Ctr Infect & Immun, New York, NY USA. [de Wit, Emmie; Munster, Vincent J.] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Hensley, Lisa E.] NIAID, Integrated Res Facil, NIH, Frederick, MD USA. [Epstein, Jonathan H.; Karesh, William B.; Daszak, Peter] EcoHlth Alliance, New York, NY USA. RP Alagaili, AN (reprint author), King Saud Univ, Coll Med, Dept Zool, KSU Mammals Res Chair, Riyadh 11461, Saudi Arabia. EM aalagaili@ksu.edu.sa; tb2047@columbia.edu OI de Wit, Emmie/0000-0002-9763-7758; Munster, Vincent/0000-0002-2288-3196 FU Deanship of Scientific Research, King Saud University; National Institutes of Health [AI057158]; United States Agency for International Development Emerging Pandemic Threats program, PREDICT project [GHN-A-OO-09-00010-00]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The KSU Mammals Research Chair is supported by the Deanship of Scientific Research, King Saud University. Work in the Center for Infection and Immunity and EcoHealth Alliance is supported by awards from the National Institutes of Health (AI057158) and the United States Agency for International Development Emerging Pandemic Threats program, PREDICT project, under the terms of cooperative agreement GHN-A-OO-09-00010-00. Work in the Rocky Mountain Laboratories (E. de Wit, V. J. Munster) and Integrated Research Facility (L. E. Hensley) was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 19 TC 39 Z9 47 U1 0 U2 22 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAR-APR PY 2014 VL 5 IS 2 AR e00884-14 DI 10.1128/mBio.00884-14 PG 6 WC Microbiology SC Microbiology GA AH1XR UT WOS:000335915600002 PM 24570370 ER PT J AU Hayes, BM Dulebohn, DP Sarkar, A Tilly, K Bestor, A Ambroggio, X Rosa, PA AF Hayes, Beth M. Dulebohn, Daniel P. Sarkar, Amit Tilly, Kit Bestor, Aaron Ambroggio, Xavier Rosa, Patricia A. TI Regulatory Protein BBD18 of the Lyme Disease Spirochete: Essential Role During Tick Acquisition? SO MBIO LA English DT Article ID OUTER-SURFACE PROTEIN; BORRELIA-BURGDORFERI GENES; LINEAR PLASMID LP17; TARGETED DELETION; MAMMALIAN HOST; IMMUNE EVASION; OSPC OPERATOR; RPOS; EXPRESSION; INFECTION AB The Lyme disease spirochete Borrelia burgdorferi senses and responds to environmental cues as it transits between the tick vector and vertebrate host. Failure to properly adapt can block transmission of the spirochete and persistence in either vector or host. We previously identified BBD18, a novel plasmid-encoded protein of B. burgdorferi, as a putative repressor of the host-essential factor OspC. In this study, we investigate the in vivo role of BBD18 as a regulatory protein, using an experimental mouse-tick model system that closely resembles the natural infectious cycle of B. burgdorferi. We show that spirochetes that have been engineered to constitutively produce BBD18 can colonize and persist in ticks but do not infect mice when introduced by either tick bite or needle inoculation. Conversely, spirochetes lacking BBD18 can persistently infect mice but are not acquired by feeding ticks. Through site-directed mutagenesis, we have demonstrated that abrogation of spirochete infection in mice by overexpression of BBD18 occurs only with bbd18 alleles that can suppress OspC synthesis. Finally, we demonstrate that BBD18-mediated regulation does not utilize a previously described ospC operator sequence required by B. burgdorferi for persistence in immunocompetent mice. These data lead us to conclude that BBD18 does not represent the putative repressor utilized by B. burgdorferi for the specific downregulation of OspC in the mammalian host. Rather, we suggest that BBD18 exhibits features more consistent with those of a global regulatory protein whose critical role occurs during spirochete acquisition by feeding ticks. IMPORTANCE Lyme disease, caused by Borrelia burgdorferi, is the most common arthropod-borne disease in North America. B. burgdorferi is transmitted to humans and other vertebrate hosts by ticks as they take a blood meal. Transmission between vectors and hosts requires the bacterium to sense changes in the environment and adapt. However, the mechanisms involved in this process are not well understood. By determining how B. burgdorferi cycles between two very different environments, we can potentially establish novel ways to interfere with transmission and limit infection of this vector-borne pathogen. We are studying a regulatory protein called BBD18 that we recently described. We found that too much BBD18 interferes with the spirochete's ability to establish infection in mice, whereas too little BBD18 appears to prevent colonization in ticks. Our study provides new insight into key elements of the infectious cycle of the Lyme disease spirochete. C1 [Hayes, Beth M.; Dulebohn, Daniel P.; Sarkar, Amit; Tilly, Kit; Bestor, Aaron; Rosa, Patricia A.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Ambroggio, Xavier] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. RP Rosa, PA (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM prosa@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 43 TC 3 Z9 3 U1 0 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAR-APR PY 2014 VL 5 IS 2 AR e01017-14 DI 10.1128/mBio.01017-14 PG 12 WC Microbiology SC Microbiology GA AH1XR UT WOS:000335915600025 PM 24692636 ER PT J AU Hu, G Chen, SH Qiu, J Bennett, JE Myers, TG Williamson, PR AF Hu, Guowu Chen, Shu Hui Qiu, Jin Bennett, John E. Myers, Timothy G. Williamson, Peter R. TI Microevolution During Serial Mouse Passage Demonstrates FRE3 as a Virulence Adaptation Gene in Cryptococcus neoformans SO MBIO LA English DT Article ID SACCHAROMYCES-CEREVISIAE; MOLECULAR CHARACTERIZATION; FUNGAL PATHOGENS; IRON ACQUISITION; COPPER UPTAKE; VAR. GRUBII; INFECTION; MICE; SUSCEPTIBILITY; EXPRESSION AB Passage in mice of opportunistic pathogens such as Cryptococcus neoformans is known to increase virulence, but little is known about the molecular mechanisms involved in virulence adaptation. Serial mouse passage of nine environmental strains of serotype A C. neoformans identified two highly adapted virulent strains that showed a 4-fold reduction in time to death after four passages. Transcriptome sequencing expression studies demonstrated increased expression of a FRE3-encoded iron reductase in the two strains but not in a control strain that did not demonstrate increased virulence during mouse passage. FRE3 was shown to express an iron reductase activity and to play a role in iron-dependent growth of C. neoformans. Overexpression of FRE3 in the two original environmental strains increased growth in the macrophage cell line J774.16 and increased virulence. These data demonstrate a role for FRE3 in the virulence of C. neoformans and demonstrate how the increased expression of such a "virulence acquisition gene" during the environment-to-mammal transition, can optimize the virulence of environmental strains in mammalian hosts. IMPORTANCE Cryptococcus neoformans is a significant global fungal pathogen that also resides in the environment. Recent studies have suggested that the organism may undergo microevolution in the host. However, little is known about the permitted genetic changes facilitating the adaptation of environmental strains to mammalian hosts. The present studies subjected environmental strains isolated from several metropolitan areas of the United States to serial passages in mice. Transcriptome sequencing expression studies identified the increased expression of an iron reductase gene, FRE3, in two strains that adapted in mice to become highly virulent, and overexpression of FRE3 recapitulated the increased virulence after mouse passage. Iron reductase in yeast is important to iron uptake in a large number of microbial pathogens. These studies demonstrate the capacity of C. neoformans to show reproducible changes in the expression levels of small numbers of genes termed "virulence adaptation genes" to effectively increase pathogenicity during the environment-to-mammal transition. C1 [Hu, Guowu; Chen, Shu Hui; Qiu, Jin; Bennett, John E.; Williamson, Peter R.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Myers, Timothy G.] NIAID, Genom Technol Sect, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Williamson, PR (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM williamsonpr@mail.nih.gov FU Intramural Research Program of the NIH, NIAID FX This research was supported by the Intramural Research Program of the NIH, NIAID. NR 67 TC 4 Z9 4 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAR-APR PY 2014 VL 5 IS 2 AR e00941-14 DI 10.1128/mBio.00941-14 PG 11 WC Microbiology SC Microbiology GA AH1XR UT WOS:000335915600027 PM 24692633 ER PT J AU Ran, WQ Kristensen, DM Koonin, EV AF Ran, Wenqi Kristensen, David M. Koonin, Eugene V. TI Coupling Between Protein Level Selection and Codon Usage Optimization in the Evolution of Bacteria and Archaea SO MBIO LA English DT Article ID ESCHERICHIA-COLI; TRANSLATIONAL ACCURACY; SEQUENCE EVOLUTION; NATURAL-SELECTION; GENE-EXPRESSION; BIAS; GENOMES; DROSOPHILA; MISTRANSLATION; SUBSTITUTION AB The relationship between the selection affecting codon usage and selection on protein sequences of orthologous genes in diverse groups of bacteria and archaea was examined by using the Alignable Tight Genome Clusters database of prokaryote genomes. The codon usage bias is generally low, with 57.5% of the gene-specific optimal codon frequencies (Fopt) being below 0.55. This apparent weak selection on codon usage contrasts with the strong purifying selection on amino acid sequences, with 65.8% of the gene-specific dN/dS ratios being below 0.1. For most of the genomes compared, a limited but statistically significant negative correlation between Fopt and dN/dS was observed, which is indicative of a link between selection on protein sequence and selection on codon usage. The strength of the coupling between the protein level selection and codon usage bias showed a strong positive correlation with the genomic GC content. Combined with previous observations on the selection for GC-rich codons in bacteria and archaea with GC-rich genomes, these findings suggest that selection for translational fine-tuning could be an important factor in microbial evolution that drives the evolution of genome GC content away from mutational equilibrium. This type of selection is particularly pronounced in slowly evolving, "high-status" genes. A significantly stronger link between the two aspects of selection is observed in free-living bacteria than in parasitic bacteria and in genes encoding metabolic enzymes and transporters than in informational genes. These differences might reflect the special importance of translational fine-tuning for the adaptability of gene expression to environmental changes. The results of this work establish the coupling between protein level selection and selection for translational optimization as a distinct and potentially important factor in microbial evolution. IMPORTANCE Selection affects the evolution of microbial genomes at many levels, including both the structure of proteins and the regulation of their production. Here we demonstrate the coupling between the selection on protein sequences and the optimization of codon usage in a broad range of bacteria and archaea. The strength of this coupling varies over a wide range and strongly and positively correlates with the genomic GC content. The cause(s) of the evolution of high GC content is a long-standing open question, given the universal mutational bias toward AT. We propose that optimization of codon usage could be one of the key factors that determine the evolution of GC-rich genomes. This work establishes the coupling between selection at the level of protein sequence and at the level of codon choice optimization as a distinct aspect of genome evolution. C1 [Ran, Wenqi; Kristensen, David M.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM koonin@ncbi.nlm.nih.gov FU U.S. Department of Health and Human Services FX Our research is funded through the intramural fund of the U.S. Department of Health and Human Services (to the National Library of Medicine). NR 65 TC 9 Z9 9 U1 1 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAR-APR PY 2014 VL 5 IS 2 AR e00956-14 DI 10.1128/mBio.00956-14 PG 11 WC Microbiology SC Microbiology GA AH1XR UT WOS:000335915600039 PM 24667707 ER PT J AU Saijo, T Chen, JH Chen, SCA Rosen, LB Yi, J Sorrell, TC Bennett, JE Holland, SM Browne, SK Kwon-Chung, KJ AF Saijo, Tomomi Chen, Jianghan Chen, Sharon C. -A. Rosen, Lindsey B. Yi, Jin Sorrell, Tania C. Bennett, John E. Holland, Steven M. Browne, Sarah K. Kwon-Chung, Kyung J. TI Anti-Granulocyte-Macrophage Colony-Stimulating Factor Autoantibodies Are a Risk Factor for Central Nervous System Infection by Cryptococcus gattii in Otherwise Immunocompetent Patients SO MBIO LA English DT Article ID PULMONARY ALVEOLAR PROTEINOSIS; HIV-ASSOCIATED CRYPTOCOCCOSIS; GM-CSF AUTOANTIBODIES; NEOFORMANS INFECTION; IMMUNE-RESPONSE; DENDRITIC CELLS; IN-VITRO; MICE; PARASITISM; DISEASE AB Cryptococcosis is caused by either Cryptococcus neoformans or C. gattii. While cryptococcal meningoencephalitis is caused mostly by C. neoformans in immunocompromised patients, the risk factors remain unclear for patients with no known immune defect. Recently, anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies were detected in the plasma of seven "immunocompetent" cryptococcosis patients, and the cryptococcal strains from these patients were reported as C. neoformans (three strains), C. gattii (one strain), and Cryptococcus (three strains not identified to the species level). We identified all three strains that had not been identified to the species level as C. gattii. Notably, the three strains that were reported as C. neoformans but were unavailable for species confirmation originated from Sothern California and Thailand where C. gattii is endemic. Most clinical laboratories designate C. neoformans without distinguishing between the two species; hence, these three strains could have been C. gattii. Since C. gattii infects more immunocompetent patients than C. neoformans, we pursued the possibility that this antibody may be more prevalent in patients infected with C. gattii than in those infected with C. neoformans. We screened the plasma of 20 healthy controls and 30 "immunocompetent" patients with cryptococcal meningoencephalitis from China and Australia (multiple ethnicities). Anti-GM-CSF autoantibodies were detected only in the plasma of seven patients infected by C. gattii and one healthy volunteer and in none infected by C. neoformans. While plasma from these C. gattii patients completely prevented GM-CSF-induced p-STAT5 in normal human peripheral blood mononuclear cells (PBMCs), plasma from one healthy volunteer positive for anti-GM-CSF autoantibodies caused only partial blockage. Our results suggest that anti-GM-CSF autoantibodies may predispose otherwise immunocompetent individuals to meningoencephalitis caused by C. gattii but not necessarily to that caused by C. neoformans. IMPORTANCE Cryptococcal meningoencephalitis is the most serious central nervous system (CNS) infection caused by Cryptococcus neoformans or C. gattii. Cryptococcus primarily infects immunocopromised patients but is also sporadically encountered in otherwise "immunocompetent" patients with no known risk. In a recent study, anti-GM-CSF autoantibodies were detected in the plasma of seven otherwise immunocompetent patients with cryptococcal meningoencephalitis. Four of seven (57%) cryptococcal isolates from these patients were identified as C. gattii, while three strains were unavailable for species confirmation. We collected plasma from 30 otherwise healthy patients with CNS cryptococcosis in China and Australia (multiethnic) and analyzed the samples for the presence of anti-GM-CSF autoantibodies. The results suggest that anti-GM-CSF autoantibodies are a risk factor for CNS infection by C. gattii but not C. neoformans. GM-CSF may have a specific role in host defense against C. gattii, thereby elevating the importance of determining the level of anti-GM-CSF autoantibodies which can impact clinical management. C1 [Saijo, Tomomi; Kwon-Chung, Kyung J.] NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Chen, Jianghan; Yi, Jin] Second Mil Med Univ, Changzheng Hosp, Dept Dermatol, Shanghai, Peoples R China. [Chen, Jianghan; Yi, Jin] Second Mil Med Univ, Changzheng Hosp, Key Lab Med Mycol, Shanghai, Peoples R China. [Chen, Sharon C. -A.; Sorrell, Tania C.] Univ Sydney, Westmead Hosp, Ctr Infect Dis & Microbiol, Westmead, NSW 2145, Australia. [Chen, Sharon C. -A.; Sorrell, Tania C.] Univ Sydney, Marie Bashir Inst, Sydney, NSW 2006, Australia. [Rosen, Lindsey B.; Holland, Steven M.; Browne, Sarah K.] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Bennett, John E.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Kwon-Chung, KJ (reprint author), NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM JKCHUNG@niaid.nih.gov FU Intramural Program of the National Institutes of Allergy and Infectious Diseases, National Institutes of Health; Shanghai Committee of Science and Technology, China [12410710000] FX This study was funded by the Intramural Program of the National Institutes of Allergy and Infectious Diseases, National Institutes of Health, and the Shanghai Committee of Science and Technology, China, 2012 (grant number 12410710000). NR 49 TC 22 Z9 22 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAR-APR PY 2014 VL 5 IS 2 AR e00912-14 DI 10.1128/mBio.00912-14 PG 8 WC Microbiology SC Microbiology GA AH1XR UT WOS:000335915600041 PM 24643864 ER PT J AU Joseph, P Fourie, N Abey, S Reddy, S Wang, D Martino, A Smyser, P Rahim-Williams, B Reed, D Henderson, W AF Joseph, Paule Fourie, Nicolaas Abey, Sarah Reddy, Swarnalatha Wang, Dan Martino, Angelina Smyser, Paul Rahim-Williams, Bridgette Reed, Danielle Henderson, Wendy TI Obesity Gene Expression Profile, Human Eating Behavior (HEB) and Clinical Outcomes SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Joseph, Paule] Univ Penn, Philadelphia, PA 19104 USA. [Rahim-Williams, Bridgette] Natl Inst Minor Hlth & Hlth Dispar, Bethesda, MD USA. [Reed, Danielle] Monell Chem Senses Ctr, Philadelphia, PA USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-6562 EI 1538-9847 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2014 VL 63 IS 2 BP E95 EP E95 PG 1 WC Nursing SC Nursing GA AE6JP UT WOS:000334098000263 ER PT J AU Kutney-Lee, A Brennan, C Meterko, M Ersek, M AF Kutney-Lee, Ann Brennan, Caitlin Meterko, Mark Ersek, Mary TI Organization of Nursing and Quality of Care for Veterans at the End of Life SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Kutney-Lee, Ann] Univ Penn, Philadelphia, PA 19104 USA. [Brennan, Caitlin] NIH, Ctr Clin, Bethesda, MD USA. [Meterko, Mark] VA Boston Healthcare Syst, Boston, MA USA. [Ersek, Mary] Univ Penn, Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-6562 EI 1538-9847 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2014 VL 63 IS 2 BP E129 EP E129 PG 1 WC Nursing SC Nursing GA AE6JP UT WOS:000334098000355 ER PT J AU Sherwin, L AF Sherwin, LeeAnne TI Illness Representation & Health-related Quality of Life in Adults with Irritable Bowel Syndrome SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Sherwin, LeeAnne] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-6562 EI 1538-9847 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2014 VL 63 IS 2 BP E83 EP E83 PG 1 WC Nursing SC Nursing GA AE6JP UT WOS:000334098000232 ER PT J AU Grabowski, MK Redd, AD AF Grabowski, Mary K. Redd, Andrew D. TI Molecular tools for studying HIV transmission in sexual networks SO CURRENT OPINION IN HIV AND AIDS LA English DT Review DE HIV; linkage; phylogenetics ID BAYESIAN PHYLOGENETIC INFERENCE; EVOLUTIONARY DYNAMICS; TYPE-1 TRANSMISSION; MAXIMUM-LIKELIHOOD; ERROR-CORRECTION; VIRAL SEQUENCES; DNA-SEQUENCES; GENITAL-TRACT; EPIDEMIC; INFECTION AB Purpose of review Phylogenetics is frequently used for studies of population-based HIV transmission. The purpose of this review is to highlight the current utilities and limitations of phylogenetics in HIV epidemiological research from sample collection through to data analysis. Recent findings Studies of HIV phylogenies can provide critical information about HIV epidemics that are otherwise difficult to obtain through traditional study design such as transmission of drug-resistant virus, mixing between demographic groups, and rapidity of viral spread within populations. However, recent results from empirical and theoretical studies of HIV phylogenies challenge some of the key assumptions and interpretations from phylogenetic studies. Recent findings include lack of transmission bottlenecks in MSM and injection drug use epidemics, evidence for preferential transmission of HIV virus in heterosexual epidemics, and limited evidence that tree topologies correlate directly with underlying network structures. Other challenges include a lack of a standardized definition for a phylogenetic transmission cluster and biased or sparse sampling of HIV transmission networks. Summary Phylogenetics is an important tool for HIV research, and offers opportunities to understand critical aspects of the HIV epidemic. Like all epidemiological research, the methods used and interpretation of results from phylogenetic studies should be made cautiously with careful consideration. C1 [Grabowski, Mary K.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Redd, Andrew D.] NIAID, Immunoregulat Lab, NIH, Baltimore, MD USA. RP Grabowski, MK (reprint author), 851 N Wolfe St,Rangos Bldg Room 527, Baltimore, MD 21205 USA. EM Aredd2@jhmi.edu FU Johns Hopkins Bloomberg School of Public Health Sommer Scholarship; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX M.K.G. is supported by the Johns Hopkins Bloomberg School of Public Health Sommer Scholarship. A.D.R. is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. 'There are no conflicts of interest. NR 81 TC 19 Z9 20 U1 3 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X EI 1746-6318 J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD MAR PY 2014 VL 9 IS 2 BP 126 EP 133 DI 10.1097/COH.0000000000000040 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AC3EQ UT WOS:000332398200005 PM 24384502 ER PT J AU Simmons, WK Rapuano, KM Ingeholm, JE Avery, J Kallman, S Hall, KD Martin, A AF Simmons, W. Kyle Rapuano, Kristina M. Ingeholm, John E. Avery, Jason Kallman, Seth Hall, Kevin D. Martin, Alex TI The ventral pallidum and orbitofrontal cortex support food pleasantness inferences SO BRAIN STRUCTURE & FUNCTION LA English DT Article DE Food; Pleasure; Ventral pallidum; Orbitofrontal cortex ID ORBITAL PREFRONTAL CORTEX; DECISION-MAKING; EATING BEHAVIOR; HEDONIC REWARD; HUMAN AMYGDALA; WEIGHT STATUS; OBESITY; BRAIN; TASTE; ACTIVATION AB Food advertisements often promote choices that are driven by inferences about the hedonic pleasures of eating a particular food. Given the individual and public health consequences of obesity, it is critical to address unanswered questions about the specific neural systems underlying these hedonic inferences. For example, although regions such as the orbitofrontal cortex (OFC) are frequently observed to respond more to pleasant food images than less hedonically pleasing stimuli, one important hedonic brain region in particular has largely remained conspicuously absent among human studies of hedonic response to food images. Based on rodent research demonstrating that activity in the ventral pallidum underlies the hedonic pleasures experienced upon eating food rewards, one might expect that activity in this important 'hedonic hotspot' might also track inferred food pleasantness. To date, however, no human studies have assessed this question. We thus asked human subjects to undergo fMRI and make item-by-item ratings of how pleasant it would be to eat particular visually perceived foods. Activity in the ventral pallidum was strongly modulated with pleasantness inferences. Additionally, activity within a region of the orbitofrontal cortex that tracks the pleasantness of tastes was also modulated with inferred pleasantness. Importantly, the reliability of these findings is demonstrated by their replication when we repeated the experiment at a new site with new subjects. These two experiments demonstrate that the ventral pallidum, in addition to the OFC, plays a central role in the moment-to-moment hedonic inferences that influence food-related decision-making. C1 [Simmons, W. Kyle; Avery, Jason] Laureate Inst Brain Res, Tulsa, OK 74136 USA. [Simmons, W. Kyle] Univ Tulsa, Fac Community Med, Tulsa, OK 74104 USA. [Simmons, W. Kyle; Rapuano, Kristina M.; Ingeholm, John E.; Kallman, Seth; Martin, Alex] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Avery, Jason] Univ Tulsa, Dept Biol Sci, Tulsa, OK 74104 USA. [Hall, Kevin D.] NIDDK, Lab Biol Modeling, Bethesda, MD 20892 USA. RP Simmons, WK (reprint author), Laureate Inst Brain Res, 6655 South Yale Ave, Tulsa, OK 74136 USA. EM wksimmons@laureateinstitute.org RI Simmons, William/K-8925-2015 OI Simmons, William/0000-0002-0399-9003 FU National Institute of Mental Health (NIMH); National Institute of Diabetes and Digestive and Kidney Diseases; NIMH [1K01MH096175-01]; Oklahoma Tobacco Research Center FX This research supported by the Intramural Research Programs of the National Institute of Mental Health (NIMH), and the National Institute of Diabetes and Digestive and Kidney Diseases, as well as NIMH Grant 1K01MH096175-01 and an Oklahoma Tobacco Research Center grant to Kyle Simmons. We would like to thank both Dr. Steve Gotts and Dr. Wayne Drevets for helpful comments on this manuscript and research. NR 58 TC 12 Z9 12 U1 4 U2 11 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2653 EI 1863-2661 J9 BRAIN STRUCT FUNCT JI Brain Struct. Funct. PD MAR PY 2014 VL 219 IS 2 BP 473 EP 483 DI 10.1007/s00429-013-0511-0 PG 11 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA AG9KG UT WOS:000335737500003 PM 23397317 ER PT J AU Prasad, V Grady, C AF Prasad, Vinay Grady, Christine TI The misguided ethics of crossover trials SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Crossover; Ethics of clinical trials; Trial validity ID RENAL-CELL CARCINOMA; EVEROLIMUS AB Crossover is increasingly favored in trials of cancer therapies; even those that seek to establish the basic efficacy of novel drugs. Crossover is done in part for trial recruitment, but also out of a sense we argue that this ethical inclination that crossover is a preferred trial choice is misguided. In seeking to sate the desires of participants, we might undermine a trial's ability to answer a meaningful clinical question. When a trial is incapable of answering a question, it becomes unethical. Using a crossover strategy in oncology clinical trials can make trials less ethical, not more. Published by Elsevier Inc. C1 [Prasad, Vinay] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Grady, Christine] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Grady, C (reprint author), NIH, Dept Bioeth, Ctr Clin, 10 Ctr Dr Bldg 10-1C118, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov; CGrady@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 13 TC 7 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 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD MAR PY 2014 VL 37 IS 2 BP 167 EP 169 DI 10.1016/j.cct.2013.12.003 PG 3 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA AG7ZA UT WOS:000335636100001 PM 24365533 ER PT J AU Amundsen, CL Richter, HE Menefee, S Vasavada, S Rahn, DD Kenton, K Harvie, HS Wallace, D Meikle, S AF Amundsen, Cindy L. Richter, Holly E. Menefee, Shawn Vasavada, Sandip Rahn, David D. Kenton, Kim Harvie, Heidi S. Wallace, Dennis Meikle, Susie TI The Refractory Overactive Bladder: Sacral NEuromodulation vs. BoTulinum Toxin Assessment: ROSETTA trial SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Urgency urinary incontinence; Sacral neuromodulation; Onabotulinum toxin A ID IDIOPATHIC DETRUSOR OVERACTIVITY; URINARY URGE INCONTINENCE; PLACEBO-CONTROLLED TRIAL; A TOXIN; SUBUROTHELIAL INJECTION; NERVE-STIMULATION; DOUBLE-BLIND; EFFICACY; QUESTIONNAIRE; ANTICHOLINERGICS AB We present the rationale for and design of a randomized, open-label, active-control trial comparing the effectiveness of 200 units of onabotulinum toxin A (Botox A (R)) versus sacral neuromodulation (InterStim (R)) therapy for refractory urgency urinary incontinence (UUI). The Refractory Overactive Bladder: Sacral NEuromodulation vs. BoTulinum Toxin Assessment (ROSETTA) trial compares changes in urgency urinary incontinence episodes over 6 months, as well as other lower urinary tract symptoms, adverse events and cost effectiveness in women receiving these two therapies. Eligible participants had previously attempted treatment with at least 2 medications and behavioral therapy. We discuss the importance of evaluating two very different interventions, the challenges related to recruitment, ethical considerations for two treatments with significantly different costs, follow-up assessments and cost effectiveness. The ROSETTA trial will provide information to healthcare providers regarding the technical attributes of these interventions as well as the efficacy and safety of these two interventions on other lower urinary tract and pelvic floor symptoms. Enrollment began in March, 2012 with anticipated end to recruitment in mid 2014. (c) 2014 Elsevier Inc. All rights reserved. C1 [Amundsen, Cindy L.] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Richter, Holly E.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Menefee, Shawn] Kaiser Perrnanente San Diego, Dept Obstet & Gynecol, San Diego, CA USA. [Vasavada, Sandip] Cleveland Clin, Dept Obstet & Gynecol, Cleveland, OH 44106 USA. [Rahn, David D.] Univ Texas Southwestern, Dept Obstet & Gynecol, Dallas, TX USA. [Kenton, Kim] Loyola Univ, Stritch Sch Med, Dept Obstet & Gynecol & Urol, Chicago, IL 60611 USA. [Harvie, Heidi S.] Univ Penn, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Wallace, Dennis] RTI Int, Res Triangle Pk, NC USA. [Meikle, Susie] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Contracept & Reprod Hlth Branch, Populat Res Ctr, NIH, Bethesda, MD 20892 USA. RP Amundsen, CL (reprint author), Duke Univ, Med Ctr, Dept Obstet & Gynecol, Div Urogynecol & Reconstruct Pelv Surg, DUMC 3192, Durham, NC 27710 USA. EM cindy.amundsen@duke.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U10-HD041267, U10 HD041261, U10 HD054214, U10 HD054215, U10 HD054241, U10 HD041250, U10 HD069031, U10 HD069010]; NIH Office of Research on Women's Health FX Supported by grants from The Eunice Kennedy Shriver National Institute of Child Health and Human Development (U10-HD041267, U10 HD041261, U10 HD054214, U10 HD054215, U10 HD054241, U10 HD041250, U10 HD069031, U10 HD069010) and the NIH Office of Research on Women's Health. NR 37 TC 8 Z9 9 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD MAR PY 2014 VL 37 IS 2 BP 272 EP 283 DI 10.1016/j.cct2014.01.009 PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA AG7ZA UT WOS:000335636100014 PM 24486637 ER PT J AU Hayes, RB Geller, A Churchill, L Jolicoeur, D Murray, DM Shoben, A David, SP Adams, M Okuyemi, K Fauver, R Gross, R Leone, F Xiao, R Waugh, J Crawford, S Ockene, JK AF Hayes, Rashelle B. Geller, Alan Churchill, Linda Jolicoeur, Denise Murray, David M. Shoben, Abigail David, Sean P. Adams, Michael Okuyemi, Kola Fauver, Randy Gross, Robin Leone, Frank Xiao, Rui Waugh, Jonathan Crawford, Sybil Ockene, Judith K. TI Teaching tobacco dependence treatment and counseling skills during medical school: Rationale and design of the Medical Students helping patients Quit tobacco (MSQuit) group randomized controlled trial SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Tobacco dependence treatment and counseling; 5As; Medical school education; Medical students; Tobacco control; Group randomized controlled trial ID ONE-MINUTE PRECEPTOR; SMOKING-CESSATION; UNITED-STATES; INTERVENTION; PHYSICIANS; EDUCATION; SMOKERS; PERCEPTIONS; CURRICULUM; PROJECT AB Introduction: Physician-delivered tobacco treatment using the 5As is clinically recommended, yet its use has been limited. Lack of adequate training and confidence to provide tobacco treatment is cited as leading reasons for limited 5A use. Tobacco dependence treatment training while in medical school is recommended, but is minimally provided. The MSQuit trial (Medical Students helping patients Quit tobacco) aims to determine if a multi-modal and theoretically-guided tobacco educational intervention will improve tobacco dependence treatment skills (i.e. 5As) among medical students. Methods/design: 10 U.S. medical schools were pair-matched and randomized in a group-randomized controlled trial to evaluate whether a multi-modal educational (MME) 'intervention compared to traditional education (TE) will improve observed tobacco treatment skills. MME is primarily composed of TE approaches (i.e. didactics) plus a 1st year web-based course and preceptor-objective score on an Objective Structured Clinical Examination (OSCE) tobacco-counseling smoking case among 3rd year medical students from schools who implemented the MME or TE. Discussion: MSQuit is the first randomized to evaluate whether a tobacco treatment educational intervention implemented during medical school will improve medical students' tobacco treatment skills. We hypothesize that the MME intervention will better prepare students in tobacco dependence treatment as measured by the OSCE. If a comprehensive tobacco treatment educational learning approach is effective, while also feasible and acceptable to implement, then medical schools may substantially influence skill development and use of the 5As among future physicians. (c) 2014 The Authors. Published by Elsevier Inc. C1 [Hayes, Rashelle B.; Churchill, Linda; Jolicoeur, Denise; Xiao, Rui; Crawford, Sybil; Ockene, Judith K.] Univ Massachusetts, Sch Med, Div Prevent & Behav Med, Dept Med, Worcester, MA 01655 USA. [Geller, Alan] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Murray, David M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. [Shoben, Abigail] Ohio State Univ, Coll Publ Hlth, Div Biostat, Columbus, OH 43210 USA. [David, Sean P.; Fauver, Randy] Stanford Univ, Sch Med, Dept Med, Div Gen Med Disciplines,Ctr Educ & Res Family & C, Palo Alto, CA 94304 USA. [Adams, Michael] Georgetown Univ Hosp, Dept Med, Div Gen Internal Med, Washington, DC USA. [Okuyemi, Kola] Univ Minnesota, Sch Med, Dept Med, Minneapolis, MN 55455 USA. [Gross, Robin] Georgetown Univ Hosp, Dept Med, Div Pulm Crit Care & Sleep Med, Washington, DC 20007 USA. [Leone, Frank] Univ Penn, Perelman Sch Med, Div Pulm Allergy & Crit Care Med, Philadelphia, PA 19104 USA. [Waugh, Jonathan] Univ Alabama Birmingham, UAB Lung Hlth Ctr, Dept Clin & Diagnost Sci, Birmingham, AL USA. RP Hayes, RB (reprint author), Univ Massachusetts, Sch Med, 55 Lake Ave North, Worcester, MA 01655 USA. EM rashelle.hayes@umassmed.edu; ageller@hsph.harvard.edu; linda.churchill@umassmed.edu; denise.jolicoeur@umassmed.edu; david.murray2@nih.gov; ashoben@cph.osu.edu; spdavid@stanford.edu; adams@gunet.georgetown.edu; kokuyemi@umn.edu; rfauver@stanford.edu; rlg4@gunet.georgetown.edu; frank.tleone@uphs.upenn.edu; rui.xiao@umassmed.edu; waughj@uab.edu; sybil.crawford@umassmed.edu; judith.ockene@umassmed.edu OI David, Sean/0000-0002-4922-2603 FU NIH/NCI [5R01 CA 136888, 5R01CA136888S] FX This work was supported by the NIH/NCI research grant 5R01 CA 136888 and 5R01CA136888S to Judith K. Ockene & Rashelle B. Hayes respectively. We also acknowledge all school site Pls, research coordinators, academic detailers, research assistants, support staff, as well as the participating medical students and preceptors who have implemented and participated in the study thus far. NR 51 TC 6 Z9 6 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD MAR PY 2014 VL 37 IS 2 BP 284 EP 293 DI 10.1016/j.cct.2014.01.008 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA AG7ZA UT WOS:000335636100015 PM 24486635 ER PT J AU Chew, EY Clemons, TE Bressler, SB Elman, MJ Danis, RP Domalpally, A Heier, JS Kim, JE Garfinkel, RA AF Chew, Emily Y. Clemons, Traci E. Bressler, Susan B. Elman, Michael J. Danis, Ronald P. Domalpally, Amitha Heier, Jeffrey S. Kim, Judy E. Garfinkel, Richard A. CA AREDS2 Home Study Res Grp TI Randomized trial of the ForeseeHome monitoring device for early detection of neovascular age-related macular degeneration. The HOme Monitoring of the Eye (HOME) study design - HOME Study report number 1 SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Age-related macular degeneration; Controlled clinical trial; Home-monitoring; Choroidal neovascularization; Best-corrected visual acuity ID FACTOR TRAP-EYE; VISUAL IMPAIRMENT; SUBGROUP ANALYSIS; UNITED-STATES; RANIBIZUMAB; BEVACIZUMAB; PREVALENCE; MULTICENTER; ACUITY AB Objective: To evaluate the effects of a home-monitoring device with tele-monitoring compared with standard care in detection of progression to choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD), the leading cause of blindness in the US. Patients and methods: Participants, aged 55 to 90 years, at high risk of developing CNV associated with AMD were recruited to the HOme Monitoring of Eye (HOME) Study, an unmasked, multi-center, randomized trial of the ForeseeHome (FH) device plus standard care vs. standard care alone. The FH device utilizes preferential hyperacuity perimetry and tele-monitoring to detect changes in vision function associated with development of CNV, potentially prior to symptom and visual acuity loss. After establishing baseline measurements, subsequent changes on follow-up are detected by the device, causing the monitoring center to alert the clinical center to recall participants for an exam. Standard care consists of instructions for self-monitoring visual changes with subsequent self-report to the clinical center. The primary objective of this study is to determine whether home monitoring plus standard care in comparison with standard care alone, results in earlier detection of incident CNV with better present visual acuity. The primary outcome is the decline in visual acuity at CNV diagnosis from baseline. Detection of CNV prior to substantial vision loss is critical as vision outcome following anti-angiogenic therapy is dependent on the visual acuity at initiation of treatment. Discussion: HOME Study is the first large scale study to test the use of home tele-monitoring system in the management of AMD patients. Published by Elsevier Inc. C1 [Chew, Emily Y.] NEI, Bethesda, MD 20892 USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. [Bressler, Susan B.] Johns Hopkins Univ Hosp, Wilmer Eye Inst, Dept Ophthalmol, Baltimore, MD 21287 USA. [Elman, Michael J.] Elman Retina Grp, Baltimore, MD USA. [Danis, Ronald P.; Domalpally, Amitha] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Heier, Jeffrey S.] Ophthalm Consultant Boston, Boston, MA USA. [Kim, Judy E.] Med Coll Wisconsin, Dept Ophthalmol, Milwaukee, WI 53226 USA. [Garfinkel, Richard A.] Retina Grp Washington, Bethesda, MD USA. RP Chew, EY (reprint author), NIH, CRC, Bldg 10,Room 3-2531,10 Ctr Dr,MSC-1204, Bethesda, MD 20892 USA. EM echew@nei.nih.gov RI Domalpally, Amitha/B-2367-2015; OI Heier, Jeffrey/0000-0003-4625-3145 FU Notal Vision through a clinical trial agreement with the NEI [CTA-00833]; EMMES Corporation; National Eye Institute/National Institutes of Health (NEI/NIH); Department of Health and Human Services, Bethesda, MD [HHS-N-260-2005-00007-C]; ADB [N01-EY-5-0007]; Office of Dietary Supplements (ODS); National Center for Complementary and Alternative Medicine (NCCAM); National Institute on Aging (NIA); National Heart, Lung and Blood Institute (NHLBI); National Institute of Neurological Disorders and Stroke (N1NDS) FX Financial support to the study was provided by the Notal Vision through a clinical trial agreement with the NEI (CTA-00833) and a service agreement with EMMES Corporation. The AREDS2 study is supported by the intramural program funds and contracts from the National Eye Institute/National Institutes of Health (NEI/NIH), Department of Health and Human Services, Bethesda, MD. Contract No. HHS-N-260-2005-00007-C. ADB Contract No. N01-EY-5-0007. Funds were generously contributed to these contracts by the following NIH institutes: Office of Dietary Supplements (ODS), National Center for Complementary and Alternative Medicine (NCCAM), National Institute on Aging (NIA), National Heart, Lung and Blood Institute (NHLBI), and National Institute of Neurological Disorders and Stroke (N1NDS). The study medications and raw materials were provided by Alcon, Bausch and Lomb, DSM, and Pfizer. NR 19 TC 9 Z9 9 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD MAR PY 2014 VL 37 IS 2 BP 294 EP 300 DI 10.1016/j.cct.2014.02.003 PG 7 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA AG7ZA UT WOS:000335636100016 PM 24530651 ER PT J AU Cochran, EK Valentine, V Samaan, KH Corey, IB Jackson, JA AF Cochran, Elaine K. Valentine, Virginia Samaan, Karen H. Corey, Ilene B. Jackson, Jeffrey A. TI Practice Tips and Tools for the Successful Use of U-500 Regular Human Insulin The Diabetes Educator Is Key SO DIABETES EDUCATOR LA English DT Article ID CLINICAL-EXPERIENCE; GLYCEMIC CONTROL; GLUCOSE CONTROL; U-100 INSULIN; THERAPY; MANAGEMENT; RESISTANCE; OBESE; HYPERGLYCEMIA; MELLITUS AB This review provides information to equip diabetes educators to instruct and guide patients in using U-500 human regular insulin (U-500R). The article includes an overview of U-500R pharmacology and clinical data, strategies for outpatient and inpatient use, and tools for patient education. U-500R is useful for treating patients with any type of diabetes who require high doses of insulin. U-500R alleviates the volume-related problems associated with high doses of U-100 insulin, making treatment with high doses of insulin more feasible (because of the need for fewer injections for patients) as well as more cost-efficient and potentially more effective. These tools can help diabetes educators feel more comfortable and confident as they advise and educate patients who receive high-dose U-500R as part of their overall diabetes care plan. The diabetes educator plays a vital role in helping patients use U-500R safely and successfully. C1 [Cochran, Elaine K.] NIDDK, NIH, Bethesda, MD 20892 USA. [Valentine, Virginia] Diabet Network Inc, Albuquerque, NM USA. [Samaan, Karen H.] St Vincents Hosp, Indianapolis, IN USA. [Corey, Ilene B.; Jackson, Jeffrey A.] Lilly USA LLC, Indianapolis, IN USA. RP Cochran, EK (reprint author), Natl Inst Diabet, NIH, 9000 Rockville Pike,10-CRC 6-5940, Bethesda, MD 20892 USA. EM elainec@intra.niddk.nih.gov NR 47 TC 5 Z9 5 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-7217 EI 1554-6063 J9 DIABETES EDUCATOR JI Diabetes Educ. PD MAR PY 2014 VL 40 IS 2 BP 153 EP 165 DI 10.1177/0145721713508822 PG 13 WC Endocrinology & Metabolism; Public, Environmental & Occupational Health SC Endocrinology & Metabolism; Public, Environmental & Occupational Health GA AD3VE UT WOS:000333173500001 PM 24159006 ER PT J AU Moshesh, M Olshan, AF Saldana, T Baird, D AF Moshesh, Malana Olshan, Andrew F. Saldana, Tina Baird, Donna TI Examining the Relationship Between Uterine Fibroids and Dyspareunia Among Premenopausal Women in the United SO JOURNAL OF SEXUAL MEDICINE LA English DT Article DE Dyspareunia; Fibroids; Sexual Dysfunction; Pelvic Pain; Sexual Pain; Pelvic Pathology ID SEXUAL FUNCTION; PREVALENCE; LEIOMYOMA; PAIN; CHILDBIRTH; DELIVERY; FEMALE; PREGNANCY; SYSTEM; HEALTH AB IntroductionDespite estimates of a high prevalence of deep dyspareunia (DD) among women in the United States, risk factors for this important area of sexual dysfunction have been largely understudied. AimsThe purpose of this study was to examine the relationship between uterine fibroids and the prevalence of DD. MethodsWe used data from the Uterine Fibroid Study (enrollment 1996-1999 in a U.S. metropolitan area). Participating women were ages 35-49 and were randomly selected from the membership rolls of a prepaid health plan. Women were asked to provide detailed health information including a symptom questionnaire with questions about DD and to have a study ultrasound to screen for fibroids 0.5cm in diameter. The analysis included 827 women, after restriction to participants who were premenopausal with an intact uterus, sexually active, completed the symptom questionnaire, and had fibroid status adequately assessed. Logistic regression was conducted to estimate the adjusted prevalence odds ratio (aPOR) for the association of DD with presence of fibroids after adjusting for age, ethnicity, education, depression, physical activity, parity, and pelvic pathology. Main Outcome MeasureOur main outcome measures were the presence and severity of DD. ResultsThe presence of fibroids was significantly associated with DD (aPOR=1.7 95% confidence interval [CI] 1.1, 2.5). The aPOR was stronger for severe DD, DD that interfered with normal activity some or a lot (aPOR=3.1 95% CI 1.2, 8.2). However, there was not a significant dose response relationship between fibroid burden (measured by uterine volume) and DD. Fundal fibroids were more strongly associated with DD than other fibroids. Additional factors associated with significantly elevated odds of DD were parity, depression, younger age, and pelvic pathology. ConclusionOur results suggest that fibroids are associated with DD. The association may not be causal but may reflect shared etiology and/or pathologic pathways. Moshesh M, Olshan AF, Saldana T, and Baird D. Examining the relationship between uterine fibroids and dyspareunia among premenopausal women in the US. J Sex Med 2014;11:800-808. C1 [Moshesh, Malana; Baird, Donna] NIEHS, NIH, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Olshan, Andrew F.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Saldana, Tina] Social & Sci Syst Inc, Durham, NC USA. RP Baird, D (reprint author), NIEHS, Epidemiol Branch, A3-05,111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM baird@niehs.nih.gov RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU NIH; National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. We would like to acknowledge Drs. Nils-Halvdan Morken and Hazel Nichols who both provided helpful comments on an earlier draft of the manuscript. NR 29 TC 7 Z9 7 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-6095 EI 1743-6109 J9 J SEX MED JI J. Sex. Med. PD MAR PY 2014 VL 11 IS 3 BP 800 EP 808 DI 10.1111/jsm.12425 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA AB9UD UT WOS:000332140300017 PM 24467730 ER PT J AU Workman, TE Fiszman, M Rindflesch, TC Nahl, D AF Workman, T. Elizabeth Fiszman, Marcelo Rindflesch, Thomas C. Nahl, Diane TI Framing Serendipitous Information-Seeking Behavior for Facilitating Literature-Based Discovery: A Proposed Model SO JOURNAL OF THE ASSOCIATION FOR INFORMATION SCIENCE AND TECHNOLOGY LA English DT Article ID FISH-OIL; GENERATING HYPOTHESES; SLEEP-DEPRIVATION; BIOMEDICAL TEXT; KNOWLEDGE; RETRIEVAL; MAGNESIUM; FRAMEWORK; MIGRAINE; RAYNAUDS AB Several researchers have studied serendipitous knowledge discovery in information-seeking behavior. Electronic data in the form of semantic predications have a potential role in literature-based discovery, which can be guided by serendipitous knowledge discovery research findings. We sought to model information-seeking behavior within the context of serendipitous knowledge discovery by leveraging existing research. These efforts were done with an eye for a potential literature-based discovery application that utilizes semantic predications. We performed a literature search, reviewed the results, and applied the findings in developing a model for serendipitous knowledge discovery as an information-seeking behavior. The literature review indicated four important themes in serendipitous knowledge discovery: iteration, change or clarification, a seeker's prior knowledge, and the role of information organization and presentation. The Interaction Flow in Serendipitous Knowledge Discovery (IF-SKD) model includes these themes, and accommodates iterative, evolving search interests. Output can be presented in a manner to enhance short-term memory conceptualization and connections with prior knowledge. Although the IF-SKD model is currently a theoretical structure, its utility is demonstrated through replicating a literature-based discovery event, using a documented search method within the model's steps. The IF-SKD model can potentially serve as the foundation for future literature-based discovery applications. C1 [Workman, T. Elizabeth; Fiszman, Marcelo; Rindflesch, Thomas C.] Natl Lib Med, Lister Hill Ctr, Bethesda, MD 20894 USA. [Nahl, Diane] Univ Hawaii, Dept Informat & Comp Sci, Lib & Informat Sci Program, Hamilton Lib 3C, Honolulu, HI 96822 USA. RP Workman, TE (reprint author), Natl Lib Med, Lister Hill Ctr, 8600 Rockville Pike,Bldg 38A,Room B1N30A4, Bethesda, MD 20894 USA. EM workmante@mail.nih.gov; fiszmanm@mail.nih.gov; tcr@nlm.nih.gov; nahl@hawaii.edu FU National Institutes of Health, National Library of Medicine; National Library of Medicine FX This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. This research was supported in part by an appointment of the first author to the Lister Hill Center Fellows Program sponsored by the National Library of Medicine and administered by the Oak Ridge Institute for Science and Education. NR 73 TC 3 Z9 3 U1 3 U2 32 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2330-1635 EI 2330-1643 J9 J ASSOC INF SCI TECH PD MAR PY 2014 VL 65 IS 3 BP 501 EP 512 DI 10.1002/asi.22999 PG 12 WC Computer Science, Information Systems; Information Science & Library Science SC Computer Science; Information Science & Library Science GA AG7EZ UT WOS:000335582300005 ER PT J AU Kahn, MG Bailey, LC Forrest, CB Padula, MA Hirschfeld, S AF Kahn, Michael G. Bailey, L. Charles Forrest, Christopher B. Padula, Michael A. Hirschfeld, Steven TI Building a Common Pediatric Research Terminology for Accelerating Child Health Research SO PEDIATRICS LA English DT Review DE terminology harmonization; clinical research; learning health system; governance; pediatric research; ontology ID EFFECTIVENESS RESEARCH CER; INHALED NITRIC-OXIDE; CLINICAL-RESEARCH; INTERNATIONAL CLASSIFICATION; RESPIRATORY-FAILURE; BIOMEDICAL ONTOLOGY; NATIONAL CENTER; DATA STANDARDS; EDM-FORUM; QUALITY AB Longitudinal observational clinical data on pediatric patients in electronic format is becoming widely available. A new era of multi-institutional data networks that study pediatric diseases and outcomes across disparate health delivery models and care settings are also enabling an innovative collaborative rapid improvement paradigm called the Learning Health System. However, the potential alignment of routine clinical care, observational clinical research, pragmatic clinical trials, and health systems improvement requires a data infrastructure capable of combining information from systems and workflows that historically have been isolated from each other. Removing barriers to integrating and reusing data collected in different settings will permit new opportunities to develop a more complete picture of a patient's care and to leverage data from related research studies. One key barrier is the lack of a common terminology that provides uniform definitions and descriptions of clinical observations and data. A well-characterized terminology ensures a common meaning and supports data reuse and integration. A common terminology allows studies to build upon previous findings and to reuse data collection tools and data management processes. We present the current state of terminology harmonization and describe a governance structure and mechanism for coordinating the development of a common pediatric research terminology that links to clinical terminologies and can be used to align existing terminologies. By reducing the barriers between clinical care and clinical research, a Learning Health System can leverage and reuse not only its own data resources but also broader extant data resources. C1 [Kahn, Michael G.] Univ Colorado, Dept Pediat, Aurora, CO 80045 USA. [Bailey, L. Charles; Forrest, Christopher B.; Padula, Michael A.] Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Bailey, L. Charles; Forrest, Christopher B.; Padula, Michael A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Hirschfeld, Steven] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Kahn, MG (reprint author), Univ Colorado, Dept Pediat, Childrens Hosp Colorado, 13123 E 16th Ave,B400, Aurora, CO 80045 USA. EM michael.kahn@childrenscolorado.org RI Hirschfeld, Steven/E-2987-2016; OI Hirschfeld, Steven/0000-0003-0627-7249; Padula, Michael/0000-0003-2050-5930 FU National Children's Study [HHSN275200800018C, HHSN267200700020C]; National Institutes of Health, National Center for Advancing Translational Sciences, Colorado Clinical and Translational Sciences Institute [UL1 TR000154]; Agency for Healthcare Research Quality [R01HS020024-03]; National Institutes of Health (NIH) FX Supported by National Children's Study contracts HHSN275200800018C (to Dr Kahn) and HHSN267200700020C (to Drs Bailey, Forrest, and Padula); National Institutes of Health, National Center for Advancing Translational Sciences, Colorado Clinical and Translational Sciences Institute grant UL1 TR000154 to Dr Kahn and Agency for Healthcare Research & Quality R01HS020024-03 (to Drs Bailey and Forrest). Funded by the National Institutes of Health (NIH). NR 54 TC 13 Z9 15 U1 2 U2 6 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD MAR PY 2014 VL 133 IS 3 BP 516 EP 525 DI 10.1542/peds.2013-1504 PG 10 WC Pediatrics SC Pediatrics GA AG3PB UT WOS:000335330700024 PM 24534404 ER PT J AU Frattarelli, DAC Galinkin, JL Green, TP Johnson, TD Neville, KA Paul, IM Van den Anker, JN Knight, M Alexander, JJ Kilpatrick, SJ Cragan, JD Rieder, MJ Robb, AS Sachs, H Zajicek, A Haro, T Koteras, RK Del Monte, M AF Frattarelli, Daniel A. C. Galinkin, Jeffrey L. Green, Thomas P. Johnson, Timothy D. Neville, Kathleen A. Paul, Ian M. Van den Anker, John N. Knight, Matthew Alexander, John J. Kilpatrick, Sarah J. Cragan, Janet D. Rieder, Michael J. Robb, Adelaide S. Sachs, Hari Zajicek, Anne Haro, Tamar Koteras, Raymond K. Del Monte, Mark CA COMM DRUGS TI Off-Label Use of Drugs in Children SO PEDIATRICS LA English DT Article DE off-label drug use; pharmaceuticals; pediatrics; infants; children; adolescents; prescribing AB The passage of the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act has collectively resulted in an improvement in rational prescribing for children, including more than 500 labeling changes. However, off-label drug use remains an important public health issue for infants, children, and adolescents, because an overwhelming number of drugs still have no information in the labeling for use in pediatrics. The purpose of off-label use is to benefit the individual patient. Practitioners use their professional judgment to determine these uses. As such, the term off-label does not imply an improper, illegal, contraindicated, or investigational use. Therapeutic decision-making must always rely on the best available evidence and the importance of the benefit for the individual patient. C1 [Alexander, John J.; Sachs, Hari] US FDA, Rockville, MD 20857 USA. [Kilpatrick, Sarah J.] Amer Coll Obstetricians & Gynecologists, Washington, DC USA. [Cragan, Janet D.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Rieder, Michael J.] Canadian Pediat Soc, Ottawa, ON, Canada. [Robb, Adelaide S.] Amer Acad Child & Adolescent Psychiat, Washington, DC USA. [Zajicek, Anne] NIH, Bethesda, MD USA. OI Paul, Ian/0000-0002-6344-8609 NR 7 TC 48 Z9 52 U1 0 U2 7 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD MAR PY 2014 VL 133 IS 3 BP 563 EP 567 DI 10.1542/peds.2013-4060 PG 5 WC Pediatrics SC Pediatrics GA AG3PB UT WOS:000335330700036 PM 24567009 ER PT J AU Lei, EP AF Lei, Elissa P. TI Special Issue: Chromatin and epigenetic regulation of animal development Preface SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Editorial Material C1 Natl Inst Diabet & Digest & Kidney Dis, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Lei, EP (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 EI 0006-3002 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD MAR PY 2014 VL 1839 IS 3 SI SI BP 117 EP 117 DI 10.1016/j.bbagrm.2014.02.003 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AE3MX UT WOS:000333881700001 PM 24530644 ER PT J AU Matzat, LH Lei, EP AF Matzat, Leah H. Lei, Elissa P. TI Surviving an identity crisis: A revised view of chromatin insulators in the genomics era SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Review DE Chromatin; Insulator; Nuclear organization; Drosophila ID DROSOPHILA-BITHORAX COMPLEX; HAIRY-WING PROTEIN; POSITION-EFFECT VARIEGATION; ENHANCER-BLOCKING ACTIVITY; CIS-REGULATORY DOMAINS; RESPONSE ELEMENT PRE; ZINC-FINGER PROTEIN; DNA-BINDING DOMAIN; ACTIVE PROMOTERS; GYPSY INSULATOR AB The control of complex, developmentally regulated loci and partitioning of the genome into active and silent domains is in part accomplished through the activity of DNA-protein complexes termed chromatin insulators. Together, the multiple, well-studied classes of insulators in Drosophila melanogaster appear to be generally functionally conserved. In this review, we discuss recent genomic-scale experiments and attempt to reconcile these newer findings in the context of previously defined insulator characteristics based on classical genetic analyses and transgenic approaches. Finally, we discuss the emerging understanding of mechanisms of chromatin insulator regulation. This article is part of a Special Issue entitled: Chromatin and epigenetic regulation of animal development. Published by Elsevier B.V. C1 [Matzat, Leah H.; Lei, Elissa P.] Natl Inst Diabet & Digest & Kidney Dis, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Lei, EP (reprint author), 9000 Rockville Pike, Bethesda, MD 20892 USA. EM leielissa@niddk.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX We would like to thank S. Henikoff and V. Studitsky for discussion of the chromatin flexibility concept. We are also grateful to R. Dale, A. Dean, J. Kassis, and members of the Lei laboratory for comments on the manuscript This work was funded by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 152 TC 16 Z9 16 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 EI 0006-3002 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD MAR PY 2014 VL 1839 IS 3 SI SI BP 203 EP 214 DI 10.1016/j.bbagrm.2013.10.007 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AE3MX UT WOS:000333881700009 PM 24189492 ER PT J AU Isbrucker, R Arciniega, J McFarland, R Chapsal, JM Xing, D Bache, C Nelson, S Costanzo, A Hoonakker, M Castiaux, A Halder, M Casey, W Johnson, N Jones, B Doelling, V Sprankle, C Rinckel, L Stokes, W AF Isbrucker, Richard Arciniega, Juan McFarland, Richard Chapsal, Jean-Michel Xing, Dorothy Bache, Christina Nelson, Sue Costanzo, Angele Hoonakker, Marieke Castiaux, Amelie Halder, Marlies Casey, Warren Johnson, Nelson Jones, Brett Doelling, Vivian Sprankle, Cathy Rinckel, Lori Stokes, William TI Report on the international workshop on alternatives to the murine histamine sensitization test (HIST) for acellular pertussis vaccines: State of the science and the path forward SO BIOLOGICALS LA English DT Article DE Pertussis toxin; Acellular pertussis vaccines; Alternative methods; Safety; Biochemical assays; Cell-based assays ID TOXIN; ASSAY; STRATEGIES AB Regulatory authorities require safety and potency testing prior to the release of each production lot of acellular pertussis (aP)-containing vaccines. Currently, the murine histamine sensitization test (HIST) is used to evaluate the presence of residual pertussis toxin in aP containing vaccines. However, the testing requires the use of a significant number of mice and results in unrelieved pain and distress. NICEATM, ICCVAM, their partners in the International Cooperation on Alternative Test Methods, and the International Working Group for Alternatives to HIST organized a workshop to discuss recent developments in alternative assays to the HIST, review data from an international collaborative study on non-animal alternative tests that might replace the HIST, and address the path toward global acceptance of this type of method. Currently, there are three potential alternative methods to HIST. Participants agreed that no single in vitro method was sufficiently developed for harmonized validation studies at this time. It is unlikely that any single in vitro method would be applicable to all aP vaccines without modification, due to differences between vaccines. Workshop participants recommended further optimization of cell-based assays under development. Participants agreed that the next international collaborative studies should commence in 2013 based on discussions during this workshop. C1 [Isbrucker, Richard] Hlth Canada, Biol & Genet Therapies Directorate, Ottawa, ON K1A 0K9, Canada. [Arciniega, Juan; McFarland, Richard] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Chapsal, Jean-Michel] Sanofi Pasteur, Lyon, France. [Xing, Dorothy] Natl Inst Biol Stand & Controls, Div Bacteriol, S Mimms EN6 3QG, Herts, England. [Bache, Christina] Paul Ehrlich Inst, D-63225 Langen, Germany. [Nelson, Sue] Sanofi Pasteur, Toronto, ON, Canada. [Costanzo, Angele] European Directorate Qual Med & Healthcare, Strasbourg, France. [Hoonakker, Marieke] Netherlands Vaccine Inst, NL-3721 MA Bilthoven, Netherlands. [Castiaux, Amelie] GlaxoSmithKline, B-1330 Rixensart, Belgium. [Halder, Marlies] Inst Hlth & Consumer Protect, European Commiss Joint Res Ctr, European Union Reference Lab Alternat Anim Testin, I-21027 Ispra, Varese, Italy. [Casey, Warren; Stokes, William] Natl Inst Environm Hlth Sci, Natl Toxicol Program, Ctr Evaluat, Alternat Toxicol Methods Div,NIH, Res Triangle Pk, NC 27709 USA. [Johnson, Nelson; Jones, Brett; Doelling, Vivian; Sprankle, Cathy; Rinckel, Lori; Stokes, William] Integrated Lab Syst Inc, Morrisville, NC 27560 USA. RP Isbrucker, R (reprint author), Hlth Canada, Biol & Genet Therapies Directorate, 100 Eglantine Dr, Ottawa, ON K1A 0K9, Canada. EM richard.isbrucker@hc-sc.gc.ca FU NICEATM; ICCVAM; EURL ECVAM; JaCVAM; International Cooperation on Alternative Test Methods FX The authors extend their sincere appreciation to all participants in the international workshop for their contributions leading to the workshop conclusions and recommendations. The members of the HIST Workshop Organizing Committee, the International Working Group for Alternatives to HIST, ICCVAM Interagency Biologics Working Group, and NICEATM staff are acknowledged for their contributions to the planning of the workshop. All of the invited experts are acknowledged for their contributions to roundtable discussions and workshop proceedings. Participating national and international validation organizations from the International Cooperation on Alternative Test Methods, including NICEATM, ICCVAM, EURL ECVAM, and JaCVAM, are gratefully acknowledged for their scientific contributions and financial support. Finally, the authors gratefully acknowledge Dr. Raymond Tice and Dr. John Bucher from the National Institute of Environmental Health Sciences, National Institutes of Health, USA, for their review of the manuscript. NR 20 TC 0 Z9 0 U1 2 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1045-1056 EI 1095-8320 J9 BIOLOGICALS JI Biologicals PD MAR PY 2014 VL 42 IS 2 BP 114 EP 122 DI 10.1016/j.biologicals.2013.11.011 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA AG1UR UT WOS:000335202200008 PM 24394373 ER PT J AU Calderon, B Sacks, DB AF Calderon, Boris Sacks, David B. TI Islet Autoantibodies and Type 1 Diabetes: Does the Evidence Support Screening? SO CLINICAL CHEMISTRY LA English DT Editorial Material C1 [Calderon, Boris] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Sacks, David B.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. RP Calderon, B (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, 660 South Euclid Ave, St Louis, MO 63110 USA. EM calderon@wustl.edu; sacksdb@mail.nih.gov OI Calderon, Boris/0000-0003-1575-0739; Sacks, David/0000-0003-3100-0735 NR 5 TC 1 Z9 1 U1 0 U2 1 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD MAR PY 2014 VL 60 IS 3 BP 438 EP 440 DI 10.1373/clinchem.2013.212381 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA AG1AI UT WOS:000335146800003 PM 24363370 ER PT J AU Knutson, KM Dal Monte, O Raymont, V Wassermann, EM Krueger, F Grafman, J AF Knutson, Kristine M. Dal Monte, Olga Raymont, Vanessa Wassermann, Eric M. Krueger, Frank Grafman, Jordan TI Neural correlates of apathy revealed by lesion mapping in participants with traumatic brain injuries SO HUMAN BRAIN MAPPING LA English DT Article DE voxel-based lesion-symptom mapping; apathy; cingulate cortex; fatigue; traumatic brain injury; insula ID PENETRATING HEAD-INJURY; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; NEUROPSYCHIATRIC INVENTORY; ORBITOFRONTAL CORTEX; MULTIPLE-SCLEROSIS; COGNITIVE FATIGUE; FUNCTIONAL MRI; RATING-SCALE; DEPRESSION AB Apathy, common in neurological disorders, is defined as disinterest and loss of motivation, with a reduction in self-initiated activity. Research in diseased populations has shown that apathy is associated with variations in the volume of brain regions such as the anterior cingulate and the frontal lobes. The goal of this study was to determine the neural signatures of apathy in people with penetrating traumatic brain injuries (pTBIs), as to our knowledge, these have not been studied in this sample. We studied 176 male Vietnam War veterans with pTBIs using voxel-based lesion-symptom mapping (VLSM) and apathy scores from the UCLA Neuropsychiatric Inventory (NPI), a structured inventory of symptoms completed by a caregiver. Our results revealed that increased apathy symptoms were associated with brain damage in limbic and cortical areas of the left hemisphere including the anterior cingulate, inferior, middle, and superior frontal regions, insula, and supplementary motor area. Our results are consistent with the literature, and extend them to people with focal pTBI. Apathy is a significant symptom since it can reduce participation of the patient in family and other social interactions, and diminish affective decision-making. Hum Brain Mapp 35:943-953, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Knutson, Kristine M.; Dal Monte, Olga; Wassermann, Eric M.] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Dal Monte, Olga] Univ Turin, Dept Neuropsychol, Turin, Italy. [Dal Monte, Olga] Henry M Jackson Fdn, Rockville, MD USA. [Raymont, Vanessa] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England. [Raymont, Vanessa] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Krueger, Frank] George Mason Univ, Mol Neurosci Dept, Fairfax, VA 22030 USA. [Krueger, Frank] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Grafman, Jordan] Rehabil Inst Chicago, Brain Injury Res Program, Chicago, IL 60611 USA. RP Grafman, J (reprint author), Rehabil Inst Chicago, Brain Injury Res Program, 345 East Super St, Chicago, IL 60611 USA. EM fkrueger@gmu.edu; jgrafman@ric.org OI Grafman, Jordan H./0000-0001-8645-4457; dal monte, olga/0000-0002-7823-4769; Knutson, Kristine/0000-0003-4626-4514 FU U.S. National Institute of Neurological Disorders and Stroke; United States Army Medical Research and Material Command [DAMD17-01-1-0675] FX This work was supported by funding from the U.S. National Institute of Neurological Disorders and Stroke intramural research program and a project grant from the United States Army Medical Research and Material Command administered by the Henry M. Jackson Foundation (Vietnam Head Injury Study Phase III: a 30-year post-injury follow-up study, grant number DAMD17-01-1-0675). NR 75 TC 10 Z9 10 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD MAR PY 2014 VL 35 IS 3 BP 943 EP 953 DI 10.1002/hbm.22225 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AF0IW UT WOS:000334398500016 PM 23404730 ER PT J AU Konig, G Pickard, FC Mei, Y Brooks, BR AF Koenig, Gerhard Pickard, Frank C. Mei, Ye Brooks, Bernard R. TI Predicting hydration free energies with a hybrid QM/MM approach: an evaluation of implicit and explicit solvation models in SAMPL4 SO JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN LA English DT Article DE Hydration free energy calculations; Non-Boltzmann Bennett; Implicit solvent; Explicit solvent; QM/MM ID PARTIAL ATOMIC CHARGES; GENERAL FORCE-FIELD; BLIND PREDICTION; DENSITY FUNCTIONALS; BINDING AFFINITIES; AMINO-ACIDS; CHALLENGE; CHARMM; SIMULATIONS; CHEMISTRY AB The correct representation of solute-water interactions is essential for the accurate simulation of most biological phenomena. Several highly accurate quantum methods are available to deal with solvation by using both implicit and explicit solvents. So far, however, most evaluations of those methods were based on a single conformation, which neglects solute entropy. Here, we present the first test of a novel approach to determine hydration free energies that uses molecular mechanics (MM) to sample phase space and quantum mechanics (QM) to evaluate the potential energies. Free energies are determined by using re-weighting with the Non-Boltzmann Bennett (NBB) method. In this context, the method is referred to as QM-NBB. Based on snapshots from MM sampling and accounting for their correct Boltzmann weight, it is possible to obtain hydration free energies that incorporate the effect of solute entropy. We evaluate the performance of several QM implicit solvent models, as well as explicit solvent QM/MM for the blind subset of the SAMPL4 hydration free energy challenge. While classical free energy simulations with molecular dynamics give root mean square deviations (RMSD) of 2.8 and 2.3 kcal/mol, the hybrid approach yields an improved RMSD of 1.6 kcal/mol. By selecting an appropriate functional and basis set, the RMSD can be reduced to 1 kcal/mol for calculations based on a single conformation. Results for a selected set of challenging molecules imply that this RMSD can be further reduced by using NBB to reweight MM trajectories with the SMD implicit solvent model. C1 [Koenig, Gerhard; Pickard, Frank C.; Mei, Ye; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Rockville, MD 20852 USA. [Mei, Ye] E China Normal Univ, Inst Theoret & Computat Sci, State Key Lab Precis Spect, Shanghai 200062, Peoples R China. RP Konig, G (reprint author), NHLBI, Lab Computat Biol, NIH, 5635 Fishers Lane,T-900 Suite, Rockville, MD 20852 USA. EM gerhard.koenig@nih.gov RI MEI, Ye/C-5843-2009 OI MEI, Ye/0000-0002-3953-8508 FU National Heart, Lung and Blood Institute of the National Institutes of Health FX The authors would like to thank Tim Miller, Richard Venable and John Legato for technical assistance with the parallelization of the QM/MM calculations. The support by Yihan Shao was invaluable during the setup of the Q-Chem scripts and we also would like to thank Florentina Tofoleanu, Tim Miller and Juyong Lee for carefully reading and commenting on the manuscript as well as Stefan Boresch and Lee Woodcock for fruitful discussions on the optimal performance of NBB. This work was supported by the intramural research program of the National Heart, Lung and Blood Institute of the National Institutes of Health and utilized the high-performance computational capabilities of the LoBoS and Biowulf Linux clusters at the National Institutes of Health. (http://www.lobos.nih.gov and http://biowulf.nih.gov). NR 52 TC 25 Z9 25 U1 5 U2 35 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-654X EI 1573-4951 J9 J COMPUT AID MOL DES JI J. Comput.-Aided Mol. Des. PD MAR PY 2014 VL 28 IS 3 SI SI BP 245 EP 257 DI 10.1007/s10822-014-9708-4 PG 13 WC Biochemistry & Molecular Biology; Biophysics; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Computer Science GA AG2GA UT WOS:000335233100010 PM 24504703 ER PT J AU Taber, DR Pratt, C Charneco, EY Dowda, M Phillips, JA Going, SB AF Taber, Daniel R. Pratt, Charlotte Charneco, Eileen Y. Dowda, Marsha Phillips, Jennie A. Going, Scott B. TI Participation in Vigorous Sports, Not Moderate Sports, Is Positively Associated With Cardiorespiratory Fitness Among Adolescent Girls SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Article DE vigorous activity; moderate activity; intervention ID RANDOMIZED CONTROLLED-TRIAL; ALL-CAUSE MORTALITY; PHYSICAL-ACTIVITY; CANCER-MORTALITY; UNITED-STATES; MEN; YOUTH; HEALTH; CHILDREN; INTENSITIES AB Background: There is controversy regarding whether moderately-intense sports can improve physical fitness, which declines throughout adolescence among girls. The objective was to estimate the association between moderate and vigorous sports participation and cardiorespiratory fitness in a racially diverse sample of adolescent girls. Methods: Cardiorespiratory fitness was measured using a modified physical work capacity test in 1029 eighth-grade girls participating in the Trial of Activity for Adolescent Girls. Girls reported sports in which they participated in the last year on an organized activity questionnaire. Using general linear mixed models, the study regressed absolute and relative fitness on the number of vigorous and moderate sports in which girls participated, race/ethnicity, age, treatment group, fat mass, fat-free mass, and an interaction between race and fat-free mass. Results: The number of vigorous sports in which girls participated was positively associated with absolute fitness (beta = 10.20, P = .04) and relative fitness (beta = 0.17, P = .04). Associations were reduced, but not eliminated, after controlling for MET-weighted MVPA. Participation in moderate sports was not associated with either fitness measure. Conclusions: Vigorous sports participation is positively associated with cardiorespiratory fitness. Future longitudinal research should analyze whether promoting vigorous sports at an early age can prevent age-related declines in cardiorespiratory fitness among adolescent girls. C1 [Taber, Daniel R.] Univ Illinois, Inst Hlth Res & Policy, Chicago, IL 60607 USA. [Pratt, Charlotte] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Charneco, Eileen Y.] Univ Puerto Rico, Sch Publ Hlth, San Juan, PR 00936 USA. [Dowda, Marsha] Univ S Carolina, Dept Exercise Sci, Columbia, SC 29208 USA. [Phillips, Jennie A.] Univ Maryland, Dept Kinesiol, College Pk, MD 20742 USA. [Going, Scott B.] Univ Arizona, Dept Physiol, Tucson, AZ USA. RP Taber, DR (reprint author), Univ Illinois, Inst Hlth Res & Policy, Chicago, IL 60607 USA. FU NHLBI NIH HHS [U01HL066858, U01HL066852, U01 HL066853, U01 HL066857, U01HL066855, U01HL066856, U01HL066853, U01 HL066845, U01HL066845, U01 HL066856, U01 HL066858, U01 HL066852, U01 HL066855, U01HL066857] NR 44 TC 0 Z9 0 U1 0 U2 0 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1543-3080 EI 1543-5474 J9 J PHYS ACT HEALTH JI J. Phys. Act. Health PD MAR PY 2014 VL 11 IS 3 BP 596 EP 603 DI 10.1123/jpah.2011-0280 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AF8RQ UT WOS:000334983700019 PM 23493300 ER PT J AU Van Domelen, DR Caserotti, P Brychta, RJ Harris, TB Patel, KV Chen, KY Arnardottir, NY Eirikdottir, G Launer, LJ Gudnason, V Sveinsson, T Johannsson, E Koster, A AF Van Domelen, Dane R. Caserotti, Paolo Brychta, Robert J. Harris, Tamara B. Patel, Kushang V. Chen, Kong Y. Arnardottir, Nanna Yr Eirikdottir, Gudny Launer, Lenore J. Gudnason, Vilmundur Sveinsson, Thorarinn Johannsson, Erlingur Koster, Annemarie TI Is There a Sex Difference in Accelerometer Counts During Walking in Older Adults? SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Article DE physical activity; 6-minute walk test; accelerometry; AGES-Reykjavik Study ID INTENSITY PHYSICAL-ACTIVITY; ENERGY-EXPENDITURE; GENDER-DIFFERENCES; ACTIVITY MONITORS; UNITED-STATES; SPEED; BALANCE; GAIT; HIP; AGE AB Background: Accelerometers have emerged as a useful tool for measuring free-living physical activity in epidemiological studies. Validity of activity estimates depends on the assumption that measurements are equivalent for males and females while performing activities of the same intensity. The primary purpose of this study was to compare accelerometer count values in males and females undergoing a standardized 6-minute walk test. Methods: The study population was older adults (78.6 +/- 4.1 years) from the AGES-Reykjavik Study (N = 319). Participants performed a 6-minute walk test at a self-selected fast pace while wearing an ActiGraph GT3X at the hip. Vertical axis counts.s(-1) was the primary outcome. Covariates included walking speed, height, weight, BMI, waist circumference, femur length, and step length. Results: On average, males walked 7.2% faster than females (1.31 vs. 1.22 m.s(-1), P < .001) and had 32.3% greater vertical axis counts.s(-1) (54.6 vs. 39.4 counts.s(-1), P < .001). Accounting for walking speed reduced the sex difference to 19.2% and accounting for step length further reduced the difference to 13.4% (P < .001). Conclusion: Vertical axis counts.s(-1) were disproportionally greater in males even after adjustment for walking speed. This difference could confound free-living activity estimates. C1 [Van Domelen, Dane R.] Emory Univ, Dept Biostat & Bioinformat, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Caserotti, Paolo] Univ Southern Denmark, Inst Sports Sci & Clin Biomech, Odense, Denmark. [Brychta, Robert J.; Chen, Kong Y.] Natl Inst Diabet Digest & Kidney Dis, Diabet Endocrinol & Obes Branch, Bethesda, MD USA. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Patel, Kushang V.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Patel, Kushang V.] Univ Washington, Ctr Pain Res Impact Measurement & Effectiveness, Seattle, WA 98195 USA. [Arnardottir, Nanna Yr; Eirikdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Arnardottir, Nanna Yr] Univ Iceland, Res Ctr Movement Sci, Reykjavik, Iceland. [Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Johannsson, Erlingur] Univ Iceland, Res Ctr Sport & Hlth Sci, Sch Educ, Reykjavik, Iceland. [Koster, Annemarie] NIA, Dept Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Koster, Annemarie] Maastricht Univ, Sch Publ Hlth & Primary Care, Dept Social Med, Med Ctr, Maastricht, Netherlands. RP Van Domelen, DR (reprint author), Emory Univ, Dept Biostat & Bioinformat, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. RI Sveinsson, Thorarinn/F-7554-2010; Koster, Annemarie/E-7438-2010; Gudnason, Vilmundur/K-6885-2015; OI Sveinsson, Thorarinn/0000-0001-8989-5514; Gudnason, Vilmundur/0000-0001-5696-0084; Van Domelen, Dane/0000-0003-0051-7790; Chen, Kong/0000-0002-0306-1904 FU Intramural NIH HHS; NIA NIH HHS [N01AG12100, N01-AG12100] NR 37 TC 4 Z9 4 U1 1 U2 10 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1543-3080 EI 1543-5474 J9 J PHYS ACT HEALTH JI J. Phys. Act. Health PD MAR PY 2014 VL 11 IS 3 BP 626 EP 637 DI 10.1123/jpah.2012-0050 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AF8RQ UT WOS:000334983700022 PM 23417023 ER PT J AU Xing, J Petranka, JG Davis, FM Desai, PN Putney, JW Bird, GS AF Xing, Juan Petranka, John G. Davis, Felicity M. Desai, Pooja N. Putney, James W. Bird, Gary S. TI Role of Orai1 and store-operated calcium entry in mouse lacrimal gland signalling and function SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID ACINAR-CELLS; MOLECULAR-BASIS; T-LYMPHOCYTES; MICE LACKING; MAST-CELLS; CHANNELS; POTENTIATION; SECRETION; DEPLETION; MODEL AB Key points Lacrimal acinar cells from mice whose gene for Orai1 has been deleted have no detectable store-operated Ca2+ entry, whether assessed by measurement of cytoplasmic Ca2+ changes or as a store-operated current. Mice lacking Orai1 have diminished lacrimal fluid secretion in response to muscarinic-cholinergic stimulation. Mice lacking Orai1 also show diminished exocytosis, both in vivo and in vitro. The development and morphology of lacrimal glands, as well as responses not dependent on Ca2+ entry were unchanged in the knockout mice. The results demonstrate the central importance of store-operated Ca2+ entry in lacrimal exocrine function, and suggest possible strategies for combating diseases associated with diminished lacrimal secretion. AbstractLacrimal glands function to produce an aqueous layer, or tear film, that helps to nourish and protect the ocular surface. Lacrimal glands secrete proteins, electrolytes and water, and loss of gland function can result in tear film disorders such as dry eye syndrome, a widely encountered and debilitating disease in ageing populations. To combat these disorders, understanding the underlying molecular signalling processes that control lacrimal gland function will give insight into corrective therapeutic approaches. Previously, in single lacrimal cells isolated from lacrimal glands, we demonstrated that muscarinic receptor activation stimulates a phospholipase C-coupled signalling cascade involving the inositol trisphosphate-dependent mobilization of intracellular calcium and the subsequent activation of store-operated calcium entry (SOCE). Since intracellular calcium stores are finite and readily exhausted, the SOCE pathway is a critical process for sustaining and maintaining receptor-activated signalling. Recent studies have identified the Orai family proteins as critical components of the SOCE channel activity in a wide variety of cell types. In this study we characterize the role of Orai1 in the function of lacrimal glands using a mouse model in which the gene for the calcium entry channel protein, Orai1, has been deleted. Our data demonstrate that lacrimal acinar cells lacking Orai1 do not exhibit SOCE following activation of the muscarinic receptor. In comparison with wild-type and heterozygous littermates, Orai1 knockout mice showed a significant reduction in the stimulated tear production following injection of pilocarpine, a muscarinic receptor agonist. In addition, calcium-dependent, but not calcium-independent exocytotic secretion of peroxidase was eliminated in glands from knockout mice. These studies indicate a critical role for Orai1-mediated SOCE in lacrimal gland signalling and function. C1 [Xing, Juan; Petranka, John G.; Davis, Felicity M.; Desai, Pooja N.; Putney, James W.; Bird, Gary S.] NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, NIH Chief Calcium Regulat Sect, POB 12233,111 Alexander Dr F255, Res Triangle Pk, NC 27709 USA. EM putney@niehs.nih.gov RI Davis, Felicity/P-1387-2016 OI Davis, Felicity/0000-0001-9112-118X FU NIH, National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 30 TC 4 Z9 5 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAR 1 PY 2014 VL 592 IS 5 BP 927 EP 939 DI 10.1113/jphysiol.2013.267740 PG 13 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA AB8DU UT WOS:000332021100013 PM 24297846 ER PT J AU Wouldes, TA LaGasse, LL Huestis, MA DellaGrotta, S Dansereau, LM Lester, BM AF Wouldes, Trecia A. LaGasse, Linda L. Huestis, Marilyn A. DellaGrotta, Sheri Dansereau, Lynne M. Lester, Barry M. TI Prenatal methamphetamine exposure and neurodevelopmental outcomes in children from 1 to 3 years SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Prenatal exposure; Methamphetamine; Neurodevelopment; Longitudinal ID INFANT DEVELOPMENT; MOTOR DEVELOPMENT; AMPHETAMINE ADDICTION; 8-YEAR-OLD CHILDREN; RECREATIONAL DRUGS; SUBSTANCE USE; LIFE-STYLE; PREGNANCY; MOTHERS; DEFICITS AB Background: Despite the evidence that women world-wide are using methamphetamine (MA) during pregnancy little is known about the neurodevelopment of their children. Design: The controlled, prospective longitudinal New Zealand (NZ) Infant Development, Environment and Lifestyle (IDEAL) study was carried out in Auckland, NZ. Participants were 103 children exposed to MA prenatally and 107 who were not exposed. The Mental Developmental Index (MDI) and the Psychomotor Developmental Index (PDI) of the Bayley Scales of Infant Development, Second Edition (BSID-II) measured cognitive and motor performances at ages 1, 2 and 3, and the Peabody Developmental Motor Scale, Second Edition (PDMSII) measured gross and fine motor performances at I and 3. Measures of the child's environment included the Home Observation of Measurement of the Environment and the Maternal Lifestyle Interview. The Substance Use Inventory measured maternal drug use. Results: After controlling for other drug use and contextual factors, prenatal MA exposure was associated with poorer motor performance at 1 and 2 years on the BSID-II. No differences were observed for cognitive development (MDI). Relative to non-MA exposed children, longitudinal scores on the PDI and the gross motor scale of the PDMS-2 were 43 and 3.2 points lower, respectively. Being male and of Maori descent predicted lower cognitive scores (MDI) and being male predicted lower fine motor scores (PDMS-2). Conclusions: Prenatal exposure to MA was associated with delayed gross motor development over the first 3 years, but not with cognitive development. However, being male and of Maori descent were both associated with poorer cognitive outcomes. Males in general did more poorly on tasks related to fine motor development. (C) 2014 Elsevier Inc All rights reserved. C1 [Wouldes, Trecia A.] Univ Auckland, Fac Med & Hlth Sci, Dept Psychol Med, Auckland 1142, New Zealand. [LaGasse, Linda L.; DellaGrotta, Sheri; Dansereau, Lynne M.; Lester, Barry M.] Brown Univ, Warren Alpert Med Sch, Brown Ctr Study Children Risk, Providence, RI 02905 USA. [Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Wouldes, TA (reprint author), Univ Auckland, Fac Med & Hlth Sci, Dept Psychol Med, Private Bag 92019, Auckland 1142, New Zealand. EM twouldes@auckland.ac.nz; Linda_LaGasse@brown.edu; SDellaGrotta@Wihri.org; LDansereau@Wihri.org; Bany_Lester@brown.edu OI Wouldes, Trecia/0000-0002-6609-8464 FU NIH [2R01DA014948]; National Institutes on Drug Abuse [RO1DA021757]; Auckland Medical Research Foundation FX Funding and support: this work is part of the US and NZ Infant Development Environment and Lifestyle Study funded by NIH grants: National Institutes on Drug Abuse, 2R01DA014948 and RO1DA021757. The NZ IDEAL study had additional support from the Auckland Medical Research Foundation. None of the funders were involved in the design, collection, analysis or interpretation of the data, the writing of the report or the decision to submit this report.; NZ IDEAL study team: Jenny Rogers, BSc (Nursing), PGCert Child & Adolescent Mental Health, Josephine Cliffe, MPH, Suzanne Cumming, BSW, Heather Stewart, RN. NR 63 TC 5 Z9 5 U1 3 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 EI 1872-9738 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD MAR-APR PY 2014 VL 42 BP 77 EP 84 DI 10.1016/j.ntt.2014.02.004 PG 8 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA AG0HH UT WOS:000335096000010 PM 24566524 ER PT J AU Turkbey, B Mena, E Shih, J Pinto, PA Merino, MJ Lindenberg, ML Bernardo, M McKinney, YL Adler, S Owenius, R Choyke, PL Kurdziel, KA AF Turkbey, Baris Mena, Esther Shih, Joanna Pinto, Peter A. Merino, Maria J. Lindenberg, Maria L. Bernardo, Marcelino McKinney, Yolanda L. Adler, Stephen Owenius, Rikard Choyke, Peter L. Kurdziel, Karen A. TI Localized Prostate Cancer Detection with F-18 FACBC PET/CT: Comparison with MR Imaging and Histopathologic Analysis SO RADIOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; ANTI-1-AMINO-3-F-18-FLUOROCYCLOBUTANE-1-CARBOXYLIC ACID; C-11-ACETATE PET/CT; INITIAL-EXPERIENCE; CARCINOMA; DIAGNOSIS AB Purpose: To characterize uptake of 1-amino-3-fluorine 18-fluorocyclobutane-1-carboxylic acid (F-18 FACBC) in patients with localized prostate cancer, benign prostatic hyperplasia (BPH), and normal prostate tissue and to evaluate its potential utility in delineation of intraprostatic cancers in histopathologically confirmed localized prostate cancer in comparison with magnetic resonance (MR) imaging. Materials and Methods: Institutional review board approval and written informed consent were obtained for this HIPAA-compliant prospective study. Twenty-one men underwent dynamic and static abdominopelvic F-18 FACBC combined positron emission tomography (PET) and computed tomography (CT) and multiparametric (MP) 3-T endorectal MR imaging before robotic-assisted prostatectomy. PET/CT and MR images were coregistered by using pelvic bones as fiducial markers; this was followed by manual adjustments. Whole-mount histopathologic specimens were sliced with an MR-based patient-specific mold. F-18 FACBC PET standardized uptake values (SUVs) were compared with those at MR imaging and histopathologic analysis for lesion- and sector-based (20 sectors per patient) analysis. Positive and negative predictive values for each modality were estimated by using generalized estimating equations with logit link function and working independence correlation structure. Results: F-18 FACBC tumor uptake was rapid but reversible. It peaked 3.6 minutes after injection and reached a relative plateau at 15-20 minutes (SUVmax[15-20min]). Mean prostate tumor SUVmax(15-20min) was significantly higher than that of the normal prostate (4.5 +/- 0.5 vs 2.7 +/- 0.5) (P <.001); however, it was not significantly different from that of BPH (4.3 +/- 0.6) (P=.27). Sector-based comparison with histopathologic analysis, including all tumors, revealed sensitivity and specificity of 67% and 66%, respectively, for F-18 FACBC PET/CT and 73% and 79%, respectively, for T2-weighted MR imaging. F-18 FACBC PET/CT and MP MR imaging were used to localize dominant tumors (sensitivity of 90% for both). Combined 18F FACBC and MR imaging yielded positive predictive value of 82% for tumor localization, which was higher than that with either modality alone(P <.001). Conclusion: F-18 FACBC PET/CT shows higher uptake in intraprostatic tumor foci than in normal prostate tissue; however, F-18 FACBC uptake in tumors is similar to that in BPH nodules. Thus, it is not specific for prostate cancer. Nevertheless, combined F-18 FACBC PET/CT and T2-weighted MR imaging enable more accurate localization of prostate cancer lesions than either modality alone. (C) RSNA, 2013 C1 [Turkbey, Baris; Mena, Esther; Lindenberg, Maria L.; Bernardo, Marcelino; McKinney, Yolanda L.; Adler, Stephen; Choyke, Peter L.; Kurdziel, Karen A.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Shih, Joanna] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Turkbey, B (reprint author), NCI, Mol Imaging Program, NIH, 10 Ctr Dr,MSC 1182 Bldg 10,Room B3B85, Bethesda, MD 20892 USA. EM turkbeyi@mail.nih.gov FU National Institutes of Health [Z1A-BC-010655] FX This research was supported by the National Institutes of Health (grant no. Z1A-BC-010655). NR 25 TC 33 Z9 34 U1 0 U2 7 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD MAR PY 2014 VL 270 IS 3 BP 849 EP 856 DI 10.1148/radiol.13130240 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AG0WQ UT WOS:000335136800023 PM 24475804 ER PT J AU Catherino, WH Britten, J Levy, G Malik, M Patel, A AF Catherino, William H. Britten, Joy Levy, Gary Malik, Minnie Patel, Amrita TI Rapid Validation of Novel Medical Therapies for Fibroids: Use of Human 3-Dimensional in Vitro Fibroid Models to Test Liarozole Treatment SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Catherino, William H.; Britten, Joy; Levy, Gary; Malik, Minnie; Patel, Amrita] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Catherino, William H.; Levy, Gary] NICHHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 90A EP 90A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813001044 ER PT J AU Vahidi, N Weitzel, R Patounakis, G Tisdale, J Wolff, E AF Vahidi, Nima Weitzel, Richard Patounakis, George Tisdale, John Wolff, Erin TI Characterization of the Putative Surface Epitope of DDX4 in Rhesus Ovarian Cells SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Weitzel, Richard; Tisdale, John] NHLBI, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 103A EP 103A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813001082 ER PT J AU Fritz, R Kilburn, BA Bolnick, JM Bolnick, A Diamond, MP Armant, DR AF Fritz, Rani Kilburn, Brian A. Bolnick, Jay M. Bolnick, Alan Diamond, Michael P. Armant, D. Randall TI Single Nucleotide Polymorphism Analysis of Trophoblast Cells Isolated from the Endocervical Canal of Ongoing Pregnancies SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Fritz, Rani; Kilburn, Brian A.; Bolnick, Jay M.; Bolnick, Alan; Armant, D. Randall] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Diamond, Michael P.] Georgia Regents Univ, Dept Obstet & Gynecol, Augusta, GA USA. [Armant, D. Randall] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 109A EP 109A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813001097 ER PT J AU Zarek, SM Nelson, LM Segars, JH DeCherney, AH Young, NS Yunce, M Dumitriu, B Wolff, EF AF Zarek, Shvetha M. Nelson, Lawrence M. Segars, James H. DeCherney, Alan H. Young, Neal S. Yunce, Muharrem Dumitriu, Bogdan Wolff, Erin F. TI Telomere Lengths Are Reduced in Women with Primary Ovarian Insufficiency Due to Fragile X Premutation Compared to Age Matched Controls. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Zarek, Shvetha M.; Nelson, Lawrence M.; Segars, James H.; DeCherney, Alan H.; Wolff, Erin F.] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Young, Neal S.; Yunce, Muharrem; Dumitriu, Bogdan] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 114A EP 115A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813001113 ER PT J AU Wolff, EF Libfraind, LL Weitzel, RP Woods, D Feng, YL Tilly, J DeCherney, AH Tisdale, JF AF Wolff, Erin F. Libfraind, Lauren L. Weitzel, R. Patrick Woods, Dori Feng, Yanling Tilly, Jonathan DeCherney, Alan H. Tisdale, John F. TI Oogonial Stem Cells Generate Mature Oocytes in an Autologous Rhesus Macaque Transplantation Model SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Wolff, Erin F.; Libfraind, Lauren L.; Feng, Yanling; DeCherney, Alan H.] NICHD, PRAE, NIH, Bethesda, MD USA. [Wolff, Erin F.; Weitzel, R. Patrick; Tisdale, John F.] NHLBI, MCHB, NIH, Bethesda, MD 20892 USA. [Woods, Dori; Tilly, Jonathan] Northeastern Univ, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 119A EP 119A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813001125 ER PT J AU Furcron, AE StLouis, D Romero, R Hassan, S Gomez-Lopez, N AF Furcron, Amy-Eunice StLouis, Derek Romero, Roberto Hassan, Sonia Gomez-Lopez, Nardhy TI Prenatal Stress in the Second Generation: Evidence of Effects on the Duration of Pregnancy and Neonatal Weight SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Furcron, Amy-Eunice; StLouis, Derek; Hassan, Sonia; Gomez-Lopez, Nardhy] Wayne State Univ, Detroit, MI USA. [StLouis, Derek; Romero, Roberto; Hassan, Sonia; Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 121A EP 122A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813001132 ER PT J AU Arenas-Hernandez, M StLouis, D Romero, R Hassan, S Gomez-Lopez, N AF Arenas-Hernandez, Marcia StLouis, Derek Romero, Roberto Hassan, Sonia Gomez-Lopez, Nardhy TI Endotoxin Expands the Pool of Regulatory T Cells in Pregnancy but Not in the Non-Pregnant State SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Arenas-Hernandez, Marcia; StLouis, Derek; Hassan, Sonia; Gomez-Lopez, Nardhy] Wayne State Univ, Detroit, MI 48202 USA. [Arenas-Hernandez, Marcia; StLouis, Derek; Romero, Roberto; Hassan, Sonia; Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 130A EP 130A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813001157 ER PT J AU Clifton, RG AF Clifton, Rebecca G. TI Insulin Resistance and Gestational Weight Gain in Non-Diabetic Women. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Clifton, Rebecca G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 152A EP 152A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813001225 ER PT J AU Bolnick, JM Kilburn, BA Bolnick, AD Fritz, R Diamond, MP Armant, DR AF Bolnick, Jay M. Kilburn, Brian A. Bolnick, Alan D. Fritz, Rani Diamond, Michael P. Armant, D. Randall TI A Protein Panel for Early Gestation Detection of Adverse Pregnancy Outcomes after Non-Invasive Retrieval and Isolation of Trophoblast Cells in the Endocervical Canal SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Bolnick, Jay M.; Kilburn, Brian A.; Bolnick, Alan D.; Fritz, Rani; Armant, D. Randall] Wayne State Univ, Detroit, MI USA. [Diamond, Michael P.] Georgia Regents Univ, Augusta, GA USA. [Armant, D. Randall] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 187A EP 187A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813002011 ER PT J AU Bolnick, AD Bolnick, JM Kilburn, BA Stewart, T Dai, J Diamond, MP Dey, SK Armant, DR AF Bolnick, Alan D. Bolnick, Jay M. Kilburn, Brian A. Stewart, Tamika Dai, Jing Diamond, Michael P. Dey, Sudhansu K. Armant, D. Randall CA NICHD Natl Cooperative Reprod TI High Throughput Analysis of Homeobox Transcription Factor MSX1 in Human Endometrial Biopsies SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Bolnick, Alan D.; Bolnick, Jay M.; Kilburn, Brian A.; Stewart, Tamika; Dai, Jing; Armant, D. Randall] Wayne State Univ, Detroit, MI USA. [Diamond, Michael P.] Georgia Regents Univ, Augusta, GA USA. [Dey, Sudhansu K.] Cincinnati Childrens Hosp, Div Reprod Sci, Cincinnati, OH USA. [NICHD Natl Cooperative Reprod] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 227A EP 228A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813002134 ER PT J AU Cantarella, R StLouis, D Milovic, T Romero, R Gomez-Lopez, N AF Cantarella, Ryan StLouis, Derek Milovic, Tatjana Romero, Roberto Gomez-Lopez, Nardhy TI NKT Cell Activation Leads to Late Preterm Birth SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [StLouis, Derek; Milovic, Tatjana; Gomez-Lopez, Nardhy] Wayne State Univ, Detroit, MI USA. [Cantarella, Ryan; StLouis, Derek; Romero, Roberto; Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 230A EP 230A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813002140 ER PT J AU Moore, G Sangi-Haghpeykar, H Galan, H Lee, W Romero, R AF Moore, Gaea Sangi-Haghpeykar, Haley Galan, Henry Lee, Wesley Romero, Roberto TI Gender Differences in the Prediction of Neonatal Adiposity Based on 28-32w Sonographic Assessments of Fetal Soft Tissue SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Moore, Gaea; Galan, Henry] Univ Colorado, Sch Med, OB GYN, Aurora, CO USA. [Sangi-Haghpeykar, Haley; Lee, Wesley] Baylor Coll Med, OB GYN, Houston, TX 77030 USA. [Romero, Roberto] NICHD, Perinatal Res Branch, NIH, DHHS, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 279A EP 279A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813002286 ER PT J AU Jeyabalan, A AF Jeyabalan, Arun TI Do Differences in Arginase, Asymmetric Dimethylarginine and Nitric Oxide Precede the Development of Preeclampsia? SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Jeyabalan, Arun] NICHD MFMU Network, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 298A EP 298A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813003001 ER PT J AU Myatt, L AF Myatt, Leslie TI Placental Histology of Low Risk Nulliparous Women: Does Preeclampsia Make a Difference? SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Myatt, Leslie] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 306A EP 306A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813003028 ER PT J AU Langenheim, JF Fru, KN Hestermann, EV Yoo, JY Jeong, JW Yuan, LW Young, SL Lessey, BA AF Langenheim, John F. Fru, Karenne N. Hestermann, Eli V. Yoo, Jung Yoon Jeong, Jae Wook Yuan, Lingwen Young, Steven L. Lessey, Bruce A. TI AhR and ARNT Are Overexpressed in the Endometrium of Women with Endometriosis, but Regulated Differentially SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Langenheim, John F.; Lessey, Bruce A.] Greenville Hlth Syst, Dept Obstet & Gynecol, Greenville, SC USA. [Fru, Karenne N.] NICHD, PRAE SIOP, Bethesda, MD USA. [Hestermann, Eli V.] Furman Univ, Dept Biol, Greenville, SC USA. [Yoo, Jung Yoon; Jeong, Jae Wook] Michigan State Univ, Coll Human Med, Dept Obstet Gynecol & Reprod Biol, E Lansing, MI 48824 USA. [Yuan, Lingwen; Young, Steven L.] Univ N Carolina, Sch Med, Dept Obstet & Gynecol, Chapel Hill, NC 27515 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 310A EP 311A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813003042 ER PT J AU Royster, GD Bochner, RZ AF Royster, G. Donald Bochner, Ronnie Z. TI Greene Stirrups: A Novel Solution to a Global Problem SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Royster, G. Donald] NIH, Bethesda, MD 20892 USA. [Bochner, Ronnie Z.] Robert Wood Johnson OB GYN Associates PA, Dept Obstet & Gynecol, Kendall Pk, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 310A EP 310A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813003040 ER PT J AU Muneyyirci-Delale, O Charles, C Nacharaju, V Dalloul, M Stratton, P AF Muneyyirci-Delale, Ozgul Charles, Cassandra Nacharaju, Vijaya Dalloul, Mudar Stratton, Pamela TI Changes in Urinary N-Telopeptide Levels in Women with Endometriosis on Leuprolide vs Norethindrone Treatment SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Muneyyirci-Delale, Ozgul; Charles, Cassandra; Nacharaju, Vijaya; Dalloul, Mudar] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Muneyyirci-Delale, Ozgul] Kings Cty Hosp Ctr, Brooklyn, NY USA. [Stratton, Pamela] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 312A EP 312A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813003047 ER PT J AU Heitmann, RJ Weitzel, RP Feng, YL Segars, JH Tisdale, JF Wolff, EF AF Heitmann, Ryan J. Weitzel, R. Pat Feng, Yanling Segars, James H. Tisdale, John F. Wolff, Erin F. TI Uterine T-Regulatory Cell Depletion Decreases Implantation and Litter Sizes in a Murine Model SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Heitmann, Ryan J.; Feng, Yanling; Segars, James H.; Wolff, Erin F.] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Weitzel, R. Pat; Tisdale, John F.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 324A EP 324A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813003082 ER PT J AU Naik, A Rutledge, N Romero, R Hassan, S Gomez-Lopez, N AF Naik, Akshata Rutledge, Nakisha Romero, Roberto Hassan, Sonia Gomez-Lopez, Nardhy TI Vaginal Progesterone, but Not 17OHP-C, Induces Changes in Decidual Macrophages and Regulatory T Cells SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Naik, Akshata; Rutledge, Nakisha; Hassan, Sonia; Gomez-Lopez, Nardhy] Wayne State Univ, Detroit, MI USA. [Naik, Akshata; Romero, Roberto; Hassan, Sonia; Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 332A EP 332A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813003107 ER PT J AU Platt, KM Jarrell, AL de Cabo, R Pearson, KJ AF Platt, Kristen M. Jarrell, Alyssa L. de Cabo, Rafael Pearson, Kevin J. TI Maternal Exercise Decreases Tumor Incidence in Mouse Offspring SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Platt, Kristen M.; Jarrell, Alyssa L.; Pearson, Kevin J.] Univ Kentucky, Grad Ctr Nutr Sci, Lexington, KY USA. [de Cabo, Rafael] NIA, Translat Gerontol Branch, Intramural Res Program, Baltimore, MD 21224 USA. RI de Cabo, Rafael/J-5230-2016 OI de Cabo, Rafael/0000-0002-3354-2442 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 364A EP 364A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813003200 ER PT J AU Zarek, SM Dumitriu, B Townsley, DM DeCherney, AH Young, NS Wolff, EF AF Zarek, Shvetha M. Dumitriu, Bogdan Townsley, Danielle M. DeCherney, Alan H. Young, Neal S. Wolff, Erin F. TI Telomere Lengths Are Not Reduced in Women with Infertility Compared to Age Matched Controls SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Zarek, Shvetha M.; DeCherney, Alan H.; Wolff, Erin F.] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Dumitriu, Bogdan; Townsley, Danielle M.; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 417A EP 417A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813003355 ER PT J AU Petralia, RS Mattson, MP Yao, PJ AF Petralia, Ronald S. Mattson, Mark P. Yao, Pamela J. TI Communication breakdown: The impact of ageing on synapse structure SO AGEING RESEARCH REVIEWS LA English DT Review DE Synapse; Ageing; Postsynaptic density; Neurotransmitter vesicles; Presynaptic bouton; Dendritic spine ID LONG-TERM POTENTIATION; MONKEY PREFRONTAL-CORTEX; HIPPOCAMPAL AREA CA1; RAT MEDIAL NUCLEUS; INNER HAIR-CELLS; AGE-RELATED LOSS; DENTATE GYRUS; CALORIC RESTRICTION; NEUROMUSCULAR-JUNCTION; DENDRITIC SPINES AB Impaired synaptic plasticity is implicated in the functional decline of the nervous system associated with ageing. Understanding the structure of ageing synapses is essential to understanding the functions of these synapses and their role in the ageing nervous system. In this review, we summarize studies on ageing synapses in vertebrates and invertebrates, focusing on changes in morphology and ultrastructure. We cover different parts of the nervous system, including the brain, the retina, the cochlea, and the neuromuscular junction. The morphological characteristics of aged synapses could shed light on the underlying molecular changes and their functional consequences. Published by Elsevier B.V. C1 [Petralia, Ronald S.] NIDCD, Adv Imaging Core, NIH, Bethesda, MD 20892 USA. [Mattson, Mark P.; Yao, Pamela J.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Yao, PJ (reprint author), NIA, Neurosci Lab, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM petralia@nidcd.nih.gov; yaopa@grc.nia.nih.gov FU NIA/NIH; NIDCD/NIH FX This work was supported by the Intramural Research Programs of the NIA/NIH and NIDCD/NIH. NR 145 TC 13 Z9 13 U1 0 U2 17 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1568-1637 EI 1872-9649 J9 AGEING RES REV JI Ageing Res. Rev. PD MAR PY 2014 VL 14 BP 31 EP 42 DI 10.1016/j.arr.2014.01.003 PG 12 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA AG0LT UT WOS:000335107700003 PM 24495392 ER PT J AU Archambeault, DR Yao, HHC AF Archambeault, Denise R. Yao, Humphrey Hung-Chang TI Loss of Smad4 in Sertoli and Leydig Cells Leads to Testicular Dysgenesis and Hemorrhagic Tumor Formation in Mice SO BIOLOGY OF REPRODUCTION LA English DT Article DE azoospermia; hemorrhage; Leydig cell hyperplasia; mouse; Smad; teratoma; testicular dysgenesis; testis ID GONADAL DEVELOPMENT; SIGNALING PATHWAYS; SEXUAL DEVELOPMENT; SOMATIC-CELLS; ACTIVIN-A; BETA-B; TESTIS; MOUSE; DIFFERENTIATION; VASCULATURE AB As the central component of canonical TGFbeta superfamily signaling, SMAD4 is a critical regulator of organ development, patterning, tumorigenesis, and many other biological processes. Because numerous TGFbeta superfamily ligands are expressed in developing testes, there may exist specific requirements for SMAD4 in individual testicular cell types. Previously, we reported that expansion of the fetal testis cords requires expression of SMAD4 by the Sertoli cell lineage. To further uncover the role of Smad4 in murine testes, we produced conditional knockout mice lacking Smad4 in either Leydig cells or in both Sertoli and Leydig cells simultaneously. Loss of Smad4 concomitantly in Sertoli and Leydig cells led to underdevelopment of the testis cords during fetal life and mild testicular dysgenesis in young adulthood (decreased testis size, partially dysgenic seminiferous tubules, and low sperm production). When the Sertoli/Leydig cell Smad4 conditional knockout mice aged (56-to 62-wk old), the testis phenotypes became exacerbated with the appearance of hemorrhagic tumors, Leydig cell adenomas, and a complete loss of spermatogenesis. In contrast, loss of Smad4 in Leydig cells alone did not appreciably alter fetal and adult testis development. Our findings support a cell type-specific requirement of Smad4 in testis development and suppression of testicular tumors. C1 [Archambeault, Denise R.; Yao, Humphrey Hung-Chang] Univ Illinois, Dept Comparat Biosci, Urbana, IL 61801 USA. [Yao, Humphrey Hung-Chang] NIEHS, Reprod Dev Biol Grp, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Yao, HHC (reprint author), NIEHS, NIH, 111 TW Alexander Dr,C4-10, Res Triangle Pk, NC 27709 USA. EM yaoh3@niehs.nih.gov RI Yao, Humphrey Hung-Chang/B-4795-2010 OI Yao, Humphrey Hung-Chang/0000-0003-2944-8469 FU National Institute of Health [HD046861]; NIEHS Intramural Research Fund [ES102965, T32 ES07326] FX Supported by National Institute of Health Grants HD046861 and NIEHS Intramural Research Fund ES102965 (to H.H.Y.) and T32 ES07326 (to D.R.A.). NR 44 TC 5 Z9 6 U1 0 U2 6 PU SOC STUDY REPRODUCTION PI MADISON PA 1691 MONROE ST,SUITE # 3, MADISON, WI 53711-2021 USA SN 0006-3363 EI 1529-7268 J9 BIOL REPROD JI Biol. Reprod. PD MAR PY 2014 VL 90 IS 3 AR 62 DI 10.1095/biolreprod.113.111393 PG 10 WC Reproductive Biology SC Reproductive Biology GA AE9SY UT WOS:000334351500012 PM 24501173 ER PT J AU Duncan, FE Padilla-Banks, E Bernhardt, ML Ord, TS Jefferson, WN Moss, SB Williams, CJ AF Duncan, Francesca E. Padilla-Banks, Elizabeth Bernhardt, Miranda L. Ord, Teri S. Jefferson, Wendy N. Moss, Stuart B. Williams, Carmen J. TI Transducin-Like Enhancer of Split-6 (TLE6) Is a Substrate of Protein Kinase A Activity During Mouse Oocyte Maturation SO BIOLOGY OF REPRODUCTION LA English DT Article DE AKAP; meiosis; oocyte maturation; phosphorylation; PKA; subcortical maternal complex ID DEVELOPMENT IN-VITRO; MEIOTIC ARREST; MAMMALIAN OOCYTES; CYCLIC-AMP; CAMP; PHOSPHORYLATION; INHIBITORS; GENE; EMBRYO; CELLS AB Fully grown oocytes in the ovary are arrested at prophase of meiosis I because of high levels of intraoocyte cAMP that maintain increased levels of cAMP-dependent protein kinase (PKA) activity. Following the luteinizing hormone surge at the time of ovulation, cAMP levels drop, resulting in a reduction in PKA activity that triggers meiotic resumption. Although much is known about the molecular mechanisms of how PKA activity fluctuations initiate the oocyte's reentry into meiosis, significantly less is known about the requirement for PKA activity in the oocyte after exit from the prophase I arrest. Here we show that although PKA activity decreases in the oocyte upon meiotic resumption, it increases throughout meiotic progression from the time of germinal vesicle breakdown (GVBD) until the metaphase II (MII) arrest. Blocking this meiotic maturation-associated increase in PKA activity using the pharmacological inhibitor H89 resulted in altered kinetics of GVBD, defects in chromatin and spindle dynamics, and decreased ability of oocytes to reach MII. These effects appear to be largely PKA specific because inhibitors targeting other kinases did not have the same outcomes. To determine potential proteins that may require PKA phosphorylation during meiosis, we separated oocyte protein extracts on an SDS-PAGE gel, extracted regions of the gel that had corresponding immune reactivity towards an anti-PKA substrate antibody, and performed mass spectrometry and microsequencing. Using this approach, we identified transducin-like enhancer of split-6 (TLE6)-a maternal effect gene that is part of the subcortical maternal complex-as a putative PKA substrate. TLE6 localized to the oocyte cortex throughout meiosis in a manner that is spatially and temporally consistent with the localization of critical PKA subunits. Moreover, we demonstrated that TLE6 becomes phosphorylated in a narrow window following meiotic resumption, and H89 treatment can completely block this phosphorylation when added prior to GVBD but not after. Taken together, these results highlight the importance of oocyte-intrinsic PKA in regulating meiotic progression after the prophase I arrest and offer new insights into downstream targets of its activity. C1 [Duncan, Francesca E.] Northwestern Univ, Feinberg Sch Med, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Duncan, Francesca E.; Ord, Teri S.; Moss, Stuart B.; Williams, Carmen J.] Univ Penn Hlth Syst, Ctr Res Reprod & Womens Hlth, Philadelphia, PA USA. [Padilla-Banks, Elizabeth; Bernhardt, Miranda L.; Jefferson, Wendy N.; Williams, Carmen J.] NIEHS, Reprod Med Grp, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Duncan, FE (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Obstet & Gynecol, 303 E Super St,Lurie 10-250, Chicago, IL 60611 USA. EM f-duncan@northwestern.edu OI Bernhardt, Miranda/0000-0001-5424-5685 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01ES102985]; NIH, National Institute of Child Health and Human Development [HD044740] FX Supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, grant number Z01ES102985, and NIH, National Institute of Child Health and Human Development, grant number HD044740 to C.J.W. and S.B.M. The authors declare no competing financial interests. NR 48 TC 2 Z9 2 U1 5 U2 8 PU SOC STUDY REPRODUCTION PI MADISON PA 1691 MONROE ST,SUITE # 3, MADISON, WI 53711-2021 USA SN 0006-3363 EI 1529-7268 J9 BIOL REPROD JI Biol. Reprod. PD MAR PY 2014 VL 90 IS 3 AR 63 DI 10.1095/biolreprod.113.112565 PG 12 WC Reproductive Biology SC Reproductive Biology GA AE9SY UT WOS:000334351500013 PM 24501176 ER PT J AU Nakajima, T Sano, K Sato, K Watanabe, R Harada, T Hanaoka, H Choyke, PL Kobayashi, H AF Nakajima, Takahito Sano, Kohei Sato, Kazuhide Watanabe, Rira Harada, Toshiko Hanaoka, Hirofumi Choyke, Peter L. Kobayashi, Hisataka TI Fluorescence-lifetime molecular imaging can detect invisible peritoneal ovarian tumors in bloody ascites SO CANCER SCIENCE LA English DT Article DE Fluorescence lifetime; fluorescence-guided surgery; hemorrhagic ascites; molecular imaging; ovarian cancer ID IN-VIVO; INDOCYANINE-GREEN; SERUM-ALBUMIN; HUMAN CANCER; MICROSCOPY; FLAP; SKIN; FLUOROPHORE; PROTEIN; GFP AB Blood contamination, such as bloody ascites or hemorrhages during surgery, is a potential hazard for clinical application of fluorescence imaging. In order to overcome this problem, we investigate if fluorescence-lifetime imaging helps to overcome this problem. Samples were prepared at concentrations ranging 0.3-2.4m and mixed with 0-10% of blood. Fluorescence intensities and lifetimes of samples were measured using a time-domain fluorescence imager. Ovarian cancer SHIN3 cells overexpressing the D-galactose receptor were injected into the peritoneal cavity 2.5weeks before the experiments. Galactosyl serum albumin-rhodamine green (GSA-RhodG), which bound to the D-galactose receptor and was internalized thereafter, was administered intraperitoneally to peritoneal ovarian cancer-bearing mice with various degrees of bloody ascites. In vitro study showed a linear correlation between fluorescence intensity and probe concentration (r(2)>0.99), whereas the fluorescence lifetime was consistent (range, 3.33 +/- 0.15-3.75 +/- 0.04ns). By adding 10% of blood to samples, fluorescence intensities decreased to <1%, while fluorescence lifetimes were consistent. Invivo fluorescence lifetime of GSA-RhodG stained tumors was longer than the autofluorescence lifetime (threshold, 2.87ns). Tumor lesions under hemorrhagic peritonitis were not depicted using fluorescence intensity imaging; however, fluorescence-lifetime imaging clearly detected tumor lesions by prolonged lifetimes. In conclusion, fluorescence-lifetime imaging with GSA-RhodG depicted ovarian cancer lesions, which were invisible in intensity images, in hemorrhagic ascites. C1 [Nakajima, Takahito; Sano, Kohei; Sato, Kazuhide; Watanabe, Rira; Harada, Toshiko; Hanaoka, Hirofumi; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, NIH, Bldg 10,Room B3B69,MSC 1088, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research NR 26 TC 3 Z9 3 U1 2 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1347-9032 EI 1349-7006 J9 CANCER SCI JI Cancer Sci. PD MAR PY 2014 VL 105 IS 3 BP 308 EP 314 DI 10.1111/cas.12343 PG 7 WC Oncology SC Oncology GA AE0QC UT WOS:000333670000009 PM 24479901 ER PT J AU Hessler, D Fisher, L Glasgow, RE Strycker, LA Dickinson, LM Arean, PA Masharani, U AF Hessler, Danielle Fisher, Lawrence Glasgow, Russell E. Strycker, Lisa A. Dickinson, L. Miriam Arean, Patricia A. Masharani, Umesh TI Reductions in Regimen Distress Are Associated With Improved Management and Glycemic Control Over Time SO DIABETES CARE LA English DT Article ID DIABETES DISTRESS; DEPRESSIVE SYMPTOMS; CLINICAL DEPRESSION; OLDER ADULTS; OUTCOMES; METAANALYSIS; ADHERENCE; STRESS; THERAPY; HUMANS AB OBJECTIVECross-sectional and longitudinal associations among regimen distress (RD), self-management, and glycemic control were undertaken to explore mechanisms of operation among these variables.RESEARCH DESIGN AND METHODSIn a behavioral randomized control trial (RCT) to reduce RD, 392 adults with type 2 diabetes were assessed for RD, diet, exercise, medication adherence, and HbA(1c) at baseline and at 4 and 12 months. Associations among RD, self-management, and HbA(1c) were examined in cross-sectional analyses at baseline, in prospective analyses using baseline values to predict change over time, and in time-varying analyses.RESULTSAt baseline, greater RD and poorer medication adherence were independently associated with higher HbA(1c) (P = 0.05 and P < 0.001, respectively), and greater RD was associated with poorer medication adherence (P = 0.03). No consistent pattern of significant prospective associations was found. Significant time-varying findings showed that decreases in RD were associated with improvements in medication adherence (P < 0.01), physical activity (P < 0.001), and HbA(1c) (P = 0.02) over time following intervention. Changes in self-management were not associated with changes in HbA(1c) over time.CONCLUSIONSIn the context of an RCT to reduce distress, RD, self-management, and HbA(1c) were interrelated in cross-sectional and time-varying analyses. Decreases in RD were associated with improvements in both self-management and HbA(1c) over 12 months. Findings point to the complex and likely multifaceted pathways of association among these key constructs, with results indicating significant linkages between RD and both self-management and glycemic control over time. C1 [Hessler, Danielle; Fisher, Lawrence; Arean, Patricia A.; Masharani, Umesh] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Strycker, Lisa A.] Oregon Res Inst, Eugene, OR 97403 USA. [Dickinson, L. Miriam] Univ Colorado, Aurora, CO USA. RP Hessler, D (reprint author), Univ Calif San Francisco, San Francisco, CA 94143 USA. EM hesslerd@fcm.ucsf.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [DK-061937] FX This research was funded by National Institute of Diabetes and Digestive and Kidney Diseases grant DK-061937. NR 38 TC 18 Z9 20 U1 1 U2 7 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 MAR PY 2014 VL 37 IS 3 BP 617 EP 624 DI 10.2337/dc13-0762 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB3RT UT WOS:000331708600014 PM 24170750 ER PT J AU Sarkar, G Alattar, M Brown, RJ Quon, MJ Harlan, DM Rother, KI AF Sarkar, Gayatri Alattar, May Brown, Rebecca J. Quon, Michael J. Harlan, David M. Rother, Kristina I. TI Exenatide Treatment for 6 Months Improves Insulin Sensitivity in Adults With Type 1 Diabetes SO DIABETES CARE LA English DT Article ID RESISTANCE; GLUCOSE; CELL AB OBJECTIVEExenatide treatment improves glycemia in adults with type 2 diabetes and has been shown to reduce postprandial hyperglycemia in adolescents with type 1 diabetes. We studied the effects of exenatide on glucose homeostasis in adults with long-standing type 1 diabetes.RESEARCH DESIGN AND METHODSFourteen patients with type 1 diabetes participated in a crossover study of 6 months' duration on exenatide (10 g four times a day) and 6 months off exenatide. We assessed changes in fasting and postprandial blood glucose and changes in insulin sensitivity before and after each study period.RESULTSHigh-dose exenatide therapy reduced postprandial blood glucose but was associated with higher fasting glucose concentrations without net changes in hemoglobin A(1c). Exenatide increased insulin sensitivity beyond the effects expected as a result of weight reduction.CONCLUSIONSExenatide is a promising adjunctive agent to insulin therapy because of its beneficial effects on postprandial blood glucose and insulin sensitivity in patients with type 1 diabetes. C1 [Sarkar, Gayatri; Alattar, May; Brown, Rebecca J.; Rother, Kristina I.] Natl Inst Diabet & Digest & Kidney Dis, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD USA. [Quon, Michael J.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Harlan, David M.] Univ Massachusetts, Sch Med, Dept Internal Med, Diabet Div, Worcester, MA USA. [Harlan, David M.] UMass Mem Hlth Care, Worcester, MA USA. RP Rother, KI (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD USA. EM kristina.rother@nih.gov OI Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health Clinical Center FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institutes of Health Clinical Center. NR 14 TC 29 Z9 29 U1 0 U2 2 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 MAR PY 2014 VL 37 IS 3 BP 666 EP 670 DI 10.2337/dc13-1473 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB3RT UT WOS:000331708600020 PM 24194508 ER PT J AU Kim, C Cleary, PA Cowie, CC Braffett, BH Dunn, RL Larkin, ME Gatcomb, PM Wessells, HB Nathan, DM Sarma, AV AF Kim, Catherine Cleary, Patricia A. Cowie, Catherine C. Braffett, Barbara H. Dunn, Rodney L. Larkin, Mary E. Gatcomb, Patricia M. Wessells, Hunter B. Nathan, David M. Sarma, Aruna V. CA DCCT EDIC Res Grp TI Effect of Glycemic Treatment and Microvascular Complications on Menopause in Women With Type 1 Diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Cohort SO DIABETES CARE LA English DT Article ID PREMATURE OVARIAN FAILURE; ANTI-MULLERIAN HORMONE; INHIBIN B LEVELS; MELLITUS; TRIAL; EPIDEMIOLOGY; AUTOIMMUNITY; DYSFUNCTION; THERAPY; HISTORY AB OBJECTIVEWe examined the impact of intensive versus conventional diabetes treatment upon menopause among women with type 1 diabetes in the Diabetes Control and Complications Trial (DCCT), a randomized controlled trial of intensive diabetes treatment, and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) study.RESEARCH DESIGN AND METHODSIn a secondary analysis of women in the DCCT/EDIC (n = 657), outcomes were the cumulative incidences of natural menopause and surgical menopause. Cox regression analyses were used to examine associations with treatment group, time-varying estimates of hemoglobin A(1c) (HbA(1c)), insulin dosage, BMI, and microvascular complications (retinopathy, nephropathy, and neuropathy).RESULTSBy EDIC year 18, after an average of 28 years of follow-up, 240 (38%) women had experienced natural menopause and 115 (18%) women had experienced surgical menopause. Age at natural menopause was similar in the intensive versus conventional groups (49.9 vs. 49.0 years; P = 0.28), and age at surgical menopause was similar in the intensive versus conventional groups (40.8 vs. 42.0 years; P = 0.31). In multivariable models, treatment group, HbA(1c), and microvascular complications were not associated with risk of natural or surgical menopause. Each 10 unit/day increase in insulin dosage decreased risk of natural menopause (hazard ratio [HR] 0.91, 95% CI 0.75-0.98) and each kg/m(2) increase in BMI increased risk of surgical menopause (HR 1.08, 95% CI 1.00-1.16).CONCLUSIONSIn the DCCT/EDIC, intensive versus conventional treatment group and HbA(1c) level were not associated with menopause risk. Greater insulin dose was associated with lower menopause risk. C1 [Kim, Catherine] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Kim, Catherine] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Cleary, Patricia A.; Braffett, Barbara H.] George Washington Univ, Biostat Ctr, Rockville, MD USA. [Cowie, Catherine C.] Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA. [Dunn, Rodney L.; Sarma, Aruna V.] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. [Larkin, Mary E.; Nathan, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Diabet, Boston, MA USA. [Gatcomb, Patricia M.] Yale Univ, Dept Med, New Haven, CT 06520 USA. [Wessells, Hunter B.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. RP Kim, C (reprint author), Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. EM cathkim@umich.edu FU Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases [U01-DK-094176, U01-DK-094157]; National Eye Institute; National Institute of Neurological Disorders and Stroke; Genetic Clinical Research Centers Program; Clinical and Translational Science Center Program, Bethesda, MD; U01 Cooperative Agreement; [R01-DK-083297] FX The DCCT/EDIC has been supported by U01 Cooperative Agreement grants (1982-93, 2011-2016) and contracts (1982-2011) with the Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (current grant numbers U01-DK-094176 and U01-DK-094157) and through support by the National Eye Institute, the National Institute of Neurological Disorders and Stroke, the Genetic Clinical Research Centers Program (1993-2007), and the Clinical and Translational Science Center Program (2006-present), Bethesda, MD. Additional support for C. K. was provided by R01-DK-083297. NR 20 TC 8 Z9 8 U1 0 U2 1 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 MAR PY 2014 VL 37 IS 3 BP 701 EP 708 DI 10.2337/dc13-1746 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB3RT UT WOS:000331708600025 PM 24170751 ER PT J AU Kalyani, RR Lazo, M Ouyang, P Turkbey, E Chevalier, K Brancati, F Becker, D Vaidya, D AF Kalyani, Rita Rastogi Lazo, Mariana Ouyang, Pamela Turkbey, Evrim Chevalier, Karinne Brancati, Frederick Becker, Diane Vaidya, Dhananjay TI Sex Differences in Diabetes and Risk of Incident Coronary Artery Disease in Healthy Young and Middle-Aged Adults SO DIABETES CARE LA English DT Article ID PRIOR MYOCARDIAL-INFARCTION; AMERICAN-HEART-ASSOCIATION; CARDIOVASCULAR-DISEASE; GENDER DISPARITIES; PRIMARY PREVENTION; FOLLOW-UP; WOMEN; MEN; MORTALITY; IMPACT AB OBJECTIVEControversy exists about the coronary artery disease (CAD) risk conveyed by diabetes in young and middle-aged women. We investigated sex differences in CAD by diabetes status among healthy individuals with different underlying risks of heart disease.RESEARCH DESIGN AND METHODSWe examined subjects aged <60 years without CAD at enrollment in the high-risk GeneSTAR Study (n = 1,448; follow-up approximate to 12 years), Multi-Ethnic Study of Atherosclerosis (MESA; n = 3,072; follow-up approximate to 7 years), and National Health and Nutrition Examination Survey III (NHANES III) Mortality Follow-up Study (n = 6,997; follow-up approximate to 15 years). Diabetes was defined by report, hypoglycemic use, and/or fasting glucose 126 mg/dL. The outcome was any CAD event during follow-up (fatal CAD in NHANES).RESULTSIn the absence of diabetes, CAD rates were lower among women in GeneSTAR, MESA, and NHANES (4.27, 1.66, and 0.40/1,000 person-years, respectively) versus men (11.22, 5.64, and 0.88/1,000 person-years); log-rank P < 0.001 (GeneSTAR/MESA) and P = 0.07 (NHANES). In the presence of diabetes, CAD event rates were similar among women (17.65, 7.34, and 2.37/1,000 person-years) versus men (12.86, 9.71, and 1.83/1,000 person-years); all log-rank P values > 0.05. Adjusting for demographics, diabetes was associated with a significant four- to fivefold higher CAD rate among women in each cohort, without differences in men. In meta-analyses of three cohorts, additionally adjusted for BMI, smoking, hypertension, HDL, and non-HDL cholesterol, antihypertensive and cholesterol-lowering medication use, the hazard ratio of CAD in men versus women among nondiabetes was 2.43 (1.76-3.35) and diabetes was 0.89 (0.43-1.83); P = 0.013 interaction by diabetes status.CONCLUSIONSThough young and middle-aged women are less likely to develop CAD in the absence of diabetes, the presence of diabetes equalizes the risk by sex. Our findings support aggressive CAD prevention strategies in women with diabetes and at similar levels to those that exist in men. C1 [Kalyani, Rita Rastogi] Johns Hopkins Univ, Div Endocrinol, Baltimore, MD 21218 USA. [Lazo, Mariana; Chevalier, Karinne; Brancati, Frederick; Becker, Diane; Vaidya, Dhananjay] Johns Hopkins Univ, Div Gen Internal Med, Baltimore, MD USA. [Ouyang, Pamela] Johns Hopkins Bayview Med Ctr, Div Cardiol, Baltimore, MD USA. [Turkbey, Evrim] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Kalyani, RR (reprint author), Johns Hopkins Univ, Div Endocrinol, Baltimore, MD 21218 USA. EM rrastogi@jhmi.edu OI Vaidya, Dhananjay/0000-0002-7164-1601 FU National Institute of Diabetes and Digestive and Kidney Diseases [K23-DK-093583, K24-DK-062222, P60-DK-079637]; National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; National Center for Research Resources [UL1-RR-024156, UL1-RR-025005]; [U01-HL-72518-05]; [R01-HL-071025]; [R18-HL-58625]; [R01-NR-08153]; [R01-HL-49762]; [R01-HL-59684]; [R01-NR-02241]; [M01-RR-00052] FX This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (grants K23-DK-093583, K24-DK-062222, and P60-DK-079637). The GeneSTAR study was supported through various grants (U01-HL-72518-05, R01-HL-071025, R18-HL-58625, R01-NR-08153, R01-HL-49762, R01-HL-59684, R01-NR-02241, and M01-RR-00052). The MESA study was supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute and grants UL1-RR-024156 and UL1-RR-025005 from the National Center for Research Resources. NR 36 TC 33 Z9 33 U1 2 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 MAR PY 2014 VL 37 IS 3 BP 830 EP 838 DI 10.2337/dc13-1755 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB3RT UT WOS:000331708600041 PM 24178997 ER PT J AU Brinton, LA Cook, MB McCormack, V Johnson, KC Olsson, H Casagrande, JT Cooke, R Falk, RT Gapstur, SM Gaudet, MM Gaziano, JM Gkiokas, G Guenel, P Henderson, BE Hollenbeck, A Hsing, AW Kolonel, LN Isaacs, C Lubin, JH Michels, KB Negri, E Parisi, D Petridou, ET Pike, MC Riboli, E Sesso, HD Snyder, K Swerdlow, AJ Trichopoulos, D Ursin, G van den Brandt, PA Van Den Eeden, SK Weiderpass, E Willett, WC Ewertz, M Thomas, DB AF Brinton, Louise A. Cook, Michael B. McCormack, Valerie Johnson, Kenneth C. Olsson, Hakan Casagrande, John T. Cooke, Rosie Falk, Roni T. Gapstur, Susan M. Gaudet, Mia M. Gaziano, J. Michael Gkiokas, Georgios Guenel, Pascal Henderson, Brian E. Hollenbeck, Albert Hsing, Ann W. Kolonel, Laurence N. Isaacs, Claudine Lubin, Jay H. Michels, Karin B. Negri, Eva Parisi, Dominick Petridou, Eleni Th. Pike, Malcolm C. Riboli, Elio Sesso, Howard D. Snyder, Kirk Swerdlow, Anthony J. Trichopoulos, Dimitrios Ursin, Giske van den Brandt, Piet A. Van Den Eeden, Stephen K. Weiderpass, Elisabete Willett, Walter C. Ewertz, Marianne Thomas, David B. CA European Rare Canc Study Grp TI Anthropometric and Hormonal Risk Factors for Male Breast Cancer: Male Breast Cancer Pooling Project Results SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID BASE-LINE CHARACTERISTICS; KLINEFELTER-SYNDROME; PROSTATE-CANCER; MEN; COHORT; EPIDEMIOLOGY; NUTRITION; HEALTH; TESTOSTERONE; MORTALITY AB The etiology of male breast cancer is poorly understood, partly because of its relative rarity. Although genetic factors are involved, less is known regarding the role of anthropometric and hormonally related risk factors. In the Male Breast Cancer Pooling Project, a consortium of 11 casecontrol and 10 cohort investigations involving 2405 case patients (n 1190 from casecontrol and n 1215 from cohort studies) and 52013 control subjects, individual participant data were harmonized and pooled. Unconditional logistic regression generated study designspecific (casecontrol/cohort) odds ratios (ORs) and 95% confidence intervals (CIs), with exposure estimates combined using fixed effects meta-analysis. All statistical tests were two-sided. Risk was statistically significantly associated with weight (highest/lowest tertile: OR 1.36; 95% CI 1.18 to 1.57), height (OR 1.18; 95% CI 1.01 to 1.38), and body mass index (BMI; OR 1.30; 95% CI 1.12 to 1.51), with evidence that recent rather than distant BMI was the strongest predictor. Klinefelter syndrome (OR 24.7; 95% CI 8.94 to 68.4) and gynecomastia (OR 9.78; 95% CI 7.52 to 12.7) were also statistically significantly associated with risk, relations that were independent of BMI. Diabetes also emerged as an independent risk factor (OR 1.19; 95% CI 1.04 to 1.37). There were also suggestive relations with cryptorchidism (OR 2.18; 95% CI 0.96 to 4.94) and orchitis (OR 1.43; 95% CI 1.02 to 1.99). Although age at onset of puberty and histories of infertility were unrelated to risk, never having had children was statistically significantly related (OR 1.29; 95% CI 1.01 to 1.66). Among individuals diagnosed at older ages, a history of fractures was statistically significantly related (OR 1.41; 95% CI 1.07 to 1.86). Consistent findings across casecontrol and cohort investigations, complemented by pooled analyses, indicated important roles for anthropometric and hormonal risk factors in the etiology of male breast cancer. Further investigation should focus on potential roles of endogenous hormones. C1 [Brinton, Louise A.; Cook, Michael B.; Falk, Roni T.; Lubin, Jay H.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [McCormack, Valerie] Int Agcy Res Canc, Sect Environm & Radiat, F-69372 Lyon, France. [Johnson, Kenneth C.] Univ Ottawa, Dept Epidemiol & Community Med, Ottawa, ON, Canada. [Olsson, Hakan] Lund Univ, Dept Oncol, Lund, Sweden. [Casagrande, John T.; Henderson, Brian E.; Pike, Malcolm C.; Ursin, Giske] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Cooke, Rosie; Swerdlow, Anthony J.] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Gapstur, Susan M.; Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Michels, Karin B.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Sesso, Howard D.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Sesso, Howard D.] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Gaziano, J. Michael] VA Boston Healthcare Syst, MAVERIC, Boston, MA USA. [Gkiokas, Georgios] Aretaie Univ Hosp, Dept Surg, Athens, Greece. [Guenel, Pascal] Univ Paris Sud, INSERM, Ctr Res Epidemiol & Populat Hlth, U1018, Villejuif, France. [Hollenbeck, Albert] AARP, AARP Res, Washington, DC USA. [Hsing, Ann W.] Canc Prevent Inst Calif, Fremont, CA USA. [Hsing, Ann W.] Stanford Univ, Div Epidemiol, Dept Hlth Res & Policy, Palo Alto, CA 94304 USA. [Hsing, Ann W.] Stanford Univ, Stanford Canc Inst, Stanford Sch Med, Stanford, CA USA. [Kolonel, Laurence N.] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Isaacs, Claudine] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Michels, Karin B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Michels, Karin B.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Negri, Eva; Trichopoulos, Dimitrios] Ist Richerche Farmacol, Milan, Italy. [Parisi, Dominick; Snyder, Kirk] IMS Inc, Rockville, MD USA. [Petridou, Eleni Th.] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Sesso, Howard D.] Inst Canc Res, Div Prevent Med, London SW3 6JB, England. [Sesso, Howard D.] Inst Canc Res, Div Aging, London SW3 6JB, England. [Swerdlow, Anthony J.] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England. [Ursin, Giske; Weiderpass, Elisabete] Canc Registry Norway, Oslo, Norway. [Ursin, Giske] Univ Oslo, Inst Basic Med Sci, Dept Nutr, Oslo, Norway. [van den Brandt, Piet A.] Maastricht Univ, Dept Epidemiol, Maastricht, Netherlands. [Van Den Eeden, Stephen K.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Weiderpass, Elisabete] Arct Univ Norway, Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, Elisabete] Samfundet Folkhalsan, Helsinki, Finland. [Ewertz, Marianne] Univ Southern Denmark, Inst Clin Res, Odense Univ Hosp, Dept Oncol, Odense, Denmark. [Thomas, David B.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. RP Brinton, LA (reprint author), NCI, NIH, Hormonal & Reprod Epidemiol Branch, 9609 Med Ctr Dr,Rm 7-E102,MSC 9774, Bethesda, MD 20892 USA. EM brinton@nih.gov RI Brinton, Louise/G-7486-2015; Cook, Michael/A-5641-2009; Weiderpass, Elisabete/M-4029-2016 OI Brinton, Louise/0000-0003-3853-8562; Cook, Michael/0000-0002-0533-7302; Weiderpass, Elisabete/0000-0003-2237-0128 FU European Research Council [ERC-2011-294576]; National Institutes of Health, Bethesda, Maryland; Institute of Cancer Research acknowledges National Health Service; Deutsche Krebshilfe; Deutsches Krebsforschungszentrum; Federal Ministry of Education and Research Germany; Swedish Cancer Society; Swedish Scientific Council; Regional Government of Skane and Vasterbotten; Cancer Research UK; UK Medical Research Council; Danish Cancer Society; Italian Association for Research on Cancer; National Research Council Italy; HuGeF Foundation, Torino, Italy; ISCIII RT ICC Red Tematica de Investigacion Cooperativa en Cancer, Spain [R06/0020]; Hellenic Health Foundation; Stavros Niarchos Foundation; Hellenic Ministry of Health and Social Solidarity FX This research was funded in part by intramural funds from the National Institutes of Health, Bethesda, Maryland. The Swedish Case-Control Study acknowledges the support of the European Research Council Advanced Grant ERC-2011-294576. The Institute of Cancer Research acknowledges National Health Service funding to the National Institute for Health Research Biomedical Research Centre. The principle investigators and funders corresponding to each of the EPIC centers that contributed cases were Heiner Boeing, Rudolph Kaaks (Germany); Goran Hallmans, Jonas Manjer (Sweden); Timothy Key, Nick Wareham (UK); Kim Overvad, Anne Tjonneland (Denmark); Domenico Palli, Paolo Vineis, Rosario Tumino (Italy); Maria Jose Sanchez (Spain); Antonia Trichopoulou (Greece); from the Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and the Federal Ministry of Education and Research Germany; the Swedish Cancer Society, Swedish Scientific Council and the Regional Government of Skane and Vasterbotten; Cancer Research UK and the UK Medical Research Council; Danish Cancer Society; Italian Association for Research on Cancer, National Research Council Italy, and HuGeF Foundation, Torino, Italy; ISCIII RT ICC Red Tematica de Investigacion Cooperativa en Cancer (R06/0020) Spain; Hellenic Health Foundation, the Stavros Niarchos Foundation and the Hellenic Ministry of Health and Social Solidarity. NR 53 TC 28 Z9 28 U1 1 U2 14 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD MAR PY 2014 VL 106 IS 3 AR djt465 DI 10.1093/jnci/djt465 PG 11 WC Oncology SC Oncology GA AF4NY UT WOS:000334691200012 PM 24552677 ER PT J AU Kristal, AR Darke, AK Morris, JS Tangen, CM Goodman, PJ Thompson, IM Meyskens, FL Goodman, GE Minasian, LM Parnes, HL Lippman, SM Klein, EA AF Kristal, Alan R. Darke, Amy K. Morris, J. Steven Tangen, Catherine M. Goodman, Phyllis J. Thompson, Ian M. Meyskens, Frank L., Jr. Goodman, Gary E. Minasian, Lori M. Parnes, Howard L. Lippman, Scott M. Klein, Eric A. TI Baseline Selenium Status and Effects of Selenium and Vitamin E Supplementation on Prostate Cancer Risk SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID PREVENTION TRIAL SELECT; RANDOMIZED CONTROLLED-TRIAL; BETA-CAROTENE; TOENAILS; MEN; CHEMOPREVENTION; CARCINOGENESIS; METAANALYSIS; HEALTH; BLOOD AB The Selenium and Vitamin E Cancer Prevention Trial found no effect of selenium supplementation on prostate cancer (PCa) risk but a 17% increased risk from vitamin E supplementation. This casecohort study investigates effects of selenium and vitamin E supplementation conditional upon baseline selenium status. There were 1739 total and 489 high-grade (Gleason 710) PCa cases and 3117 men in the randomly selected cohort. Proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for effects of supplementation within quintiles of baseline toenail selenium. Cox proportional hazards models were used to estimate hazard ratios, and all statistical tests are two-sided. Toenail selenium, in the absence of supplementation, was not associated with PCa risk. Selenium supplementation (combined selenium only and selenium vitamin E arms) had no effect among men with low selenium status (< 60th percentile of toenail selenium) but increased the risk of high-grade PCa among men with higher selenium status by 91% (P .007). Vitamin E supplementation (alone) had no effect among men with high selenium status (40th percentile of toenail selenium) but increased the risks of total, low-grade, and high-grade PCa among men with lower selenium status (63%, P .02; 46%, P .09; 111%, P .008, respectively). Selenium supplementation did not benefit men with low selenium status but increased the risk of high-grade PCa among men with high selenium status. Vitamin E increased the risk of PCa among men with low selenium status. Men should avoid selenium or vitamin E supplementation at doses that exceed recommended dietary intakes. C1 [Kristal, Alan R.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98122 USA. [Darke, Amy K.; Tangen, Catherine M.; Goodman, Phyllis J.] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, Seattle, WA 98122 USA. [Kristal, Alan R.; Goodman, Gary E.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Goodman, Gary E.] Univ Washington, Dept Environm Hlth, Seattle, WA 98195 USA. [Morris, J. Steven] Univ Missouri, Res Reactor Ctr, Columbia, MO USA. [Morris, J. Steven] Harry S Truman Mem Vet Hosp, Columbia, MO 65201 USA. [Thompson, Ian M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. [Meyskens, Frank L., Jr.] Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Irvine, CA USA. [Minasian, Lori M.; Parnes, Howard L.] NCI, NIH, Canc Prevent Div, Bethesda, MD 20892 USA. [Lippman, Scott M.] Univ Calif San Diego, Moores Canc Ctr, San Diego, CA 92103 USA. [Klein, Eric A.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. RP Kristal, AR (reprint author), Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1100 Fairview Ave N,M4-B402, Seattle, WA 98122 USA. EM akristal@fhcrc.org OI Kristal, Alan/0000-0002-7329-1617 FU Public Health Service - National Cancer Institute, Division of Cancer Prevention, National Institutes of Health, Department of Health and Human Services [U10 CA037429]; National Center for Complementary and Alternative Medicine (National Institutes of Health) FX This work was supported in part by Public Health Service Cooperative Agreement grant U10 CA037429 awarded by the National Cancer Institute, Division of Cancer Prevention, National Institutes of Health, Department of Health and Human Services, and by the National Center for Complementary and Alternative Medicine (National Institutes of Health). Study agents and packaging were provided by Sabinsa Corporation (Piscataway, NJ), Tishcon Corporation (Westbury, NY), and DSM Nutritional Products Inc (Parsipanny, NJ). Optional study multivitamins were provided by Perrigo Company (Allegan, MI). NR 32 TC 34 Z9 36 U1 2 U2 20 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD MAR PY 2014 VL 106 IS 3 AR djt456 DI 10.1093/jnci/djt456 PG 8 WC Oncology SC Oncology GA AF4NY UT WOS:000334691200003 PM 24563519 ER PT J AU Bechor, M Pettit, JW Silverman, WK Bar-Haim, Y Abend, R Pine, DS Vasey, MW Jaccard, J AF Bechor, Michele Pettit, Jeremy W. Silverman, Wendy K. Bar-Haim, Yair Abend, Rany Pine, Daniel S. Vasey, Michael W. Jaccard, James TI Attention Bias Modification Treatment for children with anxiety disorders who do not respond to cognitive behavioral therapy: a case series SO JOURNAL OF ANXIETY DISORDERS LA English DT Article DE Anxiety; Children; Attention; Treatment; Attention bias ID RANDOMIZED CLINICAL-TRIAL; SELECTIVE ATTENTION; ANXIOUS CHILDREN; SOCIAL PHOBIA; ANGRY FACES; ADOLESCENTS; DEPRESSION; INDIVIDUALS; RELIABILITY; VALIDITY AB Evidence is emerging to support the promise of Attention Bias Modification Treatment (ABMT), a computer-based attention training program, in reducing anxiety in children. ABMT has not been tested as an adjuvant for children with anxiety disorders who do not respond to Cognitive-Behavioral Therapy (CBT). This case series presents findings from an open trial of ABMT among six children (four girls; M age = 11.2 years) who completed a CBT protocol and continued to meet diagnostic criteria for an anxiety disorder. All children completed the ABMT protocol with no canceled or missed sessions. Child self-ratings on anxiety symptoms and depressive symptoms significantly decreased from pretreatment to posttreatment, as did parent ratings on child anxiety-related impairment. Parent ratings on child anxiety and internalizing symptoms displayed non-significant decreases from pretreatment to posttreatment. These findings support the potential promise of ABMT as a feasible adjuvant treatment that reduces anxiety and impairment among child anxiety CBT nonresponders. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Bechor, Michele; Pettit, Jeremy W.; Silverman, Wendy K.] Florida Int Univ, Dept Psychol, Miami, FL 33199 USA. [Bar-Haim, Yair; Abend, Rany] Tel Aviv Univ, Dept Psychol, Adler Ctr Res Child Dev & Psychopathol, IL-69978 Tel Aviv, Israel. [Pine, Daniel S.] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. [Vasey, Michael W.] Ohio State Univ, Dept Psychol, Columbus, OH 43210 USA. [Jaccard, James] NYU, Silver Sch Social Work, New York, NY USA. RP Pettit, JW (reprint author), Florida Int Univ, Dept Psychol, Miami, FL 33199 USA. EM jpettit@fiu.edu FU NIMH NIH HHS [MH079943, MH097931, R01 MH079943, R34 MH097931] NR 43 TC 9 Z9 9 U1 7 U2 27 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-6185 EI 1873-7897 J9 J ANXIETY DISORD JI J. Anxiety Disord. PD MAR PY 2014 VL 28 IS 2 BP 154 EP 159 DI 10.1016/j.janxdis.2013.09.001 PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AF2RI UT WOS:000334559300006 PM 24211147 ER PT J AU Borges, S Chen, YF Laughren, TP Temple, R Patel, HD David, PA Mathis, M Unger, E Yang, PL Khin, NA AF Borges, Silvana Chen, Yeh-Fong Laughren, Thomas P. Temple, Robert Patel, Hiren D. David, Paul A. Mathis, Mitchell Unger, Ellis Yang, Peiling Khin, Ni A. TI Review of Maintenance Trials for Major Depressive Disorder: A 25-Year Perspective From the US Food and Drug Administration SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Review ID RELAPSE PREVENTION; RESIDUAL SYMPTOMS; METAANALYSIS; ANTIDEPRESSANTS; RECURRENCE; REMISSION; RECOVERY AB Objective: The maintenance efficacy of antidepressants is usually assessed in postmarketing studies with a randomized withdrawal design. This report explores differences in relapse rates, trial characteristics, and success rates in maintenance efficacy studies submitted to the US Food and Drug Administration (FDA) over a 25-year period. Data Sources: Clinical data from all maintenance trials with antidepressants submitted to FDA between 1987 and 2012. Study Selection: Efficacy data were compiled from 15 maintenance clinical trials in adults diagnosed with major depressive disorder according to DSM-III or DSM-IV criteria. Data Extraction: Trial characteristics, relapse rates, and time to relapse in each study were examined. Results: Relapse rates were significantly lower (P <.05) in the drug arm than in the placebo arm in every study, with a mean relapse rate difference of 18% and an average percent reduction in relapse rate of 52% compared to placebo. Only 6% of the relapse events occurred in the first 2 weeks of the doubleblind phase. The separation between treatment arms continued to increase throughout the double-blind phase only in the trial with longest response stabilization period. Conclusions: Antidepressant maintenance trials have a high rate of success, indicating a benefit of continuing drug treatment after initial response to an antidepressant. This benefit appears to result mainly from a decreased rate of recurrent depression rather than from an effect of drug withdrawal in the placebo groups. C1 [Borges, Silvana; Patel, Hiren D.; David, Paul A.; Mathis, Mitchell] Food & Drug Adm 1, Div Psychiat Prod, Off New Drugs, Silver Spring, MD 20993 USA. [Temple, Robert] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Laughren, Thomas P.] Massachusetts Gen Hosp, Clin Trials Network & Inst, Boston, MA USA. [Laughren, Thomas P.] NIMH, Bethesda, MD 20892 USA. RP Borges, S (reprint author), Food & Drug Adm, Div Psychiat Prod, 10903 New Hampshire Ave,Bldg 22,Rm 4159, Silver Spring, MD 20993 USA. EM silvana.borges@fda.hhs.gov NR 24 TC 17 Z9 17 U1 4 U2 11 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD MAR PY 2014 VL 75 IS 3 BP 205 EP 214 DI 10.4088/JCP.13r08722 PG 10 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AF0RP UT WOS:000334422000005 PM 24717376 ER PT J AU Yang, Z Wu, PL Weng, XC Bandettini, PA AF Yang, Zhi Wu, Paula Weng, Xuchu Bandettini, Peter A. TI Cerebellum engages in automation of verb-generation skill SO JOURNAL OF INTEGRATIVE NEUROSCIENCE LA English DT Article DE Cerebellum; functional MRI; verb generation; skill learning ID POSITRON-EMISSION-TOMOGRAPHY; COGNITIVE-AFFECTIVE SYNDROME; WORKING-MEMORY; FUNCTIONAL TOPOGRAPHY; PREFRONTAL CORTEX; BASAL GANGLIA; ACTIVATION; ANATOMY; MOTOR; INVOLVEMENT AB Numerous studies have shown cerebellar involvement in item-specific association, a form of explicit learning. However, very few have demonstrated cerebellar participation in automation of non-motor cognitive tasks. Applying fMRI to a repeated verb-generation task, we sought to distinguish cerebellar involvement in learning of item-specific noun-verb association and automation of verb generation skill. The same set of nouns was repeated in six verb-generation blocks so that subjects practiced generating verbs for the nouns. The practice was followed by a novel block with a different set of nouns. The cerebellar vermis (IV/ V) and the right cerebellar lobule VI showed decreased activation following practice; activation in the right cerebellar Crus I was significantly lower in the novel challenge than in the initial verb-generation task. Furthermore, activation in this region during well-practiced blocks strongly correlated with improvement of behavioral performance in both the well-practiced and the novel blocks, suggesting its role in the learning of general mental skills not specific to the practiced noun-verb pairs. Therefore, the cerebellum processes both explicit verbal associative learning and automation of cognitive tasks. Different cerebellar regions predominate in this processing: lobule VI during the acquisition of item-specific association, and Crus I during automation of verb-generation skills through practice. C1 [Yang, Zhi] Chinese Acad Sci, Inst Psychol, Key Lab Behav Sci, Beijing 100101, Peoples R China. [Yang, Zhi; Wu, Paula; Bandettini, Peter A.] NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Weng, Xuchu] Hangzhou Normal Univ, Ctr Cognit & Brain Disorders, Hangzhou 310015, Zhejiang, Peoples R China. RP Yang, Z (reprint author), Chinese Acad Sci, Inst Psychol, Key Lab Behav Sci, 16 Lincui Rd, Beijing 100101, Peoples R China. EM yangz@psych.ac.cn OI Yang, Zhi/0000-0002-2222-2312 FU National Key Technologies R&D Program of China [2012BAI36B01]; Natural Science Foundation of China [81270023]; National Institute of Mental Health; National Institutes of Health FX This work was supported by National Key Technologies R&D Program of China (No. 2012BAI36B01) and Natural Science Foundation of China (81270023). ZY, PW and PAB are supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. NR 56 TC 0 Z9 1 U1 0 U2 8 PU IMPERIAL COLLEGE PRESS PI LONDON PA 57 SHELTON ST, COVENT GARDEN, LONDON WC2H 9HE, ENGLAND SN 0219-6352 EI 1757-448X J9 J INTEGR NEUROSCI JI J. Integr. Neurosci. PD MAR PY 2014 VL 13 IS 1 BP 1 EP 17 DI 10.1142/S0219635214500010 PG 17 WC Neurosciences SC Neurosciences & Neurology GA AF4OE UT WOS:000334692000001 PM 24738536 ER PT J AU Kathawala, RJ Sodani, K Chen, K Patel, A Abuznait, AH Anreddy, N Sun, YL Kaddoumi, A Ashby, CR Chen, ZS AF Kathawala, Rishil J. Sodani, Kamlesh Chen, Kang Patel, Atish Abuznait, Alaa H. Anreddy, Nagaraju Sun, Yue-Li Kaddoumi, Amal Ashby, Charles R., Jr. Chen, Zhe-Sheng TI Masitinib Antagonizes ATP-Binding Cassette Subfamily C Member 10-Mediated Paclitaxel Resistance: A Preclinical Study SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID GASTROINTESTINAL STROMAL TUMORS; REVERSES MULTIDRUG-RESISTANCE; TYROSINE KINASE INHIBITOR; CANCER-CELLS; IN-VIVO; DRUG-RESISTANCE; EFFLUX ACTIVITY; ABCC10 MRP7; B MEMBER-1; IMATINIB AB Paclitaxel displays clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multidrug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. In this study, we show that masitinib, a small molecule stem-cell growth factor receptor (cKit) tyrosine kinase inhibitor, at nontoxic concentrations, significantly attenuates paclitaxel resistance in HEK293 cells transfected with ABCC10. Our in vitro studies indicated that masitinib (2.5 mu mol/L) enhanced the intracellular accumulation and decreased the efflux of paclitaxel by inhibiting the ABCC10 transport activity without altering the expression level of ABCC10 protein. Furthermore, masitinib, in combination with paclitaxel, significantly inhibited the growth of ABCC10-expressing tumors in nude athymic mice in vivo. Masitinib administration also resulted in a significant increase in the levels of paclitaxel in the plasma, tumors, and lungs compared with paclitaxel alone. In conclusion, the combination of paclitaxel and masitinib could serve as a novel and useful therapeutic strategy to reverse paclitaxel resistance mediated by ABCC10. (C)2014 AACR. C1 [Kathawala, Rishil J.; Sodani, Kamlesh; Patel, Atish; Anreddy, Nagaraju; Sun, Yue-Li; Ashby, Charles R., Jr.; Chen, Zhe-Sheng] St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Jamaica, NY 11439 USA. [Chen, Kang] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Chen, Kang] Barbara Ann Karmanos Canc Inst, Tumor & Microenvironm Program, Detroit, MI USA. [Chen, Kang] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Bethesda, MD USA. [Chen, Kang] NIAID, Mucosal Immunol Studies Team, NIH, Bethesda, MD 20892 USA. [Abuznait, Alaa H.; Kaddoumi, Amal] Univ Louisiana, Coll Pharm, Dept Basic Pharmaceut Sci, Monroe, LA USA. RP Chen, ZS (reprint author), St Johns Univ, Dept Pharmaceut Sci, Queens, NY 11439 USA. EM ashbyc@stjohns.edu; chenz@stjohns.edu RI Patel, Atish/J-4699-2014 OI Anreddy, Nagaraju/0000-0001-8914-8404; Patel, Atish/0000-0002-5549-9166 FU NCI NIH HHS [1R15CA143701, R15 CA143701] NR 37 TC 12 Z9 13 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD MAR PY 2014 VL 13 IS 3 BP 714 EP 723 DI 10.1158/1535-7163.MCT-13-0743 PG 10 WC Oncology SC Oncology GA AE9HU UT WOS:000334318300015 PM 24431074 ER PT J AU Tuccillo, FM Palmieri, C Fiume, G de Laurentiis, A Schiavone, M Falcone, C Iaccino, E Galandrini, R Capuano, C Santoni, A D'Armiento, FP Arra, C Barbieri, A Dal Piaz, F Venzon, D Bonelli, P Buonaguro, FM Scala, I Mallardo, M Quinto, I Scala, G AF Tuccillo, Franca Maria Palmieri, Camillo Fiume, Giuseppe de Laurentiis, Annamaria Schiavone, Marco Falcone, Cristina Iaccino, Enrico Galandrini, Ricciarda Capuano, Cristina Santoni, Angela D'Armiento, Francesco Paolo Arra, Claudio Barbieri, Antonio Dal Piaz, Fabrizio Venzon, David Bonelli, Patrizia Buonaguro, Franco Maria Scala, Iris Mallardo, Massimo Quinto, Ileana Scala, Giuseppe TI Cancer-Associated CD43 Glycoforms as Target of Immunotherapy SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID KAPPA-B-ALPHA; MONOCLONAL-ANTIBODIES; FUNCTIONAL-CHARACTERIZATION; THYMIC ANTIGEN; PEPTIDE; PHAGE; MIMOTOPES; CELLS; VACCINATION; EXPRESSION AB CD43 is a sialoglycosylated membrane protein that is involved in cell proliferation and differentiation. CD43 glycoforms that are recognized by the UN1 monoclonal antibody (mAb) were expressed in lymphoblastoid T-cell lines and solid tumors, such as breast, colon, gastric, and squamous cell lung carcinomas, while unexpressed in the normal counterparts. The cancer association of UN1/CD43 epitope suggested the possibility to use the UN1 mAb for tumor diagnosis and therapy. In this study, we show that the UN1 mAb was endowed with antitumor activity in vivo because its passive transfer inhibited the growth of UN1-positive HPB-ALL lymphoblastoid T cells in mice. Furthermore, we demonstrate that tumor inhibition was due to UN1 mAb-dependent natural killer-mediated cytotoxicity. By screening a phage-displayed random peptide library, we identified the phagotope 2/165 as a mimotope of the UN1 antigen, as it harbored a peptide sequence that was specifically recognized by the UN1mAb and inhibited the binding of the UN1mAb to UN1-positive tumor cells. On the basis of sequence homology with the extracellular region of CD43 (amino acids 64 to 83), the 2/165 peptide sequence was likely mimicking the protein core of the UN1/CD43 epitope. When used as vaccine in mice, the 2/165 phagotope raised antibodies against the UN1/CD43 antigen, indicating that the 2/165 phagotope mimicked the UN1 antigen structure, and could represent a novel immunogen for cancer immunotherapy. These findings support the feasibility of using monoclonal antibodies to identify cancer associated mimotopes for immunotherapy. (C)2013 AACR. C1 [Tuccillo, Franca Maria; Bonelli, Patrizia; Buonaguro, Franco Maria] Fdn G Pascale IRCCS, Ist Nazl Studio & Cura Tumori, Lab Mol Biol & Viral Oncogenesis, Naples, Italy. [Arra, Claudio; Barbieri, Antonio] Fdn G Pascale IRCCS, Ist Nazl Studio & Cura Tumori, Anim Facil, Naples, Italy. [D'Armiento, Francesco Paolo] Univ Naples Federico II, Dept Adv Biomed Sci, Naples, Italy. [Scala, Iris] Univ Naples Federico II, Dept Pediat, Naples, Italy. [Mallardo, Massimo] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, Naples, Italy. [Palmieri, Camillo; Fiume, Giuseppe; de Laurentiis, Annamaria; Schiavone, Marco; Falcone, Cristina; Iaccino, Enrico; Quinto, Ileana; Scala, Giuseppe] Magna Graecia Univ Catanzaro, Dept Expt & Clin Med, Catanzaro, Italy. [Galandrini, Ricciarda; Capuano, Cristina] Univ Roma La Sapienza, Dept Expt Med, Rome, Italy. [Santoni, Angela] Univ Roma La Sapienza, Fdn Cenci Bolognetti, Ist Pasteur, Dept Mol Med, Rome, Italy. [Dal Piaz, Fabrizio] Univ Salerno, Dept Pharm, I-84100 Salerno, Italy. [Venzon, David] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. RP Tuccillo, FM (reprint author), IRCCS, Ist Nazl Studio & Cura Tumori Fdn G Pascale, Lab Mol Biol & Viral Oncogenesis, Via Mariano Semmola, I-80131 Naples, Italy. EM f.tuccillo@istitutotumori.na.it; quinto@unicz.it RI Buonaguro, Franco/A-1964-2008; Iaccino, Enrico/I-7333-2015; santoni, angela/K-8997-2016; Palmieri, Camillo/A-3195-2009; OI Buonaguro, Franco/0000-0002-7491-7220; Iaccino, Enrico/0000-0002-3565-7817; santoni, angela/0000-0003-1206-7731; Palmieri, Camillo/0000-0001-6707-4723; D'ARMIENTO, Francesco Paolo/0000-0002-1391-6451; CAPUANO, Cristina/0000-0002-6747-3836; Barbieri, Antonio/0000-0002-7788-6167; FIUME, Giuseppe/0000-0002-5414-6190; Arra, Claudio/0000-0003-3162-2091 FU Intramural NIH HHS [Z99 CA999999] NR 50 TC 7 Z9 7 U1 1 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD MAR PY 2014 VL 13 IS 3 BP 752 EP 762 DI 10.1158/1535-7163.MCT-13-0651 PG 11 WC Oncology SC Oncology GA AE9HU UT WOS:000334318300019 PM 24356816 ER PT J AU Smith, MA AF Smith, Malcolm A. TI Sorafenib Inhibits ABCG2 and Overcomes Irinotecan Resistance-Letter SO MOLECULAR CANCER THERAPEUTICS LA English DT Letter ID CANCER C1 NCI, Bethesda, MD 20892 USA. RP Smith, MA (reprint author), NCI, 9609 Med Ctr Dr,Room 5-W414,MSC 9737, Bethesda, MD 20892 USA. EM Malcolm.Smith@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 3 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 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD MAR PY 2014 VL 13 IS 3 BP 763 EP 763 DI 10.1158/1535-7163.MCT-13-0968 PG 1 WC Oncology SC Oncology GA AE9HU UT WOS:000334318300020 PM 24615774 ER PT J AU Oelstrom, K Goldschen-Ohm, MP Holmgren, M Chanda, B AF Oelstrom, Kevin Goldschen-Ohm, Marcel P. Holmgren, Miguel Chanda, Baron TI Evolutionarily conserved intracellular gate of voltage-dependent sodium channels SO NATURE COMMUNICATIONS LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; CRYSTAL-STRUCTURE; K+ CHANNEL; NA+-CHANNEL; BK CHANNELS; PORE; DOMAIN; INACTIVATION; ACTIVATION; RESIDUES AB Members of the voltage-gated ion channel superfamily (VGIC) regulate ion flux and generate electrical signals in excitable cells by opening and closing pore gates. The location of the gate in voltage-gated sodium channels, a founding member of this superfamily, remains unresolved. Here we explore the chemical modification rates of introduced cysteines along the S6 helix of domain IV in an inactivation-removed background. We find that state-dependent accessibility is demarcated by an S6 hydrophobic residue; substituted cysteines above this site are not modified by charged thiol reagents when the channel is closed. These accessibilities are consistent with those inferred from open-and closed-state structures of prokaryotic sodium channels. Our findings suggest that an intracellular gate composed of a ring of hydrophobic residues is not only responsible for regulating access to the pore of sodium channels, but is also a conserved feature within canonical members of the VGIC superfamily. C1 [Oelstrom, Kevin; Goldschen-Ohm, Marcel P.; Chanda, Baron] Univ Wisconsin, Dept Neurosci, Madison, WI 53706 USA. [Oelstrom, Kevin] Univ Wisconsin, Mol Pharmacol Grad Program, Madison, WI 53706 USA. [Holmgren, Miguel] NINDS, Mol Neurophysiol Sect, NIH, Bethesda, MD 20892 USA. RP Chanda, B (reprint author), Univ Wisconsin, Dept Neurosci, Madison, WI 53706 USA. EM chanda@wisc.edu OI Chanda, Baron/0000-0003-4954-7034 FU NIH [GM084140]; Shaw Scientist Award; American Heart Association [12POST9440021]; Translational Cardiovascular predoctoral training grant [T32-HL07936]; Molecular and Cellular Pharmacology training grant [T32GM008668]; National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke FX This project was supported by Research grants from NIH GM084140 and Shaw Scientist Award to B. C., the American Heart Association (Midwest Affiliate) Postdoctoral fellowship (12POST9440021) to M.P.G.-O. and Translational Cardiovascular predoctoral training grant (T32-HL07936) and Molecular and Cellular Pharmacology training grant (T32GM008668) to K.O. M. H. was supported by the intramural section of the National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke. We thank Dorothy Hanck (University of Chicago) and John Kyle (UW-Madison) for their generous gift of the sodium channel cysteine mutants S1578C-L1591C as well as Sandipan Chowdhury and Dr Brian Jarecki for useful discussions. NR 37 TC 12 Z9 12 U1 0 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2014 VL 5 AR 3420 DI 10.1038/ncomms4420 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AE9CA UT WOS:000334300400003 PM 24619022 ER PT J AU Cohn, A Hagman, BT Moore, K Mitchell, J Ehlke, S AF Cohn, Amy Hagman, Brett T. Moore, Kathleen Mitchell, Jessica Ehlke, Sarah TI Does Negative Affect Mediate the Relationship Between Daily PTSD Symptoms and Daily Alcohol Involvement in Female Rape Victims? Evidence From 14 Days of Interactive Voice Response Assessment SO PSYCHOLOGY OF ADDICTIVE BEHAVIORS LA English DT Article DE rape; alcohol; interactive voice response; daily diary; PTSD; negative affect ID POSTTRAUMATIC-STRESS-DISORDER; ECOLOGICAL MOMENTARY ASSESSMENT; SEXUAL ASSAULT SURVIVORS; SELF-MEDICATION HYPOTHESIS; TRAUMA-EXPOSED ADULTS; SUBSTANCE USE; PSYCHOMETRIC PROPERTIES; TREATED ALCOHOLICS; COLLEGE-STUDENTS; MOOD DISORDERS AB The negative reinforcement model of addiction posits that individuals may use alcohol to reduce negative affective (NA) distress. The current study investigated the mediating effect of daily NA on the relationship between daily PTSD symptoms and same-day and next-day alcohol involvement (consumption and desire to drink) in a sample of 54 non-treatment-seeking female rape victims who completed 14 days of interactive voice response assessment. The moderating effect of lifetime alcohol use disorder diagnosis (AUD) on daily relationships was also examined. Multilevel models suggested that NA mediated the relationship between PTSD and same-day, but not next-day alcohol involvement. NA was greater on days characterized by more severe PTSD symptoms, and alcohol consumption and desire to drink were greater on days characterized by higher NA. Furthermore, daily PTSD symptoms and NA were more strongly associated with same-day (but not next-day) alcohol consumption and desire to drink for women with an AUD than without. Results suggest that NA plays an important role in female rape victims' daily alcohol use. Differences between women with and without an AUD indicate the need for treatment matching to subtypes of female rape victims. C1 [Cohn, Amy; Moore, Kathleen; Mitchell, Jessica] Univ S Florida, Dept Mental Hlth Law & Policy, Tampa, FL 33620 USA. [Hagman, Brett T.] Natl Inst Alcohol Abuse & Alcoholism, Bethesda, MD USA. [Ehlke, Sarah] Univ N Carolina, Dept Psychol, Wilmington, NC USA. RP Cohn, A (reprint author), Amer Legacy Fdn, Schroeder Inst Tobacco Res & Policy Studies, 1724 Massachusetts Ave NW, Washington, DC 20036 USA. EM acohn@legacyforhealth.org FU NIDA NIH HHS [P30 DA028807, P30DA028807] NR 102 TC 6 Z9 6 U1 11 U2 19 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0893-164X EI 1939-1501 J9 PSYCHOL ADDICT BEHAV JI Psychol. Addict. Behav. PD MAR PY 2014 VL 28 IS 1 BP 114 EP 126 DI 10.1037/a0035725 PG 13 WC Substance Abuse; Psychology, Multidisciplinary SC Substance Abuse; Psychology GA AF4OR UT WOS:000334693600013 PM 24731112 ER PT J AU Robinson, CD Pickworth, WB Heishman, SJ Waters, AJ AF Robinson, Cendrine D. Pickworth, Wallace B. Heishman, Stephen J. Waters, Andrew J. TI The Acute Tobacco Withdrawal Syndrome Among Black Smokers SO PSYCHOLOGY OF ADDICTIVE BEHAVIORS LA English DT Article DE tobacco; race; menthol; health disparities; withdrawal ID FAGERSTROM TOLERANCE QUESTIONNAIRE; NICOTINE REPLACEMENT THERAPY; SMOKING-CESSATION TRIALS; CIGARETTE SMOKERS; WHITE SMOKERS; RACIAL/ETHNIC DISPARITIES; MENTHOLATED CIGARETTES; ETHNIC DISPARITIES; AFRICAN-AMERICAN; NATIONAL-HEALTH AB Black smokers have greater difficulty quitting tobacco than White smokers, but the mechanisms underlying between-race differences in smoking cessation are not clear. One possibility is that Black smokers experience greater acute withdrawal than Whites. We investigated whether Black (n = 104) and White smokers (n = 99) differed in abstinence-induced changes in self-report, physiological, and cognitive performance measures. Smokers not wishing to quit completed two counterbalanced experimental sessions. Before one session, they abstained from smoking for at least 12 hr. They smoked normally before the other session. Black smokers reported smaller abstinence-induced changes on a number of subjective measures including the total score of the 10-item Questionnaire for Smoking Urges (QSU) and the total score of the Wisconsin Smoking Withdrawal Scale (WSWS). However, on most subjective measures, and on all objective measures, there were no between-race differences in abstinence-induced change scores. Moreover, Black participants did not report lower QSU and WSWS ratings at the abstinent session, but they did experience significantly higher QSU and WSWS ratings at the nonabstinent session. Abstinence-induced changes in subjective, physiological, and cognitive measures in White smokers were similar for smokers of nonflavored and menthol-flavored cigarettes. There was no evidence that Black smokers experienced greater acute tobacco withdrawal than Whites. To the contrary, Black participants experienced smaller abstinence-induced changes in self-reported craving and withdrawal on some measures. Racial differences in smoking cessation are unlikely to be explained by acute withdrawal. C1 [Robinson, Cendrine D.; Waters, Andrew J.] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Pickworth, Wallace B.] Battelle Ctr Publ Hlth Res & Evaluat, Baltimore, MD USA. [Heishman, Stephen J.] NIDA, Nicotine Psychopharmacol Sect, Intramural Res Program, Baltimore, MD USA. RP Robinson, CD (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM crobinson@usuhs.edu FU Intramural NIH HHS NR 60 TC 5 Z9 5 U1 5 U2 8 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0893-164X EI 1939-1501 J9 PSYCHOL ADDICT BEHAV JI Psychol. Addict. Behav. PD MAR PY 2014 VL 28 IS 1 BP 173 EP 181 DI 10.1037/a0031950 PG 9 WC Substance Abuse; Psychology, Multidisciplinary SC Substance Abuse; Psychology GA AF4OR UT WOS:000334693600019 PM 23528199 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI Carl Woese's vision of cellular evolution and the domains of life SO RNA BIOLOGY LA English DT Review DE evolutionary transitions; domains of life; cellular evolution; Darwinian threshold; progenote; horizontal gene transfer ID HORIZONTAL GENE-TRANSFER; BACTERIAL PAN-GENOME; PROTEIN EVOLUTION; MICROBIAL WORLD; UNIVERSAL TREE; SCALING LAWS; VIRUS WORLD; RNA WORLD; ORIGIN; CELLS AB In a series of conceptual articles published around the millennium, Carl Woese emphasized that evolution of cells is the central problem of evolutionary biology, that the three-domain ribosomal tree of life is an essential framework for reconstructing cellular evolution, and that the evolutionary dynamics of functionally distinct cellular systems are fundamentally different, with the information processing systems "crystallizing" earlier than operational systems. The advances of evolutionary genomics over the last decade vindicate major aspects of Woese's vision. Despite the observations of pervasive horizontal gene transfer among bacteria and archaea, the ribosomal tree of life comes across as a central statistical trend in the "forest" of phylogenetic trees of individual genes, and hence, an appropriate scaffold for evolutionary reconstruction. The evolutionary stability of information processing systems, primarily translation, becomes ever more striking with the accumulation of comparative genomic data indicating that nearly all of the few universal genes encode translation system components. Woese's view on the fundamental distinctions between the three domains of cellular life also withstand the test of comparative genomics, although his non-acceptance of symbiogenetic scenarios for the origin of eukaryotes might not. Above all, Woese's key prediction that understanding evolution of microbes will be the core of the new evolutionary biology appears to be materializing. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM koonin@ncbi.nlm.nih.gov FU US Department of Health and Human Resources FX E.V.K. is supported by intramural funds of the US Department of Health and Human Resources (to the National Library of Medicine, NIH). NR 78 TC 9 Z9 10 U1 1 U2 49 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1547-6286 EI 1555-8584 J9 RNA BIOL JI RNA Biol. PD MAR 1 PY 2014 VL 11 IS 3 BP 197 EP 204 DI 10.4161/rna.27673 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AF8XR UT WOS:000334999500006 PM 24572480 ER PT J AU Dasgupta, A Szymczak, S Moore, JH Bailey-Wilson, JE Malley, JD AF Dasgupta, Abhijit Szymczak, Silke Moore, Jason H. Bailey-Wilson, Joan E. Malley, James D. TI Risk estimation using probability machines SO BIODATA MINING LA English DT Article DE Consistent nonparametric regression; Logistic regression; Probability; machine; Odds ratio; Counterfactuals; Interactions ID RANDOM FORESTS AB Background: Logistic regression has been the de facto, and often the only, model used in the description and analysis of relationships between a binary outcome and observed features. It is widely used to obtain the conditional probabilities of the outcome given predictors, as well as predictor effect size estimates using conditional odds ratios. Results: We show how statistical learning machines for binary outcomes, provably consistent for the nonparametric regression problem, can be used to provide both consistent conditional probability estimation and conditional effect size estimates. Effect size estimates from learning machines leverage our understanding of counterfactual arguments central to the interpretation of such estimates. We show that, if the data generating model is logistic, we can recover accurate probability predictions and effect size estimates with nearly the same efficiency as a correct logistic model, both for main effects and interactions. We also propose a method using learning machines to scan for possible interaction effects quickly and efficiently. Simulations using random forest probability machines are presented. Conclusions: The models we propose make no assumptions about the data structure, and capture the patterns in the data by just specifying the predictors involved and not any particular model structure. So they do not run the same risks of model mis-specification and the resultant estimation biases as a logistic model. This methodology, which we call a "risk machine", will share properties from the statistical machine that it is derived from. C1 [Dasgupta, Abhijit] NIAMSD, Clin Trials & Outcomes Branch, NIH, Bethesda, MD 20892 USA. [Szymczak, Silke; Bailey-Wilson, Joan E.] NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD 21224 USA. [Moore, Jason H.] Dartmouth Coll, Hitchcock Med Ctr, Dept Genet, Lebanon, NH 03756 USA. [Malley, James D.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Dasgupta, A (reprint author), NIAMSD, Clin Trials & Outcomes Branch, NIH, Room 4-1350,Bldg 10 CRC,10 Ctr Dr, Bethesda, MD 20892 USA. EM abhijit.dasgupta@nih.gov RI Szymczak, Silke/C-6625-2013; OI Bailey-Wilson, Joan/0000-0002-9153-2920 FU Intramural Research Programs of the National Institute of Arthritis, Musculoskeletal and Skin Disorders; National Human Genome Research Institute; Center for Information Technology, National Institutes of Health; NIH [LM009012] FX This project was supported by the Intramural Research Programs of the National Institute of Arthritis, Musculoskeletal and Skin Disorders (AD), the National Human Genome Research Institute (SS, JEBW), and the Center for Information Technology (JDM), National Institutes of Health, as well as by NIH grant LM009012 (JHM). The authors would also like to acknowledge numerous discussions with other colleagues, including Deanna Greenstein, Larry Brody and Nilanjan Chatterjee. NR 9 TC 3 Z9 3 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-0381 J9 BIODATA MIN JI BioData Min. PD MAR 1 PY 2014 VL 7 DI 10.1186/1756-0381-7-2 PG 17 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AF0AS UT WOS:000334374500001 PM 24581306 ER PT J AU Freudenthal, BD Beard, WA Wilson, SH AF Freudenthal, Bret D. Beard, William A. Wilson, Samuel H. TI Watching a DNA polymerase in action SO CELL CYCLE LA English DT Editorial Material DE DNA polymerase; DNA repair; mutagenesis; substrate channeling; time-lapse crystallography; pryophosphorolysis ID MECHANISM C1 [Freudenthal, Bret D.; Beard, William A.; Wilson, Samuel H.] NIEHS, Lab Struct Biol, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Lab Struct Biol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU NCI NIH HHS [U19 CA177547] NR 8 TC 4 Z9 4 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 MAR 1 PY 2014 VL 13 IS 5 BP 691 EP 692 DI 10.4161/cc.27789 PG 2 WC Cell Biology SC Cell Biology GA AE3UQ UT WOS:000333904200007 PM 24424116 ER PT J AU Ma, BY AF Ma, Buyong TI Protein-Protein Interaction: From Interface to Interaction Network SO CURRENT PHARMACEUTICAL DESIGN LA English DT Editorial Material ID HOT-SPOTS C1 NCI, SAIC Frederick Inc, Basic Sci Program, Ctr Canc Res Nanobiol Program,NIH, Frederick, MD 21702 USA. RP Ma, BY (reprint author), NCI, SAIC Frederick Inc, Basic Sci Program, Ctr Canc Res Nanobiol Program,NIH, Frederick, MD 21702 USA. RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X NR 7 TC 0 Z9 0 U1 2 U2 4 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 EI 1873-4286 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD MAR PY 2014 VL 20 IS 8 BP 1171 EP 1172 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AE9EY UT WOS:000334309400001 ER PT J AU Engin, HB Gursoy, A Nussinov, R Keskin, O AF Engin, H. Billur Gursoy, Attila Nussinov, Ruth Keskin, Ozlem TI Network-Based Strategies Can Help Mono-and Poly-pharmacology Drug Discovery: A Systems Biology View SO CURRENT PHARMACEUTICAL DESIGN LA English DT Article DE Poly-pharmacology; network pharmacology; protein-protein interaction inhibitors; systems biology; protein-protein interfaces; modeling. ID PROTEIN-PROTEIN INTERACTIONS; SMALL-MOLECULE INHIBITORS; DRUGGABLE BINDING-SITES; HOT-SPOTS; SIGNAL-TRANSDUCTION; TRANSIENT POCKETS; CHEMICAL SPACE; LEUKEMIA-CELLS; LEAD DISCOVERY; ARA-C AB The cellular network and its environment govern cell and organism behavior and are fundamental to the comprehension of function, misfunction and drug discovery. Over the last few years, drugs were observed to often bind to more than one target; thus, polypharmacology approaches can be advantageous, complementing the "one drug - one target" strategy. Targeting drug discovery from the systems biology standpoint can help in studies of network effects of mono- and poly-pharmacology. In this mini-review, we provide an overview of the usefulness of network description and tools for mono- and poly-pharmacology, and the ways through which protein interactions can help single- and multi-target drug discovery efforts. We further describe how, when combined with experimental data, modeled structural networks which can predict which proteins interact and provide the structures of their interfaces, can model the cellular pathways, and suggest which specific pathways are likely to be affected. Such structural networks may facilitate structure-based drug design; forecast side effects of drugs; and suggest how the effects of drug binding can propagate in multi-molecular complexes and pathways. C1 [Engin, H. Billur; Gursoy, Attila; Keskin, Ozlem] Koc Univ, Ctr Computat Biol & Bioinformat, TR-34450 Sariyer, Turkey. [Engin, H. Billur; Gursoy, Attila; Keskin, Ozlem] Koc Univ, Coll Engn, TR-34450 Sariyer, Turkey. [Nussinov, Ruth] NCI, Ctr Canc Res, Nanobiol Program, Frederick Natl Lab, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Keskin, O (reprint author), Koc Univ, Ctr Computat Biol & Bioinformat, TR-34450 Sariyer, Turkey. EM okeskin@ku.edu.tr RI Gursoy, Attila/E-9565-2015 OI Gursoy, Attila/0000-0002-2297-2113 FU TUBITAK [109T343, 109E207]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work has been supported by TUBITAK (Research Grant Numbers: 109T343 and 109E207). This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, 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 U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 116 TC 16 Z9 16 U1 0 U2 19 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 EI 1873-4286 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD MAR PY 2014 VL 20 IS 8 BP 1201 EP 1207 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AE9EY UT WOS:000334309400005 PM 23713773 ER PT J AU Flatow, D Leelananda, SP Skliros, A Kloczkowski, A Jernigan, RL AF Flatow, Daniel Leelananda, Sumudu P. Skliros, Aris Kloczkowski, Andrzej Jernigan, Robert L. TI Volumes and Surface Areas: Geometries and Scaling Relationships between Coarse-Grained and Atomic Structures SO CURRENT PHARMACEUTICAL DESIGN LA English DT Article DE Globular proteins; protein-protein interactions; drugs; drug surface areas; convex hulls; Delaunay triangulation; Delaunay tessellation; accessible volume; accessible surface area; computational efficiency; coarse-graining ID PRINCIPAL COMPONENT ANALYSIS; HARD-SPHERE MOLECULES; ELECTRON-MICROSCOPY; PROTEIN STRUCTURES; VORONOI POLYHEDRA; EXCLUDED-VOLUME; DELAUNAY TESSELLATION; GLOBULAR-PROTEINS; ENERGY MINIMIZATION; SECONDARY STRUCTURE AB Computing volumes and surface areas of molecular structures is generally considered to be a solved problem, however, comparisons presented in this review show that different ways of computing surface areas and volumes can yield dramatically different values. Volumes and surface areas are the most basic geometric properties of structures, and estimating these becomes especially important for large scale simulations when individual components are being assembled in protein complexes or drugs being fitted into proteins. Good approximations of volumes and surfaces are derived from Delaunay tessellations, but these values can differ significantly from those from the rolling ball approach of Lee and Richards (3V webserver). The origin of these differences lies in the extended parts and the less well packed parts of the proteins, which are ignored in some approaches. Even though surface areas and volumes from the two approaches differ significantly, their correlations are high. Atomic models have been compared, and the poorly packed regions of proteins are found to be most different between the two approaches. The Delaunay complexes have been explored for both fully atomic and for coarse-grained representations of proteins based on only C-alpha atoms. The scaling relationships between the fully atomic models and the coarse-grained model representations of proteins are reported, and the lines fit yield simple relationships for the surface areas and volumes as a function of the number of protein residues and the number of heavy atoms. Further, the atomic and coarse-grained values are strongly correlated and simple relationships are reported. C1 [Flatow, Daniel] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Leelananda, Sumudu P.; Skliros, Aris; Kloczkowski, Andrzej; Jernigan, Robert L.] Iowa State Univ, Laurence H Baker Ctr Bioinformat & Biol Stat, Ames, IA 50011 USA. [Leelananda, Sumudu P.; Skliros, Aris; Kloczkowski, Andrzej; Jernigan, Robert L.] Iowa State Univ, Dept Biochem Biophys & Mol Biol, Ames, IA 50011 USA. [Kloczkowski, Andrzej] Ohio State Univ, Coll Med, Nationwide Childrens Hosp, Res Inst,Battelle Ctr Math Med,Dept Pediat, Columbus, OH 43205 USA. RP Jernigan, RL (reprint author), Iowa State Univ, Laurence H Baker Ctr Bioinformat & Biol Stat, Ames, IA 50011 USA. EM jernigan@iastate.edu FU NCI Intramural Research Program; NIH [GM072014]; NSF [MCB-1021785] FX We gratefully acknowledge the support of the NCI Intramural Research Program and NIH Grant GM072014 and NSF MCB-1021785. NR 133 TC 1 Z9 1 U1 3 U2 13 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 EI 1873-4286 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD MAR PY 2014 VL 20 IS 8 BP 1208 EP 1222 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AE9EY UT WOS:000334309400006 PM 23713774 ER PT J AU Ji, XN Ma, LJ Huang, Q Li, ZJ Zhao, J Huang, WX Ma, BY Yu, L AF Ji, Xiaona Ma, Lijie Huang, Qiang Li, Zijuan Zhao, Jing Huang, Weixue Ma, Buyong Yu, Long TI Network Effect of Wt-mutant p53 Interactions and Implications on p53 Gene Therapy SO CURRENT PHARMACEUTICAL DESIGN LA English DT Article DE TP53; mutation; hepatocellular carcinoma; genome stability; apoptosis ID PRIMARY HEPATOCELLULAR-CARCINOMA; IARC TP53 DATABASE; VIRUS X PROTEIN; WILD-TYPE P53; SEGREGATION ANALYSIS; RESPONSE-ELEMENTS; BINDING MODES; MUTATIONS; TETRAMER; CANCER AB Mutant p53 could have either a dominant negative effect or a gain of function to interfere with p53's ability to maintain genomic stability. In the present study, we screened for TP53 mutations in hepatocellular carcinoma (HCC) samples from 202 Chinese patients, followed by analysis of transcriptional and apoptotic activities of 21 p53 mutants with or without wild-type p53 present. We identified a new point mutation p.P72A, and a mutation (p.E294SfsX51) with a record long frameshift. We found TP53 mutations in HCC bear mutants without a dominant wild-type p53 inhibition on p21 transcription at a higher frequency. We found an anti-correlation for p53 WT/mutant heterotetramer to activate p21 and BAX transcription, i.e., at given p53 WT/mutant concentration, the fold increase p21 transcription is proportional to the fold of decreasing BAX transcription. Our kinetic model reproduced the trend in the experimental observation and confirmed that the p53 WT-dimer/mutant-heterotetramer is the major species to confer the differential activation of p21 and BAX transcription. p53 may have different binding modes on p21 and BAX, most likely resulting from the combinational effects of core domain binding and C-terminal mediation. Our study demonstrated that p53 mutants interfere with the ability of WT p53 to maintain genomic stability. C1 [Ji, Xiaona; Ma, Lijie; Huang, Qiang; Li, Zijuan; Zhao, Jing; Huang, Weixue; Yu, Long] Fudan Univ, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. [Ma, Buyong] NCI, Bas Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. RP Yu, L (reprint author), Fudan Univ, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. EM longyu@fudan.edu.cn RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU Chinese National Science Fund for Creative Research Groups [30024001]; Chinese "973" Project Program [2004CB518605]; Key Program of the Science and Technology Ministry of China [2002BA711A02-4]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded by the Chinese National Science Fund for Creative Research Groups 30024001, Chinese "973" Project Program 2004CB518605 and Key Program of the Science and Technology Ministry of China 2002BA711A02-4. BM is funded with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. NR 31 TC 2 Z9 2 U1 0 U2 3 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 EI 1873-4286 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD MAR PY 2014 VL 20 IS 8 BP 1259 EP 1267 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AE9EY UT WOS:000334309400009 PM 23713777 ER PT J AU Ma, BY Nussinov, R AF Ma, Buyong Nussinov, Ruth TI Druggable Orthosteric and Allosteric Hot Spots to Target Protein-protein Interactions SO CURRENT PHARMACEUTICAL DESIGN LA English DT Article DE Drug discovery; allosteric drugs; protein binding site; allostery; amyloid; protein-protein interfaces; protein pockets ID DRUG DISCOVERY; EPH RECEPTORS; RAS-PROTEIN; STRUCTURAL CONSERVATION; MODULAR ARCHITECTURE; BINDING INTERFACES; SMALL MOLECULES; CANCER-THERAPY; R-RAS; RESIDUES AB Drug designing targeting protein-protein interactions is challenging. Because structural elucidation and computational analysis have revealed the importance of hot spot residues in stabilizing these interactions, there have been on-going efforts to develop drugs which bind the hot spots and out-compete the native protein partners. The question arises as to what are the key 'druggable' properties of hot spots in protein-protein interactions and whether these mimic the general hot spot definition. Identification of orthosteric (at the protein-protein interaction site) and allosteric (elsewhere) druggable hot spots is expected to help in discovering compounds that can more effectively modulate protein-protein interactions. For example, are there any other significant features beyond their location in pockets in the interface? The interactions of protein-protein hot spots are coupled with conformational dynamics of protein complexes. Currently increasing efforts focus on the allosteric drug discovery. Allosteric drugs bind away from the native binding site and can modulate the native interactions. We propose that identification of allosteric hot spots could similarly help in more effective allosteric drug discovery. While detection of allosteric hot spots is challenging, targeting drugs to these residues has the potential of greatly increasing the hot spot and protein druggability. C1 [Ma, Buyong; Nussinov, Ruth] NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Ma, BY (reprint author), NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. EM mabuyong@mail.nih.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research 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 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 U.S. Government. This research was supported ( in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 118 TC 15 Z9 15 U1 5 U2 34 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 EI 1873-4286 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD MAR PY 2014 VL 20 IS 8 BP 1293 EP 1301 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AE9EY UT WOS:000334309400012 PM 23713780 ER PT J AU Miller, DS Cannon, RE AF Miller, David S. Cannon, Ronald E. TI Signaling Pathways that Regulate Basal ABC Transporter Activity at the Blood-Brain Barrier SO CURRENT PHARMACEUTICAL DESIGN LA English DT Article DE Neuroprotection; Drug delivery; ABC transporters; Blood-brain barrier; P-gp; efflux pumps ID CANCER RESISTANCE PROTEIN; PLATELET-ACTIVATING-FACTOR; P-GLYCOPROTEIN ACTIVITY; XENOBIOTIC EFFLUX TRANSPORTERS; MEDIATED UP-REGULATION; NECROSIS-FACTOR-ALPHA; MULTIPLE-SCLEROSIS; X-RECEPTOR; DRUG-DELIVERY; SOLID TUMORS AB At the blood-brain barrier, ATP-binding cassette (ABC) transporters, such as, P-glycoprotein (MDR1, ABCB1) and breast cancer related protein (BCRP, ABCG2) limit CNS uptake of foreign chemicals. Thus, they are neuroprotective, but they also distinguish poorly between neurotoxicants and therapeutic drugs. So they are major obstacles to CNS pharmacotherapy. The present review is focused on new findings in animal models in vitro and in vivo showing that basal transport activity of P-glycoprotein and Bcrp can be rapidly and transiently reduced through targeting of specific signaling pathways within the brain capillary endothelium. Three pathways have been identified: estrogen signaling to Bcrp, vascular endothelial growth factor signaling to P-glycoprotein and TNF alpha/PKC/ sphingolipid signaling to P-glycoprotein. Translation of these results to the clinic could provide improved pharmacotherapy for a number of CNS diseases, including, brain cancer, neuroAIDS and epilepsy. C1 [Miller, David S.; Cannon, Ronald E.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Miller, DS (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. EM miller@niehs.nih.gov FU National Institutes of Health, National Institute of Environmental Health Sciences FX We thank the members of the Miller Lab for their contributions to the studies cited and their incitefull comments. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 54 TC 10 Z9 12 U1 3 U2 12 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 EI 1873-4286 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD MAR PY 2014 VL 20 IS 10 BP 1463 EP 1471 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AE9FM UT WOS:000334311000004 PM 23789954 ER PT J AU Tischler, AS Pacak, K Eisenhofer, G AF Tischler, Arthur S. Pacak, Karel Eisenhofer, Graeme TI The Adrenal Medulla and Extra-adrenal Paraganglia: Then and Now SO ENDOCRINE PATHOLOGY LA English DT Article DE Pheochromocytoma; Paraganglioma; Genetics; Biochemistry; Imaging; Pediatrics; Treatment ID GLAND SCALED SCORE; PITUITARY-ADENOMA; GENE-MUTATIONS; SDH MUTATIONS; MALIGNANT PHEOCHROMOCYTOMA; SYMPATHETIC PARAGANGLIOMAS; SPORADIC PHEOCHROMOCYTOMA; TUMOR-SUPPRESSOR; HEREDITARY; SUSCEPTIBILITY AB The past 25 years have witnessed revolutionary changes in the care of patients with pheochromocytomas and extra-adrenal paragangliomas. Germline mutations of at least 13 genes are now associated with tumor development, a greater degree of hereditary susceptibility than for any other human neoplasm. Somatic mutations, either of the same genes or of several additional ones with closely related functions, are also increasingly recognized. Clinicians are now aware of the genetic implications of a pheochromocytoma or paraganglioma. All patients are therefore offered genetic testing and receive lifelong surveillance. Almost all of the mutated genes have well-described correlations with clinical and biochemical phenotypes. Tumors arising in patients with mutations of the SDHB gene have at least a 30 % chance of metastasizing and typically produce norepinephrine and/or dopamine. Assay of plasma-free metanephrines serves as a highly sensitive and specific biochemical screen for the presence of catecholamine-producing tumors, and the dopamine metabolite methoxytyramine serves as a useful marker for detecting minimally functional tumors or their metastases. New functional imaging techniques provide highly sensitive tumor localization. In addition to differential diagnosis, pathologists play new roles in helping to identify hereditary disease and guiding the sequence of genetic testing. C1 [Tischler, Arthur S.] Tufts Med Ctr, Dept Pathol, Boston, MA 02111 USA. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Eisenhofer, Graeme] Univ Dresden, Inst Clin Chem & Lab Med, D-01307 Dresden, Germany. [Eisenhofer, Graeme] Univ Dresden, Dept Med 3, D-01307 Dresden, Germany. RP Tischler, AS (reprint author), Tufts Med Ctr, Dept Pathol, 800 Washington St, Boston, MA 02111 USA. EM ATischler@tuftsmedicalcenter.org; karel@mail.nih.gov; Graeme.Eisenhofer@uniklinikum-dresden.de NR 67 TC 7 Z9 7 U1 2 U2 5 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1046-3976 EI 1559-0097 J9 ENDOCR PATHOL JI Endocr. Pathol. PD MAR PY 2014 VL 25 IS 1 BP 49 EP 58 DI 10.1007/s12022-013-9286-3 PG 10 WC Endocrinology & Metabolism; Pathology SC Endocrinology & Metabolism; Pathology GA AF0PH UT WOS:000334416000009 PM 24362581 ER PT J AU Patzel, KA Yardeni, T Le Poec-Celic, E Leoyklang, P Dorward, H Alonzi, DS Kukushkin, NV Xu, BX Zhang, YM Sollogoub, M Bleriot, Y Gahl, WA Huizing, M Butters, TD AF Patzel, Katherine A. Yardeni, Tal Le Poec-Celic, Erell Leoyklang, Petcharat Dorward, Heidi Alonzi, Dominic S. Kukushkin, Nikolay V. Xu, Bixue Zhang, Yongmin Sollogoub, Matthieu Bleriot, Yves Gahl, William A. Huizing, Marjan Butters, Terry D. TI Non-specific accumulation of glycosphingolipids in GNE myopathy SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Article ID INCLUSION-BODY MYOPATHY; ACETYLGLUCOSAMINE 2-EPIMERASE/N-ACETYLMANNOSAMINE KINASE; SIALIC-ACID BIOSYNTHESIS; SINGLE PATIENT RESPONSE; N-ACETYLNEURAMINIC ACID; DISTAL MYOPATHY; RIMMED VACUOLES; MOUSE MODEL; KEY ENZYME; LYSOSOMAL MYOPATHIES AB UDP-GlcNAc 2-epimerase/ManNAc 6-kinase (GNE) is a bifunctional enzyme responsible for the first committed steps in the synthesis of sialic acid, a common terminal monosaccharide in both protein and lipid glycosylation. GNE mutations are responsible for a rare autosomal recessive neuromuscular disorder, GNE myopathy (also called hereditary inclusion body myopathy). The connection between the impairment of sialic acid synthesis and muscle pathology in GNE myopathy remains poorly understood. Glycosphingolipid (GSL) analysis was performed by HPLC in multiple models of GNE myopathy, including patients' fibroblasts and plasma, control fibroblasts with inhibited GNE epimerase activity through a novel imino sugar, and tissues of Gne(M712T/M712T) knock-in mice. Not only neutral GSLs, but also sialylated GSLs, were significantly increased compared to controls in all tested models of GNE myopathy. Treatment of GNE myopathy fibroblasts with N-acetylmannosamine (ManNAc), a sialic acid precursor downstream of GNE epimerase activity, ameliorated the increased total GSL concentrations. GNE myopathy models have increased total GSL concentrations. ManNAc supplementation results in decrease of GSL levels, linking abnormal increase of total GSLs in GNE myopathy to defects in the sialic acid biosynthetic pathway. These data advocate for further exploring GSL concentrations as an informative biomarker, not only for GNE myopathy, but also for other disorders of sialic acid metabolism. C1 [Patzel, Katherine A.; Alonzi, Dominic S.; Kukushkin, Nikolay V.; Butters, Terry D.] Univ Oxford, Dept Biochem, Oxford Glycobiol Inst, Oxford OX1 3QU, England. [Patzel, Katherine A.; Yardeni, Tal; Leoyklang, Petcharat; Dorward, Heidi; Gahl, William A.; Huizing, Marjan] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Yardeni, Tal] Tel Aviv Univ, Sackler Sch Med, Grad Partner Program, IL-69978 Tel Aviv, Israel. [Le Poec-Celic, Erell] Inst Natl Sci Appl, F-31400 Toulouse, France. [Xu, Bixue; Zhang, Yongmin; Sollogoub, Matthieu; Bleriot, Yves] Univ Paris 06, Inst Parisien Chim Monleculaire, F-75005 Paris, France. [Bleriot, Yves] Univ Poitiers, CNRS 7285, IC2MP, UMR, F-86022 Poitiers, France. [Gahl, William A.] NIH, Off Rare Dis Res, Off Director, Bethesda, MD 20892 USA. RP Butters, TD (reprint author), Univ Oxford, Dept Biochem, Oxford Glycobiol Inst, Oxford OX1 3QU, England. EM mhuizing@mail.nih.gov; terry.butters@bioch.ox.ac.uk OI Sollogoub, Matthieu/0000-0003-0500-5946; Alonzi, Dominic/0000-0002-1330-9109 FU Oxford Glycobiology Institute, Oxford, UK; l'Association "Vaincre les maladies lysosomales"; National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA FX This work was supported by the Oxford Glycobiology Institute, Oxford, UK (K.A.P., D.S.A., N.V.K., and T.D.B.), l'Association "Vaincre les maladies lysosomales" (Y.B.) and the Intramural Research Programs of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA (K.A.P., T.Y., P.L., H.D., W.A.G., and M.H.). The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors. NR 51 TC 3 Z9 3 U1 1 U2 9 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 EI 1573-2665 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD MAR PY 2014 VL 37 IS 2 BP 297 EP 308 DI 10.1007/s10545-013-9655-6 PG 12 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AE8TM UT WOS:000334274900017 PM 24136589 ER PT J AU Cerhan, JR Moore, SC Jacobs, EJ Kitahara, CM Rosenberg, PS Adami, HO Ebbert, JO English, DR Gapstur, SM Giles, GG Horn-Ross, PL Park, Y Patel, AV Robien, K Weiderpass, E Willett, WC Wolk, A Zeleniuch-Jacquotte, A Hartge, P Bernstein, L de Gonzalez, AB AF Cerhan, James R. Moore, Steven C. Jacobs, Eric J. Kitahara, Cari M. Rosenberg, Philip S. Adami, Hans-Olov Ebbert, Jon O. English, Dallas R. Gapstur, Susan M. Giles, Graham G. Horn-Ross, Pamela L. Park, Yikyung Patel, Alpa V. Robien, Kim Weiderpass, Elisabete Willett, Walter C. Wolk, Alicja Zeleniuch-Jacquotte, Anne Hartge, Patricia Bernstein, Leslie de Gonzalez, Amy Berrington TI A Pooled Analysis of Waist Circumference and Mortality in 650,000 Adults SO MAYO CLINIC PROCEEDINGS LA English DT Article ID BODY-MASS INDEX; ALL-CAUSE MORTALITY; ABDOMINAL OBESITY; METABOLIC SYNDROME; HEALTH OUTCOMES; BREAST-CANCER; RISK; WOMEN; ADIPOSITY; COHORT AB Objectives: To assess the independent effect of waist circumference on mortality across the entire body mass index (BMI) range and to estimate the loss in life expectancy related to a higher waist circumference. Patients and Methods: We pooled data from 11 prospective cohort studies with 650,386 white adults aged 20 to 83 years and enrolled from January 1, 1986, through December 31, 2000. We used proportional hazards regression to estimate hazard ratios (HRs) and 95% CIs for the association of waist circumference with mortality. Results: During a median follow-up of 9 years (maximum, 21 years), 78,268 participants died. After accounting for age, study, BMI, smoking status, alcohol consumption, and physical activity, a strong positive linear association of waist circumference with all-cause mortality was observed for men (HR, 1.52 for waist circumferences of >= 110 vs < 90 cm; 95% CI, 1.45-1.59; HR, 1.07 per 5-cm increment in waist circumference; 95% CI, 1.06-1.08) and women (HR, 1.80 for waist circumferences of >= 95 vs < 70 cm; 95% CI, 1.70-1.89; HR, 1.09 per 5-cm increment in waist circumference; 95% CI, 1.08-1.09). The estimated decrease in life expectancy for highest vs lowest waist circumference was approximately 3 years for men and approximately 5 years for women. The HR per 5-cm increment in waist circumference was similar for both sexes at all BMI levels from 20 to 50 kg/m(2), but it was higher at younger ages, higher for longer follow-up, and lower among male current smokers. The associations were stronger for heart and respiratory disease mortality than for cancer. Conclusions: In white adults, higher waist circumference was positively associated with higher mortality at all levels of BMI from 20 to 50 kg/m(2). Waist circumference should be assessed in combination with BMI, even for those in the normal BMI range, as part of risk assessment for obesity-related premature mortality. (C) 2014 Mayo Foundation for Medical Education and Research C1 [Cerhan, James R.] Mayo Clin, Div Epidemiol, Rochester, MN USA. [Ebbert, Jon O.] Mayo Clin, Div Primary Care Internal Med, Rochester, MN USA. [Moore, Steven C.; Kitahara, Cari M.; Rosenberg, Philip S.; Park, Yikyung; Hartge, Patricia; de Gonzalez, Amy Berrington] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Jacobs, Eric J.; Gapstur, Susan M.; Patel, Alpa V.] Amer Canc Soc, Res Program, Atlanta, GA 30329 USA. [Adami, Hans-Olov; Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Wolk, Alicja] Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, Stockholm, Sweden. [Adami, Hans-Olov] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [English, Dallas R.] Univ Melbourne, MEGA Epidemiol, Melbourne, Vic, Australia. [Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Horn-Ross, Pamela L.] Canc Prevent Inst Calif, Fremont, CA 94538 USA. [Robien, Kim] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Weiderpass, Elisabete] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Canc Register Norway, Oslo, Norway. [Weiderpass, Elisabete] Samfundet Folkhalsan, Helsinki, Finland. [Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Populat Hlth, New York, NY USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Duarte, CA USA. RP Cerhan, JR (reprint author), Mayo Clin, 200 First St SW, Rochester, MN 55905 USA. EM cerhan.james@mayo.edu RI Moore, Steven/D-8760-2016; Weiderpass, Elisabete/M-4029-2016; Kitahara, Cari/R-8267-2016; OI Moore, Steven/0000-0002-8169-1661; English, Dallas/0000-0001-7828-8188; Weiderpass, Elisabete/0000-0003-2237-0128; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303; Park, Yikyung/0000-0002-6281-489X; Cerhan, James/0000-0002-7482-178X; Robien, Kim/0000-0002-2120-2280; Giles, Graham/0000-0003-4946-9099 FU Intramural Research Program of the National Cancer Institute; National Institutes of Health; National Cancer Institute [CA77398, 97-10500, P01 CA055075, R01 CA39742, R01 CA098661, P30 CA016087, ES000260]; California Breast Cancer Research Fund; American Cancer Society; Swedish Research Council; Swedish Council for Working Life and Social Research; Swedish Cancer Society; Cancer Council Victoria; Australian National Health and Medical Research Council [209057, 251533, 396414]; Australian National Health and Medical Research Council; National Institute of Environmental Health Sciences FX The National Institutes of Healthe-AARP Diet and Health study was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The Breast Cancer Detection Demonstration Project Follow-up Study has been supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The California Teachers Study was supported by National Cancer Institute grant CA77398 and contract 97-10500 from the California Breast Cancer Research Fund. The Cancer Prevention Study II was supported by the American Cancer Society. The Cohort of Swedish Men was supported by the Swedish Research Council, the Swedish Council for Working Life and Social Research, and the Swedish Cancer Society. The Health Professionals Follow-up Study is supported by National Cancer Institute grant P01 CA055075. The Iowa Women's Health Study is supported by the National Cancer Institute grant R01 CA39742. The Melbourne Collaborative Cohort Study receives core funding from The Cancer Council Victoria and is additionally supported by grants 209057, 251533, and 396414 from the Australian National Health and Medical Research Council. The New York University Women's Health Study is supported by National Cancer Institute grants R01 CA098661 and P30 CA016087 and by center grant ES000260 from the National Institute of Environmental Health Sciences. The Swedish Mammography Cohort was supported by the Swedish Research Council, Swedish Council for Working Life and Social Research, and the Swedish Cancer Society. The Women's Lifestyle and Health project was supported by the Swedish Cancer Society and the Swedish Research Council. NR 42 TC 38 Z9 39 U1 2 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0025-6196 EI 1942-5546 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD MAR PY 2014 VL 89 IS 3 BP 335 EP 345 DI 10.1016/j.mayocp.2013.11.011 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AC3DY UT WOS:000332396400012 PM 24582192 ER PT J AU Ji, YJ Hwang, YS Mood, K Cho, HJ Lee, HS Winterbottom, E Cousin, H Daar, IO AF Ji, Yon Ju Hwang, Yoo-Seok Mood, Kathleen Cho, Hee-Jun Lee, Hyun-Shik Winterbottom, Emily Cousin, Helene Daar, Ira O. TI EphrinB2 affects apical constriction in Xenopus embryos and is regulated by ADAM10 and flotillin-1 SO NATURE COMMUNICATIONS LA English DT Article ID NEURAL-TUBE CLOSURE; NECROSIS-FACTOR-ALPHA; EPITHELIAL-CELLS; N-CADHERIN; B LIGANDS; RECEPTOR; ENDOCYTOSIS; METALLOPROTEINASE; MORPHOGENESIS; DISINTEGRIN AB The Eph/ephrin signalling pathways have a critical function in cell adhesion and repulsion, and thus play key roles in various morphogenetic events during development. Here we show that a decrease in ephrinB2 protein causes neural tube closure defects during Xenopus laevis embryogenesis. Such a decrease in ephrinB2 protein levels is observed on the loss of flotillin-1 scaffold protein, a newly identified ephrinB2-binding partner. This dramatic decline in ephrinB2 protein levels on the absence of flotillin-1 expression is specific, and is partly the result of an increased susceptibility to cleavage by the metalloprotease ADAM10. These findings indicate that flotillin-1 regulates ephrinB2 protein levels through ADAM10, and is required for appropriate neural tube morphogenesis in the Xenopus embryo. C1 [Ji, Yon Ju; Hwang, Yoo-Seok; Mood, Kathleen; Cho, Hee-Jun; Winterbottom, Emily; Daar, Ira O.] NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. [Lee, Hyun-Shik] Kyungpook Natl Univ, Coll Nat Sci, Sch Life Sci, ABRC,CMRI, Taegu 702701, South Korea. [Cousin, Helene] Univ Massachusetts, Dept Vet & Anim Sci, Amherst, MA 01003 USA. RP Daar, IO (reprint author), NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. EM daari@mail.nih.gov OI Daar, Ira/0000-0003-2657-526X FU Intramural Research Program of the National Institutes of Health, National Cancer Institute; National Institutes of Health/NIDCR [DE016289] FX We thank S. A. Moody for flotillin-1a and flotillin-1b constructs, S. Wei and D. W. DeSimone for ADAM10 and ADAM17 constructs, P. M. Helbling and A. W. Brandli for pCS-tmEphB4, F. Fagotto for Eph receptor MOs and A. Ludwig for GI254023X. We also thank G. Tosato for helpful discussions and critical reading of this manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute and National Institutes of Health/NIDCR Grant number DE016289. NR 57 TC 7 Z9 7 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2014 VL 5 AR 3516 DI 10.1038/ncomms4516 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AE9CR UT WOS:000334302400003 PM 24662724 ER PT J AU Joo, EE Yamada, KM AF Joo, E. Emily Yamada, Kenneth M. TI MYPT1 regulates contractility and microtubule acetylation to modulate integrin adhesions and matrix assembly SO NATURE COMMUNICATIONS LA English DT Article ID CELL-MIGRATION; BRANCHING MORPHOGENESIS; ACTIN CYTOSKELETON; MYOSIN-II; FOCAL ADHESIONS; DYNAMICS; FIBRONECTIN; FIBROBLASTS; ORGANIZATION; PHOSPHATASE AB Although much is known about how individual cytoskeletal systems contribute to physiological processes such as cell migration and branching morphogenesis, little is known about how these different systems actively coordinate their functions after polymerization. Here we show that both fibroblasts and developing glands reciprocally coordinate levels of cellular contractility and microtubule acetylation. We find that this balance is achieved by interaction of the myosin phosphatase target subunit of myosin phosphatase with either myosin light chain or HDAC6, a microtubule deacetylase. This balance of contractility and microtubule acetylation controls progression of adhesion maturation by regulating surface density of alpha(5)beta(1) integrin and fibronectin. Thus, we propose that a homeostatic balance between contractility and microtubule acetylation is mediated by myosin phosphatase via controlled activation and deactivation of myosin II and HDAC6. This regulates the surface density of alpha(5)beta(1) integrin to modulate fibronectin matrix assembly and governs rates of cell migration and branching morphogenesis. C1 [Joo, E. Emily; Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Yamada, KM (reprint author), Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. EM jooeu@mail.nih.gov; Kenneth.Yamada@nih.gov FU Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health FX We thank J. Hammer, E. Snapp, A. Doyle, J. Harunaga and M. Kutys for critical comments. We are grateful for technical assistance from S. Plotnikov and Q. Tseng. This work was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health. NR 70 TC 10 Z9 10 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2014 VL 5 AR 3510 DI 10.1038/ncomms4510 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AE9CQ UT WOS:000334302200001 PM 24667306 ER PT J AU Song, SB Cohen, LG AF Song, Sunbin Cohen, Leonardo G. TI Practice and sleep form different aspects of skill SO NATURE COMMUNICATIONS LA English DT Article ID REACTION-TIME-TASK; LEARNING-SYSTEMS; ORDINAL POSITION; MEMORY; IMPLICIT; CONSOLIDATION; HIPPOCAMPUS; KNOWLEDGE; EXPLICIT; ORDER AB Performance for skills such as a sequence of finger movements improves during sleep. This has widely been interpreted as evidence for a role of sleep in strengthening skill learning. Here we propose a different interpretation. We propose that practice and sleep form different aspects of skill. To show this, we train 80 subjects on a sequence of key-presses and test at different time points to determine the amount of skill stored in transition (that is, pressing `2' after `3' in `4-3-2-1') and ordinal (that is, pressing `2' in the third ordinal position in `4-3-2-1') forms. We find transition representations improve with practice and ordinal representations improve during sleep. Further, whether subjects can verbalize the trained sequence affects the formation of ordinal but not transition representations. Verbal knowledge itself does not increase over sleep. Thus, sleep encodes different representations of memory than practice, and may mediate conversion of memories between declarative and procedural forms. C1 [Song, Sunbin; Cohen, Leonardo G.] NINDS, Human Cort Physiol & Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. RP Song, SB (reprint author), NINDS, Human Cort Physiol & Neurorehabil Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM songss@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke at the National Institutes of Health; utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health and utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (http://biowulf.nih.gov). We would like to thank Dr Daniel Willingham of the University of Virginia for providing the corpus of sequences used in the SRTT. NR 39 TC 10 Z9 10 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2014 VL 5 AR 3407 DI 10.1038/ncomms4407 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AE9BR UT WOS:000334299400002 PM 24647040 ER PT J AU Lammermann, T Germain, RN AF Laemmermann, Tim Germain, Ronald N. TI The multiple faces of leukocyte interstitial migration SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Review DE Leukocyte; Interstitial migration; Plasticity; Cytoskeleton; Tissue architecture; Imaging ID DENDRITIC CELL-MIGRATION; WISKOTT-ALDRICH-SYNDROME; CENTRAL-NERVOUS-SYSTEM; LYMPHOCYTES IN-VIVO; CD8(+) T-CELLS; LYMPH-NODES; NEUTROPHIL CHEMOTAXIS; LANGERHANS CELLS; COMBINED IMMUNODEFICIENCY; MYCOBACTERIAL GRANULOMAS AB Spatiotemporal control of leukocyte dynamics within tissues is critical for successful innate and adaptive immune responses. Homeostatic trafficking and coordinated infiltration into and within sites of inflammation and infection rely on signaling in response to extracellular cues that in turn controls a variety of intracellular protein networks regulating leukocyte motility, migration, chemotaxis, positioning, and cell-cell interaction. In contrast to mesenchymal cells, leukocytes migrate in an amoeboid fashion by rapid cycles of actin polymerization and actomyosin contraction, and their migration in tissues is generally referred to as low adhesive and nonproteolytic. The interplay of actin network expansion, contraction, and adhesion shapes the exact mode of amoeboid migration, and in this review, we explore how leukocyte subsets potentially harness the same basic biomechanical mechanisms in a cell-type-specific manner. Most of our detailed understanding of these processes derives from in vitro migration studies in three-dimensional gels and confined spaces that mimic geometrical aspects of physiological tissues. We summarize these in vitro results and then critically compare them to data from intravital imaging of leukocyte interstitial migration in mouse tissues. We outline the technical challenges of obtaining conclusive mechanistic results from intravital studies, discuss leukocyte migration strategies in vivo, and present examples of mode switching during physiological interstitial migration. These findings are also placed in the context of leukocyte migration defects in primary immunodeficiencies. This overview of both in vitro and in vivo studies highlights recent progress in understanding the molecular and biophysical mechanisms that shape robust leukocyte migration responses in physiologically complex and heterogeneous environments. C1 [Laemmermann, Tim; Germain, Ronald N.] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. RP Lammermann, T (reprint author), NIAID, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM laemmermannt@niaid.nih.gov; rgermain@nih.gov FU Intramural Research Program of NIAID, NIH; Human Frontier Science Program Organization FX We thank Dr. Angelika Rambold for carefully preparing figure illustrations and critically reviewing the manuscript. This work was supported by the Intramural Research Program of NIAID, NIH. T. L. was supported by a long-term fellowship of the Human Frontier Science Program Organization. NR 182 TC 25 Z9 25 U1 5 U2 31 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2297 EI 1863-2300 J9 SEMIN IMMUNOPATHOL JI Semin. Immunopathol. PD MAR PY 2014 VL 36 IS 2 BP 227 EP 251 DI 10.1007/s00281-014-0418-8 PG 25 WC Immunology; Pathology SC Immunology; Pathology GA AF1UK UT WOS:000334499200008 PM 24573488 ER PT J AU Rudolph, KE Stuart, EA Glass, TA Merikangas, KR AF Rudolph, Kara E. Stuart, Elizabeth A. Glass, Thomas A. Merikangas, Kathleen R. TI Neighborhood disadvantage in context: the influence of urbanicity on the association between neighborhood disadvantage and adolescent emotional disorders SO SOCIAL PSYCHIATRY AND PSYCHIATRIC EPIDEMIOLOGY LA English DT Article DE Adolescent; Mental health; Psychiatric epidemiology; Neighborhood; Propensity score; Survey ID COMORBIDITY SURVEY REPLICATION; SUPPLEMENT NCS-A; MENTAL-DISORDERS; PSYCHIATRIC-DISORDERS; MULTIPLE IMPUTATION; DEPRESSIVE SYMPTOMS; HEALTH; CHILD; CONSEQUENCES; DISPARITIES AB Purpose Inconsistent evidence of a relationship between neighborhood disadvantage and adolescent mental health may be, in part, attributable to heterogeneity based on urban or rural residence. Using the largest nationally representative survey of US adolescent mental health available, we estimated the association between neighborhood disadvantage and adolescent emotional disorders and the extent to which urbanicity modified this association. Methods The National Comorbidity Survey Replication Adolescent Supplement (NCS-A) sampled adolescents aged 13-17 years (N = 10,123). Households were geocoded to Census tracts. Using a propensity score approach that addresses bias from non-random selection of individuals into neighborhoods, logistic regression models were used to estimate the relative odds of having a DSM-IV emotional disorder (any past-year anxiety disorder, major depressive disorder or dysthymia) comparing similar adolescents living in disadvantaged versus non-disadvantaged neighborhoods in urban center, urban fringe, and non-urban areas. Results The association between neighborhood disadvantage and emotional disorder was more than twice as large for adolescents living in urban centers versus non-urban areas. In urban centers, living in a disadvantaged neighborhood was associated with 59% (95% confidence interval 25-103) increased adjusted odds of emotional disorder. Conclusions Urbanicity modifies the relationship between neighborhood disadvantage and emotional disorder in adolescents. This effect modification may explain why evidence of a relationship between neighborhood disadvantage and adolescent mental health has been inconsistent. Recognizing the joint influence of neighborhood socioeconomic context and urbanicity may improve specificity in identifying relevant neighborhood processes. C1 [Rudolph, Kara E.; Glass, Thomas A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Rudolph, Kara E.; Stuart, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Stuart, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Merikangas, Kathleen R.] NIMH, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. RP Rudolph, KE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St,E6541, Baltimore, MD 21205 USA. EM krudolph@jhsph.edu OI Glass, Thomas/0000-0003-4399-612X; Stuart, Elizabeth/0000-0002-9042-8611 FU National Institute of Mental Health at the National Institutes of Health; National Institute of Mental Health [U01-MH60220]; National Institute of Drug Abuse at the National Institutes of Mental Health [R01 DA016558] FX The authors wish to express their gratitude to NCS-A participants and study team who made this work possible. The authors also wish to thank Kathy Georgiades for helpful comments on a previous version of the manuscript and Vanya Aggarwal for help with Census data abstraction. Results from this paper were presented as a poster at the 45th Annual Society for Epidemiologic Research Meeting, Minneapolis, Minnesota, June 29, 2012. The Intramural Research Program of the National Institute of Mental Health at the National Institutes of Health supported this work. The National Comorbidity Survey Replication Adolescent Supplement (NCS-A) and the larger program of related National Comorbidity Surveys are supported by the National Institute of Mental Health [U01-MH60220] and the National Institute of Drug Abuse [R01 DA016558] at the National Institutes of Mental Health. The NCS-A was carried out in conjunction with the World Health Organization World Mental Health Survey Initiative. The views and opinions expressed in this article are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies, or US Government. NR 40 TC 7 Z9 7 U1 1 U2 8 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0933-7954 EI 1433-9285 J9 SOC PSYCH PSYCH EPID JI Soc. Psychiatry Psychiatr. Epidemiol. PD MAR PY 2014 VL 49 IS 3 BP 467 EP 475 DI 10.1007/s00127-013-0725-8 PG 9 WC Psychiatry SC Psychiatry GA AE7FP UT WOS:000334162600013 PM 23754682 ER PT J AU Clayton, EW McCullough, LB Biesecker, LG Joffe, S Ross, LF Wolf, SM AF Clayton, Ellen Wright McCullough, Laurence B. Biesecker, Leslie G. Joffe, Steven Ross, Lainie Friedman Wolf, Susan M. CA Clin Sequencing Exploratory Res TI Addressing the Ethical Challenges in Genetic Testing and Sequencing of Children SO AMERICAN JOURNAL OF BIOETHICS LA English DT Article DE pediatrics; ethics; risks; exome sequencing; best interests of the child; benefits; interests of child and family; genome sequencing ID INCIDENTAL FINDINGS; BREAST-CANCER; RISK; RECOMMENDATIONS; ADOLESCENTS; ISSUES AB American Academy of Pediatrics (AAP) and American College of Medical Genetics (ACMG) recently provided two recommendations about predictive genetic testing of children. The Clinical Sequencing Exploratory Research Consortium's Pediatrics Working Group compared these recommendations, focusing on operational and ethical issues specific to decision making for children. Content analysis of the statements addresses two issues: (1) how these recommendations characterize and analyze locus of decision making, as well as the risks and benefits of testing, and (2) whether the guidelines conflict or come to different but compatible conclusions because they consider different testing scenarios. These statements differ in ethically significant ways. AAP/ACMG analyzes risks and benefits using best interests of the child and recommends that, absent ameliorative interventions available during childhood, clinicians should generally decline to order testing. Parents authorize focused tests. ACMG analyzes risks and benefits using the interests of the child and other family members and recommends that sequencing results be examined for additional variants that can lead to ameliorative interventions, regardless of age, which laboratories should report to clinicians who should contextualize the results. Parents must accept additional analysis. The ethical arguments in these statements appear to be in tension with each other. C1 [Clayton, Ellen Wright] Vanderbilt Univ, Nashville, TN 37232 USA. [McCullough, Laurence B.] Baylor Coll Med, Houston, TX 77030 USA. [Biesecker, Leslie G.] Natl Hlth Genome Res Inst, Bethesda, MD USA. [Joffe, Steven] Univ Penn, Philadelphia, PA 19104 USA. [Ross, Lainie Friedman] Univ Chicago, Chicago, IL 60637 USA. [Wolf, Susan M.] Univ Minnesota, Minneapolis, MN 55455 USA. RP Clayton, EW (reprint author), Vanderbilt Univ, Ctr Biomed Eth & Soc, 2525 West End Ave,Suite 400, Nashville, TN 37232 USA. EM Ellen.clayton@vanderbilt.edu OI Clayton, Ellen/0000-0002-0308-4110; Joffe, Steven/0000-0002-0667-7384 FU NIH/NCI/NHGRI [1R01CA154517]; Robert Wood Johnson Foundation [69763, 1U01HG006492, 1U01HG006485-01]; ClinSeq [ZIA HG 200359-05]; [NHGRI 1R21HG00612-01] FX Funding sources were NHGRI 1R21HG00612-01 (Clayton, PI), NIH/NCI/NHGRI # 1R01CA154517 (Petersen, Koenig, Wolf, PIs), Robert Wood Johnson Foundation numbers 69763 (Wolf, PI), 1U01HG006492 (Garraway, Janne, PIs), and 1U01HG006485-01 (Plon, Parsons, PIs), and ClinSeq, ZIA HG 200359-05 (Biesecker, PI). NR 18 TC 39 Z9 39 U1 5 U2 29 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD MAR 1 PY 2014 VL 14 IS 3 BP 3 EP 9 DI 10.1080/15265161.2013.879945 PG 7 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA AC0PZ UT WOS:000332198500002 PM 24592828 ER PT J AU Berkman, BE Hull, SC AF Berkman, Benjamin E. Hull, Sara Chandros TI The "Right Not to Know" in the Genomic Era: Time to Break From Tradition? SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material ID INCIDENTAL FINDINGS; HUNTINGTONS-DISEASE; CLINICAL GENOMICS; RECOMMENDATIONS; CHILDREN C1 [Berkman, Benjamin E.; Hull, Sara Chandros] Natl Inst Hlth, Bethesda, MD USA. RP Berkman, BE (reprint author), NHGRI, Dept Bioeth, Clin Ctr, NIH, Bldg 10,Room 1C141,10 Ctr Dr,MSC 1156, Bethesda, MD 20892 USA. EM berkmanbe@mail.nih.gov FU Intramural NIH HHS [Z99 HG999999] NR 19 TC 4 Z9 4 U1 0 U2 5 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD MAR 1 PY 2014 VL 14 IS 3 BP 28 EP 31 DI 10.1080/15265161.2014.880313 PG 4 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA AC0PZ UT WOS:000332198500011 PM 24592837 ER PT J AU Nugent, AC Diazgranados, N Carlson, PJ Ibrahim, L Luckenbaugh, DA Brutsche, N Herscovitch, P Drevets, WC Zarate, CA AF Nugent, Allison C. Diazgranados, Nancy Carlson, Paul J. Ibrahim, Lobna Luckenbaugh, David A. Brutsche, Nancy Herscovitch, Peter Drevets, Wayne C. Zarate, Carlos A., Jr. TI Neural correlates of rapid antidepressant response to ketamine in bipolar disorder SO BIPOLAR DISORDERS LA English DT Article DE ketamine; bipolar disorder; N-methyl d-aspartate (NMDA) antagonist; positron emission tomography (PET); imaging ID ANTERIOR CINGULATE CORTEX; MAJOR DEPRESSIVE DISORDER; TRANSCRANIAL MAGNETIC STIMULATION; MEDIAL PREFRONTAL CORTEX; ADD-ON TRIAL; DOPAMINE RELEASE; TRANSCRIPT EXPRESSION; TRYPTOPHAN DEPLETION; GLUCOSE-METABOLISM; STRIATAL DOPAMINE AB Objectives Ketamine, an N-methyl d-aspartate (NMDA) antagonist, has rapid antidepressant effects in depressed subjects with bipolar disorder (BD). Evidence supports a role for the glutamatergic system in the pathophysiology of BD. This double-blind, randomized, cross-over study sought to determine cerebral metabolic correlates of antidepressant response to ketamine. Methods Twenty-one subjects with BD currently in a depressed state underwent [F-18]-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging after receiving a placebo infusion as well as after receiving a ketamine infusion. Metabolism was compared between ketamine and placebo infusions, and correlated with clinical response. Regional metabolic rate of glucose (rMRGlu) in regions of interest (ROIs) and Montgomery-angstrom sberg Depression Rating Scale (MADRS) scores were the main outcome measures. Results The study found that change in metabolism between sessions was significantly correlated with percentage change in MADRS scores in the right ventral striatum; subjects who showed the greatest improvement had the largest metabolic increase after ketamine infusion compared to placebo. In a voxel-wise analysis, subjects with BD had significantly lower glucose metabolism in the left hippocampus following the ketamine infusion than following the placebo infusion. In addition, metabolism in the subgenual anterior cingulate cortex (ACC) following the placebo infusion was positively correlated with percentage improvement in MADRS score following the ketamine infusion. Conclusions Taken together, the results suggest that higher activity in the subgenual ACC may predict antidepressant response to ketamine. Ketamine administration altered glucose metabolism in areas known to be involved in mood disorders; these alterations may partially underlie ketamine's mechanism of action. C1 [Nugent, Allison C.; Diazgranados, Nancy; Ibrahim, Lobna; Luckenbaugh, David A.; Brutsche, Nancy; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Carlson, Paul J.] Univ Utah, Sch Med, Salt Lake City Vet Affairs Med, Salt Lake City, UT USA. [Carlson, Paul J.] Univ Utah, Sch Med, Dept Psychiat, Salt Lake City, UT 84112 USA. [Herscovitch, Peter] NIH, Ctr Clin, PET Dept, Bethesda, MD 20892 USA. [Drevets, Wayne C.] Laureate Inst Brain Res, Dept Psychiat, Tulsa, OK USA. [Drevets, Wayne C.] Univ Oklahoma, Coll Med, Tulsa, OK USA. [Drevets, Wayne C.] Johnson & Johnson Pharmaceut Res & Dev, Titusville, NJ USA. RP Zarate, CA (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, NIH, 10 Ctr Dr CRC,Room 7-5342,MSC 1282, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov OI Nugent, Allison/0000-0003-2569-2480 FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). The authors thank the 7SE research unit and staff for their support. Ioline Henter provided invaluable editorial assistance. NR 44 TC 25 Z9 25 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2014 VL 16 IS 2 BP 119 EP 128 DI 10.1111/bdi.12118 PG 10 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AC0TR UT WOS:000332208700005 PM 24103187 ER PT J AU Suppes, T Frank, E DePaulo, JR Davis, L Zarate, CA Angst, J Fawcett, J AF Suppes, Trisha Frank, Ellen DePaulo, J. Raymond Davis, Lori Zarate, Carlos A., Jr. Angst, Jules Fawcett, Jan TI Letter to the Editor in response to 2012 article by Frances and Jones SO BIPOLAR DISORDERS LA English DT Letter DE DSM-5; hypomania criteria; bipolar II disorder ID CLASSIFICATION; DSM-5 C1 [Suppes, Trisha] Stanford Univ, Sch Med, Palo Alto Vet Hlth Care Syst, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. [Frank, Ellen] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [DePaulo, J. Raymond] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Davis, Lori] Univ Alabama Birmingham, Sch Med, Dept Psychiat, Birmingham, AL USA. [Zarate, Carlos A., Jr.] NIMH, Intramural Res Program, Expt Therapeut & Pathophysiol Branch, Bethesda, MD 20892 USA. [Angst, Jules] Univ Zurich, Hosp Psychiat, Zurich, Switzerland. [Fawcett, Jan] Univ New Mexico, Sch Med, Dept Psychiat, Albuquerque, NM 87131 USA. RP Suppes, T (reprint author), Stanford Univ, Sch Med, Palo Alto Vet Hlth Care Syst, Dept Psychiat & Behav Sci, 3801 Miranda Ave 151T, Palo Alto, CA 94304 USA. EM tsuppes@stanford.edu FU Intramural NIH HHS [Z99 MH999999] NR 4 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2014 VL 16 IS 2 BP 214 EP 215 DI 10.1111/bdi.12176 PG 2 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AC0TR UT WOS:000332208700017 PM 24597757 ER PT J AU Galiatsatos, P Gibson, BR Rabiee, A Carlson, O Egan, JM Shannon, RP Andersen, DK Elahi, D AF Galiatsatos, Panagis Gibson, B. Robert Rabiee, Atoosa Carlson, Olga Egan, Josephine M. Shannon, Richard P. Andersen, Dana K. Elahi, Dariush TI The Glucoregulatory Benefits of Glucagon-Like Peptide-1 (7-36) Amide Infusion During Intensive Insulin Therapy in Critically Ill Surgical Patients: A Pilot Study SO CRITICAL CARE MEDICINE LA English DT Article DE GLP-1 (7-36) amide; hypoglycemia; intensive insulin therapy; surgical intensive care unit ID TIGHT GLYCEMIC CONTROL; GLUCOSE CONTROL; BLOOD-GLUCOSE; GLP-1; ICU; METAANALYSIS; SURGERY AB Objectives: Intensive insulin therapy for tight glycemic control in critically ill surgical patients has been shown to reduce mortality; however, intensive insulin therapy is associated with iatrogenic hypoglycemia and increased variability of blood glucose levels. The incretin glucagon-like peptide-1 (7-36) amide is both insulinotropic and insulinomimetic and has been suggested as an adjunct to improve glycemic control in critically ill patients. We hypothesized that the addition of continuous infusion of glucagon-like peptide-1 to intensive insulin therapy would result in better glucose control, reduced requirement of exogenous insulin administration, and fewer hypoglycemic events. Design: Prospective, randomized, double-blind, placebo-controlled clinical trial. Setting: Surgical or burn ICU. Patients: Eighteen patients who required intensive insulin therapy. Interventions: A 72-hour continuous infusion of either glucagon-like peptide-1 (1.5 pmol/kg/min) or normal saline plus intensive insulin therapy. Measurements and Main Results: The glucagon-like peptide-1 cohort (n = 9) and saline cohort (n = 9) were similar in age, Acute Physiology and Chronic Health Evaluation score, and history of diabetes. Blood glucose levels in the glucagon-like peptide-1 group were better controlled with much less variability. The coefficient of variation of blood glucose ranged from 7.2% to 30.4% in the glucagon-like peptide-1 group and from 19.8% to 56.8% in saline group. The mean blood glucose coefficient of variation for the glucagon-like peptide-1 and saline groups was 18.0% 2.7% and 30.3% +/- 4.0% (p = 0.010), respectively. The 72-hour average insulin infusion rates were 3.37 +/- 0.61 and 4.57 +/- 1.18 U/hr (p = not significant). The incidents of hypoglycemia ( 2.78 mmol/L) in both groups were low (one in the glucagon-like peptide-1 group, three in the saline group). Conclusions: Glucagon-like peptide-1 (7-36) amide is a safe and efficacious form of adjunct therapy in patients with hyperglycemia in the surgical ICU setting. Improved stability of blood glucose is a favorable outcome, which enhances the safety of intensive insulin therapy. Larger studies of this potentially valuable therapy for glycemic control in the ICU are justified. C1 [Galiatsatos, Panagis] Johns Hopkins Univ, Sch Med, Dept Med, Johns Hopkins Bayview Med Ctr, Baltimore, MD 21205 USA. [Gibson, B. Robert; Rabiee, Atoosa; Andersen, Dana K.] Johns Hopkins Univ, Sch Med, Dept Surg, Johns Hopkins Bayview Med Ctr, Baltimore, MD 21205 USA. [Carlson, Olga; Egan, Josephine M.] NIA, Clin Physiol Branch, Baltimore, MD 21224 USA. [Shannon, Richard P.; Elahi, Dariush] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Elahi, D (reprint author), Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. EM dariush.elahi@uphs.upenn.edu FU The Society of Critical Care Medicine; American Geriatrics Society; Pfizer; AstraZeneca/Bristol-Myers Squibb FX Dr. Gibson received support for research from The Society of Critical Care Medicine and Jahnigan Award of the American Geriatrics Society. Dr. Shannon consulted for Merck, Pfizer, and AstraZeneca/Bristol-Myers Squibb and is a board member with ABIM. He lectured for IRSW, BOMC Institute for Heart care Improvement (visiting professor). He has a patent with Ventrigen, LCC (founder). His institution received grant support from Pfizer and AstraZeneca/Bristol-Myers Squibb. Dr. Andersen is employed by Johns Hopkins University and the National Institutes of Health and consulted for Z-Medica (member scientific advisory board). He is a board member with the Association for Academic Surgery Foundation and lectured at scientific meetings and medical centers. He receives royalties from McGraw Hill (member, editorial board, textbook). Dr. Elahi consulted for Merck. The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 29 TC 6 Z9 7 U1 4 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD MAR PY 2014 VL 42 IS 3 BP 638 EP 645 DI 10.1097/CCM.0000000000000035 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA AA9AX UT WOS:000331387200046 PM 24247476 ER PT J AU Becker, RE Greig, NH AF Becker, Robert E. Greig, Nigel H. TI A New Regulatory Road-Map for Alzheimer's Disease Drug Development SO CURRENT ALZHEIMER RESEARCH LA English DT Article DE Alzheimer clinical trials; Alzheimer's disease; dementia trials; drug approval process; drug development; drug regulations ID TRIALS AB A surfeit of errors and an absence of sufficiently rigorous neuroscience theory have led to failures of neuroscience drug developments and to less effective patient care. Alzheimer's disease (AD) requires systematic grounding of drug developments with mechanistic explanations to replace current trial and error approaches to the development of potential drug products. We foresee the need for regulatory revisions that will provide better balanced supports for advancing the AD scientific knowledge required to more effectively develop clinically useful drugs and for provisions to patients of drug candidates soundly predicted, based on documented effects on AD neuropathologies and safety, to slow or arrest the progression of persons at-risk to AD dementia. We propose that investigators and regulators focus AD clinical research on understanding the inductions of reversible and irreversible neuropathologies and their roles in generating clinical dementia. In support of this, we foresee the need for regulatory changes to create a vehicle for these clinical studies; for example, conditional drug approvals based on drug induced neuropathological changes. C1 [Becker, Robert E.] Aristea Translat Med Corp, Freeport, ME USA. [Becker, Robert E.; Greig, Nigel H.] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD USA. RP Becker, RE (reprint author), Aristea Translat Med Corp, 7123 Pinebrook Rd, Park City, UT 84098 USA. EM rebecker2008@comcast.net FU Intramural NIH HHS [ZIA AG000311-14] NR 28 TC 6 Z9 6 U1 3 U2 11 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2050 EI 1875-5828 J9 CURR ALZHEIMER RES JI Curr. Alzheimer Res. PD MAR PY 2014 VL 11 IS 3 BP 215 EP 220 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AE5VT UT WOS:000334058100001 PM 24694075 ER PT J AU Greig, B Stetler-Stevenson, M Lea, J AF Greig, B. Stetler-Stevenson, M. Lea, J. TI Stabilization media increases recovery in paucicellular cerebrospinal fluid specimens submitted for flow cytometry testing SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Article DE cerebrospinal fluid; lymphoma; leukemia; stabilization media AB Background Flow cytometric immunophenotpying (FCI) of cerebrospinal fluid (CSF) and other paucicellular fluids has been demonstrated to have increased sensitivity in detection of lymphoma and leukemia when compared to cytomorphology [(1) de Graaf et al., Cytometry Part B 2011, 80B:271-281; (2) Szamosi et al., CLSI Document H56-A-Body Fluid Analysis for Cellular Composition; Approved Guideline, Wayne, PA: Clinical and Laboratory Standards Institute, 2006; (3) Kraan et al., Flow Cytometric Immunophenotyping of Cerebrospinal Fluid. Current Protocols in Cytometry, Hoboken, NJ: Wiley, 2008]. However, low cellularity has been an historical problem with these samples. Several studies indicate that immediate addition of a stabilization media (e.g., RPMI with fetal calf serum (FCS)) to CSF improves the cell yield for FCI [(1) de Graaf et al.]. Such stabilization medias can, however, significantly increase cost. Methods We compared FCI results in CSF stabilized with RPMI 1640 (without additional additives) to results obtained using non-stabilized CSF. Samples were processed according to published CLSI guidelines [(2) Szamosi et al.]. Results About 98/105 (93%) CSF specimens stabilized with RPMI had adequate numbers of viable cells (>100) for performing FCI. About 65/217 (30%) CSF specimens without stabilization had adequate numbers of viable cells for analysis (70% either quantity not sufficient (QNS) or specimen viability below analytical limits). Conclusions Utilizing RMPI without FCS as a stabilization media results in increased cell yield and improved FCI results. We have found FCS is not required to achieve high quality results in FCI of paucicellular CSF specimens. (c) 2013 International Clinical Cytometry Society C1 [Greig, B.; Lea, J.] Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37027 USA. [Stetler-Stevenson, M.] NCI, Pathol Lab, CCR, NIH, Bethesda, MD 20892 USA. RP Greig, B (reprint author), Vanderbilt Univ, Med Ctr, TVC 4518,1301 Med Ctr Dr, Nashville, TN 37027 USA. EM bruce.greig@Vanderbilt.edu NR 6 TC 3 Z9 3 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4949 EI 1552-4957 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD MAR PY 2014 VL 86 IS 2 BP 135 EP 138 DI 10.1002/cyto.b.21096 PG 4 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA AB4UY UT WOS:000331786600010 PM 23674507 ER PT J AU Teixeira-Coelho, M Guedes, J Ferreirinha, P Howes, A Pedrosa, J Rodrigues, F Lai, WS Blackshear, PJ O'Garra, A Castro, AG Saraiva, M AF Teixeira-Coelho, Maria Guedes, Joana Ferreirinha, Pedro Howes, Ashleigh Pedrosa, Jorge Rodrigues, Fernando Lai, Wi S. Blackshear, Perry J. O'Garra, Anne Castro, Antonio G. Saraiva, Margarida TI Differential post- transcriptional regulation of IL-10 by TLR2 and TLR4-activated macrophages SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE IL-10; MAPKs; Post-transcriptional regulation; TLRs ID ACTIVATED PROTEIN-KINASE; INNATE IMMUNE-RESPONSES; MYELOID DENDRITIC CELLS; MESSENGER-RNA STABILITY; TOLL-LIKE RECEPTOR-2; GENE-EXPRESSION; MEDIATED IL-10; CUTTING EDGE; P38 MAPK; POSTTRANSCRIPTIONAL REGULATION AB The activation of TLRs by microbial molecules triggers intracellular-signaling cascades and the expression of cytokines such as IL-10. Il10 expression is tightly controlled to ensure effective immune responses, while preventing pathology. Maximal TLR-induction of Il10 transcription in macrophages requires signaling through the MAPKs, ERK, and p38. Signals via p38 downstream of TLR4 activation also regulate IL-10 at the post-transcriptional level, but whether this mechanism operates downstream of other TLRs is not clear. We compared the regulation of IL-10 production in TLR2 and TLR4-stimulated BM-derived macrophages and found different stability profiles for the Il10 mRNA. TLR2 signals promoted a rapid induction and degradation of Il10 mRNA, whereas TLR4 signals protected Il10 mRNA from rapid degradation, due to the activation of Toll/IL-1 receptor domain-containing adaptor inducing IFN- (TRIF) and enhanced p38 signaling. This differential post-transcriptional mechanism contributes to a stronger induction of IL-10 secretion via TLR4. Our study provides a molecular mechanism for the differential IL-10 production by TLR2- or TLR4-stimulated BMMs, showing that p38-induced stability is not common to all TLR-signaling pathways. This mechanism is also observed upon bacterial activation of TLR2 or TLR4 in BMMs, contributing to IL-10 modulation in these cells in an infection setting. C1 [Teixeira-Coelho, Maria; Guedes, Joana; Ferreirinha, Pedro; Pedrosa, Jorge; Rodrigues, Fernando; Castro, Antonio G.; Saraiva, Margarida] Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst ICVS, P-4710057 Braga, Portugal. [Teixeira-Coelho, Maria; Guedes, Joana; Ferreirinha, Pedro; Pedrosa, Jorge; Rodrigues, Fernando; Castro, Antonio G.; Saraiva, Margarida] ICVS 3Bs PT Govt Associate Lab, Braga, Portugal. [Howes, Ashleigh; O'Garra, Anne] Natl Inst Med Res, MRC, London NW7 1AA, England. [Lai, Wi S.; Blackshear, Perry J.] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Saraiva, M (reprint author), Univ Minho, Sch Hlth Sci, ICVS, Campus Gualtar, P-4710057 Braga, Portugal. EM msaraiva@ecsaude.uminho.pt RI Ferreirinha, Pedro/J-6862-2013; Pedrosa, Jorge/H-4877-2011; OI Pedrosa, Jorge/0000-0002-8204-4888; Castro, Gil/0000-0002-4684-4183; Saraiva, Margarida/0000-0002-8180-1293; Ferreirinha, Pedro/0000-0002-9040-1099; O'Garra, Anne/0000-0001-9845-6134; Rodrigues, Fernando/0000-0001-8436-9398 FU Fundacao para a Ciencia e Tecnologia, Portugal; Programa Operacional Regional do Norte (ON.2-O Novo Norte), Quadro de Referencia Estrategico Nacional, through the Fundo Europeu de Desenvolvimento Regional [PTDC/SAU-MII/101977/2008, PTDC/BIA-BCM/102776/2008, SFRH/BD/3304/2006, UMINHO/BI/109/2010]; Medical Research Council, United Kingdom [U117565642]; NIH Intramural Research Program, NIEHS FX The authors thank the personnel at the ICVS animal house facility for excellent animal husbandry. This work has been funded by Fundacao para a Ciencia e Tecnologia, Portugal and cofunded by Programa Operacional Regional do Norte (ON.2-O Novo Norte), Quadro de Referencia Estrategico Nacional, through the Fundo Europeu de Desenvolvimento Regional. Project grants: PTDC/SAU-MII/101977/2008 and PTDC/BIA-BCM/102776/2008. Personal Grants: SFRH/BD/3304/2006 to MTC; PTDC/BIA-BCM/102776/2008, to JG; UMINHO/BI/109/2010 to PF. AOG and AH were funded by the Medical Research Council, United Kingdom (U117565642). Work performed in PJB laboratory was supported by the NIH Intramural Research Program, NIEHS. MS was a Ciencia 2007 fellow and is currently an FCT Investigator fellow. NR 50 TC 9 Z9 9 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD MAR PY 2014 VL 44 IS 3 BP 856 EP 866 DI 10.1002/eji.201343734 PG 11 WC Immunology SC Immunology GA AD0OG UT WOS:000332933200026 PM 24227629 ER PT J AU Maravillas-Montero, JL Lopez-Ortega, O Patino-Lopez, G Santos-Argumedo, L AF Maravillas-Montero, Jose L. Lopez-Ortega, Orestes Patino-Lopez, Genaro Santos-Argumedo, Leopoldo TI Myosin 1g regulates cytoskeleton plasticity,cell migration,exocytosis,and endocytosis in B lymphocytes SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE B lymphocyte; Chemotaxis; Cytoskeleton; Exo-endocytosis; Myosin ID CLASS-I MYOSIN; MEMBRANE TENSION; ENTAMOEBA-HISTOLYTICA; SIGNAL-TRANSDUCTION; PLASMA-MEMBRANE; IMMUNE CELLS; BINDING; PROTEIN; LOCALIZATION; PHAGOCYTOSIS AB Myosin 1g (Myo1g) is a hematopoietic-specific myosin expressed mainly by lymphocytes. Here, we report the localization of Myo1g in B-cell membrane compartments such as lipid rafts, microvilli, and membrane extensions formed during spreading. By using Myo1g-deficient mouse B cells, we detected abnormalities in the adhesion ability and chemokine-induced directed migration of these lymphocytes. We also assessed a role for Myo1g in phagocytosis and exocytosis processes, as these were also irregular in Myo1g-deficient B cells. Taken together, our results show that Myo1g acts as a main regulator of different membrane/cytoskeleton-dependent processes in B lymphocytes. C1 [Maravillas-Montero, Jose L.; Lopez-Ortega, Orestes; Santos-Argumedo, Leopoldo] Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Biomed Mol, Mexico City, DF, Mexico. [Patino-Lopez, Genaro] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Santos-Argumedo, L (reprint author), IPN, Ctr Invest & Estudios Avanzados, Dept Biomed Mol, Ave IPN 2508, Mexico City 07360, DF, Mexico. EM lesantos@cinvestav.mx OI Santos-Argumedo, Leopoldo/0000-0002-4772-0713; Patino-Lopez, Genaro/0000-0002-8716-722X FU CONACyT [153733, 203768, 219624] FX We thank Steve Shaw from NCI, NIH for providing Myo1g-/- mice, Eduardo Garcia-Zepeda for the CXCL13, Karina Chavez-Rueda and Araceli Perez-Lopez for the ELISA reagents, Rommel Chacon-Salinas for the anti-CXCR5, Maria Eugenia Mendoza-Garrido for the anti-prolactin, and Amanda M. Burkhardt and Tristan K. Zimmerman for the review of the manuscript. We also thank Hector Romero-Ramirez and Julio Garcia-Cordero for their help at different stages of this work. This work was supported by CONACyT (grant 153733). J.L.M.M. and O.L.O. were supported by fellowships 203768 and 219624 from CONACyT. NR 52 TC 7 Z9 7 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD MAR PY 2014 VL 44 IS 3 BP 877 EP 886 DI 10.1002/eji.201343873 PG 10 WC Immunology SC Immunology GA AD0OG UT WOS:000332933200028 PM 24310084 ER PT J AU Quagliata, L Matter, MS Piscuoglio, S Arabi, L Ruiz, C Procino, A Kovac, M Moretti, F Makowska, Z Boldanova, T Andersen, JB Hammerle, M Tornillo, L Heim, MH Diederichs, S Cillo, C Terracciano, LM AF Quagliata, Luca Matter, Matthias S. Piscuoglio, Salvatore Arabi, Leila Ruiz, Christian Procino, Alfredo Kovac, Michal Moretti, Francesca Makowska, Zuzanna Boldanova, Tujana Andersen, Jesper B. Haemmerle, Monika Tornillo, Luigi Heim, Markus H. Diederichs, Sven Cillo, Clemente Terracciano, Luigi M. TI Long Noncoding RNA HOTTIP/HOXA13 Expression is Associated With Disease Progression and Predicts Outcome in Hepatocellular Carcinoma Patients SO HEPATOLOGY LA English DT Article ID HOX GENES; LIVER-CANCER; IN-VITRO; CHROMATIN; HOMEOBOX; PATHOGENESIS; PROTEINS; HOTAIR; CELLS; CARCINOGENESIS AB Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death. Despite the advances in diagnosis and management of HCC, the biology of this tumor remains poorly understood. Recent evidence highlighted long noncoding RNAs (lncRNAs) as crucial determinants of HCC development. In this study we report the lncRNA HOXA transcript at the distal tip (HOTTIP) as significantly up-regulated in HCC specimens. The HOTTIP gene is located in physical contiguity with HOXA13 and directly controls the HOXA locus gene expression by way of interaction with the WDR5/MLL complex. HOX genes encode transcription factors regulating embryonic development and cell fate. We previously described HOX genes deregulation to be involved in hepatocarcinogenesis. Indeed, we observed the marked up-regulation of HOXA13 in HCC. Here, by correlating clinicopathological and expression data, we demonstrate that the levels of HOTTIP and HOXA13 are associated with HCC patients' clinical progression and predict disease outcome. In contrast to the majority of similar studies, our data were obtained from snap-frozen needle HCC biopsies (n=52) matched with their nonneoplastic counterparts collected from patients who had not yet received any HCC-tailored therapeutic treatments at the time of biopsy. In addition, taking advantage of gain and loss of function experiments in liver cancer-derived cell lines (HuH-6 and HuH-7), we uncover a novel bidirectional regulatory loop between HOTTIP/HOXA13. Conclusion: Our study highlights the key role of HOTTIP and HOXA13 in HCC development by associating their expression with metastasis and survival in HCC patients, provides novel insights on the function of lncRNA-driven hepatocarcinogenesis, and paves the way for further investigation about the possible role of HOTTIP as a predictive biomarker of HCC. (Hepatology 2014;59:911-923) C1 [Quagliata, Luca; Matter, Matthias S.; Piscuoglio, Salvatore; Arabi, Leila; Ruiz, Christian; Kovac, Michal; Tornillo, Luigi; Terracciano, Luigi M.] Univ Basel Hosp, Mol Pathol Div, Inst Pathol, CH-4003 Basel, Switzerland. [Matter, Matthias S.; Andersen, Jesper B.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Piscuoglio, Salvatore] Univ Basel, Res Grp Human Genet, Dept Biomed, Basel, Switzerland. [Piscuoglio, Salvatore] Univ Childrens Hosp, Div Med Genet, Basel, Switzerland. [Procino, Alfredo; Cillo, Clemente] Univ Naples Federico II, Sch Med, Dept Clin Med & Surg, I-80031 Naples, Italy. [Moretti, Francesca] Univ Basel, Inst Biochem & Genet, Dept Biomed, Basel, Switzerland. [Makowska, Zuzanna; Boldanova, Tujana; Heim, Markus H.] Univ Basel, Hepatol Lab, Dept Biomed, Basel, Switzerland. [Haemmerle, Monika; Diederichs, Sven] German Canc Res Ctr, Helmholtz Univ Grp Mol RNA Biol & Canc, Heidelberg, Germany. [Haemmerle, Monika; Diederichs, Sven] Univ Heidelberg Hosp, Inst Pathol, Heidelberg, Germany. RP Terracciano, LM (reprint author), Univ Basel Hosp, Mol Pathol Div, Inst Pathol, Schonbeinstr 40, CH-4003 Basel, Switzerland. EM clecillo@unina.it; lterracciano@uhbs.ch RI Diederichs, Sven/J-6237-2012; Quagliata, Luca/B-8321-2015; OI Diederichs, Sven/0000-0001-7901-4752; Quagliata, Luca/0000-0001-8249-9914; Procino, Alfredo/0000-0002-2729-2133; Tornillo, Luigi/0000-0003-3610-3733; Andersen , Jesper B/0000-0003-1760-5244; Piscuoglio, Salvatore/0000-0003-2686-2939; Heim, Markus/0000-0002-7523-4894 FU Swiss Cancer League (Oncosuisse) [KLS-2867-08-2011]; Schweizerische Stifung fur Medizinisch-Biologische Stipendien [PASMP-3_140071]; German Research Foundation [DFG TRR77 TP B03] FX Supported by Swiss Cancer League (Oncosuisse) grant KLS-2867-08-2011 to L. M. T.; M. S. M. is supported by Schweizerische Stifung fur Medizinisch-Biologische Stipendien (PASMP-3_140071); HCC research in the lab of S. D. is supported by the German Research Foundation (DFG TRR77 TP B03). NR 50 TC 108 Z9 112 U1 9 U2 52 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 MAR PY 2014 VL 59 IS 3 BP 911 EP 923 DI 10.1002/hep.26740 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AB4VH UT WOS:000331787500022 PM 24114970 ER PT J AU Kwon, HJ Won, YS Park, O Feng, DC Gao, B AF Kwon, Hyo-Jung Won, Young-Suk Park, Ogyi Feng, Dechun Gao, Bin TI Opposing Effects of Prednisolone Treatment on T/NKT Cell- and Hepatotoxin-Mediated Hepatitis in Mice SO HEPATOLOGY LA English DT Article ID SEVERE ALCOHOLIC HEPATITIS; INFLAMMATORY LIVER-INJURY; AUTOIMMUNE HEPATITIS; DISEASE; MECHANISMS; CORTICOSTEROIDS; GLUCOCORTICOIDS; PATHOGENESIS; MACROPHAGES; NEUTROPHILS AB Prednisolone is a corticosteroid that has been used to treat inflammatory liver diseases such as autoimmune hepatitis and alcoholic hepatitis. However, the results have been controversial, and how prednisolone affects liver disease progression remains unknown. In the current study we examined the effect of prednisolone treatment on several models of liver injury, including T/NKT cell hepatitis induced by concanavalin A (ConA) and -galactosylceramide (-GalCer), and hepatotoxin-mediated hepatitis induced by carbon tetrachloride (CCl4) and/or ethanol. Prednisolone administration attenuated ConA- and -GalCer-induced hepatitis and systemic inflammatory responses. Treating mice with prednisolone also suppressed inflammatory responses in a model of hepatotoxin (CCl4)-induced hepatitis, but surprisingly exacerbated liver injury and delayed liver repair. In addition, administration of prednisolone also enhanced acetaminophen-, ethanol-, or ethanol plus CCl4-induced liver injury. Immunohistochemical and flow cytometric analyses demonstrated that prednisolone treatment inhibited hepatic macrophage and neutrophil infiltration in CCl4-induced hepatitis and suppressed their phagocytic activities in vivo and in vitro. Macrophage and/or neutrophil depletion aggravated CCl4-induced liver injury and impeded liver regeneration. Finally, conditional disruption of glucocorticoid receptor in macrophages and neutrophils abolished prednisolone-mediated exacerbation of hepatotoxin-induced liver injury. Conclusion: Prednisolone treatment prevents T/NKT cell hepatitis but exacerbates hepatotoxin-induced liver injury by inhibiting macrophage- and neutrophil-mediated phagocytic and hepatic regenerative functions. These findings may not only increase our understanding of the steroid treatment mechanism but also help us to better manage steroid therapy in liver diseases. (Hepatology 2014;59:1094-1106) C1 [Kwon, Hyo-Jung; Won, Young-Suk; Park, Ogyi; Feng, Dechun; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. [Kwon, Hyo-Jung] Chungnam Natl Univ, Coll Vet Med, Taejon, South Korea. [Won, Young-Suk] Korea Res Inst Biosci & Biotechnol, Lab Anim Resource Ctr, Chungbuk, South Korea. RP Gao, B (reprint author), NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov RI Feng, Dechun/Q-5962-2016 FU NIAAA, NIH FX Supported by the intramural program of the NIAAA, NIH. NR 45 TC 12 Z9 14 U1 0 U2 5 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 MAR PY 2014 VL 59 IS 3 BP 1094 EP 1106 DI 10.1002/hep.26748 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AB4VH UT WOS:000331787500038 PM 24115096 ER PT J AU Everhart, JE Wright, E AF Everhart, James E. Wright, Elizabeth TI Relating Serum GGT to ALT Activity Enhances Its Predictability on Treatment Outcome in Chronic Hepatitis C Reply SO HEPATOLOGY LA English DT Letter C1 [Everhart, James E.; Wright, Elizabeth] NIDDK, NIH, Bethesda, MD 20892 USA. RP Everhart, JE (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 DK999999] NR 2 TC 0 Z9 0 U1 0 U2 2 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 MAR PY 2014 VL 59 IS 3 BP 1214 EP 1215 DI 10.1002/hep.26650 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AB4VH UT WOS:000331787500056 PM 23913832 ER PT J AU Terse, P Engelke, K Chan, K Ling, YH Sharpnack, D Saunthararajah, Y Covey, JM AF Terse, Pramod Engelke, Kory Chan, Kenneth Ling, Yonghua Sharpnack, Douglas Saunthararajah, Yogen Covey, Joseph M. TI Subchronic Oral Toxicity Study of Decitabine in Combination With Tetrahydrouridine in CD-1 Mice SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Article DE hematopoietic tissue; tetrahydrouridine; decitabine; combination therapy; lymphoid tissue; CD-1 mice ID FETAL-HEMOGLOBIN LEVELS; SICKLE-CELL-ANEMIA; GAMMA-GLOBIN; PAPIO-ANUBIS; 5-AZA-2'-DEOXYCYTIDINE; PHARMACOKINETICS; GEMCITABINE; 3,4,5,6-TETRAHYDROURIDINE; BIOAVAILABILITY; 5-AZACYTIDINE AB Decitabine (5-aza-2 '-deoxycytidine; DAC) in combination with tetrahydrouridine (THU) is a potential oral therapy for sickle cell disease and beta-thalassemia. A study was conducted in mice to assess safety of this combination therapy using oral gavage of DAC and THU administered 1 hour prior to DAC on 2 consecutive days/week for up to 9 weeks followed by a 28-day recovery to support its clinical trials up to 9-week duration. Tetrahydrouridine, a competitive inhibitor of cytidine deaminase, was used in the combination to improve oral bioavailability of DAC. Doses were 167 mg/kg THU followed by 0, 0.2, 0.4, or 1.0 mg/kg DAC; THU vehicle followed by 1.0 mg/kg DAC; or vehicle alone. End points evaluated were clinical observations, body weights, food consumption, clinical pathology, gross/histopathology, bone marrow micronuclei, and toxicokinetics. There were no treatment-related effects noticed on body weight, food consumption, serum chemistry, or urinalysis parameters. Dose- and gender-dependent changes in plasma DAC levels were observed with a C-max within 1 hour. At the 1 mg/kg dose tested, THU increased DAC plasma concentration (similar to 10-fold) as compared to DAC alone. Severe toxicity occurred in females receiving high-dose 1 mg/kg DAC + THU, requiring treatment discontinuation at week 5. Severity and incidence of microscopic findings increased in a dose-dependent fashion; findings included bone marrow hypocellularity (with corresponding hematologic changes and decreases in white blood cells, red blood cells, hemoglobin, hematocrit, reticulocytes, neutrophils, and lymphocytes), thymic/lymphoid depletion, intestinal epithelial apoptosis, and testicular degeneration. Bone marrow micronucleus analysis confirmed bone marrow cytotoxicity, suppression of erythropoiesis, and genotoxicity. Following the recovery period, a complete or trend toward resolution of these effects was observed. In conclusion, the combination therapy resulted in an increased sensitivity to DAC toxicity correlating with DAC plasma levels, and females are more sensitive compared to their male counterparts. C1 [Terse, Pramod] Natl Ctr Adv Translat Sci, Bethesda, MD USA. [Engelke, Kory] AVANZA Labs LLC, Gaithersburg, MD USA. [Chan, Kenneth; Ling, Yonghua] Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. [Sharpnack, Douglas] Vet Path Serv Inc, Mason, OH USA. [Saunthararajah, Yogen] Cleveland Clin, Cleveland, OH 44106 USA. [Covey, Joseph M.] NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. RP Terse, P (reprint author), Natl Ctr Adv Translat Sci, Div Preclin Innovat, Bethesda, MD 20892 USA. EM tersep@mail.nih.gov FU NCI [N01-CM-42204, N01-CM-52205]; NHLBI; NIDDK under NIH-BrIDGs Program; National Institutes of Health [1R01CA138858]; Department of Defense [PR081404] FX The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This study was supported by NCI contract N01-CM-42204, N01-CM-52205, and NHLBI and NIDDK under NIH-BrIDGs Program. YS is supported by National Institutes of Health (1R01CA138858) and Department of Defense (PR081404). NR 20 TC 1 Z9 1 U1 0 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1091-5818 EI 1092-874X J9 INT J TOXICOL JI Int. J. Toxicol. PD MAR PY 2014 VL 33 IS 2 BP 75 EP 85 DI 10.1177/1091581814524994 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA AE4TN UT WOS:000333976700001 PM 24639139 ER PT J AU Picard, N Trompf, K Yang, CL Miller, RL Carrel, M Loffing-Cueni, D Fenton, RA Ellison, DH Loffing, J AF Picard, Nicolas Trompf, Katja Yang, Chao-Ling Miller, R. Lance Carrel, Monique Loffing-Cueni, Dominique Fenton, Robert A. Ellison, David H. Loffing, Johannes TI Protein Phosphatase 1 Inhibitor-1 Deficiency Reduces Phosphorylation of Renal NaCl Cotransporter and Causes Arterial Hypotension SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID NA+-CL-COTRANSPORTER; SODIUM-CHLORIDE COTRANSPORTER; BLOOD-PRESSURE; GENE-EXPRESSION; MOUSE KIDNEY; PHOSPHOPROTEIN DARPP-32; TRANSPORTER ABUNDANCES; GITELMANS-SYNDROME; CAUSE HYPERTENSION; BARTTERS-SYNDROME AB The thiazide-sensitive NaCl cotransporter (NCC) of the renal distal convoluted tubule (DCT) controls ion homeostasis and arterial BP. Loss-of-function mutations of NCC cause renal salt wasting with arterial hypotension (Gitelman syndrome). Conversely, mutations in the NCC-regulating WNK kinases or kelch-like 3 protein cause familial hyperkalemic hypertension. Here, we performed automated sorting of mouse DCTs and microarray analysis for comprehensive identification of novel DCT-enriched gene products, which may potentially regulate DCT and NCC function. This approach identified protein phosphatase 1 inhibitor-1 (I-1) as a DCT-enriched transcript, and immunohistochemistry revealed I-1 expression in mouse and human DCTs and thick ascending limbs. In heterologous expression systems, coexpression of NCC with I-1 increased thiazide-dependent Na+ uptake, whereas RNAi-mediated knockdown of endogenous I-1 reduced NCC phosphorylation. Likewise, levels of phosphorylated NCC decreased by approximately 50% in I-1 (I-1(-/-)) knockout mice without changes in total NCC expression. The abundance and phosphorylation of other renal sodium-transporting proteins, including NaPi-IIa, NKCC2, and ENaC, did not change, although the abundance of pendrin increased in these mice. The abundance, phosphorylation, and subcellular localization of SPAK were similar in wild-type (WT) and I-1(-/-) mice. Compared with WT mice, I-1(-/-) mice exhibited significantly lower arterial BP but did not display other metabolic features of NCC dysregulation. Thus, I-1 is a DCT-enriched gene product that controls arterial BP, possibly through regulation of NCC activity. C1 [Picard, Nicolas; Trompf, Katja; Carrel, Monique; Loffing-Cueni, Dominique; Loffing, Johannes] Univ Zurich, Inst Anat, CH-8057 Zurich, Switzerland. [Picard, Nicolas] Univ Paris 05, INSERM, Paris Cardiovasc Res Ctr, U970, Paris, France. [Yang, Chao-Ling; Ellison, David H.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Miller, R. Lance] NHLBI, NIH, Bethesda, MD 20892 USA. [Fenton, Robert A.] Aarhus Univ, Dept Biomed, Aarhus, Denmark. RP Loffing, J (reprint author), Univ Zurich, Inst Anat, Winterthurerstr 190, CH-8057 Zurich, Switzerland. EM johannes.loffing@anatom.uzh.ch RI Picard, Nicolas/B-6677-2012; OI Picard, Nicolas/0000-0002-1695-3389; Ellison, David/0000-0003-2915-265X FU Societe francaise d'Hypertension Arterielle; Fondation du Rein; Agence Nationale de la Recherche [BLANC 2010-R10164DD]; Danish Medical Research Council; Lundbeck Foundation; National Institutes of Health [R01 DK51496, R01 1RO1 DK095841]; Department of Veterans Affairs; Swiss National Science Foundation [310000-122243/1, 310030_143929/1]; National Centre of Competence in Research Kidney.CH; Zurich Centre for Integrative Human Physiology; EMDO Foundation FX N.P. is supported by grants from the Societe francaise d'Hypertension Arterielle and Fondation du Rein and Agence Nationale de la Recherche Programme Grant BLANC 2010-R10164DD. Funding to R.A.F. is provided by the Danish Medical Research Council and Lundbeck Foundation. The laboratory of D.H.E. is supported by Grants R01 DK51496 and R01 1RO1 DK095841 from the National Institutes of Health and Merit Review funds from the Department of Veterans Affairs. The laboratory of J.L. is supported by Swiss National Science Foundation Project Grants 310000-122243/1 and 310030_143929/1, the National Centre of Competence in Research Kidney.CH, and the Zurich Centre for Integrative Human Physiology.; This study is part of the thesis of K.T., who received salary support from the EMDO Foundation. NR 60 TC 17 Z9 17 U1 0 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD MAR PY 2014 VL 25 IS 3 BP 511 EP 522 DI 10.1681/ASN.2012121202 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA AB9YB UT WOS:000332150500012 PM 24231659 ER PT J AU Vaisman, A McDonald, JP Noll, S Huston, D Loeb, G Goodman, MF Woodgate, R AF Vaisman, Alexandra McDonald, John P. Noll, Stephan Huston, Donald Loeb, Gregory Goodman, Myron F. Woodgate, Roger TI Investigating the mechanisms of ribonucleotide excision repair in Escherichia coli SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE Y-family DNA polymerase; Steric gate mutant; Ribonucleotide excision repair; UmuC: spontaneous mutagenesis; RNase H ID DNA-POLYMERASE-I; 5'-3' EXONUCLEOLYTIC ACTIVITY; SOS MUTATOR ACTIVITY; ACTIVE-SITE; RNASE-H; GENETIC REQUIREMENTS; KLENOW FRAGMENT; RECA730 MUTANTS; K12 DEFICIENT; POLA GENE AB Low fidelity Escherichia coli DNA polymerase V (pal V/UmuD'C-2) is best characterized for its ability to perform translesion synthesis (TLS). However, in recA730 lexA(Def) strains, the enzyme is expressed under optimal conditions allowing it to compete with the cell's replicase for access to undamaged chromosomal DNA and leads to a substantial increase in spontaneous mutagenesis. We have recently shown that a Y11A substitution in the "steric gate" residue of UmuC reduces both base and sugar selectivity of pol V, but instead of generating an increased number of spontaneous mutations, strains expressing umuC_Y11A are poorly mutable in vivo. This phenotype is attributed to efficient RNase HII-initiated repair of the misincorporated ribonucleotides that concomitantly removes adjacent misincorporated deoxyribonucleotides. We have utilized the ability of the pol V steric gate mutant to promote incorporation of large numbers of errant ribonucleotides into the E. coli genome to investigate the fundamental mechanisms underlying ribonucleotide excision repair (RER). Here, we demonstrate that RER is normally facilitated by DNA polymerase I (pol I) via classical "nick translation". In vitro, pol I displaces 1-3 nucleotides of the RNA/DNA hybrid and through its 5'-> 3' (exo/endo) nuclease activity releases ribo- and deoxyribonucleotides from DNA. In vivo, umuC_Y11A-dependent mutagenesis changes significantly in polymerase-deficient, or proofreading-deficient polA strains, indicating a pivotal role for pol I in ribonucleotide excision repair (RER). However, there is also considerable redundancy in the RER pathway in E. coli. Poll's strand displacement and FLAP-exo/endonuclease activities can be facilitated by alternate enzymes, while the DNA polymerization step can be assumed by high-fidelity pol III. We conclude that RNase HII and poll normally act to minimize the genomic instability that is generated through errant ribonucleotide incorporation, but that the "nick-translation" activities encoded by the single poll polypeptide can be undertaken by a variety of back-up enzymes. Published by Elsevier B.V. C1 [Vaisman, Alexandra; McDonald, John P.; Huston, Donald; Loeb, Gregory; Woodgate, Roger] NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. [Noll, Stephan] Gene Bridges GmbH, D-69120 Heidelberg, Germany. [Goodman, Myron F.] Univ So Calif, Dept Biol Sci & Chem, Los Angeles, CA 90089 USA. RP Woodgate, R (reprint author), 9800 Med Ctr Dr,Bldg C,Room 320, Bethesda, MD 20892 USA. EM woodgate@nih.gov FU NICHD/NIH Intramural Research Program; National Institutes of Health [GM21422, ES012259] FX This work was funded in part by the NICHD/NIH Intramural Research Program to R.W., and from the National Institutes of Health (GM21422 and ES012259) to M.F.G. We thank Iwona Fijalkowska for kindly providing the pSKpolAint plasmid vector and the polA 3'-> 5' exo- CmR strain, KA796; Martin Marinus for the mutL460::cat strain, KM52; Roel Schaaper for the mutD5 strain, NR9548; and Cathy Joyce for polyclonal rabbit antibodies raised against E. coli pol I. NR 54 TC 10 Z9 10 U1 0 U2 12 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 MAR PY 2014 VL 761 BP 21 EP 33 DI 10.1016/j.mrfmmm.2014.01.005 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA AE5DR UT WOS:000334008500003 PM 24495324 ER PT J AU Dalal, Y McNally, JG AF Dalal, Yamini McNally, James G. TI Now you see it, now you don't: A biochemist's primer for advances in high-resolution microscopy Comment on "Biomolecular dynamics and binding studies in the living cell" by Stephan Diekmann and Christian Hoischen SO PHYSICS OF LIFE REVIEWS LA English DT Editorial Material C1 [Dalal, Yamini; McNally, James G.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Dalal, Y (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM dalaly@mail.nih.gov NR 0 TC 1 Z9 1 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1571-0645 EI 1873-1457 J9 PHYS LIFE REV JI Phys. Life Rev. PD MAR PY 2014 VL 11 IS 1 BP 36 EP 37 DI 10.1016/j.plrev.2013.11.007 PG 2 WC Biology; Biophysics SC Life Sciences & Biomedicine - Other Topics; Biophysics GA AE5EF UT WOS:000334009900004 PM 24291566 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI The double-edged sword of Lamarck Comment on "Diversity, evolution, and therapeutic applications of small RNAs in prokaryotic and eukaryotic immune systems" by Edwin L. Cooper and Nicola Overstreet SO PHYSICS OF LIFE REVIEWS LA English DT Editorial Material ID CRISPR-CAS SYSTEMS; ARCHAEA; BACTERIA; DEFENSE C1 Natl Ctr Biotechnol Informat, Natl Lib Med, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Ctr Biotechnol Informat, Natl Lib Med, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU Intramural NIH HHS NR 12 TC 5 Z9 5 U1 1 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1571-0645 EI 1873-1457 J9 PHYS LIFE REV JI Phys. Life Rev. PD MAR PY 2014 VL 11 IS 1 BP 141 EP 143 DI 10.1016/j.plrev.2013.12.002 PG 3 WC Biology; Biophysics SC Life Sciences & Biomedicine - Other Topics; Biophysics GA AE5EF UT WOS:000334009900021 PM 24365235 ER PT J AU Chartier, KG Scott, DM Wall, TL Covault, J Karriker-Jaffe, KJ Mills, BA Luczak, SE Caetano, R Arroyo, JA AF Chartier, Karen G. Scott, Denise M. Wall, Tamara L. Covault, Jonathan Karriker-Jaffe, Katherine J. Mills, Britain A. Luczak, Susan E. Caetano, Raul Arroyo, Judith A. TI Framing Ethnic Variations in Alcohol Outcomes from Biological Pathways to Neighborhood Context SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Alcohol; Race; Ethnicity; Health Disparities; Associated Factors ID POSTTRAUMATIC-STRESS-DISORDER; DIAGNOSTIC INTERVIEW SCHEDULE; BORDER MEXICAN-AMERICANS; UNITED-STATES; ALDEHYDE DEHYDROGENASE; 5-HTTLPR POLYMORPHISM; HEALTH DISPARITIES; GENETIC-VARIATION; COLLEGE-STUDENTS; LIFE EVENTS AB BackgroundHealth disparities research seeks to eliminate disproportionate negative health outcomes experienced in some racial/ethnic minority groups. This brief review presents findings on factors associated with drinking and alcohol-related problems in racial/ethnic groups. MethodsThose discussed are as follows: (i) biological pathways to alcohol problems, (ii) gene x stress interactions, (iii) neighborhood disadvantage, stress, and access to alcohol, and (iv) drinking cultures and contexts. ResultsThese factors and their interrelationships are complex, requiring a multilevel perspective. ConclusionsThe use of interdisciplinary teams and an epigenetic focus are suggested to move the research forward. The application of multilevel research to policy, prevention, and intervention programs may help prioritize combinations of the most promising intervention targets. C1 [Chartier, Karen G.] Virginia Commonwealth Univ, Sch Social Work, Richmond, VA 23284 USA. [Scott, Denise M.] Howard Univ, Sch Med, Washington, DC 20059 USA. [Wall, Tamara L.; Luczak, Susan E.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Covault, Jonathan] Univ Connecticut, Sch Med, Farmington, CT USA. [Karriker-Jaffe, Katherine J.] Alcohol Res Grp, Emeryville, CA USA. [Mills, Britain A.; Caetano, Raul] Univ Texas Dallas, Sch Publ Hlth, Dallas, TX 75230 USA. [Luczak, Susan E.] Univ So Calif, Dept Psychol, Los Angeles, CA 90089 USA. [Arroyo, Judith A.] NIAAA, Bethesda, MD USA. RP Chartier, KG (reprint author), Virginia Commonwealth Univ, Sch Social Work, 1000 Floyd Ave,POB 842027, Richmond, VA 23284 USA. EM kgchartier@vcu.edu OI Wall, Tamara/0000-0003-0605-8660 FU National Institutes of Health [K01AA021145, R21AA017584, K02AA00269, R01AA112571, R21AA019175, R01AA013642] FX This work was supported by National Institutes of Health grants K01AA021145 to KGC, R21AA017584 to DMS and JC, K02AA00269 and R01AA112571 to TLW, R21AA019175 to KJK-J, and R01AA013642 to RC. NR 56 TC 3 Z9 3 U1 4 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAR PY 2014 VL 38 IS 3 BP 611 EP 618 DI 10.1111/acer.12304 PG 8 WC Substance Abuse SC Substance Abuse GA AC8BO UT WOS:000332758200003 PM 24483624 ER PT J AU Terracciano, A Sutin, AR An, Y O'Brien, RJ Ferrucci, L Zonderman, AB Resnick, SM AF Terracciano, Antonio Sutin, Angelina R. An, Yang O'Brien, Richard J. Ferrucci, Luigi Zonderman, Alan B. Resnick, Susan M. TI Personality and risk of Alzheimer's disease: New data and meta-analysis SO ALZHEIMERS & DEMENTIA LA English DT Article DE Alzheimer's disease; Dementia; Observational prospective study; Meta-analysis; Neuroticism; Anxiety; Depression; Conscientiousness; Order; Self-discipline; APOE ID MILD COGNITIVE IMPAIRMENT; DEPRESSIVE SYMPTOMS; PSYCHOLOGICAL DISTRESS; LIFE-SPAN; DEMENTIA; TRAITS; AGE; ASSOCIATION; PREDICTORS; OUTCOMES AB Background: We examine whether broad factors and specific facets of personality are associated with increased risk of incident Alzheimer's disease (AD) in a long-run longitudinal study and a meta-analysis of published studies. Methods: Participants (n = 1671) were monitored for up to 22 years from a baseline personality assessment. The meta-analysis pooled results from up to five prospective studies (n = 5054). Results: Individuals with scores in the top quartile of neuroticism (hazard ratio = 3.1; 95% confidence interval = 1.6-6.0) or the lowest quartile of conscientiousness (hazard ratio = 3.3; 95% confidence interval = 14-7.4) had a threefold increased risk of incident AD. Among the components of these traits, self-discipline and depression had the strongest associations with incident AD. The meta-analysis confirmed the associations of neuroticism (P = 2 X 10(-9)) and conscientiousness (P = 2 X 10(-6)), along with weaker effects for openness and agreeableness (P <.05). Conclusions: The current study and meta-analysis indicate that personality traits are associated with increased risk of AD, with effect sizes similar to those of well-established clinical and lifestyle risk factors. (c) 2014 The Alzheimer's Association. All rights reserved. C1 [Terracciano, Antonio; Sutin, Angelina R.; An, Yang; Ferrucci, Luigi; Zonderman, Alan B.; Resnick, Susan M.] NIA, NIH, Baltimore, MD 21224 USA. [Terracciano, Antonio; Sutin, Angelina R.] Florida State Univ, Coll Med, Tallahassee, FL 32306 USA. [O'Brien, Richard J.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. RP Terracciano, A (reprint author), NIA, NIH, Baltimore, MD 21224 USA. EM antonio.terracciano@med.fsu.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 51 TC 31 Z9 32 U1 2 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 EI 1552-5279 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD MAR PY 2014 VL 10 IS 2 BP 179 EP 186 DI 10.1016/j.jalz.2013.03.002 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA AD5VS UT WOS:000333321900006 PM 23706517 ER PT J AU Brawman-Mintzer, O Durkalski, V Wu, Q Romagnuolo, J Fogel, E Tarnasky, P Aliperti, G Freeman, M Kozarek, R Jamidar, P Wilcox, M Elta, G Orrell, K Wood, A Mauldin, P Serrano, J Drossman, D Robuck, P Cotton, P AF Brawman-Mintzer, Olga Durkalski, Valerie Wu, Qi Romagnuolo, Joseph Fogel, Evan Tarnasky, Paul Aliperti, Giuseppe Freeman, Martin Kozarek, Richard Jamidar, Priya Wilcox, Mel Elta, Grace Orrell, Kyle Wood, April Mauldin, Patrick Serrano, Jose Drossman, Douglas Robuck, Patricia Cotton, Peter TI Psychosocial Characteristics and Pain Burden of Patients With Suspected Sphincter of Oddi Dysfunction in the EPISOD Multicenter Trial SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; IRRITABLE-BOWEL-SYNDROME; FUNCTIONAL GASTROINTESTINAL DISORDERS; NATIONAL-COMORBIDITY-SURVEY; SELF-REPORTED ABUSE; FINDINGS TYPE-I; ABDOMINAL-PAIN; PHYSICAL ABUSE; HEALTH-STATUS; DSM-IV AB OBJECTIVES: Patients with several painful functional gastrointestinal disorders (FGIDs) are reported to have a high prevalence of psychosocial disturbance. These aspects have not been studied extensively in patients with suspected Sphincter of Oddi dysfunction (SOD). METHODS: A total of 214 patients with post-cholecystectomy pain and suspected SOD were enrolled in seven US centers in a multicenter-randomized trial (Evaluating Predictors and Interventions in Sphincter of Oddi Dysfunction). Baseline assessments included pain descriptors and burden, structured psychosocial assessments of anxiety/depression, coping, trauma, and health-related quality of life. Patients with high levels of depression, suicidal ideation, or psychosis were excluded. RESULTS: The study population (92% female, mean age 38) reported anxiety (9%), depression (8%), past sexual trauma (18%), and physical abuse (10%). Of the total screened population (n = 1460), 3.9% of the patients were excluded because of the presence of defined severe psychological problems. The mean medical outcomes study short-form-36 (SF-36) physical and mental composite scores were 38.70 (s.d. = 7.89) and 48.74 (s.d. = 9.60), respectively. Most subjects reported symptoms of other FGIDs. There were no correlations between the extent of the pain burden in the 3 months before enrollment and the baseline anxiety scores or victimization history. However, those with greater pain burden were significantly more depressed. There were no meaningful differences in the psychosocial parameters in subjects with or without irritable bowel, and those who had cholecystectomy for stones or functional gallbladder disease. Those declining randomization were comparable to those randomized. CONCLUSIONS: Psychosocial comorbidity in SOD is high. However, it does not appear to differ significantly from that reported in surveys of age-and gender-matched general populations, and may be lower than reported with other FGIDs. C1 [Brawman-Mintzer, Olga; Durkalski, Valerie; Wu, Qi; Romagnuolo, Joseph; Orrell, Kyle; Wood, April; Mauldin, Patrick; Cotton, Peter] Med Univ S Carolina, Ctr Digest Dis, Charleston, SC 29425 USA. [Brawman-Mintzer, Olga] Ralph H Johnson VAMC, Charleston, SC USA. [Fogel, Evan] Indiana Univ, Indianapolis, IN 46204 USA. [Tarnasky, Paul] Methodist Dallas Med Ctr, Dallas, TX USA. [Aliperti, Giuseppe] Midwest Therapeut Endoscopy Consultants, St Louis, MO USA. [Freeman, Martin] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Kozarek, Richard] Virginia Mason Med Ctr, Seattle, WA 98101 USA. [Jamidar, Priya] Yale Univ, Newhaven, CT USA. [Wilcox, Mel] Univ Alabama Birmingham, Birmingham, AL USA. [Elta, Grace] Univ Michigan, Ann Arbor, MI 48109 USA. [Serrano, Jose; Robuck, Patricia] NIDDK, Bethesda, MD 20892 USA. [Drossman, Douglas] Univ N Carolina, Chapel Hill, NC USA. [Drossman, Douglas] Drossman Gastroenterol PLLC, Chapel Hill, NC USA. RP Cotton, P (reprint author), Med Univ S Carolina, Ctr Digest Dis, 25 Courtney Dr,ART 7100A,MSC 290, Charleston, SC 29425 USA. EM cottonp@musc.edu FU NIDDK [U01 DK074739] FX This work was funded by NIDDK, study number U01 DK074739. NR 39 TC 10 Z9 10 U1 4 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD MAR PY 2014 VL 109 IS 3 BP 436 EP 442 DI 10.1038/ajg.2013.467 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AD4RX UT WOS:000333239300017 PM 24445573 ER PT J AU Liu, RY Huang, XP Yeliseev, A Xi, J Roth, BL AF Liu, Renyu Huang, Xi-Ping Yeliseev, Alexei Xi, Jin Roth, Bryan L. TI Novel Molecular Targets of Dezocine and Their Clinical Implications SO ANESTHESIOLOGY LA English DT Article ID KAPPA-OPIOID RECEPTOR; NOREPINEPHRINE TRANSPORTER; AGONIST-ANTAGONIST; CRYSTAL-STRUCTURE; PAIN; DEPRESSION; MORPHINE; BUPRENORPHINE; INHIBITION; SEROTONIN AB Background: Although dezocine is a partial -opioid receptor agonist, it is not a controlled substance. Thus, the characterization of the molecular targets of dezocine is critical for scientific and clinical implications. The goal of this study is to characterize molecular targets for dezocine and determine their implications. Methods: A binding screen for dezocine was performed on 44 available receptors and transporter proteins. Functional assays for the novel targets were performed along with computation calculations to locate the binding site. A G protein activation study was performed for the human opioid receptor to determine whether dezocine is a -antagonist. Data are presented as mean standard error. Results: The affinities for dezocine were 3.7 +/- 0.7 nM for the receptor, 527 +/- 70 nM for the -receptor, and 31.9 +/- 1.9 nM for the -receptor. Dezocine failed to induce G protein activation with -opioid receptor and concentration dependently inhibited -agonist (salvinorin A and nalbuphine)-induced receptor activation, indicating that dezocine is a -antagonist. Two novel molecular targets (norepinephrine transporter and serotonin transporter) were identified. Dezocine concentration-dependently inhibited norepinephrine and serotonin reuptake in vitro. The half maximal inhibitory concentrations (expressed as pIC50) were 5.68 +/- 0.11 for norepinephrine transporter and 5.86 +/- 0.17 for serotonin transporter. Dezocine occupied the binding site for known norepinephrine transporter and serotonin transporter inhibitors. Conclusions: The unique molecular pharmacological profile of dezocine as a partial -receptor agonist, a -receptor antagonist, and a norepinephrine and serotonin reuptake inhibitor (via norepinephrine transporter and serotonin transporter) was revealed. These discoveries reveal potentially important novel clinical implications and drug interactions of dezocine. C1 [Liu, Renyu; Xi, Jin] Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Huang, Xi-Ping; Roth, Bryan L.] NIMH, Psychoact Drug Screening Program, Chapel Hill, NC USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC USA. [Yeliseev, Alexei] NIAAA, NIH, Rockville, MD 20852 USA. RP Liu, RY (reprint author), Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care, 336 John Morgan Bldg,3620 Hamilton Walk, Philadelphia, PA 19104 USA. EM liur@uphs.upenn.edu RI Roth, Bryan/F-3928-2010 FU National Institutes of Health (NIH) [K08-GM-093115]; Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism (NIAAA, Bethesda, Maryland); Department of Anesthesiology and Critical Care at the University of Pennsylvania; National Institute of Mental Health's Psychoactive Drug Screening Program, Chapel Hill, North Carolina (NIMH PDSP) [HHSN-271-2008-00025-C] FX This research was supported by National Institutes of Health (NIH, K08-GM-093115) (PI: R.L.) and the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism (NIAAA, Bethesda, Maryland) (PI: A.Y.). This research was also supported by funding from the Department of Anesthesiology and Critical Care at the University of Pennsylvania (PI: R.L.), and by the National Institute of Mental Health's Psychoactive Drug Screening Program, Chapel Hill, North Carolina (NIMH PDSP; Contract # HHSN-271-2008-00025-C). NR 46 TC 13 Z9 24 U1 3 U2 16 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 MAR PY 2014 VL 120 IS 3 BP 714 EP 723 DI 10.1097/ALN.0000000000000076 PG 10 WC Anesthesiology SC Anesthesiology GA AC9FR UT WOS:000332840300024 PM 24263237 ER PT J AU Li, Y Hamilton, KJ Lai, AY Burns, KA Li, LP Wade, PA Korach, KS AF Li, Yin Hamilton, Katherine J. Lai, Anne Y. Burns, Katherine A. Li, Leping Wade, Paul A. Korach, Kenneth S. TI Diethylstilbestrol (DES)-Stimulated Hormonal Toxicity Is Mediated by ER alpha Alteration of Target Gene Methylation Patterns and Epigenetic Modifiers (DNMT3A, MBD2, and HDAC2) in the Mouse Seminal Vesicle SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID ESTROGEN-RECEPTOR-ALPHA; HISTONE DEACETYLASE 1; SECRETORY PROTEIN-IV; DNA METHYLTRANSFERASES; LACTOFERRIN GENE; NEONATAL EXPOSURE; CELL-DIFFERENTIATION; REPRODUCTIVE-TRACT; PRENATAL EXPOSURE; GENOMIC DNA AB BACKGROUND: Diethylstilbestrol (DES) is a synthetic estrogen associated with adverse effects on reproductive organs. DES-induced toxicity of the mouse seminal vesicle (SV) is mediated by estrogen receptor alpha (ER alpha), which alters expression of seminal vesicle secretory protein IV (Svs4) and lactoferrin (Ltf) genes. OBJECTIVES: We examined a role for nuclear receptor activity in association with DNA methylation and altered gene expression. METHODS: We used the neonatal DES exposure mouse model to examine DNA methyla-tion patterns via bisulfite conversion sequencing in SVs of wild-type (WT) and ER alpha-knockout (alpha ERKO) mice. RESULTS: The DNA methylation status at four specific CpGs (-160, -237, -306, and -367) in the Svs4 gene promoter changed during mouse development from methylated to unmethylated, and DES prevented this change at 10 weeks of age in WT SV. At two specific CpGs (-449 and -459) of the Ltf gene promoter, DES altered the methylation status from methylated to unmethylated. Alterations in DNA methylation of Svs4 and Ltf were not observed in alpha ERKO SVs, suggesting that changes of methylation status at these CpGs are ERa dependent. The methylation status was associated with the level of gene expression. In addition, gene expression of three epigenetic modifiers-DNMT3A, MBD2, and HDAC2-increased in the SV of DES-exposed WT mice. CONCLUSION: DES-induced hormonal toxicity resulted from altered gene expression of Svs4 and Ltf associated with changes in DNA methylation that were mediated by ER alpha. Alterations in gene expression of DNMT3A, MBD2, and HDAC2 in DES-exposed male mice may be involved in mediating the changes in methylation status in the SV. C1 [Li, Yin; Hamilton, Katherine J.; Burns, Katherine A.; Korach, Kenneth S.] NIEHS, Lab Reprod & Dev Toxicol, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Lai, Anne Y.; Wade, Paul A.] NIEHS, Lab Mol Carcinogenesis, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Li, Leping] NIEHS, Biostat Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Korach, KS (reprint author), NIEHS, Lab Reprod & Dev Toxicol, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU Division of Intramural Research, National Institute of Environmental Health Sciences [Z01 ES70065] FX Research support was provided by the Division of Intramural Research, National Institute of Environmental Health Sciences, to K.S.K. through Z01 ES70065. NR 63 TC 11 Z9 12 U1 0 U2 6 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD MAR PY 2014 VL 122 IS 3 BP 262 EP 268 DI 10.1289/ehp.1307351 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AE0QH UT WOS:000333670500016 PM 24316720 ER PT J AU Andreotti, G Karami, S Pfeiffer, RM Hurwitz, L Liao, LM Weinstein, SJ Albanes, D Virtamo, J Silverman, DT Rothman, N Moore, LE AF Andreotti, Gabriella Karami, Sara Pfeiffer, Ruth M. Hurwitz, Lauren Liao, Linda M. Weinstein, Stephanie J. Albanes, Demetrius Virtamo, Jarmo Silverman, Debra T. Rothman, Nathaniel Moore, Lee E. TI LINE1 methylation levels associated with increased bladder cancer risk in pre-diagnostic blood DNA among US ( PLCO) and European ( ATBC) cohort study participants SO EPIGENETICS LA English DT Article DE global methylation; bladder cancer; nested case-control; pre-diagnostic blood DNA; PLCO; ATBC ID GLOBAL METHYLATION; BREAST-CANCER; HYPOMETHYLATION; BIOMARKER; TRIAL; LUNG AB Global methylation in blood DNA has been associated with bladder cancer risk in case-control studies, but has not been examined prospectively. We examined the association between LINE1 total percent 5-methylcytosine and bladder cancer risk using pre-diagnostic blood DNA from the United States-based, Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial (PLCO) (299 cases/676 controls), and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) cohort of Finnish male smokers (391 cases/778 controls). Logistic regression adjusted for age at blood draw, study center, pack-years of smoking, and sex was used to estimate odd ratios (ORs) and 95% confidence intervals (CIs) using study- and sex-specific methylation quartiles. In PLCO, higher, although non-significant, bladder cancer risks were observed for participants in the highest three quartiles (Q2-Q4) compared with the lowest quartile (Q1) (OR = 1.36, 95% CI: 0.96 -1.92). The association was stronger in males (Q2-Q4 vs. Q1 OR = 1.48, 95% CI: 1.00-2.20) and statistically significant among male smokers (Q2-Q4 vs. Q1 OR = 1.83, 95% CI: 1.14-2.95). No association was found among females or female smokers. Findings for male smokers were validated in ATBC (Q2-Q4 vs. Q1: OR = 2.31, 95% CI: 1.62-3.30) and a highly significant trend was observed (P = 8.7 x 10(-7)). After determining that study data could be combined, pooled analysis of PLCO and ATBC male smokers (580 cases/1119 controls), ORs were significantly higher in Q2-Q4 compared with Q1 (OR = 2.03, 95% CI: 1.52-2.72), and a trend across quartiles was observed (P = 0.0001). These findings suggest that higher global methylation levels prior to diagnosis may increase bladder cancer risk, particularly among male smokers. C1 [Andreotti, Gabriella; Karami, Sara; Pfeiffer, Ruth M.; Hurwitz, Lauren; Liao, Linda M.; Weinstein, Stephanie J.; Albanes, Demetrius; Silverman, Debra T.; Rothman, Nathaniel; Moore, Lee E.] US Natl Canc Inst NCI, DCEG, NIH, DHHS, Bethesda, MD 20892 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Moore, LE (reprint author), US Natl Canc Inst NCI, DCEG, NIH, DHHS, Bethesda, MD 20892 USA. EM moorele@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; OI Liao, Linda/0000-0002-1923-5294 FU Intramural Research Program of the National Cancer Institute; US National Institutes of Health; Department of Health and Human Services; US. Public Health Service from the National Cancer Institute, National Institutes of Health, and Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C] FX This research was supported in part by the Intramural Research Program of the National Cancer Institute, US National Institutes of Health, and Department of Health and Human Services. Additionally, this research was supported by US. Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004 and HHSN261201000006C from the National Cancer Institute, National Institutes of Health, and Department of Health and Human Services. NR 27 TC 11 Z9 11 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1559-2294 EI 1559-2308 J9 EPIGENETICS-US JI Epigenetics PD MAR 1 PY 2014 VL 9 IS 3 BP 404 EP 415 DI 10.4161/epi.27386 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AE0JC UT WOS:000333649600009 PM 24316677 ER PT J AU Wasserman, D AF Wasserman, David TI Adrienne Asch: Memories of a Close Friend and Collaborator SO HASTINGS CENTER REPORT LA English DT Article AB Adrienne Asch inspired, challenged, and provoked a generation of bioethicists and philosophers who were discovering the subject of disability. For Adrienne, disability was a complex phenomenon that raised universal issues of embodiment, justice, well-being, and identity. She insisted that bioethicists and philosophers who invoked disability in discussions about these issues first learn something about it, for which her own work provided critical insights. She argued eloquently that those who relied on unsupported assumptions about disability, even in the most arcane debates, reinforced harmful stereotypes and impoverished their own thinking. At the same time, she urged that the claims of disability scholars concerning discrimination, fairness, and kindred issues be made with philosophical clarity. She was fearless with the smug and insular in both fields, but generous with those, like me, who were merely naive. RP Wasserman, D (reprint author), NIH, Dept Bioeth, Bethesda, MD 20892 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 0093-0334 EI 1552-146X J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD MAR PY 2014 VL 44 IS 2 BP 15 EP 17 DI 10.1002/hast.281 PG 3 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA AE0QG UT WOS:000333670400011 PM 24634041 ER PT J AU Brock, DW Park, JK Wendler, D AF Brock, Dan W. Park, John K. Wendler, David TI Making Treatment Decisions for Oneself: Weighing the Value SO HASTINGS CENTER REPORT LA English DT Article ID ADVANCE DIRECTIVES; GLIOBLASTOMA AB Competent adults should be permitted to determine the course of their own lives. We may try to influence them. We may ask them, perhaps even implore them, to change their minds. But in the end, they are in charge of their lives. They get to choose their careers, whether and whom to marry, whether to exercise, and whether to have surgery. This emphasis on respect for patients' autonomy may seem to imply that allowing patients to make their own decisions should always take precedence over other considerations. Given this presumption, there has been almost no discussion in the medical literature or elsewhere about how important this value is and whether it should sometimes be balanced against and give way to other values. This absence of guidance is especially problematic in cases where respect for patient autonomy conflicts with promoting patients' clinical interests. C1 [Brock, Dan W.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Park, John K.] NINDS, Surg & Mol Neurooncol Unit, Bethesda, MD 20892 USA. [Wendler, David] NIH, Unit Vulnerable Populat, Ctr Clin, Bethesda, MD 20892 USA. RP Brock, DW (reprint author), Harvard Univ, Sch Med, Cambridge, MA 02138 USA. FU Intramural NIH HHS [Z99 CL999999] NR 8 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0093-0334 EI 1552-146X J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD MAR PY 2014 VL 44 IS 2 BP 22 EP 25 DI 10.1002/hast.284 PG 4 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA AE0QG UT WOS:000333670400014 PM 24634044 ER PT J AU Rich, JD Chandler, R Williams, BA Dumont, D Wang, EA Taxman, FS Allen, SA Clarke, JG Greifinger, RB Wildeman, C Osher, FC Rosenberg, S Haney, C Mauer, M Western, B AF Rich, Josiah D. Chandler, Redonna Williams, Brie A. Dumont, Dora Wang, Emily A. Taxman, Faye S. Allen, Scott A. Clarke, Jennifer G. Greifinger, Robert B. Wildeman, Christopher Osher, Fred C. Rosenberg, Steven Haney, Craig Mauer, Marc Western, Bruce TI How Health Care Reform Can Transform The Health Of Criminal Justice-Involved Individuals SO HEALTH AFFAIRS LA English DT Article ID UNITED-STATES; PUBLIC-HEALTH; JAIL INMATES; HIGH-RISK; RELEASE; INCARCERATION; PRISONERS; DEATH AB Provisions of the Affordable Care Act offer new opportunities to apply a public health and medical perspective to the complex relationship between involvement in the criminal justice system and the existence of fundamental health disparities. Incarceration can cause harm to individual and community health, but prisons and jails also hold enormous potential to play an active and beneficial role in the health care system and, ultimately, to improving health. Traditionally, incarcerated populations have been incorrectly viewed as isolated and self-contained communities with only peripheral importance to the public health at large. This misconception has resulted in missed opportunities to positively affect the health of both the individuals and the imprisoned community as a whole and potentially to mitigate risk behaviors that may contribute to incarceration. Both community and correctional health care professionals can capitalize on these opportunities by working together to advocate for the health of the criminal justice-involved population and their communities. We present a set of recommendations for the improvement of both correctional health care, such as improving systems of external oversight and quality management, and access to community-based care, including establishing strategies for postrelease care and medical record transfers. C1 [Rich, Josiah D.] Brown Univ, Providence, RI 02912 USA. [Rich, Josiah D.] Miriam Hosp, Ctr Prisoner Hlth & Human Rights, Providence, RI 02906 USA. [Chandler, Redonna] NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. [Williams, Brie A.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. [Williams, Brie A.] San Francisco Vet Affairs Geriatr Clin, San Francisco, CA USA. [Dumont, Dora] Rhode Isl Dept Hlth, Providence, RI 02908 USA. [Dumont, Dora] Miriam Hosp, Providence, RI 02906 USA. [Wang, Emily A.; Wildeman, Christopher] Yale Univ, New Haven, CT USA. [Taxman, Faye S.] George Mason Univ, Criminol Law & Soc Dept, Manassas, VA USA. [Taxman, Faye S.] George Mason Univ, Ctr Adv Excellence, Manassas, VA USA. [Allen, Scott A.] Univ Calif Riverside, Riverside Sch Med, Riverside, CA 92521 USA. [Clarke, Jennifer G.] Brown Univ, Mem Hosp Rhode Isl, Ctr Primary Care & Prevent, Pawtucket, RI 02860 USA. [Greifinger, Robert B.] CUNY John Jay Coll Criminal Justice, New York, NY 10019 USA. [Osher, Fred C.] Council State Govt Justice Ctr, Johns Isl, SC USA. [Rosenberg, Steven] Community Oriented Correct Hlth Serv, Oakland, CA USA. [Haney, Craig] Univ Calif Santa Cruz, Santa Cruz, CA 95064 USA. [Mauer, Marc] Sentencing Project, Washington, DC USA. [Western, Bruce] Harvard Univ, Cambridge, MA 02138 USA. RP Rich, JD (reprint author), Brown Univ, Providence, RI 02912 USA. EM JRich@lifespan.org RI Allen, Scott/D-2403-2015 OI Allen, Scott/0000-0001-8815-4714 FU National Institute of Justice; John D. and Catherine T. MacArthur Foundation; Robert Wood Johnson Foundation; National Institute on Drug Abuse [NIDA K24DA022112, NIDA 5R01DA030778, NIDA U01 DA016213]; Centers for AIDS Research, National Institutes of Health [CFAR P30AI042853]; National Institute on Aging [NIA K23AG033102]; Jacob and Valeria Langeloth Foundation; University of California, San Francisco, Program for the Aging Century; National Heart, Lung, and Blood Institute [NHLBI K23 HL103720]; Bureau of Justice Assistance [BJA 2009-DG-BX-K026]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHHD R01 HD054890] FX This article was inspired by a workshop organized by the National Research Council and the Institute of Medicine as a way to address the charge to the Committee on the Causes and Consequences of High Rates of Incarceration funded by the National Institute of Justice and the John D. and Catherine T. MacArthur Foundation. A summary of that workshop was prepared by a grant from the Robert Wood Johnson Foundation. Josiah Rich is supported by grants from the National Institute on Drug Abuse, Nos. NIDA K24DA022112 and NIDA 5R01DA030778, and from the Centers for AIDS Research, National Institutes of Health, No. CFAR P30AI042853. Brie Williams is supported by a grant from the National Institute on Aging, NIA K23AG033102, and by the Jacob and Valeria Langeloth Foundation and the University of California, San Francisco, Program for the Aging Century. Emily Wang is supported by a grant from the National Heart, Lung, and Blood Institute, No. NHLBI K23 HL103720. Faye Taxman is supported by a grant from the Bureau of Justice Assistance, No. BJA 2009-DG-BX-K026, and the National Institute on Drug Abuse, No. NIDA U01 DA016213. Jennifer Clarke is supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, No. NICHHD R01 HD054890. The statements in this article are those of the authors and not necessarily those of the National Institute on Drug Abuse, the National Institutes of Health, the Department of Health and Human Services, or the Department of Veterans Affairs. NR 32 TC 20 Z9 20 U1 4 U2 20 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD MAR PY 2014 VL 33 IS 3 BP 462 EP 467 DI 10.1377/hlthaff.2013.1133 PG 6 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AD8NF UT WOS:000333522200017 PM 24590946 ER PT J AU Piwowar-Manning, E Fogel, JM Laeyendecker, O Wolf, S Cummings, V Marzinke, MA Clarke, W Breaud, A Wendel, S Wang, L Swanson, P Hackett, J Mannheimer, S del Rio, C Kuo, I Harawa, NT Koblin, BA Moore, R Blankson, JN Eshleman, SH AF Piwowar-Manning, Estelle Fogel, Jessica M. Laeyendecker, Oliver Wolf, Shauna Cummings, Vanessa Marzinke, Mark A. Clarke, William Breaud, Autumn Wendel, Sarah Wang, Lei Swanson, Priscilla Hackett, John, Jr. Mannheimer, Sharon del Rio, Carlos Kuo, Irene Harawa, Nina T. Koblin, Beryl A. Moore, Richard Blankson, Joel N. Eshleman, Susan H. TI Failure to Identify HIV-Infected Individuals in a Clinical Trial Using a Single HIV Rapid Test for Screening SO HIV CLINICAL TRIALS LA English DT Article DE antiretroviral therapy; elite controller; HIV; rapid test; viral suppression ID UNITED-STATES; PERFORMANCE; PREVENTION; DIAGNOSIS; THERAPY AB Background: In the HIV Prevention Trials Network (HPTN) 061 study, 8 (2.3%) of 348 HIV-infected participants identified as HIV uninfected at study enrollment using a single HIV rapid test for screening were found to be HIV infected after additional testing. Objectives: To evaluate the performance of different HIV assays for detection of HIV infection in HPTN 061 participants with missed infection and individuals with viral suppression. Methods: Plasma samples from 8 HPTN 061 participants, 17 elite controllers, and 101 individuals on antiretroviral treatment (ART) were tested for HIV with 3 rapid tests, 2 laboratory-based immunoassays, and a Western blot assay. The HPTN 061 samples were also tested with 2 HIV RNA assays and an antiretroviral drug assay. Results: Of the 8 HPTN 061 participants with missed infection, 1 was an elite controller, 1 was taking ART, 2 were missed because of testing or clerical errors, 1 had recent HIV infection (identified using a multi-assay algorithm), and 3 had acute HIV infection. Two (1.7%) of 118 individuals with viral suppression (both taking ART) had at least 1 false-negative test. Conclusions: In clinical trials, HIV infections can be missed for a variety of reasons. Using more than one assay to screen for HIV infection may reduce the number of missed infections. C1 [Piwowar-Manning, Estelle; Fogel, Jessica M.; Wolf, Shauna; Cummings, Vanessa; Marzinke, Mark A.; Clarke, William; Breaud, Autumn; Eshleman, Susan H.] Johns Hopkins Univ, Dept Pathol, Sch Med, Baltimore, MD 21205 USA. [Laeyendecker, Oliver; Moore, Richard; Blankson, Joel N.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Laeyendecker, Oliver; Wendel, Sarah] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Wang, Lei] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Swanson, Priscilla; Hackett, John, Jr.] Abbott Diagnost, Infect Dis Res, Abbott Pk, IL USA. [Mannheimer, Sharon] Columbia Univ, Mailman Sch Publ Hlth, Harlem Hosp, Dept Med, New York, NY USA. [del Rio, Carlos] Emory Univ, Rollins Sch Publ Hlth, Dept Global Hlth, Atlanta, GA 30322 USA. [Kuo, Irene] George Washington Univ, Dept Epidemiol & Biostat, Washington, DC USA. [Harawa, Nina T.] Charles R Drew Univ Med & Sci, Dept Res, Los Angeles, CA 90059 USA. [Koblin, Beryl A.] New York Blood Ctr, Lindsley F Kimball Res Inst, Lab Infect Dis Prevent, New York, NY 10021 USA. RP Eshleman, SH (reprint author), Johns Hopkins Univ, Dept Pathol, Sch Med, 646 Ross Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. EM seshlem@jhmi.edu RI del Rio, Carlos/B-3763-2012; OI del Rio, Carlos/0000-0002-0153-3517; Laeyendecker, Oliver/0000-0002-6429-4760 FU National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Child Health and Human Development (NICH/HD); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Office of AIDS Research; National Institutes of Health (NIH) [R01-AI080328, P30-AI094189, R01-DA011602]; Department of Health and Human Services [UM1-AI068613] FX The HIV Prevention Trials Network (HPTN) is funded by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Child Health and Human Development (NICH/HD), National Institute of Drug Abuse (NIDA) and the National Institute of Mental Health (NIMH), Office of AIDS Research, National Institutes of Health (NIH), Department of Health and Human Services (UM1-AI068613 - Eshleman). Funding for the studies that collected the samples used for analysis was provided by the NIH (R01-AI080328 - Blankson; P30-AI094189 and R01-DA011602 - Moore). Additional support was provided by the Division of Intramural Research, NIAID, NIH. ARCHITECT HIV Ag/Ab Combo kits and testing support were provided by Abbott Laboratories. NR 21 TC 5 Z9 5 U1 0 U2 2 PU THOMAS LAND PUBLISHERS, INC PI ST LOUIS PA 255 JEFFERSON RD, ST LOUIS, MO 63119-3627 USA SN 1528-4336 EI 1945-5771 J9 HIV CLIN TRIALS JI HIV Clin. Trials PD MAR-APR PY 2014 VL 15 IS 2 BP 62 EP 68 DI 10.1310/hct1502-62 PG 7 WC Infectious Diseases; Pharmacology & Pharmacy SC Infectious Diseases; Pharmacology & Pharmacy GA AD8BU UT WOS:000333492300003 PM 24710920 ER PT J AU Kumar, A Zhao, L Fariss, RN McMenamin, PG Wong, WT AF Kumar, Anil Zhao, Lian Fariss, Robert N. McMenamin, Paul G. Wong, Wai T. TI Vascular Associations and Dynamic Process Motility in Perivascular Myeloid Cells of the Mouse Choroid: Implications for Function and Senescent Change SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE eye; choroid; mouse; myeloid cell; macrophage; dendritic cell; vasculature; live imaging; motility ID MACROPHAGE-LIKE MELANOCYTES; II-POSITIVE CELLS; MACULAR DEGENERATION; UVEAL TRACT; DENDRITIC CELLS; BRUCHS MEMBRANE; AUTOIMMUNE UVEORETINITIS; MORPHOMETRIC-ANALYSIS; RETINAL MICROGLIA; BLOOD-VESSELS AB PURPOSE. Immune and vascular alterations in the choroid are implicated in age-related macular degeneration (AMD). As choroidal immune cells are incompletely understood with regard to their physiology and interactions with choroidal vessels, we examined the associations between myeloid and vascular components of the choroid in young and aged mice. METHODS. Albino CX3CR1(GFP/+) transgenic mice, whose choroidal myeloid cells possess green fluorescence, were perfused intraluminally with the vital dye DiI to label choroidal vessels. The distribution, morphology, behavior, and vascular associations of resident myeloid cells were examined using time-lapse live confocal imaging and immunohistochemical analysis. RESULTS. Dendritiform myeloid cells, comprising most of the resident immune cell population in the choroid, were widely distributed across the choroid and demonstrated close associations with choroidal vessels that varied with their position in the vascular tree. Notably, myeloid cells associated with choroidal arteries and arterioles appeared as elongated cells flanking the long axes of vessels, whereas those associated with the choriocapillaris were distributed as a layer of stellate cells on the scleral but not vitreal choriocapillaris surface. While stationary in position, dendritiform myeloid cells demonstrated the rapid process dynamism well suited to comprehensive immunosurveillance of the perivascular space. Myeloid cells also increased in density as a function of aging, correlating locally with greater choroidal vascular attenuation. CONCLUSIONS. Resident myeloid cells demonstrated close but dynamic physical interactions with choroidal vessels, indicative of constitutive immune-vascular interactions in the normal choroid. These interactions may alter progressively with aging, providing a basis for understanding age-related choroidal dysfunction underlying AMD. C1 [Kumar, Anil; Zhao, Lian; Wong, Wai T.] NEI, Unit Neuron Glia Interact Retinal Dis, NIH, Bethesda, MD 20892 USA. [Fariss, Robert N.] NEI, Biol Imaging Core, NIH, Bethesda, MD 20892 USA. [McMenamin, Paul G.] Monash Univ, Dept Anat & Dev Biol, Clayton, Vic, Australia. RP Wong, WT (reprint author), NEI, Unit Neuron Glia Interact Retinal Dis, NIH, Bldg 6,Room 215, Bethesda, MD 20892 USA. EM wongw@nei.nih.gov RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU Intramural Research Program of the National Eye Institute, National Institutes of Health FX Supported by the Intramural Research Program of the National Eye Institute, National Institutes of Health. NR 53 TC 6 Z9 6 U1 1 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR PY 2014 VL 55 IS 3 BP 1787 EP 1796 DI 10.1167/iovs.13-13522 PG 10 WC Ophthalmology SC Ophthalmology GA AE0HZ UT WOS:000333645900011 PM 24458147 ER PT J AU Wood, RA Togias, A Wildfire, J Visness, CM Matsui, EC Gruchalla, R Hershey, G Liu, AH O'Connor, GT Pongracic, JA Zoratti, E Little, F Granada, M Kennedy, S Durham, SR Shamji, MH Busse, WW AF Wood, Robert A. Togias, Alkis Wildfire, Jeremy Visness, Cynthia M. Matsui, Elizabeth C. Gruchalla, Rebecca Hershey, Gurjit Liu, Andrew H. O'Connor, George T. Pongracic, Jacqueline A. Zoratti, Edward Little, Frederic Granada, Mark Kennedy, Suzanne Durham, Stephen R. Shamji, Mohamed H. Busse, William W. TI Development of cockroach immunotherapy by the Inner-City Asthma Consortium SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Cockroach; immunotherapy; sublingual immunotherapy; subcutaneous immunotherapy; inner city asthma ID SUBLINGUAL IMMUNOTHERAPY; ALLERGEN; CHILDREN AB Background: Cockroach allergy is a key contributor to asthma morbidity in children living in urban environments. Objective: We sought to document immune responses to cockroach allergen and provide direction for the development of immunotherapy for cockroach allergy. Methods: Four pilot studies were conducted: (1) an open-label study to assess the safety of cockroach sublingual immunotherapy (SLIT) in adults and children; (2) a randomized, double-blind biomarker study of cockroach SLIT versus placebo in adults; (3) a randomized, double-blind biomarker study of 2 doses of cockroach SLIT versus placebo in children; and (4) an open-label safety and biomarker study of cockroach subcutaneous immunotherapy (SCIT) in adults. Results: The adult SLIT trial (n = 54; age, 18-54 years) found a significantly greater increase in cockroach-specific IgE levels between the active and placebo groups (geometric mean ratio, 1.92; P < .0001) and a trend toward increased cockroach-specific IgG(4) levels in actively treated subjects (P = .09) but no evidence of functional blocking antibody response. The pediatric SLIT trial (n = 99; age, 5-17 years) found significant differences in IgE, IgG, and IgG(4) responses between both active groups and the placebo group but no consistent differences between the high-and low-dose groups. In the SCIT study the treatment resulted in significant changes from baseline in cockroach IgE, IgG(4), and blocking antibody levels. The safety profile of cockroach immunotherapy was reassuring in all studies. Conclusions: The administration of cockroach allergen by means of SCIT is immunologically more active than SLIT, especially with regard to IgG(4) levels and blocking antibody responses. No safety concerns were raised in any age group. These pilot studies suggest that immunotherapy with cockroach allergen is more likely to be effective with SCIT. C1 [Wood, Robert A.; Matsui, Elizabeth C.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Togias, Alkis] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. [Wildfire, Jeremy; Visness, Cynthia M.; Kennedy, Suzanne] Rho Fed Syst Div, Chapel Hill, NC USA. [Gruchalla, Rebecca] Univ Texas Dallas, Dept Med, SW Med Sch, Dallas, TX 75230 USA. [Gruchalla, Rebecca] Univ Texas Dallas, Dept Pediat, SW Med Sch, Dallas, TX 75230 USA. [Hershey, Gurjit] Cincinnati Childrens Hosp, Dept Pediat, Cincinnati, OH USA. [Liu, Andrew H.] Natl Jewish Hlth, Denver, CO USA. [Liu, Andrew H.] Univ Colorado, Sch Med, Denver, CO USA. [O'Connor, George T.; Little, Frederic; Granada, Mark] Boston Univ, Sch Med, Dept Med, Boston, MA USA. [Pongracic, Jacqueline A.] Ann & Robert H Lurie Childrens Hosp Chicago, Dept Pediat, Chicago, IL USA. [Zoratti, Edward] Henry Ford Hlth Syst, Dept Med, Detroit, MI USA. [Durham, Stephen R.; Shamji, Mohamed H.] Univ London Imperial Coll Sci Technol & Med, London, England. [Busse, William W.] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. RP Wood, RA (reprint author), Johns Hopkins Univ Hosp, CMSC 1102,600 N Wolfe St, Baltimore, MD 21287 USA. EM rwood@jhmi.edu OI O'Connor, George/0000-0002-6476-3926 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [NO1-AI-25496, NO1-AI-25482, HHSN272200900052C, HHSN2722010000521]; National Center for Research Resources, National Institutes of Health [RR00052, 1UL1RR025771, UL1 RR024982, UL1 TR000077-04]; National Center for Advancing Translational Sciences, National Institutes of Health [RR00052, 1UL1RR025771, UL1 RR024982, UL1 TR000077-04] FX Supported in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, under contract nos. NO1-AI-25496, NO1-AI-25482, HHSN272200900052C, and HHSN2722010000521 and from the National Center for Research Resources and National Center for Advancing Translational Sciences, National Institutes of Health, under grants RR00052, 1UL1RR025771, UL1 RR024982, and UL1 TR000077-04. Immunologic extracts were donated for some studies by Greer Pharmaceuticals (Lenoir, NC). NR 16 TC 19 Z9 19 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2014 VL 133 IS 3 BP 846 EP + DI 10.1016/j.jaci.2013.08.047 PG 13 WC Allergy; Immunology SC Allergy; Immunology GA AC3EK UT WOS:000332397600029 PM 24184147 ER PT J AU Chen, K Wu, W Mathew, D Zhang, YH Browne, SK Rosen, LB McManus, MP Pulsipher, MA Yandell, M Bohnsack, JF Jorde, LB Notarangelo, LD Walter, JE AF Chen, Karin Wu, Wilfred Mathew, Divij Zhang, Yuhua Browne, Sarah K. Rosen, Lindsey B. McManus, Meghann P. Pulsipher, Michael A. Yandell, Mark Bohnsack, John F. Jorde, Lynn B. Notarangelo, Luigi D. Walter, Jolan E. TI Autoimmunity due to RAG deficiency and estimated disease incidence in RAG1/2 mutations SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID SEVERE COMBINED IMMUNODEFICIENCY; V(D)J RECOMBINATION; AUTOANTIBODIES; LYMPHOPENIA; INFECTION C1 [Chen, Karin; Bohnsack, John F.] Univ Utah, Sch Med, Dept Pediat, Div Allergy Immunol & Rheumatol, Salt Lake City, UT 84112 USA. [Wu, Wilfred; Yandell, Mark; Jorde, Lynn B.] Univ Utah, Dept Human Genet, Salt Lake City, UT USA. [Mathew, Divij; Notarangelo, Luigi D.; Walter, Jolan E.] Harvard Univ, Sch Med, Div Immunol, Boston, MA USA. [Mathew, Divij; Notarangelo, Luigi D.; Walter, Jolan E.] Harvard Univ, Sch Med, Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA USA. [Zhang, Yuhua] Rutgers State Univ, RUCDR, Piscataway, NJ USA. [Browne, Sarah K.; Rosen, Lindsey B.] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [McManus, Meghann P.; Pulsipher, Michael A.] Univ Utah, Sch Med, Div Hematol Blood & Marrow Transplantat, Salt Lake City, UT USA. [Notarangelo, Luigi D.] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA USA. [Walter, Jolan E.] Massachusetts Gen Hosp Children, Pediat Immunodeficiency Program, Div Allergy, Boston, MA USA. RP Chen, K (reprint author), Univ Utah, Sch Med, Dept Pediat, Div Allergy Immunol & Rheumatol, Salt Lake City, UT 84112 USA. EM karin.chen@hsc.utah.edu RI Notarangelo, Luigi/F-9718-2016 OI Notarangelo, Luigi/0000-0002-8335-0262 FU NIAID NIH HHS [1K08AI103035-01, 5P01AI076210-04, K08 AI103035, P01 AI076210, U54 AI082973, U54AI082973]; NIGMS NIH HHS [R01 GM104390, GM59290, R01 GM059290] NR 18 TC 19 Z9 19 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2014 VL 133 IS 3 BP 880 EP + DI 10.1016/j.jaci.2013.11.038 PG 13 WC Allergy; Immunology SC Allergy; Immunology GA AC3EK UT WOS:000332397600033 PM 24472623 ER PT J AU Simon, KL Anderson, SM Garabedian, EK Moratto, D Sokolic, RA Candotti, F AF Simon, Karen L. Anderson, Stacie M. Garabedian, Elizabeth K. Moratto, Daniele Sokolic, Robert A. Candotti, Fabio TI Molecular and phenotypic abnormalities of B lymphocytes in patients with Wiskott-Aldrich syndrome SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID COMMON VARIABLE IMMUNODEFICIENCY; CELLS; AUTOIMMUNITY; DEFICIENCY C1 [Simon, Karen L.; Anderson, Stacie M.; Garabedian, Elizabeth K.; Moratto, Daniele; Sokolic, Robert A.; Candotti, Fabio] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Simon, KL (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM fabio@nhgri.nih.gov FU Intramural NIH HHS [ZIA HG000121-15, Z99 HG999999] NR 12 TC 9 Z9 9 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2014 VL 133 IS 3 BP 896 EP 899 DI 10.1016/j.jaci.2013.08.050 PG 10 WC Allergy; Immunology SC Allergy; Immunology GA AC3EK UT WOS:000332397600039 PM 24210885 ER PT J AU Klion, AD AF Klion, Amy D. TI Idiopathic, asymptomatic, and durable blood hypereosinophilia-still many unknowns Reply SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter C1 NIH, Eosinophil Pathol Unit, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Klion, AD (reprint author), NIH, Eosinophil Pathol Unit, Parasit Dis Lab, Bldg 10, Bethesda, MD 20892 USA. EM aklion@nih.gov OI Klion, Amy/0000-0002-4986-5326 FU Intramural NIH HHS [ZIA AI001130-04] NR 2 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2014 VL 133 IS 3 BP 933 EP 933 DI 10.1016/j.jaci.2013.12.022 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA AC3EK UT WOS:000332397600055 PM 24439079 ER PT J AU Zakharov, AV Peach, ML Sitzmann, M Nicklaus, MC AF Zakharov, Alexey V. Peach, Megan L. Sitzmann, Markus Nicklaus, Marc C. TI QSAR Modeling of Imbalanced High-Throughput Screening Data in PubChem SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID PIPELINE PILOT; ACUTE TOXICITY; RANDOM FOREST; PREDICTION; DISCOVERY; NETWORKS AB Many of the structures in Pub Chem are annotated with activities determined in high-throughput screening (HTS) assays. Because of the nature of these assays, the activity data are typically strongly imbalanced, with a small number of active compounds contrasting with a very large number of inactive compounds. We have used several such imbalanced Pub Chem HTS assays to test and develop strategies to efficiently build robust QSAR models from imbalanced data sets. Different descriptor types [Quantitative Neighborhoods of Atoms (QNA) and "biological" descriptors] were used to generate a variety of QSAR models in the program GUSAR. The models obtained were compared using external test and validation sets. We also report on our efforts to incorporate the most predictive of our models in the publicly available NCI/CADD Group Web services (http://cactus.nci.nih.gov/chemical/apps/cap). C1 [Zakharov, Alexey V.; Sitzmann, Markus; Nicklaus, Marc C.] NCI, CADD Grp, Biol Chem Lab, Ctr Canc Res,NIH,DHHS,NCI Frederick, 376 Boyles St, Frederick, MD 21702 USA. [Peach, Megan L.] Frederick Natl Lab Canc Res, Basic Sci Program, Leidos Biomed Inc, Comp Aided Drug Design Grp,Chem Biol Lab, Frederick, MD 21702 USA. RP Nicklaus, MC (reprint author), NCI, CADD Grp, Biol Chem Lab, Ctr Canc Res,NIH,DHHS,NCI Frederick, 376 Boyles St, Frederick, MD 21702 USA. EM mn1@helix.nih.gov RI Nicklaus, Marc/N-4183-2014; OI Nicklaus, Marc/0000-0002-4775-7030 FU Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E] FX This project has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, 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 United States government. NR 28 TC 16 Z9 16 U1 1 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 EI 1549-960X J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD MAR PY 2014 VL 54 IS 3 BP 705 EP 712 DI 10.1021/ci400737s PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA AD7WS UT WOS:000333478800002 PM 24524735 ER PT J AU Zakharov, AV Peach, ML Sitzmann, M Nicklaus, MC AF Zakharov, Alexey V. Peach, Megan L. Sitzmann, Markus Nicklaus, Marc C. TI A New Approach to Radial Basis Function Approximation and Its Application to QSAR SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID NEURAL-NETWORKS; ACUTE TOXICITY; PREDICTION AB We describe a novel approach to RBF approximation, which combines two new elements: (1) linear radial basis functions and (2) weighting the model by each descriptor's contribution. Linear radial basis functions allow one to achieve more accurate predictions for diverse data sets. Taking into account the contribution of each descriptor produces more accurate similarity values used for model development. The method was validated on 14 public data sets comprising nine physicochemical properties and five toxicity endpoints. We also compared the new method with five different QSAR methods implemented in the EPA T.E.S.T. program. Our approach, implemented in the program GUSAR, showed a reasonable accuracy of prediction and high coverage for all external test sets, providing more accurate prediction results than the comparison methods and even the consensus of these methods. Using our new method, we have created models for physicochemical and toxicity endpoints, which we have made freely available in the form of an online service at http://cactus.nci.nih.gov/chemical/apps/cap. C1 [Zakharov, Alexey V.; Sitzmann, Markus; Nicklaus, Marc C.] NCI, CADD Grp, Biol Chem Lab, Ctr Canc Res,NIH,DHHS,NCI Frederick, Frederick, MD 21702 USA. [Peach, Megan L.] Frederick Natl Lab Canc Res, Basic Sci Program, Leidos Biomed Inc, Comp Aided Drug Design Grp,Chem Biol Lab, Frederick, MD 21702 USA. RP Nicklaus, MC (reprint author), NCI, CADD Grp, Biol Chem Lab, Ctr Canc Res,NIH,DHHS,NCI Frederick, 376 Boyles St, Frederick, MD 21702 USA. EM mn1@helix.nih.gov RI Nicklaus, Marc/N-4183-2014; OI Nicklaus, Marc/0000-0002-4775-7030 FU Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E] FX We are thankful to Dmitry Filimonov for many helpful suggestions made in the course of this project. This project has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, 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 United States government. NR 19 TC 5 Z9 5 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 EI 1549-960X J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD MAR PY 2014 VL 54 IS 3 BP 713 EP 719 DI 10.1021/ci400704f PG 7 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA AD7WS UT WOS:000333478800003 PM 24451033 ER PT J AU Wang, HD Boyce, AM Tsai, JY Gafni, RI Farley, FA Kasa-Vubu, JZ Molinolo, AA Collins, MT AF Wang, Howard D. Boyce, Alison M. Tsai, Jeffrey Y. Gafni, Rachel I. Farley, Frances A. Kasa-Vubu, Josephine Z. Molinolo, Alfredo A. Collins, Michael T. TI Effects of Denosumab Treatment and Discontinuation on Human Growth Plates SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID BISPHOSPHONATE-INDUCED OSTEOPETROSIS; CYCLICAL INTRAVENOUS PAMIDRONATE; OSTEOGENESIS IMPERFECTA; POSTMENOPAUSAL WOMEN; FIBROUS DYSPLASIA; BONE METASTASES; BREAST-CANCER; CHILDREN; OSTEOPOROSIS; ADOLESCENTS AB Context: Denosumab is a humanized monoclonal antibody to receptor activator of nuclear factor-kappa B ligand used primarily for postmenopausal osteoporosis and skeletal-related events from metastatic cancer. Its safety in children has not been established. Objective: The objective of the study was to investigate the effects of denosumab treatment on skeletal growth and histology. Design: This was an observational case report with radiological and histopathological analyses. Setting: The study was conducted at a clinical research center. Patients: A 9-year-old boy with fibrous dysplasia treated with a 7-month course of denosumab participated in the study. Intervention: Histological analyses were performed and compared on growth plates from limbs that had been amputated before and 17 months after denosumab treatment. Main Outcome Measures: Skeletal radiographs and bone histopathology from before and after treatment were measured. Results: After initiating denosumab, sclerotic metaphyseal bands appeared on radiographs. Post-treatment radiographs revealed migration of the bands away from the growth plates, consistent with continued linear growth. Histologically, the bands were composed of horizontally arranged trabeculae containing calcified cartilage. This cartilage appeared to derive from unresorbed primary spongiosa as a result of osteoclast inhibition by denosumab, similar to what has been observed with bisphosphonates. By 17 months after treatment, active bone resorption and formation had returned, as evidenced by the presence of active osteoclasts in resorption pits and osteoid surfaces. Conclusions: Further studies are needed to determine the safety of denosumab on the growing skeleton. However, in this child there was continued epiphyseal activity both during and after treatment and reversal of bone turnover suppression after treatment discontinuation, suggesting that denosumab did not have significant adverse effects on growth. C1 [Wang, Howard D.; Tsai, Jeffrey Y.; Gafni, Rachel I.; Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Molinolo, Alfredo A.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Wang, Howard D.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Wang, Howard D.] Johns Hopkins Univ Hosp, Dept Plast & Reconstruct Surg, Baltimore, MD 21231 USA. [Boyce, Alison M.] Childrens Natl Med Ctr, Div Endocrinol & Diabet, Washington, DC 20010 USA. [Boyce, Alison M.] Childrens Natl Med Ctr, Div Orthopaed & Sports Med, Bone Hlth Program, Washington, DC 20010 USA. [Tsai, Jeffrey Y.] Tufts Univ, Sch Dent Med, Boston, MA 02111 USA. [Farley, Frances A.; Kasa-Vubu, Josephine Z.] Univ Michigan Hlth Syst, Ann Arbor, MI 48109 USA. RP Collins, MT (reprint author), Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, 30 Convent Dr,Bldg 30,Room 228,MSC 4320, Bethesda, MD 20892 USA. EM mc247@nih.gov FU National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services; Medical Research Scholars Program; National Institutes of Health FX This work was supported by the intramural research program of the National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, and was additionally supported in part by the Medical Research Scholars Program, a public-private partnership supported jointly by the National Institutes of Health and generous contributions to the Foundation for the National Institutes of Health from Pfizer Inc, The Leona M. and Harry B. Helmsley Charitable Trust, and the Howard Hughes Medical Institute as well as other private donors. NR 30 TC 9 Z9 9 U1 2 U2 5 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2014 VL 99 IS 3 BP 891 EP 897 DI 10.1210/jc.2013-3081 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AD7RD UT WOS:000333461600050 PM 24423331 ER PT J AU Howard, B Wang, YH Xekouki, P Faucz, FR Jain, M Zhang, LS Meltzer, PG Stratakis, CA Kebebew, E AF Howard, Brandi Wang, Yonghong Xekouki, Paraskevi Faucz, Fabio R. Jain, Meenu Zhang, Lisa Meltzer, Paul G. Stratakis, Constantine A. Kebebew, Electron TI Integrated Analysis of Genome-Wide Methylation and Gene Expression Shows Epigenetic Regulation of CYP11B2 in Aldosteronomas SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID SOMATIC MUTATIONS; KCNJ5 MUTATIONS; ADRENAL-HYPERPLASIA; CHANNEL MUTATIONS; MESSENGER-RNA; IN-VITRO; ADENOMAS; HYPERTENSION; SECRETION; VASOPRESSIN AB Context: Differential methylation of CpG regions is the best-defined mechanism of epigenetic regulation of gene expression. Objective: Our objective was to determine whether any changes in methylation are associated with aldosteronomas. Methods: We performed integrated genome-wide methylation and gene expression profiling in aldosteronomas (n = 25) as compared with normal adrenal cortical tissue (n = 10) and nonfunctioning adrenocortical tumors (n = 13). To determine the effect of demethylation on gene expression of CYP11B2, the H295R cell line was used. Results: The methylome of aldosteronomas, normal adrenal cortex, and nonfunctioning adrenocortical tumors was distinct, with hypomethylation of aldosteronomas. Integrated analysis of gene expression and methylation status showed that 53 of 60 genes were hypermethylated and downregulated, or hypomethylated and upregulated, in aldosteronomas. Of these, 3 genes that regulate steroidogenic signals and synthesis in adrenocortical cells were differentially methylated: AVPR1 alpha and PRKCA were downregulated and hypermethylated, and CYP11B2 was upregulated and hypomethylated. Demethylation treatment resulted in upregulation of these genes, with direct hypomethylation of CpG sites associated with the genes. The CpG island in the promoter region of CYP11B2 was hypomethylated in aldosteronomas but not in blood DNA from the same patients (P = .0004). Conclusions: Altered methylation in aldosteronomas is associated with dysregulated expression of genes involved in steroid biosynthesis. Aldosteronomas are hypomethylated, and CYP11B2 is over-expressed and hypomethylated in these tumors. C1 [Howard, Brandi; Jain, Meenu; Zhang, Lisa; Kebebew, Electron] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Wang, Yonghong; Meltzer, Paul G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Genet Branch, NIH, Bethesda, MD 20892 USA. [Xekouki, Paraskevi; Faucz, Fabio R.; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX The study was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 24 TC 9 Z9 9 U1 0 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2014 VL 99 IS 3 BP E536 EP E543 DI 10.1210/jc.2013-3495 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AD7RD UT WOS:000333461600020 PM 24423307 ER PT J AU Esmailpour, T Riazifar, H Liu, LN Donkervoort, S Huang, VH Madaan, S Shoucri, BM Busch, A Wu, J Towbin, A Chadwick, RB Sequeira, A Vawter, MP Sun, GL Johnston, JJ Biesecker, LG Kawaguchi, R Sun, H Kimonis, V Huang, TS AF Esmailpour, Taraneh Riazifar, Hamidreza Liu, Linan Donkervoort, Sandra Huang, Vincent H. Madaan, Shreshtha Shoucri, Bassem M. Busch, Anke Wu, Jie Towbin, Alexander Chadwick, Robert B. Sequeira, Adolfo Vawter, Marquis P. Sun, Guoli Johnston, Jennifer J. Biesecker, Leslie G. Kawaguchi, Riki Sun, Hui Kimonis, Virginia Huang, Taosheng TI A splice donor mutation in NAA10 results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID ACETYLTRANSFERASE COMPLEX; MEMBRANE-RECEPTOR; CELLULAR UPTAKE; GENE; PHOSPHORYLATION; LOCALIZATION; ANOPHTHALMIA; VARIANTS; DISORDER; CELLS AB Introduction Lenz microphthalmia syndrome (LMS) is a genetically heterogeneous X-linked disorder characterised by microphthalmia/anophthalmia, skeletal abnormalities, genitourinary malformations, and anomalies of the digits, ears, and teeth. Intellectual disability and seizure disorders are seen in about 60% of affected males. To date, no gene has been identified for LMS in the microphthalmia syndrome 1 locus (MCOPS1). In this study, we aim to find the disease-causing gene for this condition. Methods and results Using exome sequencing in a family with three affected brothers, we identified a mutation in the intron 7 splice donor site (c.471+2T -> A) of the N-acetyltransferase NAA10 gene. NAA10 has been previously shown to be mutated in patients with Ogden syndrome, which is clinically distinct from LMS. Linkage studies for this family mapped the disease locus to Xq27-Xq28, which was consistent with the locus of NAA10. The mutation co-segregated with the phenotype and cDNA analysis showed aberrant transcripts. Patient fibroblasts lacked expression of full length NAA10 protein and displayed cell proliferation defects. Expression array studies showed significant dysregulation of genes associated with genetic forms of anophthalmia such as BMP4, STRA6, and downstream targets of BCOR and the canonical WNT pathway. In particular, STRA6 is a retinol binding protein receptor that mediates cellular uptake of retinol/vitamin A and plays a major role in regulating the retinoic acid signalling pathway. A retinol uptake assay showed that retinol uptake was decreased in patient cells. Conclusions We conclude that the NAA10 mutation is the cause of LMS in this family, likely through the dysregulation of the retinoic acid signalling pathway. C1 [Esmailpour, Taraneh; Riazifar, Hamidreza; Liu, Linan; Donkervoort, Sandra; Huang, Vincent H.; Madaan, Shreshtha; Shoucri, Bassem M.; Kimonis, Virginia; Huang, Taosheng] Univ Calif Irvine, Dept Pediat, Div Human Genet, Irvine, CA 92717 USA. [Esmailpour, Taraneh; Huang, Taosheng] Univ Calif Irvine, Dept Pathol, Irvine, CA 92717 USA. [Donkervoort, Sandra] NINDS, Neuromuscular & Neurogenet Disorders Childhood Se, NIH, Neurogenet Branch, Bethesda, MD 20892 USA. [Busch, Anke] Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA. [Wu, Jie; Chadwick, Robert B.] Univ Calif Irvine, Dept Biol Chem, UCI Genom High Throughput Facil, Irvine, CA 92717 USA. [Towbin, Alexander] Cincinnati Childrens Hosp Med Ctr, Div Radiol, Cincinnati, OH 45229 USA. [Sequeira, Adolfo; Vawter, Marquis P.] Univ Calif Irvine, Dept Psychiat & Human Behav, Funct Genom Lab, Irvine, CA 92717 USA. [Sun, Guoli; Huang, Taosheng] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA. [Johnston, Jennifer J.; Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. [Kawaguchi, Riki; Sun, Hui] Univ Calif Los Angeles, Dept Physiol, Jules Stein Eye Inst, Los Angeles, CA 90024 USA. [Kawaguchi, Riki; Sun, Hui] Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90024 USA. [Huang, Taosheng] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92717 USA. [Huang, Taosheng] Univ Calif Irvine, Dept Ophthalmol, Irvine, CA USA. [Huang, Taosheng] Univ Calif Irvine, Dept Pathol, MitoMed Mol Diagnost Lab, Irvine, CA 92717 USA. RP Huang, TS (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Human Genet, 3333 Burnet Ave,Bldg R,Room 1027,MLC 7016, Cincinnati, OH 45229 USA. EM Taosheng.Huang@cchmc.org RI Sequeira, Adolfo/K-7278-2015; OI Sequeira, Adolfo/0000-0003-3040-1190; Towbin, Alexander/0000-0003-1729-5071 FU UC Irvine Foundation; NEI [1R01EY018876] FX This work is supported in part by UC Irvine Foundation and NEI 1R01EY018876 (TH). NR 34 TC 17 Z9 19 U1 1 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 EI 1468-6244 J9 J MED GENET JI J. Med. Genet. PD MAR PY 2014 VL 51 IS 3 BP 185 EP 196 DI 10.1136/jmedgenet-2013-101660 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA AD8QT UT WOS:000333531400007 PM 24431331 ER PT J AU Castle, IJP Yi, HY Hingson, RW White, AM AF Castle, I-Jen P. Yi, Hsiao-Ye Hingson, Ralph W. White, Aaron M. TI State Variation in Underreporting of Alcohol Involvement on Death Certificates: Motor Vehicle Traffic Crash Fatalities as an Example SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID UNITED-STATES; MORTALITY; INJURY; DRINKING; RISK AB Objective: We used motor vehicle traffic (MVT) crash fatalities as an example to examine the extent of underreporting of alcohol involvement on death certificates and state variations. Method: We compared MVT-related death certificates identified from national mortality data (Multiple Cause of Death [MCoD] data) with deaths in national traffic census data from the Fatality Analysis Reporting System (FAIRS). Because MCoD data were not individually linked to FAIRS data, the comparisons were at the aggregate level. Reporting ratio of alcohol involvement on death certificates was thus computed as the prevalence of any mention of alcohol-related conditions among MVT deaths in MCoD, divided by the prevalence of decedents with blood alcohol concentration (BAC) test results (not imputed) of .08% or greater in FAIRS. Through bivariate analysis and multiple regression, we explored state characteristics correlated with state reporting ratios. Results: Both MCoD and FAIRS identified about 450,000 MVT deaths in 1999-2009. Reporting ratio was only 0.16 for all traffic deaths and 0.18 for driver deaths nationally, reflecting that death certificates captured only a small percentage of MVT deaths involving BAC of .08% or more. Reporting ratio did not improve over time, even though FAIRS indicated that the prevalence of BAC of at least .08% in MVT deaths increased from 19.9% in 1999 to 24.2% in 2009. State reporting ratios varied widely, from 0.02 (Nevada and New Jersey) to 0.81 (Delaware). Conclusions: The comparison of MCoD with FAIRS revealed a large discrepancy in reporting alcohol involvement in MVT deaths and considerable state variation in the magnitude of underreporting. We suspect similar underreporting and state variations in alcohol involvement in other types of injury deaths. C1 [Castle, I-Jen P.; Yi, Hsiao-Ye] CSR Inc, Arlington, VA 22201 USA. [Hingson, Ralph W.; White, Aaron M.] NIAAA, Div Epidemiol & Prevent Res, NIH, Bethesda, MD USA. RP Castle, IJP (reprint author), CSR Inc, 2107 Wilson Blvd,Suite 1000, Arlington, VA 22201 USA. EM icastle@csrincorporated.com FU National Institute on Alcohol Abuse and Alcoholism [HHSN267200800023C] FX This article is based on a study conducted for the Alcohol Epidemiologic Data System project funded by the National Institute on Alcohol Abuse and Alcoholism through Contract No. HHSN267200800023C to CSR, Incorporated. The views and opinions expressed in this article are those of the authors and should not be construed to represent the views of the sponsoring agency or the federal government. NR 44 TC 3 Z9 3 U1 0 U2 1 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 EI 1938-4114 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD MAR PY 2014 VL 75 IS 2 BP 299 EP 312 PG 14 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA AE0LL UT WOS:000333657700012 PM 24650824 ER PT J AU Greenfield, TK Ye, Y Bond, J Kerr, WC Nayak, MB Kaskutas, LA Anton, RF Litten, RZ Kranzler, HR AF Greenfield, Thomas K. Ye, Yu Bond, Jason Kerr, William C. Nayak, Madhabika B. Kaskutas, Lee Ann Anton, Raymond F. Litten, Raye Z. Kranzler, Henry R. TI Risks of Alcohol Use Disorders Related to Drinking Patterns in the US General Population SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID MAXIMUM NUMBER; UNITED-STATES; CONSEQUENCES; CONSUMPTION; GUIDELINES; DEPENDENCE; TRENDS; DRUNK; DRUNKENNESS; QUANTITY AB Objective: The purpose of this study was to examine the relations between drinking (mean quantity and heavy drinking patterns) and alcohol use disorders (AUDs) in the U.S. general population. Method: Data from three telephone National Alcohol Surveys (in 2000, 2005, and 2010) were pooled, with separate analyses for men and women restricted to current drinkers (ns = 5,922 men, 6,270 women). Predictors were 12-month volume (mean drinks per day), rates of heavy drinking (5+14+ drinks in a day for men/women), and very heavy drinking (8+, 12+, and 24+ drinks in a day). Outcomes were negative alcohol-related consequences constituting abuse (1+ of 4 DSM-IV-based domains assessed by 13 items) and alcohol dependence (symptoms in 3+ of 7 DSM-IV based domains), together taken to indicate an AUD. Segmentation analyses were used to model risks of problem outcomes from drinking patterns separately by gender. Results: In the general population, men and women who consumed <= 1 drink/day on average with no heavy drinking days did not incur substantial risks of an AUD (<10%). Men who drank from 1 to 2 drinks/day on average but never 5+ incurred a 16% risk of reporting an AUD (3.5% alcohol dependence). At higher volumes, men and women who indicated higher rates of drinking larger amounts per day and/or involving 8+ and 12+ drinks/day (and even 24+ drinks/day for men) showed much higher risks of experiencing AUDs. Conclusions: The findings provide quantitative guidance for primary care practitioners who wish to make population-based recommendations to patients who might benefit by reducing both overall intake and amounts per occasion in an effort to lower their risks of developing AUDs. C1 [Greenfield, Thomas K.; Ye, Yu; Bond, Jason; Kerr, William C.; Nayak, Madhabika B.; Kaskutas, Lee Ann] Inst Publ Hlth, Alcohol Res Grp, Emeryville, CA USA. [Greenfield, Thomas K.] Univ Calif San Francisco, Dept Psychiat, Clin Serv Res Training Program, San Francisco, CA USA. [Kaskutas, Lee Ann] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Anton, Raymond F.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Litten, Raye Z.] NIAAA, Div Treatment & Recovery Res, Bethesda, MD USA. [Kranzler, Henry R.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kranzler, Henry R.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Greenfield, TK (reprint author), Alcohol Res Grp, 6475 Christie Ave,Suite 400, Oakland, CA 94608 USA. EM tgreenfield@arg.org OI /0000-0002-3108-4812 FU National Institute on Alcohol Abuse and Alcoholism (NIAAA) [P50 AA005595, K24 AA13736]; American Society of Clinical Psychopharmacology; Eli Lilly; Alkermes; Lundbeck; AbbVie FX This research was supported by Center Grant P50 AA005595 (to the Public Health Institute, Alcohol Research Group), including a supplement from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and Grant K24 AA13736 to Dr. Kranzler. Dr. Litten's contribution was supported by NIAAA. Drs. Anton and Kranzler performed this work in conjunction with their affiliation with the Alcohol Clinical Trials Initiative (ACTIVE) sponsored by the American Society of Clinical Psychopharmacology and funded in part by the following pharmaceutical companies: Eli Lilly, Alkermes, Lundbeck, and AbbVie (formerly Abbott Laboratories). In addition, Dr. Anton in the last 12 months was a member of the Scientific Advisory Board for Lundbeck and acted as a consultant for GlaxoSmithKline. In the last 12 months, Dr. Kranzler was a consultant to Alkermes, Lilly, Lundbeck, Pfizer, and Roche. Opinions are those of the authors and not the sponsoring institutions. Pharmaceutical companies listed herein have not reviewed or commented on the research. NR 50 TC 14 Z9 14 U1 3 U2 9 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 EI 1938-4114 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD MAR PY 2014 VL 75 IS 2 BP 319 EP 327 PG 9 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA AE0LL UT WOS:000333657700014 PM 24650826 ER PT J AU Falk, DE Litten, RZ Anton, RF Kranzler, HR Johnson, BA AF Falk, Daniel E. Litten, Raye Z. Anton, Raymond F. Kranzler, Henry R. Johnson, Bankole A. CA Active Workgrp TI Cumulative Proportion of Responders Analysis (CPRA) as a Tool to Assess Treatment Outcome in Alcohol Clinical Trials SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; PAIN TRIALS; DEPENDENCE; DRINKING; EFFICACY; INTERVENTIONS; NALTREXONE AB Objective: Several definitions of treatment response have been proposed for alcohol clinical trials (e.g., abstinence and no heavy drinking). However, each of these outcomes allows only one definition of successful response. In contrast, the cumulative proportion of responders analysis (CPRA) includes all of the possible drinking response cutoff points, providing a more complete picture of the therapeutic effects of a treatment. CPRA has been used to examine the efficacy of analgesics but not alcohol pharmacotherapy. To demonstrate its potential utility, we conducted CPRA in two large alcohol treatment trials: the COMBINE (Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence) trial (naltrexone) and a multisite topiramate trial. CPRA was used to demonstrate the efficacy of naltrexone and topiramate on continuous measures of in-treatment drinking heavy drinking days and drinks per day and their reductions from pretreatment. Method: All possible cutoff points were portrayed for each measure. We provide graphs to illustrate the effects of the active medications compared with placebo and examined them statistically over a number of salient drinking outcomes to evaluate their efficacy. Results: Treatment group responder curves were not parallel across the entire range of cutoff points; rather, they separated only at lower levels of drinking. In general, effect sizes increased by 0.10-0.15 when going from the lowest drinking level cutoff (i.e., abstinence and no heavy drinking) to the cutoff associated with the maximal treatment effect. Conclusions: CPRA may be useful in designing subsequent trials and helping to illustrate for treatment providers the likelihood of treatment success given various definitions of a positive response. C1 [Falk, Daniel E.; Litten, Raye Z.] NIAAA, Div Treatment & Recovery Res, Rockville, MD 20852 USA. [Anton, Raymond F.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Kranzler, Henry R.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kranzler, Henry R.] Philadelphia Vet Affairs Med Ctr, Mental Illness Res Educ & Clin Ctr, Vet Integrated Serv Network 4, Philadelphia, PA USA. [Johnson, Bankole A.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. RP Falk, DE (reprint author), NIAAA, NIH, 5635 Fishers Lane,Room 2040, Rockville, MD 20852 USA. EM falkde@mail.nih.gov FU NIAAA NIH HHS [K05 AA017435] NR 33 TC 4 Z9 4 U1 0 U2 3 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 EI 1938-4114 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD MAR PY 2014 VL 75 IS 2 BP 335 EP 346 PG 12 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA AE0LL UT WOS:000333657700016 PM 24650828 ER PT J AU DeGrazia, D AF DeGrazia, David TI The Case for Moderate Gun Control SO KENNEDY INSTITUTE OF ETHICS JOURNAL LA English DT Article ID UNINTENTIONAL FIREARM DEATHS; HOMICIDE RATES; UNITED-STATES; RISK-FACTOR; SUICIDE; OWNERSHIP; AVAILABILITY; HOME; US AB In addressing the shape of appropriate gun policy, this essay assumes for the sake of discussion that there is a legal and moral right to private gun ownership. My thesis is that, against the background of this right, the most defensible policy approach in the United States would feature moderate gun control. The first section summarizes the American gun control status quo and characterizes what I call "moderate gun control." The next section states and rebuts six leading arguments against this general approach to gun policy. The section that follows presents a positive case for moderate gun control that emphasizes safety in the home and society as well as rights whose enforcement entails some limits or qualifications on the right to bear arms. A final section shows how the recommended gun regulations address legitimate purposes, rather than imposing arbitrary restrictions on gun rights, and offers concluding reflections. C1 [DeGrazia, David] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [DeGrazia, David] George Washington Univ, Washington, DC 20052 USA. RP DeGrazia, D (reprint author), NIH, Dept Bioeth, Bethesda, MD 20892 USA. NR 52 TC 1 Z9 1 U1 2 U2 25 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1054-6863 EI 1086-3249 J9 KENNEDY INST ETHIC J JI Kennedy Inst. Ethics J. PD MAR PY 2014 VL 24 IS 1 BP 1 EP 25 PG 25 WC Ethics; Philosophy; Social Issues SC Social Sciences - Other Topics; Philosophy; Social Issues GA AD9FY UT WOS:000333571400002 PM 24783322 ER PT J AU Ljubica, C Feldman, B Tuchman, M AF Ljubica, Caldovic Feldman, B. Tuchman, M. TI NEUROPROTECTION FROM HYPERAMMONEMIA: A SMALL MOLECULE SCREEN SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 09-12, 2014 CL Pacific Grove, CA SP Soc Inherited Metab Disorders C1 [Ljubica, Caldovic; Tuchman, M.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Feldman, B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2014 VL 111 IS 3 BP 236 EP 236 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AC4OI UT WOS:000332500200030 ER PT J AU Brown, D Sloan, J Manoli, I Conway, R Venditti, CP AF Brown, Donna Sloan, Jennifer Manoli, Irini Conway, Rob Venditti, Charles P. TI MATERNAL METHYLMALONIC ACIDEMIA (MMA) IN PREGNANCY SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 09-12, 2014 CL Pacific Grove, CA SP Soc Inherited Metab Disorders C1 [Brown, Donna; Sloan, Jennifer; Manoli, Irini; Venditti, Charles P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Brown, Donna] Medstar Washington Hosp Ctr, Dept Obstet & Gynecol, Washington, DC USA. [Conway, Rob] Wayne State Univ, Dept Pediat, Childrens Hosp Michigan, Detroit, MI 48202 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2014 VL 111 IS 3 BP 243 EP 244 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AC4OI UT WOS:000332500200039 ER PT J AU Lam, C Gallo, L Dineen, R Dorward, H Ciccone, C Hoganson, GE Wetzel, H Wolfe, L Gahl, WA Huizing, M AF Lam, Christina Gallo, Linda Dineen, Richard Dorward, Heidi Ciccone, Carla Hoganson, George E. Wetzel, Heather Wolfe, Lynne Gahl, William A. Huizing, Marjan TI TWO NOVEL COMPOUND HETEROZYGOUS MUTATIONS IN OPA3 IN TWO SIBLINGS WITH 3-METHYLGLUTACONIC ACIDURIA TYPE III SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 09-12, 2014 CL Pacific Grove, CA SP Soc Inherited Metab Disorders C1 [Lam, Christina; Dorward, Heidi; Ciccone, Carla; Wolfe, Lynne; Gahl, William A.; Huizing, Marjan] NHGRI, NIH, Bethesda, MD 20892 USA. [Gallo, Linda; Dineen, Richard; Hoganson, George E.; Wetzel, Heather] Univ Illinois, Chicago, IL 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2014 VL 111 IS 3 BP 243 EP 243 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AC4OI UT WOS:000332500200037 ER PT J AU Celeste, F de Dios, JK Ciccone, C Malicdan, MC Leoyklang, P Vilboux, T McKew, JC Gahl, WA Carrillo-Carrasco, N Huizing, M AF Celeste, F. de Dios, J. K. Ciccone, C. Malicdan, M. C. Leoyklang, P. Vilboux, T. McKew, J. C. Gahl, W. A. Carrillo-Carrasco, N. Huizing, M. TI GNE GENE MUTATIONS ASSOCIATED WITH GNE MYOPATHY SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 09-12, 2014 CL Pacific Grove, CA SP Soc Inherited Metab Disorders C1 [Celeste, F.; de Dios, J. K.; McKew, J. C.; Gahl, W. A.; Carrillo-Carrasco, N.] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Ciccone, C.; Malicdan, M. C.; Leoyklang, P.; Vilboux, T.; Huizing, M.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [de Dios, J. K.; Gahl, W. A.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. RI Carrillo-Carrasco, Nuria/B-9034-2009 OI Carrillo-Carrasco, Nuria/0000-0003-0374-0808 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2014 VL 111 IS 3 BP 245 EP 245 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AC4OI UT WOS:000332500200042 ER PT J AU MacLeod, E Hall, KD McGuire, PJ AF MacLeod, Erin Hall, Kevin D. McGuire, Peter J. TI PREDICTING NITROGEN BALANCE DURING ACUTE METABOLIC DECOMPENSATION USING A COMPUTATIONAL MODEL OF METABOLISM SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 09-12, 2014 CL Pacific Grove, CA SP Soc Inherited Metab Disorders C1 [MacLeod, Erin] Childrens Natl Med Ctr, Div Genet & Metab, Washington, DC 20010 USA. [Hall, Kevin D.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD USA. [McGuire, Peter J.] NHGRI, 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2014 VL 111 IS 3 BP 250 EP 250 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AC4OI UT WOS:000332500200053 ER PT J AU Tarasenko, TN Matsumoto, S Saito, K Senac, J Singh, LN Cologna, S McGuire, PJ AF Tarasenko, Tatiana N. Matsumoto, Shingo Saito, Keita Senac, Julien Singh, Larry N. Cologna, Stephanie McGuire, Peter J. TI HEPATIC MITOCHONRIAL ADAPTATIONS DURING SYSTEMIC IMMUNE ACTIVATION: IMPLICATIONS FOR INBORN ERRORS OF METABOLISM SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 09-12, 2014 CL Pacific Grove, CA SP Soc Inherited Metab Disorders C1 [Tarasenko, Tatiana N.; Senac, Julien; Singh, Larry N.; McGuire, Peter J.] NHGRI, NIH, Bethesda, MD 20892 USA. [Matsumoto, Shingo; Saito, Keita] NCI, NIH, Bethesda, MD 20892 USA. [Cologna, Stephanie] NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2014 VL 111 IS 3 BP 252 EP 253 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AC4OI UT WOS:000332500200058 ER PT J AU Linares, RA Toro, C Cullinane, AR Vega, HH Boerkoel, CF Gahl, WA AF Linares, Ricardo A. Toro, Camilo Cullinane, Andrew R. Vega, Hugo H. Boerkoel, Cornelius F. Gahl, William A. TI CLINICAL AND GENETIC ASSESSMENT OF A PATIENT PRESENTING WITH GENERALIZED CHOREA FROM THE NIH UNDIAGNOSED DISEASES PROGRAM (UDP) SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 09-12, 2014 CL Pacific Grove, CA SP Soc Inherited Metab Disorders C1 [Linares, Ricardo A.; Toro, Camilo; Vega, Hugo H.; Boerkoel, Cornelius F.; Gahl, William A.] NIH, Undiagnosed Dis Program, Bethesda, MD 20892 USA. [Cullinane, Andrew R.; Gahl, William A.] NHGRI, Med Genet Branch, 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2014 VL 111 IS 3 BP 253 EP 253 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AC4OI UT WOS:000332500200059 ER PT J AU Adams, DR Wolfe, LA Regier, DS Zein, WM Lee, P Baker, E Thurm, AE Gahl, WA AF Adams, David R. Wolfe, Lynne A. Regier, Debra S. Zein, Wadih M. Lee, Paul Baker, Eva Thurm, Audrey E. Gahl, William A. TI COMPLEX PRESENTATION OF 2-METHYL-3-HYDROXYBUTRYL-CoA-DEHYDROGENASE (MHBD) DEFICIENCY, STEROID SULFATASE DEFICIENCY AND MULTIPLE CHROMOSOMAL DEFECTS SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 09-12, 2014 CL Pacific Grove, CA SP Soc Inherited Metab Disorders C1 [Adams, David R.; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Adams, David R.; Wolfe, Lynne A.; Gahl, William A.] NIH, Undiagnosed Dis Program, Bethesda, MD 20892 USA. [Regier, Debra S.; Gahl, William A.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Zein, Wadih M.] NEI, NIH, Bethesda, MD 20892 USA. [Lee, Paul] NINDS, NIH, Bethesda, MD 20892 USA. [Baker, Eva] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Thurm, Audrey E.] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2014 VL 111 IS 3 BP 258 EP 259 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AC4OI UT WOS:000332500200069 ER PT J AU Freehauf, CL Venditti, C Gallagher, RC AF Freehauf, Cynthia L. Venditti, Charles Gallagher, Renata C. TI FIRST REPORT OF PRENATAL HYDROXOCOBALAMIN (VITAMIN B12) THERAPY IN cblA CLASS METHYLMALONIC ACIDEMIA SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 09-12, 2014 CL Pacific Grove, CA SP Soc Inherited Metab Disorders C1 [Freehauf, Cynthia L.; Gallagher, Renata C.] Univ Colorado, Dept Pediat, Sch Med, Boulder, CO 80309 USA. [Venditti, Charles] NHGRI, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2014 VL 111 IS 3 BP 259 EP 260 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AC4OI UT WOS:000332500200071 ER PT J AU Ng, BG Wolfe, LA Ichikawa, M Eroshkin, AM Markello, T Tifft, C He, M Gahl, WA Freeze, HH AF Ng, Bobby G. Wolfe, Lynne A. Ichikawa, Mie Eroshkin, Alexey M. Markello, Thomas Tifft, Cynthia He, Miao Gahl, William A. Freeze, Hudson H. TI MUTATIONS IN CAD IMPAIR DE NOVO PYRIMIDINE BIOSYNTHESIS AND DECREASE GLYCOSYLATION PRECURSORS SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 09-12, 2014 CL Pacific Grove, CA SP Soc Inherited Metab Disorders C1 [Ng, Bobby G.; Ichikawa, Mie; Eroshkin, Alexey M.; Freeze, Hudson H.] Sanford Burnham Med Res Inst, Genet Dis Program, La Jolla, CA USA. [Wolfe, Lynne A.; Markello, Thomas; Tifft, Cynthia] NIH, Undiagnosed Dis Program, Bethesda, MD 20892 USA. [Tifft, Cynthia; Gahl, William A.] NHGRI, NIH, Bethesda, MD 20892 USA. [He, Miao] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2014 VL 111 IS 3 BP 261 EP 262 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AC4OI UT WOS:000332500200074 ER PT J AU Anikster, Y Vilboux, T Markello, TC Heimer, G Kenet, G Ben-Zeev, B Rozenthal, E Huizing, M Levinkopf, D Weiss, B Gahl, WA Pode-Shakked, B AF Anikster, Yair Vilboux, Thierry Markello, Thomas C. Heimer, Gali Kenet, Gili Ben-Zeev, Bruria Rozenthal, Ester Huizing, Marjan Levinkopf, Dana Weiss, Batia Gahl, William A. Pode-Shakked, Ben TI INHERITED GLYCOSYL PHOSPHATIDYLINOSITOL DEFICIENCY DUE TO A MUTATION IN PIGM CAUSES PORTAL VEIN THROMBOSIS AND ABSENCE SEIZURES SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 09-12, 2014 CL Pacific Grove, CA SP Soc Inherited Metab Disorders C1 [Anikster, Yair; Levinkopf, Dana; Pode-Shakked, Ben] Edmond & Lily Safra Childrens Hosp, Sheba Med Ctr, Metab Dis Unit, Tel Hashomer, Israel. [Vilboux, Thierry; Markello, Thomas C.; Huizing, Marjan; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Heimer, Gali] Edmond & Lily Safra Childrens Hosp, Sheba Med Ctr, Pediat Neurol Unit, Tel Hashomer, Israel. [Kenet, Gili; Ben-Zeev, Bruria] Chaim Sheba Med Ctr, Israel Natl Hemophilia Ctr, Thrombosis Unit, IL-52621 Tel Hashomer, Israel. [Rozenthal, Ester] Edmond & Lily Safra Childrens Hosp, Sheba Med Ctr, Hematol Lab, Tel Hashomer, Israel. [Weiss, Batia] Edmond & Lily Safra Childrens Hosp, Sheba Med Ctr, Div Pediat Gastroenterol Hepatol & Nutr, Tel Hashomer, Israel. [Anikster, Yair; Kenet, Gili; Ben-Zeev, Bruria; Weiss, Batia] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. NR 0 TC 0 Z9 0 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2014 VL 111 IS 3 BP 263 EP 264 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AC4OI UT WOS:000332500200077 ER PT J AU Ljubica, C Haskins, N Heibel, SK McGuire, PJ Rayavarapu, S Nagaraju, K Hathout, Y Brown, K Tuchman, M AF Ljubica, Caldovic Haskins, N. Heibel, S. K. McGuire, P. J. Rayavarapu, S. Nagaraju, K. Hathout, Y. Brown, K. Tuchman, M. TI UNRAVELING A NEUROMETABOLIC HEREDITARY SPASTIC PARAPLEGIA: B4GALNT1 DEFICIENCY AS NEW INBORN ERROR OF METABOLISM AFFECTING GLYCOSPHINGOLIPID BIOSYNTHESIS SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 09-12, 2014 CL Pacific Grove, CA SP Soc Inherited Metab Disorders C1 [Ljubica, Caldovic; Haskins, N.; Rayavarapu, S.; Nagaraju, K.; Hathout, Y.; Brown, K.; Tuchman, M.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Heibel, S. K.] ARS, USDA, Beltsville, MD USA. [McGuire, P. J.] NHGRI, 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2014 VL 111 IS 3 BP 265 EP 265 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AC4OI UT WOS:000332500200081 ER PT J AU Wolfe, LA Regier, D Saneto, R Parikh, S Goldstein, A Boerkorl, N AF Wolfe, Lynne A. Regier, Debra Saneto, Russell Parikh, Sumit Goldstein, Amy Boerkorl, Neal TI FAILURE TO THRIVE IN CHILDREN WITH MITOCHONDRIAL DISEASES SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 09-12, 2014 CL Pacific Grove, CA SP Soc Inherited Metab Disorders C1 [Wolfe, Lynne A.; Regier, Debra; Boerkorl, Neal] NHGRI, Undiagnosed Dis Program, Bethesda, MD 20892 USA. [Regier, Debra] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Saneto, Russell] Neurol Seattle, Seattle, WA USA. [Parikh, Sumit] Neurosci Cleveland Clin, Cleveland, OH USA. [Goldstein, Amy] UPMC, Childrens Hosp, Dept Pediat, Div Pediat Neurol, Pittsburgh, PA 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2014 VL 111 IS 3 BP 265 EP 265 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AC4OI UT WOS:000332500200080 ER PT J AU Manoli, I Myles, JG Sloan, JL Shchelochkov, OA Venditti, CP AF Manoli, I Myles, J. G. Sloan, J. L. Shchelochkov, O. A. Venditti, C. P. TI CRITICAL REAPPRAISAL OF MEDICAL FOODS UTILIZATION IN METHYLMALONIC ACIDEMIA SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 09-12, 2014 CL Pacific Grove, CA SP Soc Inherited Metab Disorders C1 [Manoli, I; Sloan, J. L.; Venditti, C. P.] NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Myles, J. G.] NIH, Dept Nutr, Bethesda, MD 20892 USA. [Shchelochkov, O. A.] Univ Iowa Hosp & Clin, Div Genet, Iowa City, IA 52242 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2014 VL 111 IS 3 BP 278 EP 279 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AC4OI UT WOS:000332500200107 ER PT J AU Camp, KM Parisi, MA Coates, PM Groft, SC AF Camp, Kathryn M. Parisi, Melissa A. Coates, Paul M. Groft, Stephen C. TI PHENYLKETONURIA SCIENTIFIC REVIEW CONFERENCE: FINDINGS AND RESEARCH AGENDA SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 09-12, 2014 CL Pacific Grove, CA SP Soc Inherited Metab Disorders C1 [Camp, Kathryn M.; Coates, Paul M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Parisi, Melissa A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Groft, Stephen C.] NIH, Off Rare Dis Res, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2014 VL 111 IS 3 BP 282 EP 283 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AC4OI UT WOS:000332500200114 ER PT J AU Estrada-Veras, J Alvarado-Enriquez, J Gahl, W AF Estrada-Veras, Juvianee Alvarado-Enriquez, Jhonell Gahl, William TI CEREBELLAR HYPOMETABOLISM IN ERDHEIM CHESTER DISEASE: HISTIOCYTIC INFILTRATION, EARLY NEURODEGENERATION OR UNDERLYING METABOLIC DEFICIT? SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 09-12, 2014 CL Pacific Grove, CA SP Soc Inherited Metab Disorders C1 [Estrada-Veras, Juvianee; Alvarado-Enriquez, Jhonell; Gahl, William] NHGRI, Sect Human Biochem Genet, Med Genet Branch, 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2014 VL 111 IS 3 BP 291 EP 291 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AC4OI UT WOS:000332500200129 ER PT J AU Huizing, M Leoyklang, P Malicdan, MC Celeste, F Gahl, WA He, M Carrillo-Carrasco, N AF Huizing, Marjan Leoyklang, Petcharat Malicdan, May C. Celeste, Frank Gahl, William A. He, Miao Carrillo-Carrasco, Nuria TI SIALYLATION OF THOMSEN-FRIEDENREICH ANTIGEN IS A NONINVASIVE BLOOD-BASED BIOMARKER FOR GNE MYOPATHY SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 09-12, 2014 CL Pacific Grove, CA SP Soc Inherited Metab Disorders C1 [Huizing, Marjan; Leoyklang, Petcharat; Malicdan, May C.; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Celeste, Frank] NIH, NCATS, Bethesda, MD 20892 USA. [He, Miao; Carrillo-Carrasco, Nuria] Univ Penn, Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RI Carrillo-Carrasco, Nuria/B-9034-2009 OI Carrillo-Carrasco, Nuria/0000-0003-0374-0808 NR 0 TC 0 Z9 0 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2014 VL 111 IS 3 BP 293 EP 293 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AC4OI UT WOS:000332500200133 ER PT J AU Frazier, DM VanCalcar, S Enns, GM McGuire, PJ AF Frazier, Dianne M. VanCalcar, Sandra Enns, Gregory M. McGuire, Peter. J. TI NEED FOR EVIDENCE-BASED RESEARCH TO ASSESS BENEFITS OF NUTRITION TREATMENTS FOR RARE INBORN ERRORS OF METABOLISM SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 09-12, 2014 CL Pacific Grove, CA SP Soc Inherited Metab Disorders C1 [Frazier, Dianne M.] Univ N Carolina, Div Genet & Metab, Chapel Hill, NC USA. [VanCalcar, Sandra] Univ Wisconsin, Dept Pediat, Sch Med & Publ Hlth, Div Genet & Metab, Madison, WI USA. [Enns, Gregory M.] Stanford Univ, Dept Pediat, Div Med Genet, Stanford, CA 94305 USA. [McGuire, Peter. J.] NHGRI, 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2014 VL 111 IS 3 BP 295 EP 296 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AC4OI UT WOS:000332500200139 ER PT J AU Song, T Park, Y Shamputa, IC Seo, S Lee, SY Jeon, HS Choi, H Lee, M Glynne, RJ Barnes, SW Walker, JR Batalov, S Yusim, K Feng, SH Tung, CS Theiler, J Via, LE Boshoff, HIM Murakami, KS Korber, B Barry, CE Cho, SN AF Song, Taeksun Park, Yumi Shamputa, Isdore Chola Seo, Sunghwa Lee, Sun Young Jeon, Han-Seung Choi, Hongjo Lee, Myungsun Glynne, Richard J. Barnes, S. Whitney Walker, John R. Batalov, Serge Yusim, Karina Feng, Shihai Tung, Chang-Shung Theiler, James Via, Laura E. Boshoff, Helena I. M. Murakami, Katsuhiko S. Korber, Bette Barry, Clifton E., III Cho, Sang-Nae TI Fitness costs of rifampicin resistance in Mycobacterium tuberculosis are amplified under conditions of nutrient starvation and compensated by mutation in the beta ' subunit of RNA polymerase SO MOLECULAR MICROBIOLOGY LA English DT Article ID DRUG-RESISTANCE; ANTIBIOTIC-RESISTANCE; TRANSCRIPTION ELONGATION; GENE-EXPRESSION; SOUTH-AFRICA; EVOLUTION; PPGPP; ADAPTATION; MECHANISMS; VIRULENCE AB Rifampicin resistance, a defining attribute of multidrug-resistant tuberculosis, is conferred by mutations in the subunit of RNA polymerase. Sequencing of rifampicin-resistant (RIF-R) clinical isolates of Mycobacterium tuberculosis revealed, in addition to RIF-R mutations, enrichment of potential compensatory mutations around the double-psi -barrel domain of the subunit comprising the catalytic site and the exit tunnel for newly synthesized RNA. Sequential introduction of the resistance allele followed by the compensatory allele in isogenic Mycobacterium smegmatis showed that these mutations respectively caused and compensated a starvation enhanced growth defect by altering RNA polymerase activity. While specific combinations of resistance and compensatory alleles converged in divergent lineages, other combinations recurred among related isolates suggesting transmission of compensated RIF-R strains. These findings suggest nutrient poor growth conditions impose larger selective pressure on RIF-R organisms that results in the selection of compensatory mutations in a domain involved in catalysis and starvation control of RNA polymerase transcription. C1 [Song, Taeksun; Park, Yumi; Seo, Sunghwa; Lee, Sun Young; Jeon, Han-Seung; Choi, Hongjo; Lee, Myungsun; Barry, Clifton E., III; Cho, Sang-Nae] Int TB Res Ctr, Chang Won, South Korea. [Shamputa, Isdore Chola; Via, Laura E.; Boshoff, Helena I. M.; Barry, Clifton E., III] NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. [Glynne, Richard J.; Barnes, S. Whitney; Walker, John R.; Batalov, Serge] Novartis Res Fdn, Genom Inst, San Diego, CA USA. [Yusim, Karina; Feng, Shihai; Tung, Chang-Shung; Theiler, James; Korber, Bette] Los Alamos Natl Lab, Los Alamos, NM USA. [Murakami, Katsuhiko S.] Penn State Univ, Ctr RNA Mol Biol, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Cho, Sang-Nae] Yonsei Univ, Coll Med, Dept Microbiol, Seoul, South Korea. [Cho, Sang-Nae] Yonsei Univ, Coll Med, Inst Immunol & Immunol Dis, Seoul, South Korea. RP Barry, CE (reprint author), Int TB Res Ctr, Chang Won, South Korea. EM cbarry@niaid.nih.gov; raycho@yonsei.kr RI Barry, III, Clifton/H-3839-2012 OI Via, Laura/0000-0001-6074-9521; FU NIAID, NIH; Korean Centers for Disease Control of the Korean Ministry of Health and Welfare; NIH [GM087350-A1] FX This work was supported (in part) by the Intramural Research Program of the NIAID, NIH, (in part) by continuous support from the Korean Centers for Disease Control of the Korean Ministry of Health and Welfare to the International Tuberculosis Research Center, and (in part) by NIH Grant GM087350-A1 (K. S. M.). We would like to thank the subjects who enrolled in this research study for their active participation and donation of specimens (ClinicalTrials.gov identifier: NCT00341601) and the clinical staff who supported that trial. The authors of this study declare that they have no conflicts of interest with respect to any aspect of this research. NR 47 TC 14 Z9 14 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD MAR PY 2014 VL 91 IS 6 BP 1106 EP 1119 DI 10.1111/mmi.12520 PG 14 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA AD7LV UT WOS:000333446300006 PM 24417450 ER PT J AU Simmons, JK Patel, J Michalowski, A Zhang, SL Wei, BR Sullivan, P Gamache, B Felsenstein, K Kuehl, WM Simpson, RM Zingone, A Landgren, O Mock, BA AF Simmons, John K. Patel, Jyoti Michalowski, Aleksandra Zhang, Shuling Wei, Bih-Rong Sullivan, Patrick Gamache, Ben Felsenstein, Kenneth Kuehl, W. Michael Simpson, R. Mark Zingone, Adriana Landgren, Ola Mock, Beverly A. TI TORC1 and class I HDAC inhibitors synergize to suppress mature B cell neoplasms SO MOLECULAR ONCOLOGY LA English DT Article DE Plasmacytoma; Myeloma; Burkitt's lymphoma; Mantle cell lymphoma; Entinostat; Siroliumus ID HISTONE DEACETYLASE INHIBITOR; MULTIPLE-MYELOMA CELLS; REFRACTORY SOLID TUMORS; PHASE-I; MOLECULAR CLASSIFICATION; MAMMALIAN TARGET; CYCLIN D1; PLASMACYTOMA SUSCEPTIBILITY; CLINICAL-IMPLICATIONS; DRUG-COMBINATION AB Enhanced proliferative signaling and loss of cell cycle regulation are essential for cancer progression. Increased mitogenic signaling through activation of the mTOR pathway, coupled with deregulation of the Cyclin D/retinoblastoma (Rb) pathway is a common feature of lymphoid malignancies, including plasmacytoma (PCT), multiple myeloma (MM), Burkitt's lymphoma (BL), and mantle cell lymphoma (MCL). Here we evaluate the synergy of pharmacologically affecting both of these critical pathways using the mTOR inhibitor sirolimus and the histone deacetylase inhibitor entinostat. A dose-matrix screening approach found this combination to be highly active and synergistic in a panel of genetically diverse human MM cell lines. Synergy and activity was observed in mouse PCT and human BL and MCL cell lines tested in vitro, as well as in freshly isolated primary MM patient samples tested ex vivo. This combination had minimal effects on healthy donor cells and retained activity when tested in a co-culture system simulating the protective interaction of cancer cells with the tumor microenvironment. Combining sirolimus with entinostat enhanced cell cycle arrest and apoptosis. At the molecular level, entinostat increased the expression of cell cycle negative regulators including CDKN1A (p21) and CDKN2A (p16), while the combination decreased critical growth and survival effectors including Cyclin D, BCL-XL, BIRC5, and activated MAPK. Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies. C1 [Simmons, John K.; Patel, Jyoti; Michalowski, Aleksandra; Zhang, Shuling; Wei, Bih-Rong; Sullivan, Patrick; Gamache, Ben; Felsenstein, Kenneth; Simpson, R. Mark; Mock, Beverly A.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Kuehl, W. Michael] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Zingone, Adriana; Landgren, Ola] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Mock, BA (reprint author), NCI, NIH, Bldg 37,Rm 3146,37 Convent Dr,MSC 4258, Bethesda, MD 20892 USA. EM mockb@mail.nih.gov RI Mock, Beverly/B-3110-2015 OI Mock, Beverly/0000-0003-2479-4549 FU Intramural Research Program of the 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. Comments and suggestions from Doug Lowy, Peter Blumberg, Lee Helman, Ke Zhang, Peter Ordentlich, Wyndham Wilson, Lou Staudt, Kevin Camphausen, Brigitte Widemann, Val Bliskovsky, Richard Robinson and the NCI JDC contributed significantly to the project and the manuscript. 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 70 TC 8 Z9 9 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1574-7891 EI 1878-0261 J9 MOL ONCOL JI Mol. Oncol. PD MAR PY 2014 VL 8 IS 2 BP 261 EP 272 DI 10.1016/j.molonc.2013.11.007 PG 12 WC Oncology SC Oncology GA AD8HL UT WOS:000333507000009 PM 24429254 ER PT J AU Gindin, Y Valenzuela, MS Aladjem, MI Meltzer, PS Bilke, S AF Gindin, Yevgeniy Valenzuela, Manuel S. Aladjem, Mirit I. Meltzer, Paul S. Bilke, Sven TI A chromatin structure-based model accurately predicts DNA replication timing in human cells SO MOLECULAR SYSTEMS BIOLOGY LA English DT Article DE DNA replication timing; computational model; DNase hypersensitivity; systems analysis ID ACUTE LYMPHOBLASTIC-LEUKEMIA; GENOME-SCALE ANALYSIS; REVEALS; CANCER; BIOINFORMATICS; TRANSLOCATION; INITIATION; METAZOANS; DATABASE; ORIGINS AB A mechanistic model predicts cell lineage-specific DNA replication timing based on the location of DNase-hypersensitivity data alone. With essentially no parameters to adjust for different cell types, the model is truly predictive even for cells where timing data are not available.image C1 [Gindin, Yevgeniy; Meltzer, Paul S.; Bilke, Sven] Ctr Canc Res, Genet Branch, Bethesda, MD USA. [Gindin, Yevgeniy] Boston Univ, Grad Program Bioinformat, Boston, MA 02215 USA. [Valenzuela, Manuel S.] Meharry Med Coll, Sch Med, Dept Biochem & Canc Biol, Nashville, TN 37208 USA. [Aladjem, Mirit I.] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Meltzer, PS (reprint author), Ctr Canc Res, Genet Branch, Bethesda, MD USA. EM pmeltzer@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; NIH [SC1CA1 138180] FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. MSV was supported by NIH grant SC1CA1 138180. We thank Sean Davis, Kevin Gardner, and Subhajyoti De for discussions. NR 47 TC 22 Z9 22 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1744-4292 J9 MOL SYST BIOL JI Mol. Syst. Biol. PD MAR PY 2014 VL 10 IS 3 DI 10.1002/msb.134859 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AE0CY UT WOS:000333632300002 PM 24682507 ER PT J AU O'Sullivan, CC Connolly, RM AF O'Sullivan, Ciara C. Connolly, Roisin M. TI Pertuzumab and Its Accelerated Approval: Evolving Treatment Paradigms and New Challenges in the Management of HER2-Positive Breast Cancer SO ONCOLOGY-NEW YORK LA English DT Article ID MONOCLONAL-ANTIBODY; DIMERIZATION INHIBITOR; PLUS TRASTUZUMAB; PHASE-II; DOCETAXEL; GROWTH; SURVIVAL; ERBB2; HER2 AB The addition of trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), to standard chemotherapy in patients with HER2-positive breast cancer has resulted in major improvements in breast cancer outcomes, including improved survival, in both the adjuvant and metastatic settings. However, some patients experience disease relapse despite adjuvant trastuzumab-containing therapy, and resistance to trastuzumab develops in the majority of patients in the metastatic setting. An understanding of the molecular mechanisms underlying trastuzumab resistance has aided the development of novel HER2-targeted therapies. In June 2012, the HER2 dimerization inhibitor pertuzumab was approved by the US Food and Drug Administration (FDA) for use with chemotherapy and trastuzumab in the first-line treatment of metastatic HER2-positive breast cancer. In September 2013, accelerated approval was granted for use of pertuzumab in the neoadjuvant setting, representing a landmark decision by the FDA. This article discusses the development of pertuzumab to date, with a particular focus on the accelerated approval decision. We highlight the need to identify reliable biomarkers of sensitivity and resistance to HER2-targeted therapy, which would make possible the individualization of treatment for patients with HER2-positive breast cancer. C1 [O'Sullivan, Ciara C.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Connolly, Roisin M.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP Connolly, RM (reprint author), Johns Hopkins Sch Med, Sidney Kimmel Comprehens Canc Ctr, 1650 Orleans St,CRB 1,Room 153, Baltimore, MD 21287 USA. EM rconnol2@jhmi.edu FU Novartis; Puma Biotechnology; Genentech; QVC; Fashion Footwear Association of New York FX Dr. Connolly has received research grants from Novartis, Puma Biotechnology, and Genentech; she also receives research support from QVC and the Fashion Footwear Association of New York. Dr. O'Sullivan has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article. NR 36 TC 8 Z9 8 U1 0 U2 3 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD MAR PY 2014 VL 28 IS 3 BP 186 EP + PG 10 WC Oncology SC Oncology GA AD8YF UT WOS:000333550900005 PM 24855725 ER PT J AU Grabowski, MK Lessler, J Redd, AD Kagaayi, J Laeyendecker, O Ndyanabo, A Nelson, MI Cummings, DAT Bwanika, JB Mueller, AC Reynolds, SJ Munshaw, S Ray, SC Lutalo, T Manucci, J Tobian, AAR Chang, LW Beyrer, C Jennings, JM Nalugoda, F Serwadda, D Wawer, MJ Quinn, TC Gray, RH AF Grabowski, Mary K. Lessler, Justin Redd, Andrew D. Kagaayi, Joseph Laeyendecker, Oliver Ndyanabo, Anthony Nelson, Martha I. Cummings, Derek A. T. Bwanika, John Baptiste Mueller, Amy C. Reynolds, Steven J. Munshaw, Supriya Ray, Stuart C. Lutalo, Tom Manucci, Jordyn Tobian, Aaron A. R. Chang, Larry W. Beyrer, Chris Jennings, Jacky M. Nalugoda, Fred Serwadda, David Wawer, Maria J. Quinn, Thomas C. Gray, Ronald H. CA Rakai Hlth Sci Program TI The Role of Viral Introductions in Sustaining Community-Based HIV Epidemics in Rural Uganda: Evidence from Spatial Clustering, Phylogenetics, and Egocentric Transmission Models SO PLOS MEDICINE LA English DT Article ID SEXUALLY-TRANSMITTED-DISEASES; INFECTIOUS-DISEASES; POPULATION; PREVENTION; NETWORKS; TRIALS; RAKAI; RECOMBINATION; MIGRATION; DYNAMICS AB Background It is often assumed that local sexual networks play a dominant role in HIV spread in sub-Saharan Africa. The aim of this study was to determine the extent to which continued HIV transmission in rural communities-home to two-thirds of the African population-is driven by intra-community sexual networks versus viral introductions from outside of communities. Methods and Findings We analyzed the spatial dynamics of HIV transmission in rural Rakai District, Uganda, using data from a cohort of 14,594 individuals within 46 communities. We applied spatial clustering statistics, viral phylogenetics, and probabilistic transmission models to quantify the relative contribution of viral introductions into communities versus community- and household-based transmission to HIV incidence. Individuals living in households with HIV-incident (n = 189) or HIV-prevalent (n = 1,597) persons were 3.2 (95% CI: 2.7-3.7) times more likely to be HIV infected themselves compared to the population in general, but spatial clustering outside of households was relatively weak and was confined to distances gag and env genes suggest that chains of transmission frequently cross community boundaries. A total of 95 phylogenetic clusters were identified, of which 44% (42/95) were two individuals sharing a household. Among the remaining clusters, 72% (38/53) crossed community boundaries. Using the locations of self-reported sexual partners, we estimate that 39% (95% CI: 34%-42%) of new viral transmissions occur within stable household partnerships, and that among those infected by extra-household sexual partners, 62% (95% CI: 55%-70%) are infected by sexual partners from outside their community. These results rely on the representativeness of the sample and the quality of self-reported partnership data and may not reflect HIV transmission patterns outside of Rakai. Conclusions Our findings suggest that HIV introductions into communities are common and account for a significant proportion of new HIV infections acquired outside of households in rural Uganda, though the extent to which this is true elsewhere in Africa remains unknown. Our results also suggest that HIV prevention efforts should be implemented at spatial scales broader than the community and should target key populations likely responsible for introductions into communities. Please see later in the article for the Editors' Summary Editors' Summary Background About 35 million people (25 million of whom live in sub-Saharan Africa) are currently infected with HIV, the virus that causes AIDS, and about 2.3 million people become newly infected every year. HIV destroys immune system cells, leaving infected individuals susceptible to other infections. HIV infection can be controlled by taking antiretroviral drugs (antiretroviral therapy, or ART) daily throughout life. Although originally available only to people living in wealthy countries, recent political efforts mean that 9.7 million people in low- and middle-income countries now have access to ART. However, ART does not cure HIV infection, so prevention of viral transmission remains extremely important. Because HIV is usually transmitted through unprotected sex with an infected partner, individuals can reduce their risk of infection by abstaining from sex, by having one or a few partners, and by using condoms. Male circumcision also reduces HIV transmission. In addition to reducing illness and death among HIV-positive people, ART also reduces HIV transmission. Why Was This Study Done? ? Effective HIV control requires an understanding of how HIV spreads through sexual networks. These networks include sexual partnerships between individuals in households, between community members in different households, and between individuals from different communities. Local sexual networks (household and intra-community sexual partnerships) are sometimes assumed to be the dominant driving force in HIV spread in sub-Saharan Africa, but are viral introductions from sexual partnerships with individuals outside the community also important? This question needs answering because the effectiveness of interventions such as ART as prevention partly depends on how many new infections in an intervention area are attributable to infection from partners residing in that area and how many are attributable to infection from partners living elsewhere. Here, the researchers use three analytical methods-spatial clustering statistics, viral phylogenetics, and egocentric transmission modeling-to ask whether HIV transmission in rural Uganda is driven predominantly by intra-community sexual networks. Spatial clustering analysis uses the geographical coordinates of households to measure the tendency of HIV-infected people to cluster spatially at scales consistent with community transmission. Viral phylogenetic analysis examines the genetic relatedness of viruses; if transmission is through local networks, viruses in newly infected individuals should more closely resemble viruses in other community members than those in people outside the community. Egocentric transmission modelling uses information on the locations of recent sexual partners to estimate the proportions of new transmissions from household, intra-community, and extra-community partners. What Did the Researchers Do and Find? ? The researchers applied their three analytical methods to data collected from 14,594 individuals living in 46 communities (governmental administrative units) in Rakai District, Uganda. Spatial clustering analysis indicated that individuals who lived in households with individuals with incident HIV (newly diagnosed) or prevalent HIV (previously diagnosed) were 3.2 times more likely than the general population to be HIV-positive themselves. Spatial clustering outside households was relatively weak, however, and was confined to distances of less than half a kilometer. Viral phylogenetic analysis indicated that 44% of phylogenetic clusters (viruses with related genetic sequences found in more than one individual) were within households, but that 40% of clusters crossed community borders. Finally, analysis of the locations of self-reported sexual partners indicated that 39% of new viral transmissions occurred within stable household partnerships, but that among people newly infected by extra-household partners, nearly two-thirds were infected by partners from outside their community. What Do These Findings Mean? ? The results of all three analyses suggest that HIV introductions into communities are frequent and are likely to play an important role in sustaining HIV transmission in the Rakai District. Specifically, within this rural HIV-endemic region (a region where HIV infection is always present), viral introductions combined with intra-household transmission account for the majority of new infections, although community-based sexual networks also play a critical role in HIV transmission. These findings may not be generalizable to the broader Ugandan population or to other regions of Africa, and their accuracy is likely to be limited by the use of self-reported sexual partner data. Nevertheless, these findings indicate that the dynamics of HIV transmission in rural Uganda (and probably elsewhere) are complex. Consequently, to halt the spread of HIV, prevention efforts will need to be implemented at spatial scales broader than individual communities, and key populations that are likely to introduce HIV into communities will need to be targeted. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001610. Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV and AIDS in Uganda and on HIV prevention strategies (in English and Spanish) The UNAIDS Report on the Global AIDS Epidemic 2013 provides up-to-date information about the AIDS epidemic and efforts to halt it The Center for AIDS Prevention Studies (University of California, San Francisco) has a fact sheet about sexual networks and HIV prevention Wikipedia provides information on spatial clustering analysis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages) A PLOS Computational Biology Topic Page (a review article that is a published copy of record of a dynamic version of the article as found in Wikipedia) about viral phylodynamics is available Personal stories about living with HIV/AIDS are available through Avert, NAM/aidsmap, and Healthtalkonline C1 [Grabowski, Mary K.; Lessler, Justin; Laeyendecker, Oliver; Cummings, Derek A. T.; Tobian, Aaron A. R.; Beyrer, Chris; Wawer, Maria J.; Gray, Ronald H.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD 21218 USA. [Redd, Andrew D.; Laeyendecker, Oliver; Reynolds, Steven J.; Quinn, Thomas C.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Kagaayi, Joseph; Ndyanabo, Anthony; Bwanika, John Baptiste; Reynolds, Steven J.; Lutalo, Tom; Tobian, Aaron A. R.; Chang, Larry W.; Nalugoda, Fred; Serwadda, David; Wawer, Maria J.; Gray, Ronald H.] Rakai Hlth Sci Program, Kalisizo, Uganda. [Laeyendecker, Oliver; Mueller, Amy C.; Reynolds, Steven J.; Munshaw, Supriya; Ray, Stuart C.; Manucci, Jordyn; Tobian, Aaron A. R.; Chang, Larry W.; Jennings, Jacky M.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Nelson, Martha I.] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Coll Med, Kampala, Uganda. RP Grabowski, MK (reprint author), Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD 21218 USA. EM jlessler@jhsph.edu RI Ray, Stuart/B-7527-2008; OI Ray, Stuart/0000-0002-1051-7260; Laeyendecker, Oliver/0000-0002-6429-4760; Lessler, Justin/0000-0002-9741-8109 FU Division of Intramural Research; NIAID [R01 A134826, K22 AI092150-01, R01 A134265]; NIH; World Bank STI Project, Uganda; Henry M. Jackson Foundation; Fogarty Foundation [5D43TW00010]; Johns Hopkins Sommer Scholarship; Bill & Melinda Gates Foundation [22006]; Bill & Melinda Gates Institute for Population and Reproductive Health at JHU FX This study was supported in part by funding from the Division of Intramural Research, NIAID, NIH; NIAID (R01 A134826, K22 AI092150-01, and R01 A134265); NICHD (R01 HD 050180); NIMH (K23 MH086338); the World Bank STI Project, Uganda; the Henry M. Jackson Foundation; the Fogarty Foundation (5D43TW00010); the Johns Hopkins Sommer Scholarship; the Bill & Melinda Gates Foundation (22006); and the Bill & Melinda Gates Institute for Population and Reproductive Health at JHU. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 31 Z9 31 U1 4 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD MAR PY 2014 VL 11 IS 3 DI 10.1371/journal.pmed.1001610 PG 18 WC Medicine, General & Internal SC General & Internal Medicine GA AD6YR UT WOS:000333408000012 ER PT J AU Hays, RD Reeve, BB Smith, AW Clauser, SB AF Hays, Ron D. Reeve, Bryce B. Smith, Ashley Wilder Clauser, Steven B. TI Associations of cancer and other chronic medical conditions with SF-6D preference-based scores in Medicare beneficiaries SO QUALITY OF LIFE RESEARCH LA English DT Article DE Cancer and comorbidity; Health-related quality of life; Preference-based measures; Utilities ID QUALITY-OF-LIFE; HEALTH; SF-36; SF-12 AB Documenting the impact of different types of cancer on daily functioning and well-being is important for understanding burden relative to other chronic medical conditions. This study examined the impact of 10 different cancers and 13 other chronic medical conditions on health-related quality of life. Health-related quality of life data were gathered on the Medicare Health Outcomes Survey (MHOS) between 1998 and 2002. Cancer information was ascertained using the National Cancer Institute's surveillance, epidemiology, and end results program and linked to MHOS data. The average SF-6D score was 0.73 (SD = 0.14). Depressive symptoms had the largest unique association with the SF-6D, followed by arthritis of the hip, chronic obstructive pulmonary disease/asthma, stroke, and sciatica. In addition, the majority of cancer types were significantly associated with the SF-6D score, with significant negative weights ranging from -0.01 to -0.02 on the 0-1 health utility scale. Distant stage of cancer was associated with large decrements in the SF-6D ranging from -0.04 (prostate) to -0.08 (female breast). A large number of chronic conditions, including cancer, are associated uniquely with decrements in health utility. The cumulative effects of comorbid conditions have substantial impact on daily functioning and well-being of Medicare beneficiaries. C1 [Hays, Ron D.] Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90095 USA. [Reeve, Bryce B.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Gillings Sch Global Publ Hlth, Dept Hlth Policy & Management, Chapel Hill, NC 27599 USA. [Smith, Ashley Wilder; Clauser, Steven B.] NCI, Bethesda, MD 20892 USA. RP Hays, RD (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90095 USA. EM drhays@ucla.edu FU NCI internal funds; NIA [P30AG021684]; NIMHD [2P20MD000182] FX This project was supported by NCI internal funds. Dr. Hays was also supported in part by grants from NIA (P30AG021684) and the NIMHD (2P20MD000182). The SEER-MHOS linked data set is now in the public domain. More information about the data set is available at http://outcomes.cancer.gov/surveys/seer-mhos/. For questions, technical support is available at SEER-MHOS@azqio.sdps.org. NR 22 TC 9 Z9 9 U1 1 U2 1 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 MAR PY 2014 VL 23 IS 2 BP 385 EP 391 DI 10.1007/s11136-013-0503-9 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AD8MY UT WOS:000333521500002 PM 23990395 ER PT J AU McCarrey, AC Pacheco, J Carlson, OD Egan, JM Thambisetty, M An, Y Ferrucci, L Resnick, SM AF McCarrey, Anna C. Pacheco, Jennifer Carlson, Olga D. Egan, Josephine M. Thambisetty, Madhav An, Yang Ferrucci, Luigi Resnick, Susan M. TI Interleukin-6 is linked to longitudinal rates of cortical thinning in aging SO TRANSLATIONAL NEUROSCIENCE LA English DT Article DE Aging; MRI; Biomarker; Inflammation ID MAGNETIC-RESONANCE IMAGES; HUMAN CEREBRAL-CORTEX; PROINFLAMMATORY CYTOKINES; GEOMETRICALLY ACCURATE; SURFACE RECONSTRUCTION; ALZHEIMER-DISEASE; OLDER-ADULTS; BRAIN; MRI; SEGMENTATION AB Interleukin-6 (IL-6) is a pro-inflammatory cytokine produced by immune cells and other cell types such as microglia throughout the brain. Higher levels of IL-6 in older adults have been cross-sectionally and longitudinally associated with physical and cognitive impairment, as well as increased dementia risk. The association between IL-6 levels and structural and functional brain changes is less clear. In the present study, we investigated the relationship between IL-6 concentrations and cortical thinning with aging. Magnetic Resonance Imaging (MRI) scans from the Baltimore Longitudinal Study of Aging were analyzed for 121 older subjects (M = 69.3; SD = 7.3; range = 56.1-85.9 yrs) who were repeatedly tested over an average period of 7.5 yrs, and who remained non-demented for the entire follow-up period. The Freesurfer longitudinal processing stream was utilized for image processing, and IL-6 measures were based on serum ELISA assays averaged across time points. Results showed that higher mean IL-6 concentrations were associated with accelerated annual rates of cortical thinning in the inferior temporal poles bilaterally. Additional pronounced regions of IL-6 -accelerated thinning included the transverse frontopolar gyri within the left hemisphere, and subcentral gyrus and sulcus within the right hemisphere. Our results indicate that sustained high levels of the inflammatory biomarker IL-6 are associated with regionally increased rates of age-related cortical thinning. These data build on previous findings that link IL-6 to chronic disease and demonstrate one mechanism through which high levels of inflammation may have adverse effects on physical and cognitive function. C1 [McCarrey, Anna C.; Thambisetty, Madhav; An, Yang; Resnick, Susan M.] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Pacheco, Jennifer] Walter Reed Natl Mil Med Ctr, Natl Intrepid Ctr Excellence, Bethesda, MD 20889 USA. [Carlson, Olga D.; Egan, Josephine M.] NIA, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. [Ferrucci, Luigi] NIA, NIH, Baltimore, MD 21224 USA. RP McCarrey, AC (reprint author), NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. EM anna.mccarrey@nih.gov FU Intramural Research Program of the NIH, National Institute on Aging; Research and Development Contract [N01-AG-3-2124] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging and by Research and Development Contract N01-AG-3-2124. We are grateful to the BLSA participants and staff for their dedication to these studies and the staff of the MRI facility for their assistance. Data share arrangements can be made ad hoc by contacting the Laboratory of Behavioral Neuroscience. The authors declare no conflict of interest. NR 42 TC 0 Z9 0 U1 0 U2 2 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 MAR PY 2014 VL 5 IS 1 BP 1 EP 7 DI 10.2478/s13380-014-0203-0 PG 7 WC Neurosciences SC Neurosciences & Neurology GA AE1EB UT WOS:000333709000001 PM 27066268 ER PT J AU Gandini, NA Fermento, ME Salomon, DG Obiol, DJ Andres, NC Zenklusen, JC Arevalo, J Blasco, J Romero, AL Facchinetti, MM Curino, AC AF Gandini, Norberto A. Fermento, Maria E. Salomon, Debora G. Obiol, Diego J. Andres, Nancy C. Zenklusen, Jean C. Arevalo, Julian Blasco, Jorge Lopez Romero, Alejandro Facchinetti, Maria M. Curino, Alejandro C. TI Heme oxygenase-1 expression in human gliomas and its correlation with poor prognosis in patients with astrocytoma SO TUMOR BIOLOGY LA English DT Article DE Heme oxygenase-1; Glioma; Survival; Tissue microarray ID SQUAMOUS-CELL CARCINOMAS; CHRONIC MYELOID-LEUKEMIA; CENTRAL-NERVOUS-SYSTEM; PROSTATE-CANCER CELLS; NUCLEAR TRANSLOCATION; UP-REGULATION; COLORECTAL-CANCER; OXIDATIVE STRESS; CARBON-MONOXIDE; NITRIC-OXIDE AB In human glioma tumors, heme oxygenase-1 (HO-1) has been shown to be upregulated both when compared with normal brain tissues and also during oligodendroglioma progression. The cell types that express HO-1 have been shown to be mainly macrophages/microglia and T cells. However, many other reports also demonstrated that cell lines derived from glioma tumors and astrocytes express HO-1 after the occurrence of a wide variety of cell injuries and stressors. In addition, the significance of HO-1 upregulation in glioma had not, so far, been addressed. We therefore aimed at investigating the expression and significance of HO-1 in human glial tumors. For this purpose, we performed a wide screening of HO-1 expression in gliomas by using tissue microarrays containing astrocytomas, oligodendrogliomas, mixed tumors, and normal brain tissues. We subsequently correlated protein expression with patient clinicopathological data. We found differences in HO-1 positivity rates between non-malignant brain (22 %) and gliomas (54 %, p = 0.01). HO-1 was expressed by tumor cells and showed cytoplasmic localization, although 19 % of tumor samples also depicted nuclear staining. Importantly, a significant decrease in the overall survival time of grade II and III astrocytoma patients with HO-1 expression was observed. This result was validated at the mRNA level in a cohort of 105 samples. However, no association of HO-1 nuclear localization with patient survival was detected. In vitro experiments aimed at investigating the role of HO-1 in glioma progression showed that HO-1 modulates glioma cell proliferation, but has no effects on cellular migration. In conclusion, our results corroborate the higher frequency of HO-1 protein expression in gliomas than in normal brain, demonstrate that HO-1 is expressed by glial malignant cells, and show an association of HO-1 expression with patients' shorter survival time. C1 [Gandini, Norberto A.; Fermento, Maria E.; Salomon, Debora G.; Obiol, Diego J.; Andres, Nancy C.; Facchinetti, Maria M.; Curino, Alejandro C.] Inst Invest Bioquim Bahia Blanca INIBIBB CONICET, Lab Biol Canc, RA-8000 Bahia Blanca, Buenos Aires, Argentina. [Zenklusen, Jean C.] NCI, Canc Genome Atlas Program Off, NIH, Bethesda, MD 20892 USA. [Arevalo, Julian; Blasco, Jorge] Hosp Interzonal Agudos Dr Jose Penna, Serv Patol, Bahia Blanca, Buenos Aires, Argentina. [Lopez Romero, Alejandro] Lab IACA, Bahia Blanca, Buenos Aires, Argentina. RP Curino, AC (reprint author), Inst Invest Bioquim Bahia Blanca INIBIBB CONICET, Lab Biol Canc, Camino La Carrindanga Km 7, RA-8000 Bahia Blanca, Buenos Aires, Argentina. EM acurino@criba.edu.ar OI Andres, Nancy Carolina/0000-0002-6756-8878 FU CONICET; ANPCyT; Universidad Nacional del Sur FX This work was supported by grants from CONICET, ANPCyT and from the Technical Secretary of the Universidad Nacional del Sur. Gandini NA, Fermento ME, Andres NC, Obiol DJ, and Salomon DG are recipients of a fellowship from CONICET. NR 64 TC 10 Z9 10 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1010-4283 EI 1423-0380 J9 TUMOR BIOL JI Tumor Biol. PD MAR PY 2014 VL 35 IS 3 BP 2803 EP 2815 DI 10.1007/s13277-013-1373-z PG 13 WC Oncology SC Oncology GA AD8SQ UT WOS:000333536300135 PM 24234335 ER PT J AU Gremel, C Costa, R Lovinger, D AF Gremel, Christina Costa, Rui Lovinger, David TI Endocannabinoid signaling in orbitofrontal cortex modulates habit formation SO ALCOHOL LA English DT Meeting Abstract CT Conference on Alcoholism and Stress - A Framework for Future Treatment Strategies CY MAY 06-09, 2014 CL Volterra, ITALY SP Natl Inst Hlth Natl Inst Alcohol Abuse & Alcoholism, Fondazione Cassa Risparmio Volterra, Cassa Risparmio Volterra Spa, Univ Camerino, Mitsubishi Pharma, Volterra Rotary Club, Lundbeck, Soc Study Addict, European Fdn Alcohol Res, Distilled Spirits Council US, Comune Volterra, ULS 5, Auxilium Vitae Volterra Spa, Consorzio Turistico Volterra Valdicecina Valdera, Toscana Sempre C1 [Gremel, Christina; Costa, Rui; Lovinger, David] NIAAA, Lab Integrat Neurosci, NIH, Rockville, MD 20892 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 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD MAR PY 2014 VL 48 IS 2 BP 172 EP 172 PG 1 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA AD8GR UT WOS:000333505000059 ER PT J AU Teshima, K Stopponi, S Economidou, D Kuriyama, M Kinoshita, H Heilig, M Roberto, M Weiss, F Ciccocioppo, R AF Teshima, K. Stopponi, S. Economidou, D. Kuriyama, M. Kinoshita, H. Heilig, M. Roberto, M. Weiss, F. Ciccocioppo, R. TI A selective NOP receptor agonist MT-7716 with efficacy in animal models of alcoholism SO ALCOHOL LA English DT Meeting Abstract CT Conference on Alcoholism and Stress - A Framework for Future Treatment Strategies CY MAY 06-09, 2014 CL Volterra, ITALY SP Natl Inst Hlth Natl Inst Alcohol Abuse & Alcoholism, Fondazione Cassa Risparmio Volterra, Cassa Risparmio Volterra Spa, Univ Camerino, Mitsubishi Pharma, Volterra Rotary Club, Lundbeck, Soc Study Addict, European Fdn Alcohol Res, Distilled Spirits Council US, Comune Volterra, ULS 5, Auxilium Vitae Volterra Spa, Consorzio Turistico Volterra Valdicecina Valdera, Toscana Sempre C1 [Teshima, K.; Kuriyama, M.; Kinoshita, H.] Mitsubishi Tanabe Pharma Corp, Pharmacol Res Labs 1, Osaka, Japan. [Stopponi, S.; Economidou, D.; Ciccocioppo, R.] Univ Camerino, Sch Pharm, Pharmacol Unit, I-62032 Camerino, Italy. [Heilig, M.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. [Roberto, M.] Comm Neurobiol Addict Disorders, La Jolla, CA USA. [Weiss, F.] Scripps Res Inst, Dept Mol & Cellular Neurosci, La Jolla, CA 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 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD MAR PY 2014 VL 48 IS 2 BP 174 EP 174 PG 1 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA AD8GR UT WOS:000333505000069 ER PT J AU Fertig, JB Ryan, ML Litten, R Falk, DE AF Fertig, Joanne B. Ryan, Megan L. Litten, Raye Falk, Daniel E. TI A Double-Blind, Placebo Controlled Trial Assessing the Efficacy and Safety of Varenicline Tartrate for Alcohol Dependence SO ALCOHOL LA English DT Meeting Abstract CT Conference on Alcoholism and Stress - A Framework for Future Treatment Strategies CY MAY 06-09, 2014 CL Volterra, ITALY SP Natl Inst Hlth Natl Inst Alcohol Abuse & Alcoholism, Fondazione Cassa Risparmio Volterra, Cassa Risparmio Volterra Spa, Univ Camerino, Mitsubishi Pharma, Volterra Rotary Club, Lundbeck, Soc Study Addict, European Fdn Alcohol Res, Distilled Spirits Council US, Comune Volterra, ULS 5, Auxilium Vitae Volterra Spa, Consorzio Turistico Volterra Valdicecina Valdera, Toscana Sempre C1 [Fertig, Joanne B.; Ryan, Megan L.; Litten, Raye; Falk, Daniel E.] NIAAA, 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 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD MAR PY 2014 VL 48 IS 2 BP 175 EP 175 PG 1 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA AD8GR UT WOS:000333505000072 ER PT J AU Helig, M Rice, KC Schank, JR AF Helig, Markus Rice, Kenner C. Schank, Jesse R. TI Anti-stress properties of NK1 antagonists as a therapeutic approach in alcoholism SO ALCOHOL LA English DT Meeting Abstract CT Conference on Alcoholism and Stress - A Framework for Future Treatment Strategies CY MAY 06-09, 2014 CL Volterra, ITALY SP Natl Inst Hlth Natl Inst Alcohol Abuse & Alcoholism, Fondazione Cassa Risparmio Volterra, Cassa Risparmio Volterra Spa, Univ Camerino, Mitsubishi Pharma, Volterra Rotary Club, Lundbeck, Soc Study Addict, European Fdn Alcohol Res, Distilled Spirits Council US, Comune Volterra, ULS 5, Auxilium Vitae Volterra Spa, Consorzio Turistico Volterra Valdicecina Valdera, Toscana Sempre C1 [Helig, Markus; Schank, Jesse R.] NIAAA, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. [Rice, Kenner C.] NIDA, Chem Biol Branch, 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 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD MAR PY 2014 VL 48 IS 2 BP 176 EP 177 PG 2 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA AD8GR UT WOS:000333505000077 ER PT J AU Marchant, NJ Rabei, R Kaganovsky, K Caprioli, D Bossert, JM Bonci, A Shaham, Y AF Marchant, Nathan J. Rabei, Rana Kaganovsky, Konstanin Caprioli, Daniele Bossert, Jennifer M. Bonci, Antonello Shaham, Yavin TI Lateral hypothalamus is critical for context-induced relapse to alcohol seeking after punishment SO ALCOHOL LA English DT Meeting Abstract CT Conference on Alcoholism and Stress - A Framework for Future Treatment Strategies CY MAY 06-09, 2014 CL Volterra, ITALY SP Natl Inst Hlth Natl Inst Alcohol Abuse & Alcoholism, Fondazione Cassa Risparmio Volterra, Cassa Risparmio Volterra Spa, Univ Camerino, Mitsubishi Pharma, Volterra Rotary Club, Lundbeck, Soc Study Addict, European Fdn Alcohol Res, Distilled Spirits Council US, Comune Volterra, ULS 5, Auxilium Vitae Volterra Spa, Consorzio Turistico Volterra Valdicecina Valdera, Toscana Sempre C1 [Marchant, Nathan J.; Rabei, Rana; Kaganovsky, Konstanin; Caprioli, Daniele; Bossert, Jennifer M.; Shaham, Yavin] NIDA, Behav Neurosci Res Branch, NIH, DHHS, Baltimore, MD USA. [Bonci, Antonello] NIDA, Cellular Neurobiol Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD USA. [Marchant, Nathan J.] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3052, Australia. 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 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD MAR PY 2014 VL 48 IS 2 BP 177 EP 177 PG 1 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA AD8GR UT WOS:000333505000078 ER PT J AU Schwandt, ML Kwako, L Brown, V George, DT Hommer, D Heilig, M Ramchandani, VA AF Schwandt, M. L. Kwako, L. Brown, V. George, D. T. Hommer, D. Heilig, M. Ramchandani, V. A. TI Effects of early life trauma on alcohol- and stress-related phenotypes in alcoholics with and without posttraumatic stress disorder (PTSD) SO ALCOHOL LA English DT Meeting Abstract CT Conference on Alcoholism and Stress - A Framework for Future Treatment Strategies CY MAY 06-09, 2014 CL Volterra, ITALY SP Natl Inst Hlth Natl Inst Alcohol Abuse & Alcoholism, Fondazione Cassa Risparmio Volterra, Cassa Risparmio Volterra Spa, Univ Camerino, Mitsubishi Pharma, Volterra Rotary Club, Lundbeck, Soc Study Addict, European Fdn Alcohol Res, Distilled Spirits Council US, Comune Volterra, ULS 5, Auxilium Vitae Volterra Spa, Consorzio Turistico Volterra Valdicecina Valdera, Toscana Sempre C1 [Schwandt, M. L.; Kwako, L.; Brown, V.; George, D. T.; Hommer, D.; Heilig, M.; Ramchandani, V. A.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD MAR PY 2014 VL 48 IS 2 BP 186 EP 186 PG 1 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA AD8GR UT WOS:000333505000113 ER PT J AU Stangl, BL Schwandt, ML Kwako, L Yan, J Zametkin, M Ramchandani, VA AF Stangl, B. L. Schwandt, M. L. Kwako, L. Yan, J. Zametkin, M. Ramchandani, V. A. TI Adverse childhood experiences predict heavier drinking and greater alcohol intake during intravenous (IV) alcohol self-administration in non-dependent drinkers SO ALCOHOL LA English DT Meeting Abstract CT Conference on Alcoholism and Stress - A Framework for Future Treatment Strategies CY MAY 06-09, 2014 CL Volterra, ITALY SP Natl Inst Hlth Natl Inst Alcohol Abuse & Alcoholism, Fondazione Cassa Risparmio Volterra, Cassa Risparmio Volterra Spa, Univ Camerino, Mitsubishi Pharma, Volterra Rotary Club, Lundbeck, Soc Study Addict, European Fdn Alcohol Res, Distilled Spirits Council US, Comune Volterra, ULS 5, Auxilium Vitae Volterra Spa, Consorzio Turistico Volterra Valdicecina Valdera, Toscana Sempre C1 [Stangl, B. L.; Schwandt, M. L.; Kwako, L.; Yan, J.; Zametkin, M.; Ramchandani, V. A.] NIAAA, Sect Human Psychopharmacol, LCTS, 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 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD MAR PY 2014 VL 48 IS 2 BP 187 EP 187 PG 1 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA AD8GR UT WOS:000333505000115 ER PT J AU Tapocik, JD Schank, JR Mayo, CL Pincus, A King, C Koenig, JI Heilig, M Elmer, GI AF Tapocik, J. D. Schank, J. R. Mayo, C. L. Pincus, A. King, C. Koenig, J. I. Heilig, M. Elmer, G. I. TI Comorbidity of posttraumatic stress disorder (PTSD) and alcoholism: a rat model of PTSD leads to escalated context-induced alcohol consumption SO ALCOHOL LA English DT Meeting Abstract CT Conference on Alcoholism and Stress - A Framework for Future Treatment Strategies CY MAY 06-09, 2014 CL Volterra, ITALY SP Natl Inst Hlth Natl Inst Alcohol Abuse & Alcoholism, Fondazione Cassa Risparmio Volterra, Cassa Risparmio Volterra Spa, Univ Camerino, Mitsubishi Pharma, Volterra Rotary Club, Lundbeck, Soc Study Addict, European Fdn Alcohol Res, Distilled Spirits Council US, Comune Volterra, ULS 5, Auxilium Vitae Volterra Spa, Consorzio Turistico Volterra Valdicecina Valdera, Toscana Sempre C1 [Tapocik, J. D.; Schank, J. R.; Mayo, C. L.; Pincus, A.; King, C.; Koenig, J. I.; Heilig, M.; Elmer, G. I.] NIAAA, Bethesda, MD 20892 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 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD MAR PY 2014 VL 48 IS 2 BP 187 EP 187 PG 1 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA AD8GR UT WOS:000333505000116 ER PT J AU George, O Vendruscolo, L Schlosburg, JE Brennan, M Hope, B Koob, GF AF George, Olivier Vendruscolo, Leandro Schlosburg, Joel E. Brennan, Molly Hope, Bruce Koob, George F. TI Prevention of alcohol drinking using optogenetic and pharmacogenetic inhibition of CRF neurons in the central nucleus of the amygdala SO ALCOHOL LA English DT Meeting Abstract CT Conference on Alcoholism and Stress - A Framework for Future Treatment Strategies CY MAY 06-09, 2014 CL Volterra, ITALY SP Natl Inst Hlth Natl Inst Alcohol Abuse & Alcoholism, Fondazione Cassa Risparmio Volterra, Cassa Risparmio Volterra Spa, Univ Camerino, Mitsubishi Pharma, Volterra Rotary Club, Lundbeck, Soc Study Addict, European Fdn Alcohol Res, Distilled Spirits Council US, Comune Volterra, ULS 5, Auxilium Vitae Volterra Spa, Consorzio Turistico Volterra Valdicecina Valdera, Toscana Sempre C1 [George, Olivier; Vendruscolo, Leandro; Schlosburg, Joel E.; Brennan, Molly; Koob, George F.] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Hope, Bruce] NIDA, Neurobiol Relapse Sect, NIH, Baltimore, MD 21224 USA. RI George, Olivier/G-9921-2011; koob, george/P-8791-2016 OI George, Olivier/0000-0002-3700-5003; 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 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD MAR PY 2014 VL 48 IS 2 BP 190 EP 190 PG 1 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA AD8GR UT WOS:000333505000130 ER PT J AU Teshima, K Stopponi, S Economidou, D Kuriyama, M Kinoshita, H Heilig, M Weiss, F Roberto, M Ciccocioppo, R AF Teshima, Koji Stopponi, Serena Economidou, Daina Kuriyama, Makoto Kinoshita, Hiroshi Heilig, Markus Weiss, Friedbert Roberto, Marisa Ciccocioppo, Roberto TI A selective NOP receptor agonist MT-7716 if a potent inhibitor of alcohol drinking and relapse to alcohol seeking in msP rats SO ALCOHOL LA English DT Meeting Abstract CT Conference on Alcoholism and Stress - A Framework for Future Treatment Strategies CY MAY 06-09, 2014 CL Volterra, ITALY SP Natl Inst Hlth Natl Inst Alcohol Abuse & Alcoholism, Fondazione Cassa Risparmio Volterra, Cassa Risparmio Volterra Spa, Univ Camerino, Mitsubishi Pharma, Volterra Rotary Club, Lundbeck, Soc Study Addict, European Fdn Alcohol Res, Distilled Spirits Council US, Comune Volterra, ULS 5, Auxilium Vitae Volterra Spa, Consorzio Turistico Volterra Valdicecina Valdera, Toscana Sempre C1 [Teshima, Koji; Kuriyama, Makoto; Kinoshita, Hiroshi] Mitsubishi Tanabe Pharma Corp, Div Res, Dept CNS 2, Pharmacol Res Labs 1, Yokohama, Kanagawa 1000, Japan. [Stopponi, Serena; Economidou, Daina; Ciccocioppo, Roberto] Univ Camerino, Sch Pharm, Pharmacol Unit, I-62032 Camerino, Italy. [Heilig, Markus] NIAAA, Bethesda, MD USA. [Weiss, Friedbert; Roberto, Marisa] Scripps Res Inst, La Jolla, CA 92037 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 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD MAR PY 2014 VL 48 IS 2 BP 193 EP 193 PG 1 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA AD8GR UT WOS:000333505000139 ER PT J AU Manolio, TA Green, ED AF Manolio, Teri A. Green, Eric D. TI Leading the way to genomic medicine SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Editorial Material ID CONSORTIUM; MUTATIONS; NETWORK AB The National Human Genome Research Institute, in close collaboration with its research community, is pursuing an ambitious research agenda to facilitate and promote the implementation of genomics in clinical care. Since 2011, research programs utilizing next-generation sequencing in the management of cancer and other multigenic conditions, workup of undiagnosed conditions, and evaluation of disorders of the newborn period have been initiated, along with projects identifying clinically actionable variants and exploring the ethical and social implications of reporting these findings. Several genomic medicine symposia and other consultations have helped to shape these research initiatives and develop educational materials for physicians and others working to implement the use of genomic findings in clinical care. These efforts provide a valuable complement to the highly successful basic genomics research enterprise that has at last enabled the transition of genomics from the bench to the bedside. (c) 2014 Wiley Periodicals, Inc. C1 [Manolio, Teri A.] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA. [Green, Eric D.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Manolio, TA (reprint author), NHGRI, Div Genom Med, 5635 Fishers Lane,Room 4113,MSC 9305, Bethesda, MD 20892 USA. EM manolio@nih.gov NR 27 TC 13 Z9 13 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4868 EI 1552-4876 J9 AM J MED GENET C JI Am. J. Med. Genet. C PD MAR PY 2014 VL 166 IS 1 SI SI BP 1 EP 7 DI 10.1002/ajmg.c.31384 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA AD1AL UT WOS:000332966100001 PM 24619573 ER PT J AU Ramos, EM Din-Lovinescu, C Berg, JS Brooks, LD Duncanson, A Dunn, M Good, P Hubbard, TJP Jarvik, GP O'Donnell, C Sherry, ST Aronson, N Biesecker, LG Blumberg, B Calonge, N Colhoun, HM Epstein, RS Flicek, P Gordon, ES Green, ED Green, RC Hurles, M Kawamoto, K Knaus, W Ledbetter, DH Levy, HP Lyon, E Maglott, D Mcleod, HL Rahman, N Randhawa, G Wicklund, C Manolio, TA Chisholm, RL Williams, MS AF Ramos, Erin M. Din-Lovinescu, Corina Berg, Jonathan S. Brooks, Lisa D. Duncanson, Audrey Dunn, Michael Good, Peter Hubbard, Tim J. P. Jarvik, Gail P. O'Donnell, Christopher Sherry, Stephen T. Aronson, Naomi Biesecker, Leslie G. Blumberg, Bruce Calonge, Ned Colhoun, Helen M. Epstein, Robert S. Flicek, Paul Gordon, Erynn S. Green, Eric D. Green, Robert C. Hurles, Matthew Kawamoto, Kensaku Knaus, William Ledbetter, David H. Levy, Howard P. Lyon, Elaine Maglott, Donna Mcleod, Howard L. Rahman, Nazneen Randhawa, Gurvaneet Wicklund, Catherine Manolio, Teri A. Chisholm, Rex L. Williams, Marc S. TI Characterizing genetic variants for clinical action SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Article DE pharmacogenomics; genomic medicine; DNA sequencing; database; clinical actionability; electronic health records (EHR) ID ELECTRONIC MEDICAL-RECORDS; GENOME-WIDE ASSOCIATION; EMERGE NETWORK; BASE-PAIRS; HEALTH; DISEASES; BEDSIDE; UTILITY; FUTURE; RETURN AB Genome-wide association studies, DNA sequencing studies, and other genomic studies are finding an increasing number of genetic variants associated with clinical phenotypes that may be useful in developing diagnostic, preventive, and treatment strategies for individual patients. However, few variants have been integrated into routine clinical practice. The reasons for this are several, but two of the most significant are limited evidence about the clinical implications of the variants and a lack of a comprehensive knowledge base that captures genetic variants, their phenotypic associations, and other pertinent phenotypic information that is openly accessible to clinical groups attempting to interpret sequencing data. As the field of medicine begins to incorporate genome-scale analysis into clinical care, approaches need to be developed for collecting and characterizing data on the clinical implications of variants, developing consensus on their actionability, and making this information available for clinical use. The National Human Genome Research Institute (NHGRI) and the Wellcome Trust thus convened a workshop to consider the processes and resources needed to: (1) identify clinically valid genetic variants; (2) decide whether they are actionable and what the action should be; and (3) provide this information for clinical use. This commentary outlines the key discussion points and recommendations from the workshop. (c) 2014 Wiley Periodicals, Inc. C1 [Ramos, Erin M.; Good, Peter; Manolio, Teri A.] NHGRI, Div Genom Med, Bethesda, MD 20892 USA. [Ramos, Erin M.] Characterizing & Displaying Genet Variants Clin A, Washington, DC USA. [Berg, Jonathan S.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Brooks, Lisa D.] NHGRI, Genet Variat Program, Div Genome Sci, Bethesda, MD 20892 USA. [Duncanson, Audrey] Wellcome Trust Res Labs, London, England. [Dunn, Michael] Genet & Mol Sci team Sci Funding, Cambridge, England. [Hubbard, Tim J. P.] Kings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England. [Hubbard, Tim J. P.] Kings Hlth Partners, Bioinformat, London, England. [Jarvik, Gail P.] Univ Washington, Seattle, WA 98195 USA. [Jarvik, Gail P.] Northwest Inst Genet Med, Washington, DC USA. [O'Donnell, Christopher] NHLBI, Bethesda, MD USA. [O'Donnell, Christopher] NHLBI, Div Intramural Res, Bethesda, MD USA. [O'Donnell, Christopher] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Bethesda, MD USA. [O'Donnell, Christopher] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Sherry, Stephen T.] Natl Ctr Biotechnol Informat, Informat Engn Branch, Reference Collect Sect, Bethesda, MD USA. [Aronson, Naomi] Blue Cross & Blue Shield Assoc Technol Evaluat Ct, Chicago, IL USA. [Blumberg, Bruce] Kaiser Permanente Northern Calif, Grad Med Educ, Oakland, CA USA. [Blumberg, Bruce] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Blumberg, Bruce] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Calonge, Ned] Colorado Trust, Denver, CO USA. [Calonge, Ned] Univ Colorado, Sch Med, Boulder, CO 80309 USA. [Calonge, Ned] Univ Colorado, Sch Publ Hlth, Boulder, CO 80309 USA. [Colhoun, Helen M.] Univ Dundee, Dundee DD1 4HN, Scotland. [Epstein, Robert S.] Univ Maryland Med Syst, Dept Epidemiol & Publ Hlth, Baltimore, MD USA. [Flicek, Paul] European Bioinformat Inst, Vertebrate Genom Team, Hinxton, England. [Green, Eric D.] NHGRI, Bethesda, MD 20892 USA. [Green, Eric D.] NIH, Intramural Sequencing Ctr, Bethesda, MD USA. [Green, Robert C.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Green, Robert C.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Hurles, Matthew] Univ Cambridge, McDonald Inst Archaeol Res, Cambridge CB2 1TN, England. [Kawamoto, Kensaku] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT 84112 USA. [Knaus, William] NorthShore Univ Hlth Syst, Ctr Biomed Res Informat, Appl Genom Res & Hlth Heritage Family Med Hist Pr, Evanston, IL USA. [Levy, Howard P.] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Lyon, Elaine] Univ Utah, Sch Med, Salt Lake City, UT 84112 USA. [Lyon, Elaine] ARUP Labs, Salt Lake City, UT USA. [Maglott, Donna] NCBI, Bethesda, MD USA. [Mcleod, Howard L.] Univ S Florida, H Lee Moffitt Canc Ctr, DeBartolo Family Personalized Med Inst, Tampa, FL 33682 USA. [Rahman, Nazneen] Inst Canc Res, London, England. [Rahman, Nazneen] Royal Marsden Hosp, Clin Canc Genet Unit, London, England. [Randhawa, Gurvaneet] US Prevent Serv Task Force Program, Rockville, MD USA. [Wicklund, Catherine] Northwestern Univ, Feinberg Sch Med, Ctr Genet Med, Grad Program Genet Counseling, Evanston, IL 60208 USA. [Chisholm, Rex L.] Northwestern Univ, Feinberg Sch Med, Evanston, IL 60208 USA. [Williams, Marc S.] Geisinger Hlth Syst, GMI, Danville, PA USA. [Williams, Marc S.] Characterizing & Displaying Genet Variants Clin A, Washington, DC USA. RP Ramos, EM (reprint author), NHGRI, Div Genom Med, NIH, 5635 Fishers Lane,Suite 4076,MSC 9305, Bethesda, MD 20892 USA. EM ramoser@nih.gov RI Jarvik, Gail/N-6476-2014; Hubbard, Tim/C-2567-2008; Rahman, Nazneen/D-2802-2013; OI Jarvik, Gail/0000-0002-6710-8708; Hubbard, Tim/0000-0002-1767-9318; Rahman, Nazneen/0000-0003-4376-0440; Flicek, Paul/0000-0002-3897-7955; Colhoun, Helen/0000-0002-8345-3288 FU Intramural NIH HHS [Z99 HG999999]; NHGRI NIH HHS [U01 HG006375] NR 29 TC 18 Z9 19 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4868 EI 1552-4876 J9 AM J MED GENET C JI Am. J. Med. Genet. C PD MAR PY 2014 VL 166 IS 1 SI SI BP 93 EP 104 DI 10.1002/ajmg.c.31386 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA AD1AL UT WOS:000332966100011 PM 24634402 ER PT J AU Lateef, DM Abreu-Vieira, G Xiao, CY Reitman, ML AF Lateef, Dalya M. Abreu-Vieira, Gustavo Xiao, Cuiying Reitman, Marc L. TI Regulation of body temperature and brown adipose tissue thermogenesis by bombesin receptor subtype-3 SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE bombesin receptor subtype-3; obesity; sympathetic nervous system; brown adipose tissue; thermoregulation; CL316243; MK-5046 ID UNCOUPLING PROTEIN; NERVOUS-SYSTEM; MICE; OBESITY; EXPRESSION; AGONIST; MK-5046; LEPTIN; PHARMACOLOGY; DISCOVERY AB Bombesin receptor subtype-3 (BRS-3) regulates energy homeostasis, with Brs3 knockout (Brs3(-/y)) mice being hypometabolic, hypothermic, and hyperphagic and developing obesity. We now report that the reduced body temperature is more readily detected if body temperature is analyzed as a function of physical activity level and light/dark phase. Physical activity level correlated best with body temperature 4 min later. The Brs3(-/y) metabolic phenotype is not due to intrinsically impaired brown adipose tissue function or in the communication of sympathetic signals from the brain to brown adipose tissue, since Brs3(-/y) mice have intact thermogenic responses to stress, acute cold exposure, and beta 3-adrenergic activation, and Brs3(-/y) mice prefer a cooler environment. Treatment with the BRS-3 agonist MK-5046 increased brown adipose tissue temperature and body temperature in wild-type but not Brs3(-/y) mice. Intrahypothalamic infusion of MK5046 increased body temperature. These data indicate that the BRS-3 regulation of body temperature is via a central mechanism, upstream of sympathetic efferents. The reduced body temperature in Brs3(-/y) mice is due to altered regulation of energy homeostasis affecting higher center regulation of body temperature, rather than an intrinsic defect in brown adipose tissue. C1 [Lateef, Dalya M.; Xiao, Cuiying; Reitman, Marc L.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Abreu-Vieira, Gustavo] Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, S-10691 Stockholm, Sweden. RP Reitman, ML (reprint author), Bldg 10-CRC,Rm 5-5940,10 Ctr Dr, Bethesda, MD 20892 USA. EM marc.reitman@nih.gov RI Reitman, Marc/B-4448-2013; OI Reitman, Marc/0000-0002-0426-9475; Abreu-Vieira, Gustavo/0000-0003-2861-4023 FU Intramural Research Program (NIDDK) [ZIA DK-075057, ZIA DK-075063]; Swedish Research Council; Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University FX This research was supported by the Intramural Research Program (NIDDK Grants ZIA DK-075057 and ZIA DK-075063). The visit of G. Abreu-Vieira to NIH was supported within a grant from the Swedish Research Council to Jan Nedergaard and from institutional funds from the Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University. NR 37 TC 12 Z9 12 U1 0 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 EI 1522-1555 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD MAR PY 2014 VL 306 IS 6 BP E681 EP E687 DI 10.1152/ajpendo.00615.2013 PG 7 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA AD5ZQ UT WOS:000333332700010 PM 24452453 ER PT J AU Tong, G Aponte, AM Kohr, MJ Steenbergen, C Murphy, E Sun, JH AF Tong, Guang Aponte, Angel M. Kohr, Mark J. Steenbergen, Charles Murphy, Elizabeth Sun, Junhui TI Postconditioning leads to an increase in protein S-nitrosylation SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE nitric oxide; ischemic postconditioning; protein S-nitrosylation; soluble guanylyl cyclase/cGMP ID NITRIC-OXIDE; KINASE-G; REPERFUSION; MYOCARDIUM; PROTECTION; ISCHEMIA; MITOCHONDRIA; INHIBITION; ACTIVATION; RECEPTORS AB Previous studies have shown a role for nitric oxide and S-nitrosylation (SNO) in postconditioning (PostC), but specific SNO proteins and sites have not been identified in the myocardium after PostC. In this study, we examined SNO signaling in PostC using a Langendorff-perfused mouse heart model. After 20 min of equilibrium perfusion and 25 min of global ischemia, PostC was applied at the beginning of reperfusion with six cycles of 10 s of reperfusion and 10 s of ischemia. The total period of reperfusion was 90 min. Compared with the ischemia-reperfusion (I/R) control, PostC significantly reduced postischemic contractile dysfunction and infarct size. PostC-induced protection was blocked by treatment with N-G-nitro-L-arginine methyl ester (L-NAME) (10 mu mol/l; a constitutive NO synthase inhibitor), but not by either ODQ (10 mu mol/l, a highly selective soluble guanylyl cyclase inhibitor) or KT5823 (1 mu mol/l, a specific protein kinase G inhibitor). Two biotin switch based methods, two dimensional CyDye-maleimide difference gel electrophoresis (2D CyDye-maleimide DIGE) and SNO-resin-assisted capture (SNO-RAC), were utilized to identify SNO-modified proteins and sites. Using 2D CyDye-maleimide DIGE analysis, PostC was found to cause a 25% or greater increase in SNO of a number of proteins, which was blocked by treatment with L-NAME in parallel with the loss of protection. Using SNO-RAC, we identified 77 unique proteins with SNO sites after PostC. These results suggest that NO-mediated SNO signaling is involved in PostC-induced cardioprotection and these data provide the first set of candidate SNO proteins in PostC hearts. C1 [Tong, Guang] Guangzhou Gen Hosp Guangzhou Mil Command, Dept Cardiovasc Surg, Guangzhou, Guangdong, Peoples R China. [Tong, Guang; Aponte, Angel M.; Kohr, Mark J.; Murphy, Elizabeth; Sun, Junhui] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Aponte, Angel M.] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. [Kohr, Mark J.; Steenbergen, Charles] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. RP Sun, JH (reprint author), NHLBI, Syst Biol Ctr, NIH, 10 Ctr Dr,Bldg 10 Rm 8N206, Bethesda, MD 20892 USA. EM sun1@mail.nih.gov OI Kohr, Mark/0000-0002-6034-5962 FU National Institutes of Health; American Heart Association [12BGIA11780030]; National Heart, Lung, and Blood Institute [5R-01-HL-039752, 1K99-HL-114721]; China Scholarship Council [2011659007] FX This work was supported by the National Institutes of Health Intramural Program (A. M. Aponte, J. Sun, and E. Murphy), the American Heart Association (12BGIA11780030, M. J. Kohr), and National Heart, Lung, and Blood Institute Grants 5R-01-HL-039752 (C. Steenbergen) and 1K99-HL-114721 (M. J. Kohr). G. Tong was supported by the China Scholarship Council No. 2011659007. NR 34 TC 24 Z9 24 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD MAR PY 2014 VL 306 IS 6 BP H825 EP H832 DI 10.1152/ajpheart.00660.2013 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA AD6AC UT WOS:000333333900006 PM 24441547 ER PT J AU McCallum, MM Pawlak, AJ Shadrick, WR Simeonov, A Jadhav, A Yasgar, A Maloney, DJ Arnold, LA AF McCallum, Megan M. Pawlak, Alan J. Shadrick, William R. Simeonov, Anton Jadhav, Ajit Yasgar, Adam Maloney, David J. Arnold, Leggy A. TI A fluorescence-based high throughput assay for the determination of small molecule-human serum albumin protein binding SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Drug-protein binding; High throughput screening; Red Mega 500; Human serum albumin ID INHIBITORS; ELECTROPHORESIS; DRUGS AB Herein, we describe the development of a fluorescence-based high throughput assay to determine the small molecule binding towards human serum albumin (HSA). This innovative competition assay is based on the use of a novel fluorescent small molecule Red Mega 500 with unique spectroscopic and binding properties. The commercially available probe displays a large fluorescence intensity difference between the protein-bound and protein-unbound state. The competition of small molecules for HSA binding in the presence of probe resulted in low fluorescence intensities. The assay was evaluated with the library of pharmacological active compounds (LOPAC) small molecule library of 1,280 compounds identifying known high protein binders. The small molecule competition of HSA-Red Mega 500 binding was saturable at higher compound concentrations and exhibited IC50 values between 3 and 24 mu M. The compound affinity toward HSA was confirmed by isothermal titration calorimetry indicating that the new protein binding assay is a valid high throughput assay to determine plasma protein binding. C1 [McCallum, Megan M.; Pawlak, Alan J.; Shadrick, William R.; Arnold, Leggy A.] Univ Wisconsin, Dept Chem & Biochem, Milwaukee, WI 53211 USA. [Simeonov, Anton; Jadhav, Ajit; Yasgar, Adam; Maloney, David J.] NIH, NIH Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Arnold, LA (reprint author), Univ Wisconsin, Dept Chem & Biochem, 3210 N Cramer St, Milwaukee, WI 53211 USA. EM arnold2@uwm.edu FU University of Wisconsin-Milwaukee; University of Wisconsin-Milwaukee Research Growth Initiative (RGI); National Institute of Drug Abuse [DA031090]; University of Wisconsin-Milwaukee Research Foundation; Lynde and Harry Bradley Foundation; Richard and Ethel Herzfeld Foundation FX The work was supported by the University of Wisconsin-Milwaukee, the University of Wisconsin-Milwaukee Research Growth Initiative (RGI), National Institute of Drug Abuse DA031090, the University of Wisconsin-Milwaukee Research Foundation, the Lynde and Harry Bradley Foundation, and the Richard and Ethel Herzfeld Foundation. Further support was enabled by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research and the Intramural Research Program of the NHGRI, NIH. We also thank Dr. Frick to enable the use of the ITC instrument. NR 29 TC 5 Z9 5 U1 1 U2 20 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD MAR PY 2014 VL 406 IS 7 BP 1867 EP 1875 DI 10.1007/s00216-013-7560-3 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AD3BK UT WOS:000333111700008 PM 24390461 ER PT J AU Himes, SK Concheiro, M Scheidweiler, KB Huestis, MA AF Himes, Sarah K. Concheiro, Marta Scheidweiler, Karl B. Huestis, Marilyn A. TI Validation of a novel method to identify in utero ethanol exposure: simultaneous meconium extraction of fatty acid ethyl esters, ethyl glucuronide, and ethyl sulfate followed by LC-MS/MS quantification SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Meconium; Ethyl glucuronide; Fatty acid ethyl esters; Alcohol; Liquid chromatography-tandem mass spectrometry ID TANDEM MASS-SPECTROMETRY; HUMAN-LIVER-MICROSOMES; SOLID-PHASE EXTRACTION; FETAL ALCOHOL SPECTRUM; POPULATION BASE-LINE; LIQUID-CHROMATOGRAPHY; NONDRINKING WOMEN; PRENATAL EXPOSURE; URINE; BIOMARKERS AB Presence of fatty acid ethyl esters (FAEE), ethyl glucuronide (EtG), and ethyl sulfate (EtS) in meconium, the first neonatal feces, identifies maternal alcohol consumption during pregnancy. Current meconium alcohol marker assays require separate analyses for FAEE and EtG/EtS. We describe development and validation of the first quantitative liquid chromatography tandem mass spectrometry assay for 9 FAEEs, EtG, and EtS in 100 mg meconium. For the first time, these alcohol markers are analyzed in the same meconium aliquot, enabling comparison of the efficiency of gestational ethanol exposure detection. 100 mg meconium was homogenized in methanol and centrifuged. The supernatant was divided, and applied to two different solid phase extraction columns for optimized analyte recovery. Limits of quantification for ethyl laurate, myristate, linolenate, palmitoleate, arachidonate, linoleate, palmitate, oleate, and stearate ranged from 25-50 ng/g, with calibration curves to 2,500-5,000 ng/g. EtG and EtS linear dynamic ranges were 5-1,000 and 2.5500 ng/g, respectively. Mean bias and between-day imprecision were <15 %. Extraction efficiencies were 51.2-96.5 %. Matrix effects ranged from -84.7 to 16.0 %, but were compensated for by matched deuterated internal standards when available. All analytes were stable (within +/- 20% change from baseline) in 3 authentic positive specimens, analyzed in triplicate, after 3 freeze/thaw cycles (-20 degrees C). Authentic EtG and EtS also were stable after 12 h at room temperature and 72 h at 4 degrees C; some FAEE showed instability under these conditions, although there was large inter-subject variability. This novel method accurately detects multiple alcohol meconium markers and enables comparison of markers for maternal alcohol consumption. C1 [Himes, Sarah K.; Concheiro, Marta; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural NIH HHS [Z01 DA000412-10, Z01 DA000412-11, ZIA DA000433-10, ZIA DA000433-11, ZIA DA000433-12, ZIA DA000433-13, ZIA DA000433-14] NR 47 TC 12 Z9 12 U1 1 U2 25 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD MAR PY 2014 VL 406 IS 7 BP 1945 EP 1955 DI 10.1007/s00216-013-7600-z PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AD3BK UT WOS:000333111700016 PM 24408304 ER PT J AU Chen, MC Chang, C Glover, GH Gotlib, IH AF Chen, Michael C. Chang, Catie Glover, Gary H. Gotlib, Ian H. TI Increased insula coactivation with salience networks in insomnia SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE Insomnia; fMRI; EEG; Resting state; Insula; Salience networks ID COGNITIVE-BEHAVIORAL THERAPY; FMRI DATA; BOLD FMRI; DSM-IV; SLEEP; VALIDATION; ARTIFACTS; BRAIN; CONNECTIVITY; HYPERAROUSAL AB Insomnia is among the most prevalent and costly of all sleep-related disorders. To characterize the neural mechanisms underlying subjective dysfunction in insomnia, we examined brain activity in 17 female insomniacs and 17 female healthy controls using simultaneous functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) while they were resting and while they were trying to fall asleep. In examining the dynamic regional activity within intrinsic brain networks, we found that, compared with controls, insomniacs had greater involvement of the anterior insula with salience networks, as well as insula BOLD correlation with EEG gamma frequency power during rest in insomniacs. This increased involvement of the anterior insula was associated with negative affect in insomniacs. Aberrant activation of the insula, which integrates temporal and bodily states, in arousal networks may underlie the misperception of sleep quality and subjective distress in insomnia. (C) 2014 Elsevier B.V. All rights reserved. C1 [Chen, Michael C.] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02115 USA. [Chen, Michael C.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Chen, Michael C.; Gotlib, Ian H.] Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. [Chang, Catie] NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Chang, Catie; Glover, Gary H.] Stanford Univ, Dept Elect Engn, Stanford, CA 94305 USA. [Chang, Catie; Glover, Gary H.] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. RP Chen, MC (reprint author), 450 Serra Mall, Stanford, CA 94305 USA. EM mcchen@alumni.stanford.edu FU Stanford Graduate Research Opportunity Grant; American Psychological Association Dissertation Research Award; Norman H. Anderson Research Grant; National Institute of Mental Health [T32 MH019956] FX We thank Arkadiy Maksimovskiy, Rebecca Sacks, and Sarah Victor for their assistance with participant recruitment and data collection. This work was supported by a Stanford Graduate Research Opportunity Grant, an American Psychological Association Dissertation Research Award, and a Norman H. Anderson Research Grant awarded to M.C.C., who was also supported by National Institute of Mental Health grant T32 MH019956. NR 52 TC 18 Z9 20 U1 0 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 EI 1873-6246 J9 BIOL PSYCHOL JI Biol. Psychol. PD MAR PY 2014 VL 97 BP 1 EP 8 DI 10.1016/j.biopsycho.2013.12.016 PG 8 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA AD2JC UT WOS:000333060000001 PM 24412227 ER PT J AU Schmitz, A Grillon, C Avenevoli, S Cui, LH Merikangas, KR AF Schmitz, Anja Grillon, Christian Avenevoli, Shelli Cui, Lihong Merikangas, Kathleen R. TI Developmental investigation of fear-potentiated startle across puberty SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE Fear-potentiated startle; Adolescence; Puberty; Sex differences; Anxiety; Development ID UNPREDICTABLE AVERSIVE EVENTS; ANXIETY DISORDERS; ADOLESCENT BRAIN; ANXIOUS RESPONSES; CONDUCT DISORDER; SEX-DIFFERENCES; PANIC DISORDER; ANIMAL-MODELS; YOUNG-ADULTS; BED NUCLEUS AB The goal of this study was to examine the association between affective development, puberty, and gender using the startle reflex as a marker of defensive mechanisms. Thirty-one male and thirty-five female adolescents aged ten to thirteen participated in a prospective study with up to five assessments. Longitudinal analyses revealed a significant effect of sex, with girls showing stronger fear-potentiation at all pubertal stages. Post hoc tests revealed that fear-potentiation increased in girls but not boys over the course of puberty. Furthermore, baseline startle decreased over the course of puberty. Because age was included as a covariate in all analyses, the puberty effect cannot be accounted for by age. To the best of our knowledge, this study provides the first evidence for a significant increase in fear-potentiated startle across the pubertal transition. Attribution of these changes to pubertal status rather than age has important implications for our understanding of the neurobiology of anxiety and affect regulation. Published by Elsevier B.V. C1 [Schmitz, Anja; Cui, Lihong; Merikangas, Kathleen R.] NIMH, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. [Grillon, Christian] NIMH, Sect Neurobiol Fear & Anxiety, Bethesda, MD 20892 USA. [Avenevoli, Shelli] NIMH, Div Dev Translat Res, Bethesda, MD 20892 USA. RP Merikangas, KR (reprint author), NIMH, Intramural Res Program, 35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. EM Kathleen.Merikangas@nih.gov FU National Institute of Mental Health FX This research was supported by the Intramural Research Program of the National Institute of Mental Health. NR 66 TC 3 Z9 3 U1 6 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 EI 1873-6246 J9 BIOL PSYCHOL JI Biol. Psychol. PD MAR PY 2014 VL 97 BP 15 EP 21 DI 10.1016/j.biopsycho.2013.12.002 PG 7 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA AD2JC UT WOS:000333060000003 PM 24334108 ER PT J AU Varshney, GK Burgess, SM AF Varshney, Gaurav Kumar Burgess, Shawn Michael TI Mutagenesis and phenotyping resources in zebrafish for studying development and human disease SO BRIEFINGS IN FUNCTIONAL GENOMICS LA English DT Article DE zebrafish; mutagenesis; phenotyping; resources; knockouts ID ZINC-FINGER NUCLEASES; TARGETED GENE DISRUPTION; GUIDED CAS9 NUCLEASE; INSERTIONAL MUTAGENESIS; HUMAN GENOME; CAENORHABDITIS-ELEGANS; EFFICIENT CONSTRUCTION; VERTEBRATE DEVELOPMENT; CHROMOSOMAL DELETIONS; POSITIONAL CLONING AB The zebrafish (Danio rerio) is an important model organism for studying development and human disease. The zebrafish has an excellent reference genome and the functions of hundreds of genes have been tested using both forward and reverse genetic approaches. Recent years have seen an increasing number of large-scale mutagenesis projects and the number of mutants or gene knockouts in zebrafish has increased rapidly, including for the first time conditional knockout technologies. In addition, targeted mutagenesis techniques such as zinc finger nucleases, transcription activator-like effector nucleases and clustered regularly interspaced short sequences (CRISPR) or CRISPR-associated (Cas), have all been shown to effectively target zebrafish genes as well as the first reported germline homologous recombination, further expanding the utility and power of zebrafish genetics. Given this explosion of mutagenesis resources, it is now possible to perform systematic, high-throughput phenotype analysis of all zebrafish gene knockouts. C1 [Varshney, Gaurav Kumar; Burgess, Shawn Michael] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. RP Burgess, SM (reprint author), NHGRI, Dev Genom Sect, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM burgess@mail.nih.gov RI Varshney, Gaurav/L-5261-2014; OI Burgess, Shawn/0000-0003-1147-0596; Varshney, Gaurav K./0000-0002-0429-1904 FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 118 TC 9 Z9 9 U1 1 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2041-2649 EI 2041-2657 J9 BRIEF FUNCT GENOMICS JI Brief. Funct. Genomics PD MAR PY 2014 VL 13 IS 2 SI SI BP 82 EP 94 DI 10.1093/bfgp/elt042 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AD2EU UT WOS:000333047300002 PM 24162064 ER PT J AU Donekal, S Venkatesh, BA Liu, YC Liu, CY Yoneyama, K Wu, CO Nacif, M Gomes, AS Hundley, WG Bluemke, DA Lima, JAC AF Donekal, Sirisha Venkatesh, Bharath A. Liu, Yuan Chang Liu, Chia-Ying Yoneyama, Kihei Wu, Colin O. Nacif, Marcelo Gomes, Antoinette S. Hundley, W. Gregory Bluemke, David A. Lima, Joao A. C. TI Interstitial Fibrosis, Left Ventricular Remodeling, and Myocardial Mechanical Behavior in a Population-Based Multiethnic Cohort The Multi-Ethnic Study of Atherosclerosis (MESA) Study SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE circumferential strain; tagging; expressed sequence tags; T1 mapping; LV torsion; interstitial myocardial fibrosis ID CARDIOVASCULAR MAGNETIC-RESONANCE; AMERICAN-HEART-ASSOCIATION; MYOCYTE CELL LOSS; AGING RAT-HEART; DILATED CARDIOMYOPATHY; DIASTOLIC DYSFUNCTION; STRAIN ANALYSIS; FAILURE; AGE; HYPERTROPHY AB Background- Tagged cardiac magnetic resonance provides detailed information on regional myocardial function and mechanical behavior. T1 mapping by cardiac magnetic resonance allows noninvasive quantification of myocardial extracellular expansion (ECE), which has been related to interstitial fibrosis in previous clinical and subclinical studies. We assessed sex-associated differences in the relation of ECE to left ventricular (LV) remodeling and myocardial systolic and diastolic deformation in a large community-based multiethnic population. Methods and Results- Midventricular midwall peak circumferential shortening and early diastolic strain rate and LV torsion and torsional recoil rate were determined using cardiac magnetic resonance tagging. Midventricular short-axis T1 maps were acquired in the same examination pre- and postcontrast injection using Modified Look-Locker Inversion-Recovery sequence. Multivariable linear regression (estimated regression coefficient, B) was used to adjust for risk factors and subclinical disease measures. Of 1230 participants, 114 had a visible myocardial scar by late gadolinium enhancement. Participants without a visible myocardial scar (n=1116) had no history of previous clinical events. In the latter group, multivariable linear regression demonstrated that lower postcontrast T1 times, reflecting greater ECE, were associated with lower circumferential shortening (B=-0.1; P=0.0001), lower LV end-diastolic volume index (B=0.6; P=0.0001), and lower LV end-diastolic mass index (B=0.4; P=0.0001). In addition, lower postcontrast T1 times were associated with lower early diastolic strain rate (B=0.01; P=0.03) in women only and lower LV torsion (B=0.005; P=0.03) and lower LV ejection fraction (B=0.2, P=0.01) in men only. Conclusions- Greater ECE is associated with reduced LV end-diastolic volume index and LV end-diastolic mass index in a large multiethnic population without history of previous cardiovascular events. In addition, greater ECE is associated with reduced circumferential shortening, lower early diastolic strain rate, and a preserved ejection fraction in women, whereas in men, greater ECE is associated with greater LV dysfunction manifested as reduced circumferential shortening, reduced LV torsion, and reduced ejection fraction. C1 [Donekal, Sirisha; Venkatesh, Bharath A.; Liu, Yuan Chang; Yoneyama, Kihei; Lima, Joao A. C.] Johns Hopkins Univ, Dept Cardiol, Baltimore, MD USA. [Wu, Colin O.] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Hundley, W. Gregory] Wake Forest Univ Hlth Sci, Dept Internal Med Cardiol, Winston Salem, NC USA. [Gomes, Antoinette S.] Univ Calif Los Angeles, Sch Med, Dept Radiol, Los Angeles, CA 90024 USA. [Liu, Chia-Ying; Nacif, Marcelo; Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Natl Inst Hlth Clin Ctr, Bethesda, MD USA. RP Lima, JAC (reprint author), Johns Hopkins Univ Hosp, 600 North Wolfe St,Blalock 524D1, Baltimore, MD 21287 USA. EM jlima@jhmi.edu RI Ambale Venkatesh, Bharath/F-4941-2016; OI Ambale Venkatesh, Bharath/0000-0002-2330-2373; Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95168]; National Center for Research Resources [UL1-RR-024156, UL1-RR-025005]; National Institutes of Health FX This research was supported by contracts N01-HC-95159 through N01-HC-95168 from the National Heart, Lung, and Blood Institute, grants UL1-RR-024156 and UL1-RR-025005 from National Center for Research Resources, and the National Institutes of Health intramural research program. NR 45 TC 22 Z9 23 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD MAR PY 2014 VL 7 IS 2 BP 292 EP 302 DI 10.1161/CIRCIMAGING.113.001073 PG 11 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AD1LB UT WOS:000332994400011 PM 24550436 ER PT J AU Andersson, C Vasan, RS AF Andersson, Charlotte Vasan, Ramachandran S. TI Is There a Role for Coronary Artery Calcium Scoring for Management of Asymptomatic Patients at Risk for Coronary Artery Disease? Clinical Risk Scores Are Sufficient To Define Primary Prevention Treatment Strategies Among Asymptomatic Patients SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article ID BEAM COMPUTED-TOMOGRAPHY; HEART-DISEASE; CARDIOVASCULAR-DISEASE; LIFETIME RISK; BEHAVIORAL-CHANGE; AMERICAN-COLLEGE; FAMILY-HISTORY; TASK-FORCE; ATHEROSCLEROSIS; PREDICTION C1 [Andersson, Charlotte; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Andersson, Charlotte; Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med & Cardiol, Boston, MA 02118 USA. [Andersson, Charlotte] Univ Copenhagen, Gentofte Hosp, Dept Cardiol, Hellerup, Denmark. RP Vasan, RS (reprint author), Boston Univ, Sch Med, Sect Prevent Med & Epidemiol, 801 Massachusetts Ave,Suite 470, Boston, MA 02118 USA. EM vasan@bu.edu RI Andersson, Charlotte/P-4849-2014 FU Danish agency for science, technology, and innovation (the Danish Medical Research Council) [FSS-11-120873]; [N01-HC-25195] FX This work was funded in part by N01-HC-25195. Dr Andersson was supported by an independent research grant from the Danish agency for science, technology, and innovation (the Danish Medical Research Council, grant no. FSS-11-120873). NR 62 TC 4 Z9 4 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD MAR PY 2014 VL 7 IS 2 BP 390 EP 397 DI 10.1161/CIRCIMAGING.113.000470 PG 8 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AD1LB UT WOS:000332994400022 PM 24642921 ER PT J AU Ahuja, M Muallem, S AF Ahuja, Malini Muallem, Shmuel TI The gatekeepers of mitochondrial calcium influx: MICU1 and MICU2 SO EMBO REPORTS LA English DT Editorial Material ID UNIPORTER AB The receptor-evoked Ca2+ signal is sensed and translated by mitochondria. Physiological cytoplasmic Ca2+ ([Ca2+](c)) oscillations result in mitochondrial Ca2+ ([Ca2+](m)) oscillations, while large and sustained [Ca2+](c) increase results in a pathologic increase in basal [Ca2+](m) and in Ca2+ accumulation. The physiological [Ca2+](m) signal regulates [Ca2+](c) and stimulates oxidative metabolism, while excess Ca2+ accumulation causes cell stress leading to cell death. [Ca2+](m) is determined by Ca2+ uptake mediated by the mitochondria Ca2+ uniporter (MCU) channel and by Na+- and H+-coupled Ca2+ extrusion . C1 [Ahuja, Malini; Muallem, Shmuel] NIDCR, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Ahuja, M (reprint author), NIDCR, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM Shmuel.Muallem@nih.gov NR 10 TC 11 Z9 12 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1469-221X EI 1469-3178 J9 EMBO REP JI EMBO Rep. PD MAR PY 2014 VL 15 IS 3 BP 205 EP 206 DI 10.1002/embr.201438446 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AC3BO UT WOS:000332390200005 PM 24531720 ER PT J AU Breithaupt, H Taubenberger, JK AF Breithaupt, Holger Taubenberger, Jeffery K. TI Flu season An interview with Jeffery K. Taubenberger, Chief of the Viral Pathogenesis and Evolution Section at the US National Institute of Allergy and Infectious Diseases SO EMBO REPORTS LA English DT Editorial Material AB An interview with Jeffery Taubenberger from NIAID about how understanding the evolution of influenza could inform vaccine development and public health measures to deal with flu pandemics.image C1 [Breithaupt, Holger] EMBO, Heidelberg, Germany. [Taubenberger, Jeffery K.] US Natl Inst Allergy & Infect Dis, Viral Pathogenesis & Evolut Sect, Bethesda, MD USA. RP Breithaupt, H (reprint author), EMBO, Heidelberg, Germany. EM breithau@embl-heidelberg.de NR 0 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1469-221X EI 1469-3178 J9 EMBO REP JI EMBO Rep. PD MAR PY 2014 VL 15 IS 3 BP 212 EP 217 DI 10.1002/embr.201438423 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AC3BO UT WOS:000332390200008 ER PT J AU Wong, TC Piehler, KM Kang, IA Kadakkal, A Kellman, P Schwartzman, DS Mulukutla, SR Simon, MA Shroff, SG Kuller, LH Schelbert, EB AF Wong, Timothy C. Piehler, Kayla M. Kang, Ian A. Kadakkal, Ajay Kellman, Peter Schwartzman, David S. Mulukutla, Suresh R. Simon, Marc A. Shroff, Sanjeev G. Kuller, Lewis H. Schelbert, Erik B. TI Myocardial extracellular volume fraction quantified by cardiovascular magnetic resonance is increased in diabetes and associated with mortality and incident heart failure admission SO EUROPEAN HEART JOURNAL LA English DT Article DE MRI; extracellular matrix; fibrosis; collagen; diabetes; extracellular volume fraction ID DILATED CARDIOMYOPATHY; INVERSION-RECOVERY; FIBROSIS; INFARCTION; VALIDATION; DISEASE; HUMANS; RISK; REGISTRATION; ALDOSTERONE AB Aims Diabetes may promote myocardial extracellular matrix (ECM) expansion that increases vulnerability. We hypothesized that: (i) type 2 diabetes would be associated with quantitative cardiovascular magnetic resonance (CMR) measures of myocardial ECM expansion, i. e. extracellular volume fraction (ECV); (ii) medications blocking the renin-angiotensin-aldosterone system (RAAS) would be associated with lower ECV; and (iii) ECV in diabetic individuals would be associated with mortality and/or incident hospitalization for heart failure. Methods and results We enrolled 1176 consecutive patients referred for CMR without amyloidosis and computed ECV from measures of the haematocrit and myocardial and blood T1 pre- and post-contrast. Linear regression modelled ECV; Cox regression modelled mortality and/or hospitalization for heart failure. Diabetic individuals (n = 231) had higher median ECV than those without diabetes (n = 945): 30.2% (IQR: 26.9-32.7) vs. 28.1% (IQR: 25.9-31.0), respectively, P < 0.001). Diabetes remained associated with higher ECV in models adjusting for demographics, comorbidities, and medications (P < 0.001). Renin-angiotensin-aldosterone system blockade was associated with lower ECV (P = 0.028) in multivariable linear models. Over a median of 1.3 years (IQR: 0.8-1.9), 38 diabetic individuals had events (21 incident hospitalizations for heart failure; 24 deaths), and ECV was associated with these events (HR: 1.52, 95% CI: 1.21-1.89 per 3% ECV increase) in multivariable Cox regression models. Conclusion Diabetes is associated with increased ECV. Extracellular volume fraction detects amelioration of ECM expansion associated with RAAS blockade, and is associated with mortality and/or incident hospitalization for heart failure in diabetic individuals. Extracellular matrix expansion may be an important intermediate phenotype in diabetic individuals that is detectable and treatable. C1 [Wong, Timothy C.; Kadakkal, Ajay; Schwartzman, David S.; Mulukutla, Suresh R.; Simon, Marc A.; Schelbert, Erik B.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Wong, Timothy C.; Piehler, Kayla M.; Kang, Ian A.; Schelbert, Erik B.] UPMC, Cardiovasc Magnet Resonance Ctr, Pittsburgh, PA USA. [Wong, Timothy C.; Kadakkal, Ajay; Schwartzman, David S.; Mulukutla, Suresh R.; Simon, Marc A.; Schelbert, Erik B.] UPMC, Inst Heart & Vasc, Pittsburgh, PA USA. [Kellman, Peter] NHLBI, Bethesda, MD 20892 USA. [Mulukutla, Suresh R.; Simon, Marc A.] UPMC, Ctr Qual Outcomes & Clin Res, Pittsburgh, PA USA. [Simon, Marc A.; Schelbert, Erik B.] Univ Pittsburgh, Clin & Translat Sci Inst, Pittsburgh, PA 15101 USA. [Shroff, Sanjeev G.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15213 USA. [Kuller, Lewis H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. RP Schelbert, EB (reprint author), Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. EM schelberteb@upmc.edu OI Wong, Timothy/0000-0002-1045-2698 FU Pittsburgh Foundation [M2009-0068]; American Heart Association Scientist Development [09SDG2180083]; Atlantic Philanthropies, Inc.; John A. Hartford Foundation; American Heart Association; Agency for Healthcare Research and Quality [K12 HS19461-01]; McGinnis Endowed Chair funds; National Center for Research Resources (NCRR) [UL1 RR024153]; National Institutes of Health (NIH); NIH Roadmap for Medical Research; Association of Specialty Professors FX E.B.S. is supported by a grant from The Pittsburgh Foundation, Grant M2009-0068, and an American Heart Association Scientist Development grant (09SDG2180083) including a T. Franklin Williams Scholarship Award; funding provided by: Atlantic Philanthropies, Inc., the John A. Hartford Foundation, the Association of Specialty Professors, and the American Heart Association. Dr. T.C.W. is supported by a grant K12 HS19461-01 from the Agency for Healthcare Research and Quality. S.G.S.'s research efforts are partially supported by the McGinnis Endowed Chair funds. This work was also supported by Grant Number UL1 RR024153 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. NR 34 TC 67 Z9 70 U1 2 U2 16 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 MAR PY 2014 VL 35 IS 10 BP 657 EP 664 DI 10.1093/eurheartj/eht193 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AD2DO UT WOS:000333043700014 PM 23756336 ER PT J AU Foster, B Bagci, U Xu, ZY Dey, B Luna, B Bishai, W Jain, S Mollura, DJ AF Foster, Brent Bagci, Ulas Xu, Ziyue Dey, Bappaditya Luna, Brian Bishai, William Jain, Sanjay Mollura, Daniel J. TI Segmentation of PET Images for Computer-Aided Functional Quantification of Tuberculosis in Small Animal Models SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Affinity propagation; image segmentation; infectious diseases; nuclear medicine; positron emission tomography (PET); radiology; small animal models; tuberculosis (TB) ID POSITRON-EMISSION-TOMOGRAPHY; CELL LUNG-CANCER; DENSITY-ESTIMATION; TUMOR VOLUME; F-18-FDG PET; ALGORITHM; RADIOTHERAPY; TARGET; CT; DELINEATION AB Pulmonary infections often cause spatially diffuse and multi-focal radiotracer uptake in positron emission tomography (PET) images, which makes accurate quantification of the disease extent challenging. Image segmentation plays a vital role in quantifying uptake due to the distributed nature of immuno-pathology and associated metabolic activities in pulmonary infection, specifically tuberculosis (TB). For this task, thresholding-based segmentation methods may be better suited over other methods; however, performance of the thresholding-based methods depend on the selection of thresholding parameters, which are often suboptimal. Several optimal thresholding techniques have been proposed in the literature, but there is currently no consensus on how to determine the optimal threshold for precise identification of spatially diffuse and multi-focal radiotracer uptake. In this study, we propose a method to select optimal thresholding levels by utilizing a novel intensity affinity metric within the affinity propagation clustering framework. We tested the proposedmethod against 70 longitudinal PET images of rabbits infected with TB. The overall dice similarity coefficient between the segmentation fromthe proposed method and two expert segmentations was found to be 91.25 +/- 8.01% with a sensitivity of 88.80 +/- 12.59% and a specificity of 96.01 +/- 9.20%. High accuracy and heightened efficiency of our proposed method, as compared to other PET image segmentation methods, were reported with various quantification metrics. C1 [Foster, Brent; Bagci, Ulas; Xu, Ziyue; Mollura, Daniel J.] NIH, CIDI, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Dey, Bappaditya; Luna, Brian; Bishai, William; Jain, Sanjay] Johns Hopkins Univ Hosp, Sch Med, Ctr TB Res, Baltimore, MD 21205 USA. [Bishai, William] KwaZulu Natal Res Inst TB & HIV, ZA-4001 Durban, South Africa. [Bishai, William] Howard Hughes Med Inst, Chevy Chase, MD 90095 USA. RP Bagci, U (reprint author), NIH, CIDI, Dept Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. EM brent.foster@nih.gov; ulasbagci@gmail.com; ziyue.xu@nih.gov; bdey1@jhmi.edu; brianluna@jhmi.edu; wbishai1@jhmi.edu; sjain5@jhmi.edu; daniel.mollura@nih.gov OI Dey, Bappaditya/0000-0003-2728-4683; Bagci, Ulas/0000-0001-7379-6829; Luna, PhD, Brian/0000-0001-6718-4551 FU Center for Infectious Disease Imaging; National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Biomedical Imaging and Bioengineering (NIBIB); NIH [OD006492]; Howard Hughes Medical Institute [NIAD R01AI079590, R01A1035272] FX This work was supported in part by the Center for Infectious Disease Imaging, in part by the intramural research program of the National Institute of Allergy and Infectious Diseases (NIAID), and in part by the National Institute of Biomedical Imaging and Bioengineering (NIBIB). The work of S. Jain was supported by the NIH Director's New Innovator Award (OD006492). The rabbit infection study is funded by The Howard Hughes Medical Institute, NIAD R01AI079590, and R01A1035272. Asterisk indicates corresponding author. NR 44 TC 10 Z9 11 U1 3 U2 21 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 EI 1558-2531 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD MAR PY 2014 VL 61 IS 3 BP 711 EP 724 DI 10.1109/TBME.2013.2288258 PG 14 WC Engineering, Biomedical SC Engineering GA AD5DX UT WOS:000333273000010 PM 24235292 ER PT J AU Ferreira, MC Whibley, N Mamo, AJ Siebenlist, U Chan, YR Gaffen, SL AF Ferreira, Maria Carolina Whibley, Natasha Mamo, Anna J. Siebenlist, Ulrich Chan, Yvonne R. Gaffen, Sarah L. TI Interleukin-17-Induced Protein Lipocalin 2 Is Dispensable for Immunity to Oral Candidiasis SO INFECTION AND IMMUNITY LA English DT Article ID CHRONIC MUCOCUTANEOUS CANDIDIASIS; TUMOR-NECROSIS-FACTOR; HOST-DEFENSE; FACTOR-ALPHA; TH17 CELLS; IRON; INFLAMMATION; INFECTIONS; RECEPTOR; ALBICANS AB Oropharyngeal candidiasis (OPC; thrush) is an opportunistic fungal infection caused by the commensal microbe Candida albicans. Immunity to OPC is strongly dependent on CD4(+) T cells, particularly those of the Th17 subset. Interleukin-17 (IL-17) deficiency in mice or humans leads to chronic mucocutaneous candidiasis, but the specific downstream mechanisms of IL-17 mediated host defense remain unclear. Lipocalin 2 (Lcn2; 24p3; neutrophil gelatinase-associated lipocalin [NGAL]) is an antimicrobial host defense factor produced in response to inflammatory cytokines, particularly IL-17. Lcn2 plays a key role in preventing iron acquisition by bacteria that use catecholate-type siderophores, and lipocalin 2(-/-) mice are highly susceptible to infection by Escherichia coli and Klebsiella pneumoniae. The role of Lcn2 in mediating immunity to fungi is poorly defined. Accordingly, in this study, we evaluated the role of Lcn2 in immunity to oral infection with C. albicans. Lcn2 is strongly upregulated following oral infection with C. albicans, and its expression is almost entirely abrogated in mice with defective IL-17 signaling (IL-17RA(-/-) or Act1(-/-) mice). However, Lcn2(-/-) mice were completely resistant to OPC, comparably to wild-type (WT) mice. Moreover, Lcn2 deficiency mediated protection from OPC induced by steroid immunosuppression. Therefore, despite its potent regulation during C. albicans infection, Lcn2 is not required for immunity to mucosal candidiasis. C1 [Ferreira, Maria Carolina; Whibley, Natasha; Mamo, Anna J.; Gaffen, Sarah L.] Univ Pittsburgh, Dept Med, Div Rheumatol & Clin Immunol, Pittsburgh, PA 15260 USA. [Ferreira, Maria Carolina] Univ Estadual Campinas, UNICAMP, Dept Clin Pathol, Campinas, SP, Brazil. [Siebenlist, Ulrich] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Chan, Yvonne R.] Univ Pittsburgh, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. RP Gaffen, SL (reprint author), Univ Pittsburgh, Dept Med, Div Rheumatol & Clin Immunol, Pittsburgh, PA 15260 USA. EM sig65@pitt.edu OI Ferreira dos Santos, Maria/0000-0003-0231-6538 FU NIH [DE022550, DE023815]; Novartis (Basel, Switzerland); Howard Hughes Medical Institute; Intramural Research Program of NIAID, NIH FX S.L.G. was supported by the NIH (DE022550 and DE023815) and Novartis (Basel, Switzerland). Y.R.C. was funded by the Howard Hughes Medical Institute. U.S. was supported by the Intramural Research Program of NIAID, NIH. NR 40 TC 17 Z9 17 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD MAR PY 2014 VL 82 IS 3 BP 1030 EP 1035 DI 10.1128/IAI.01389-13 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AD4BL UT WOS:000333190900012 PM 24343647 ER PT J AU Trovoada, MD Martins, M Ben Mansour, R Sambo, MD Fernandes, AB Goncalves, LA Borja, A Moya, R Almeida, P Costa, J Marques, I Macedo, MP Coutinho, A Narum, DL Penha-Goncalves, C AF Trovoada, Maria de Jesus Martins, Madalena Ben Mansour, Riadh Sambo, Maria do Rosario Fernandes, Ana B. Goncalves, Ligia Antunes Borja, Artur Moya, Roni Almeida, Paulo Costa, Joao Marques, Isabel Paula Macedo, M. Coutinho, Antonio Narum, David L. Penha-Goncalves, Carlos TI NOS2 Variants Reveal a Dual Genetic Control of Nitric Oxide Levels, Susceptibility to Plasmodium Infection, and Cerebral Malaria SO INFECTION AND IMMUNITY LA English DT Article ID FALCIPARUM INFECTION; PROMOTER POLYMORPHISM; CHILDREN; PARASITEMIA; TRANSMISSION; PROTECTION; RESISTANCE; BIOAVAILABILITY; ASSOCIATION; POPULATIONS AB Nitric oxide (NO) is a proposed component of malaria pathogenesis, and the inducible nitric oxide synthase gene (NOS2) has been associated to malaria susceptibility. We analyzed the role of NOS2 polymorphisms on NO bioavailability and on susceptibility to infection, Plasmodium carrier status and clinical malaria. Two distinct West African sample collections were studied: a population-based collection of 1,168 apparently healthy individuals from the Principe Island and a hospital-based cohort of 269 Angolan children. We found that two NOS2 promoter single-nucleotide polymorphism (SNP) alleles associated to low NO plasma levels in noninfected individuals were also associated to reduced risk of pre-erythrocytic infection as measured anti-CSP antibody levels (6.25E-04 < P < 7.57E-04). In contrast, three SNP alleles within the NOS2 cistronic region conferring increased NO plasma levels in asymptomatic carriers were strongly associated to risk of parasite carriage (8.00E-05 < P < 7.90E-04). Notwithstanding, three SNP alleles in this region protected from cerebral malaria (7.90E-4 < P < 4.33E-02). Cohesively, the results revealed a dual regimen in the genetic control of NO bioavailability afforded by NOS2 depending on the infection status. NOS2 promoter variants operate in noninfected individuals to decrease both NO bioavailability and susceptibility to pre-erythrocytic infection. Conversely, NOS2 cistronic variants (namely, rs6505469) operate in infected individuals to increase NO bioavailability and confer increased susceptibility to unapparent infection but protect from cerebral malaria. These findings corroborate the hypothesis that NO anti-inflammatory properties impact on different steps of malaria pathogenesis, explicitly by favoring infection susceptibility and deterring severe malaria syndromes. C1 [Trovoada, Maria de Jesus; Martins, Madalena; Ben Mansour, Riadh; Sambo, Maria do Rosario; Goncalves, Ligia Antunes; Moya, Roni; Almeida, Paulo; Costa, Joao; Marques, Isabel; Coutinho, Antonio; Penha-Goncalves, Carlos] Inst Gulbenkian Ciencias, Oeiras, Portugal. [Trovoada, Maria de Jesus] Ctr Natl Endemias, Sao Tome, Sao Tome & Prin. [Martins, Madalena] Univ Lisbon, Fac Med, Inst Med Mol, Neurol Clin Res Unit, P-1699 Lisbon, Portugal. [Sambo, Maria do Rosario] Univ Agostinho Neto, Fac Med, Luanda, Angola. [Fernandes, Ana B.; Paula Macedo, M.] Univ Nova Lisboa, Fac Ciencias Med, CEDOC, P-1200 Lisbon, Portugal. [Borja, Artur] Hosp Dr Manuel Quaresma Dias da Graca, Principe, Sao Tome & Prin. [Narum, David L.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. RP Penha-Goncalves, C (reprint author), Inst Gulbenkian Ciencias, Oeiras, Portugal. EM cpenha@igc.gulbenkian.pt RI Goncalves, Ligia/F-6242-2014; Penha-Goncalves, Carlos/F-4640-2012; Costa, Joao/M-6128-2015; Faculdade de Ciencias Medicas, Nova Medical School/K-6209-2013; OI Goncalves, Ligia/0000-0001-9804-6899; Costa, Joao/0000-0003-3590-5849; Macedo, Maria Paula/0000-0002-2549-0275; Marques, Maria Isabel/0000-0003-2261-7338; Penha-Goncalves, Carlos/0000-0001-7225-1907; Martins, Madalena/0000-0001-8360-6806 FU Fundacao Gulbenkian de Ciencia; Fundacao para a Ciencia e Tecnologia [HMSP-CT/SAU-ICT/0068/2009]; FCT [SFRH/BPD/35062/2007, SFRH/BPD/29354/2006]; Intramural Research Program of the National Institutes of Health FX We acknowledge financial support from the Fundacao Gulbenkian de Ciencia and the Fundacao para a Ciencia e Tecnologia (grant HMSP-CT/SAU-ICT/0068/2009). M.D.J.T. and M.M. were funded by FCT fellowships SFRH/BPD/35062/2007 and SFRH/BPD/29354/2006, respectively). This research was also supported in part by the Intramural Research Program of the National Institutes of Health. NR 41 TC 4 Z9 4 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD MAR PY 2014 VL 82 IS 3 BP 1287 EP 1295 DI 10.1128/IAI.01070-13 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AD4BL UT WOS:000333190900039 ER PT J AU Ma, L Mancuso, M Williams, JA Van der Pol, B Fortenberry, JD Jia, QY Myers, L Martin, DH AF Ma, Liang Mancuso, Miriam Williams, James A. Van der Pol, Barbara Fortenberry, J. Dennis Jia, Qiuyao Myers, Leann Martin, David H. TI Extensive Variation and Rapid Shift of the MG192 Sequence in Mycoplasma genitalium Strains from Patients with Chronic Infection SO INFECTION AND IMMUNITY LA English DT Article ID REPETITIVE CHROMOSOMAL SEQUENCES; ANTIGENIC VARIATION; TREPONEMA-PALLIDUM; TANDEM REPEATS; GENE; PNEUMONIAE; GENERATION; URETHRITIS; GENOME; RECOMBINATION AB Mycoplasma genitalium causes persistent urogenital tract infection in humans. Antigenic variation of the protein encoded by the MG192 gene has been proposed as one of the mechanisms for persistence. The aims of this study were to determine MG192 sequence variation in patients with chronic M. genitalium infection and to analyze the sequence structural features of the MG192 gene and its encoded protein. Urogenital specimens were obtained from 13 patients who were followed for 10 days to 14 months. The variable region of the MG192 gene was PCR amplified, subcloned into plasmids, and sequenced. Sequence analysis of 220 plasmid clones yielded 97 unique MG192 variant sequences. MG192 sequence shift was identified between sequential specimens from all but one patient. Despite great variation of the MG192 gene among and within clinical specimens from different patients, MG192 sequences were more related within M. genitalium specimens from an individual patient than between patients. The MG192 variable region consisted of 11 discrete subvariable regions with different degrees of variability. Analysis of the two most variable regions (V4 and V6) in five sequential specimens from one patient showed that sequence changes increased over time and that most sequences were present at only one time point, suggesting immune selection. Topology analysis of the deduced MG192 protein predicted a surface-exposed membrane protein. Extensive variation of the MG192 sequence may not only change the antigenicity of the protein to allow immune evasion but also alter the mobility and adhesion ability of the organism to adapt to diverse host microenvironments, thus facilitating persistent infection. C1 [Ma, Liang; Mancuso, Miriam; Jia, Qiuyao; Martin, David H.] Louisiana State Univ, Hlth Sci Ctr, Dept Med, Infect Dis Sect, New Orleans, LA USA. [Williams, James A.] Indiana Univ Sch Med, Dept Med, Div Infect Dis, Indianapolis, IN 46202 USA. [Van der Pol, Barbara] Univ Alabama Birmingham, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. [Fortenberry, J. Dennis] Indiana Univ Sch Med, Dept Pediat, Sect Adolescent Med, Indianapolis, IN 46202 USA. [Myers, Leann] Tulane Sch Publ Hlth & Trop Med, Dept Biostat & Bioinformat, New Orleans, LA USA. RP Ma, L (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. EM LMa1@lsuhsc.edu FU U.S. Department of Defense [W81XWH-08-1-0676]; Gulf South Sexually Transmitted Infections/Topical Microbicide Cooperative Research Center grant from the NIH NIAID [5 U19 AI061972]; Louisiana Vaccine Center; Louisiana Board of Regents [149752505J] FX This work was supported by a U.S. Department of Defense grant (W81XWH-08-1-0676), by a Gulf South Sexually Transmitted Infections/Topical Microbicide Cooperative Research Center grant from the NIH NIAID (5 U19 AI061972), and by the Louisiana Vaccine Center and the South Louisiana Institute for Infectious Disease Research sponsored by the Louisiana Board of Regents (grant 149752505J). NR 47 TC 4 Z9 4 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD MAR PY 2014 VL 82 IS 3 BP 1326 EP 1334 DI 10.1128/IAI.01526-13 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AD4BL UT WOS:000333190900043 PM 24396043 ER PT J AU Sultan, E Pourrezaei, K Ghandjbakhche, A Daryoush, AS AF Sultan, E. Pourrezaei, K. Ghandjbakhche, A. Daryoush, A. S. TI 3D Numerical modeling and its experimental verifications for an inhomogeneous head phantom using broadband fNIR system SO INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING LA English DT Article DE IP; IL; CW; tri-wavelength; VCSEL; COMSOL; optical receiver Rx; DE; fNIR; optical transmitter Tx; TBI; TD; FEM; FD; PDW ID TISSUE OPTICAL-PROPERTIES; DIFFUSE-REFLECTANCE; SCATTERING MEDIA; HUMAN BRAIN; SPECTROSCOPY; PROPAGATION; LIGHT AB Modeling behavior of broadband (30-1000 MHz) frequency modulated near infrared photons through a multilayer phantom is of interest to optical bio-imaging research. Photon dynamics in phantom are predicted using three-dimension (3D) finite element numerical simulation and are related to the measured insertion loss and phase for a given human head geometry in this paper based on three layers of phantom each with distinct optical parameter properties. Simulation and experimental results are achieved for single, two, and three layers solid phantoms using COMSOL (COMSOL AB, Tegnergatan 23, SE-111 40, Stockholm, Sweden) (for FEM) simulation and custom-designed broadband free space optical transmitter (Tx) and receiver (Rx) modules that are developed for photon migration at wavelengths of 680, 795, and 850 nm. Standard error is used to compute error between two-dimension and 3D FE modeling along with experimental results by fitting experimental data to the functional form of afrequency+b. Error results are shown at narrowband and broadband frequency modulation. Confidence in numerical modeling of the photonic behavior using 3D FEM for human head has been established here by comparing the reflection mode's experimental results with the predictions made by COMSOL for known commercial solid brain phantoms. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Sultan, E.; Daryoush, A. S.] Drexel Univ, Dept Elect & Comp Engn, Philadelphia, PA 19104 USA. [Pourrezaei, K.] Drexel Univ, Sch Biomed Engn Sci & Hlth Syst, Philadelphia, PA 19104 USA. [Ghandjbakhche, A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Daryoush, AS (reprint author), Drexel Univ, Dept Elect & Comp Engn, Philadelphia, PA 19104 USA. EM daryoush@coe.drexel.edu NR 21 TC 0 Z9 0 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2040-7939 EI 2040-7947 J9 INT J NUMER METH BIO JI Int. J. Numer. Meth. Biomed. PD MAR PY 2014 VL 30 IS 3 BP 353 EP 364 DI 10.1002/cnm.2606 PG 12 WC Engineering, Biomedical; Mathematical & Computational Biology; Mathematics, Interdisciplinary Applications SC Engineering; Mathematical & Computational Biology; Mathematics GA AD1YN UT WOS:000333029700004 PM 24259456 ER PT J AU King, SB Dickert, NW Miller, FG AF King, Spencer B., III Dickert, Neal W. Miller, Franklin G. TI Learning From FAME: The Need for Sham Controls in Trials of Stable Coronary Disease SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Editorial Material ID MAMMARY-ARTERY LIGATION; MYOCARDIAL REVASCULARIZATION; MEDICAL THERAPY; PCI AB The placebo effect in treating angina is powerful. Trials of internal mammary artery (IMA) ligation in the 1950s using sham control arms revealed dramatic placebo effects with regard to anginal symptoms. However, sham controls are rarely used in interventional trials for stable coronary disease today. The FAME 2 (Fractional Flow Reserve Versus Angiography for Multi-vessel Evaluation 2) trial, stopped early by its data safety and monitoring committee because of increased urgent hospitalization and revascularization in the medical therapy arm, illustrates the hazards of not including a sham control. A sham arm would have been ethically advantageous; it would have posed little to no additional risk and would have substantially increased the social and clinical value of the results. The lessons from this trial should prompt greater consideration and use of sham controls in trials for stable coronary disease. C1 [Dickert, Neal W.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. [Dickert, Neal W.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Dickert, Neal W.] Atlanta VA Med Ctr, Atlanta, GA USA. [Miller, Franklin G.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Dickert, NW (reprint author), Emory Univ, Sch Med, 1462 Clifton Rd,508, Atlanta, GA 30322 USA. EM njr@emory.edu NR 11 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD MAR PY 2014 VL 7 IS 3 BP 342 EP 344 DI 10.1016/j.jcin.2014.02.001 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AD5FN UT WOS:000333277600026 PM 24650413 ER PT J AU Williamson, JD Launer, LJ Bryan, RN Coker, LH Lazar, RM Gerstein, HC Murray, AM Sullivan, MD Horowitz, KR Ding, JZ Marcovina, S Lovato, L Lovato, J Margolis, KL Davatzikos, C Barzilay, J Ginsberg, HN Linz, PE Miller, ME AF Williamson, Jeff D. Launer, Lenore J. Bryan, R. Nick Coker, Laura H. Lazar, Ronald M. Gerstein, Hertzel C. Murray, Anne M. Sullivan, Mark D. Horowitz, Karen R. Ding, Jingzhong Marcovina, Santica Lovato, Laura Lovato, James Margolis, Karen L. Davatzikos, Christos Barzilay, Joshua Ginsberg, Henry N. Linz, Peter E. Miller, Michael E. CA Action To Control Cardiovasc Risk TI Cognitive Function and Brain Structure in Persons With Type 2 Diabetes Mellitus After Intensive Lowering of Blood Pressure and Lipid Levels A Randomized Clinical Trial SO JAMA INTERNAL MEDICINE LA English DT Article ID WHITE-MATTER LESIONS; DEMENTIA; DEPRESSION; ATROPHY; PEOPLE; IMAGES; RISK AB IMPORTANCE Persons with type 2 diabetes mellitus (T2DM) are at increased risk for decline in cognitive function, reduced brain volume, and increased white matter lesions in the brain. Poor control of blood pressure (BP) and lipid levels are risk factors for T2DM-related cognitive decline, but the effect of intensive treatment on brain function and structure is unknown. OBJECTIVE To examine whether intensive therapy for hypertension and combination therapy with a statin plus a fibrate reduces the risk of decline in cognitive function and total brain volume (TBV) in patients with T2DM. DESIGN, SETTING, AND PARTICIPANTS A North American multicenter clinical trial including 2977 participants without baseline clinical evidence of cognitive impairment or dementia and with hemoglobin A(1c) (HbA(1c)) levels less than 7.5% randomized to a systolic BP goal of less than 120 vs less than 140 mm Hg (n = 1439) or to a fibrate vs placebo in patients with low-density lipoprotein cholesterol levels less than 100 mg/dL (n = 1538). Participants were recruited from August 1, 2003, through October 31, 2005, with the final follow-up visit by June 30, 2009. MAIN OUTCOME MEASURES Cognition was assessed at baseline and 20 and 40 months. A subset of 503 participants underwent baseline and 40-month brain magnetic resonance imaging to assess for change in TBV and other structural measures of brain health. RESULTS Baseline mean HbA(1c) level was 8.3%; mean age, 62 years; and mean duration of T2DM, 10 years. At 40 months, no differences in cognitive function were found in the intensive BP-lowering trial or in the fibrate trial. At 40 months, TBV had declined more in the intensive vs standard BP-lowering group (difference, -4.4 [95% CI, -7.8 to -1.1] cm(3); P = .01). Fibrate therapy had no effect on TBV compared with placebo. CONCLUSIONS AND RELEVANCE In participants with long-standing T2DM and at high risk for cardiovascular events, intensive BP control and fibrate therapy in the presence of controlled low-density lipoprotein cholesterol levels did not produce a measurable effect on cognitive decline at 40 months of follow-up. Intensive BP control was associated with greater decline in TBV at 40 months relative to standard therapy. C1 [Williamson, Jeff D.; Ding, Jingzhong] Wake Forest Sch Med, Dept Internal Med, Roena B Kulynych Ctr Memory & Cognit Res, Winston Salem, NC 27157 USA. [Launer, Lenore J.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Bryan, R. Nick; Davatzikos, Christos] Univ Penn Hlth Syst, Dept Radiol, Philadelphia, PA USA. [Coker, Laura H.] Wake Forest Univ, Dept Social Sci & Hlth Policy, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [Lazar, Ronald M.] Columbia Univ Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA. [Gerstein, Hertzel C.] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Gerstein, Hertzel C.] Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada. [Murray, Anne M.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Murray, Anne M.] Chron Dis Res Grp, Minneapolis, MN USA. [Sullivan, Mark D.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Horowitz, Karen R.] Case Western Reserve Univ, Sch Med, Dept Med, Cleveland, OH 44106 USA. [Marcovina, Santica] Univ Washington, Northwest Lipid Metab & Diabet Res Labs, Seattle, WA 98195 USA. [Lovato, Laura; Lovato, James; Miller, Michael E.] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Margolis, Karen L.] Univ Minnesota, Sch Med, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Barzilay, Joshua] Crescent Ctr Med Off, Tucker, Rep of Georgia. [Ginsberg, Henry N.] Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA. [Linz, Peter E.] Naval Med Ctr San Diego, Div Cardiol, San Diego, CA USA. RP Williamson, JD (reprint author), Wake Forest Sch Med, Dept Internal Med, Roena B Kulynych Ctr Memory & Cognit Res, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jwilliam@wakehealth.edu FU National Institute of Aging; National Heart, Lung, and Blood Institute of the National Institutes of Health FX This study was supported by the National Institute of Aging and the National Heart, Lung, and Blood Institute of the National Institutes of Health. NR 32 TC 33 Z9 34 U1 0 U2 19 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAR PY 2014 VL 174 IS 3 BP 324 EP 333 DI 10.1001/jamainternmed.2013.13656 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AD2GK UT WOS:000333052100007 PM 24493100 ER PT J AU Chinn, GM Liu, PH Klabunde, CN Kahn, KL Keating, NL AF Chinn, Garrett M. Liu, Pang-Hsiang Klabunde, Carrie N. Kahn, Katherine L. Keating, Nancy L. TI Physicians' Preferences for Hospice if They Were Terminally Ill and the Timing of Hospice Discussions With Their Patients SO JAMA INTERNAL MEDICINE LA English DT Letter ID OF-LIFE CARE C1 [Chinn, Garrett M.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Chinn, Garrett M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Liu, Pang-Hsiang; Keating, Nancy L.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Klabunde, Carrie N.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Kahn, Katherine L.] RAND Corp, Santa Monica, CA USA. [Kahn, Katherine L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Gen Internal Med, Los Angeles, CA 90095 USA. [Keating, Nancy L.] Brigham & Womens Hosp, Dept Med, Div Gen Internal Med & Primary Care, Boston, MA 02115 USA. RP Keating, NL (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM keating@hcp.med.harvard.edu RI Liu, Michael Pang-Hsiang/B-9903-2015 OI Liu, Michael Pang-Hsiang/0000-0001-8842-2264 FU NCI NIH HHS [R01 CA164021, 1R01CA164021-01A1, U01 CA093324, U01 CA093326, U01 CA093329, U01 CA093332, U01 CA093339, U01 CA093344, U01 CA093348, U01CA093329] NR 6 TC 4 Z9 4 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAR PY 2014 VL 174 IS 3 BP 466 EP 468 DI 10.1001/jamainternmed.2013.12825 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA AD2GK UT WOS:000333052100037 PM 24342971 ER PT J AU Burklow, JT Johnson, L Humphreys, B AF Burklow, John T. Johnson, Lenora Humphreys, Betsy TI Privacy Protection During Internet Search for Health-Related Information SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Burklow, John T.] NIH, Off Commun & Publ Liaison, Bethesda, MD 20892 USA. [Johnson, Lenora] NCI, Off Commun & Educ, NIH, Bethesda, MD 20892 USA. [Humphreys, Betsy] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Burklow, JT (reprint author), NIH, Off Commun & Publ Liaison, 1 Ctr Dr,MSC 0188,Bldg 1,Room 344, Bethesda, MD 20892 USA. EM BurklowJ@od.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAR PY 2014 VL 174 IS 3 BP 476 EP 476 DI 10.1001/jamainternmed.2013.13516 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AD2GK UT WOS:000333052100045 PM 24590088 ER PT J AU Fender, EA Sibley, CT Nazarian, S Cheng, A Spragg, DD Marine, JE Berger, RD Calkins, H Lima, JAC Brinker, JA Henrikson, CA AF Fender, Erin A. Sibley, Christopher T. Nazarian, Saman Cheng, Alan Spragg, David D. Marine, Joseph E. Berger, Ronald D. Calkins, Hugh Lima, Joao A. C. Brinker, Jeffery A. Henrikson, Charles A. TI Atrial Septal Angulation Varies Widely in Patients Undergoing Pulmonary Vein Isolation SO JOURNAL OF INVASIVE CARDIOLOGY LA English DT Article DE atrial fibrillation ablation; interatrial septum; transseptal puncture; intracardiac echocardiography; cardiac computed tomography; cardiac tamponade ID RADIOFREQUENCY CATHETER ABLATION; LEFT-HEART CATHETERIZATION; INTRACARDIAC ECHOCARDIOGRAPHY; TRANSSEPTAL CATHETERIZATION; FOSSA OVALIS; FIBRILLATION; COMPLICATIONS; EFFICACY; IMPACT; SAFETY AB Purpose. Transseptal puncture (TSP) allows left atrial access for curative procedures. Intracardiac echocardiography (ICE) provides direct visualization of the interatrial septum (IAS), but adds time and expense. We reviewed 100 cardiac multidetector computed tomography (MDCT) scans of patients undergoing AF ablation to determine if the angulation and orientation of the IAS are conserved or variable. Significant variability may suggest a potential role for direct visualization of the IAS during TSP. Methods. We reviewed 100 MDCT scans obtained prior to AF ablation. The IAS plane at the fossa ovalis was identified in axial and coronal images. We measured the angle of the septum relative to an orthogonal plane. Optimal needle orientation was defined as perpendicular to the fossa ovalis. Results. The mean axial plane angle was -60.6 +/- 10.6 degrees; range, -29.5 degrees to -88.7 degrees. The mean coronal plane angle was 142.6 +/- 9.1 degrees; range, 115 degrees to 162 degrees). The axial angle corresponded to variation in the "clock-face" orientation of the needle during puncture, and was calculated between 4 and 6 o'clock. Coronal plane angulation corresponds to the curvature of the needle tip, which varied by 47 degrees. We found no association between patient characteristics and IAS angle. Conclusion. The septal orientation in the axial plane varied widely and was not predicted by clinical variables such as atrial size or prior valve surgery. The high degree of interpatient variability observed suggests that direct visualization of the septum may be helpful in the performance of TSP. C1 [Fender, Erin A.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97239 USA. [Sibley, Christopher T.; Henrikson, Charles A.] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Portland, OR 97239 USA. [Sibley, Christopher T.; Nazarian, Saman; Cheng, Alan; Spragg, David D.; Marine, Joseph E.; Berger, Ronald D.; Calkins, Hugh; Lima, Joao A. C.; Brinker, Jeffery A.; Henrikson, Charles A.] Johns Hopkins Univ Hosp, Div Cardiol, Baltimore, MD 21287 USA. [Sibley, Christopher T.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Henrikson, CA (reprint author), Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM henrikso@ohsu.edu FU Biosense Webster FX The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Henrikson reports a minor research grant from Biosense Webster; Dr Nazarian reports research grant and consultant fees from Biosense Webster. The remaining authors report no conflicts of interest regarding the content herein. NR 21 TC 1 Z9 1 U1 0 U2 1 PU H M P COMMUNICATIONS PI MALVERN PA 83 GENERAL WARREN BLVD, STE 100, MALVERN, PA 19355 USA SN 1042-3931 EI 1557-2501 J9 J INVASIVE CARDIOL JI J. Invasive Cardiol. PD MAR PY 2014 VL 26 IS 3 BP 128 EP 131 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AD4PB UT WOS:000333231900006 PM 24610507 ER PT J AU Danquah, V Simonsick, D Ferrucci, D AF Danquah, V. Simonsick, D. Ferrucci, D. TI Does Emotional Vitality Protect Against Functional Decline? Findings from the Baltimore Longitudinal Study of Aging SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 15-17, 2014 CL Orlando, FL SP Amer Geriatr Soc C1 [Danquah, V.] Univ Texas Med Branch, Galveston, TX 77555 USA. [Simonsick, D.; Ferrucci, D.] NIA, Baltimore, MD 21224 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAR PY 2014 VL 62 SU 1 SI SI BP S292 EP S292 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AD6XT UT WOS:000333405500804 ER PT J AU Hoffelder, J Albert, SM Lunney, J Ives, D Newman, A Satterfield, S Garcia, M AF Hoffelder, J. Albert, S. M. Lunney, J. Ives, D. Newman, A. Satterfield, S. Garcia, M. TI Perceptions of very-old adults on their informed care and shared decision-making SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 15-17, 2014 CL Orlando, FL SP Amer Geriatr Soc C1 [Hoffelder, J.] Univ New England, Coll Osteopath Med, Biddeford, England. [Albert, S. M.; Lunney, J.; Ives, D.; Newman, A.] Univ Pittsburgh, Pittsburgh, PA USA. [Satterfield, S.] Univ Tennessee, Memphis, TN USA. [Lunney, J.] Hosp & Palliat Nurses Assoc, Pittsburgh, PA USA. [Garcia, M.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAR PY 2014 VL 62 SU 1 SI SI BP S277 EP S277 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AD6XT UT WOS:000333405500763 ER PT J AU Huh, J Ross, GW Chen, R Bell, C Wilcox, B Abbott, R Launer, L Kaya, B Masaki, K AF Huh, J. Ross, G. W. Chen, R. Bell, C. Wilcox, B. Abbott, R. Launer, L. Kaya, B. Masaki, K. TI Total and Differential White Blood Cell Counts Predict Eight-Year Incident Stroke in Elderly Japanese-American Men: The Honolulu Heart Program SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 15-17, 2014 CL Orlando, FL SP Amer Geriatr Soc C1 [Huh, J.; Ross, G. W.; Bell, C.; Wilcox, B.; Abbott, R.; Kaya, B.; Masaki, K.] Univ Hawaii, Honolulu, HI 96822 USA. [Chen, R.; Wilcox, B.; Masaki, K.] Kuakini Med Ctr, Honolulu, HI USA. [Ross, G. W.] Vet Affairs Pacif Islands Healthcare Syst, Honolulu, HI USA. [Launer, L.] NIA, Bethesda, MD 20892 USA. 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAR PY 2014 VL 62 SU 1 SI SI BP S78 EP S79 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AD6XT UT WOS:000333405500213 ER PT J AU Inaba, M Ross, GW Chen, R Launer, LJ White, L Petrovitch, H Abbott, RD Masaki, K AF Inaba, M. Ross, G. W. Chen, R. Launer, L. J. White, L. Petrovitch, H. Abbott, R. D. Masaki, K. TI Low Hippocampal Volume on MRI is Associated with Five-Year Cognitive Decline: The Honolulu-Asia Aging Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 15-17, 2014 CL Orlando, FL SP Amer Geriatr Soc C1 [Inaba, M.; Ross, G. W.; White, L.; Petrovitch, H.; Abbott, R. D.; Masaki, K.] Univ Hawaii, Honolulu, HI 96822 USA. [Ross, G. W.] Vet Affairs Pacific Islands Healthcare Syst, Honolulu, HI USA. [Chen, R.; Masaki, K.] Kuakini Med Ctr, Honolulu, HI USA. [Launer, L. J.] NIA, Bethesda, MD 20892 USA. [White, L.; Petrovitch, H.] Pacific Hlth Res & Educ Inst, Honolulu, HI USA. 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAR PY 2014 VL 62 SU 1 SI SI BP S147 EP S147 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AD6XT UT WOS:000333405500400 ER PT J AU Rosen, AS Gillinov, A Shi, W O'Gara, P Welsh, S Bagiella, E Neill, A Williams, D Gelijns, A D'Alessandro, D Horvath, K Mayer, M Keim-Malpass, J Gupta, L Greco, G AF Rosen, A. S. Gillinov, A. Shi, W. O'Gara, P. Welsh, S. Bagiella, E. Neill, A. Williams, D. Gelijns, A. D'Alessandro, D. Horvath, K. Mayer, M. Keim-Malpass, J. Gupta, L. Greco, G. TI Costs of Postoperative Hyperglycemia in Cardiac Surgery Patients SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 15-17, 2014 CL Orlando, FL SP Amer Geriatr Soc C1 [Rosen, A. S.; Shi, W.; Bagiella, E.; Williams, D.; Gelijns, A.; Gupta, L.; Greco, G.] Icahn Sch Med Mt Sinai, New York, NY USA. [Gillinov, A.] Cleveland Clin, Cleveland, OH 44106 USA. [O'Gara, P.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Welsh, S.] Duke Univ, Durham, NC USA. [Neill, A.] Emory Univ, Atlanta, GA 30322 USA. [D'Alessandro, D.] Montefiore Einstein Heart Ctr, Bronx, NY USA. [Horvath, K.] Suburban Hosp, NIH Heart Ctr, Bethesdas, MD USA. [Mayer, M.] Univ Penn, Philadelphia, PA 19104 USA. [Keim-Malpass, J.] Univ Virginia Hlth Sysltem, Charlottesville, VA USA. 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAR PY 2014 VL 62 SU 1 SI SI BP S160 EP S160 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AD6XT UT WOS:000333405500436 ER PT J AU Sabri, SS Abi-Jaoudeh, N Swee, W Saad, WE Turba, UC Caldwell, SH Angle, JF Matsumoto, AH AF Sabri, Saher S. Abi-Jaoudeh, Nadine Swee, Warren Saad, Wael E. Turba, Ulku C. Caldwell, Stephen H. Angle, John F. Matsumoto, Alan H. TI Short-Term Rebleeding Rates for Isolated Gastric Varices Managed by Transjugular Intrahepatic Portosystemic Shunt versus Balloon-Occluded Retrograde Transvenous Obliteration SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; CYANOACRYLATE INJECTION; FUNDAL VARICES; N-BUTYL-2-CYANOACRYLATE INJECTION; PORTAL-HYPERTENSION; BAND LIGATION; STENT-GRAFTS; HEMORRHAGE; TIPS; PREVENTION AB Purpose: To assess the short-term rebleeding rate associated with the use of a transjugular intrahepatic portosystemic shunt (TIPS) compared with balloon-occluded retrograde transvenous obliteration (BRTO) for management of gastric varices (GV). Materials and Methods: A single-center retrospective comparison of 50 patients with bleeding from GV treated with a TIPS or BRTO was performed. Of 50 patients, 27 (17 men and 10 women; median age, 55 y; range, 31-79 y) received a TIPS with covered stents, and 23 (12 men and 11 women; median age, 52 y; range, 23-83 y) underwent a BRTO procedure with a foam sclerosant. All study subjects had clinical and endoscopic evidence of isolated bleeding GV and were hemodynamically stable at the time of the procedure. Clinical and endoscopic follow-up was performed. Kaplan-Meier analysis was used to evaluate rebleeding rates from the GV. Results: The technical success rate was 100% in the TIPS group and 91% in the BRTO group (P = .21). Major complications occurred in 4% of the patients receiving TIPS and 9% of patients the undergoing BRTO (P = .344). Encephalopathy was reported in 4 of 27 (15%) patients in the TIPS group and in none Of the patients in the BRTO group (0%; P = .12), At 12 months, the incidence of rebleeding from a GV source was 11% in the TIPS group and 0% in the BRTO group (P = .25). Conclusions: BRTO appears to be equivalent to TIPS in the short-term for management of bleeding GV. Further comparative studies are warranted to determine optimal management strategies in individual patients. C1 [Sabri, Saher S.; Saad, Wael E.; Turba, Ulku C.; Angle, John F.; Matsumoto, Alan H.] Univ Virginia Hlth Syst, Div Angiog Intervent Radiol & Special Procedures, Dept Radiol & Med Imaging, Charlottesville, VA 22908 USA. [Caldwell, Stephen H.] Univ Virginia Hlth Syst, Dept Med, Div Gastroenterol, Charlottesville, VA 22908 USA. [Abi-Jaoudeh, Nadine] NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. [Swee, Warren] South Florida Vasc Associates, Coconut Creek, FL USA. RP Sabri, SS (reprint author), Univ Virginia Hlth Syst, Div Angiog Intervent Radiol & Special Procedures, Dept Radiol & Med Imaging, 1215 Lee St,Box 800170, Charlottesville, VA 22908 USA. EM Ss2bp@virgnia.edu NR 36 TC 16 Z9 17 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD MAR PY 2014 VL 25 IS 3 BP 355 EP 361 DI 10.1016/j.jvir.2013.12.001 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA AD2LO UT WOS:000333067400005 PM 24468043 ER PT J AU Liu, CK Lyass, A Massaro, JM D'Agostino, RB Fox, CS Murabito, JM AF Liu, Christine K. Lyass, Asya Massaro, Joseph M. D'Agostino, Ralph B., Sr. Fox, Caroline S. Murabito, Joanne M. TI Chronic Kidney Disease Defined by Cystatin C Predicts Mobility Disability and Changes in Gait Speed: The Framingham Offspring Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Chronic kidney disease; Cystatin C; Disability; Gait speed ID GLOMERULAR-FILTRATION-RATE; OLDER-ADULTS; BODY-COMPOSITION; COLLABORATIVE METAANALYSIS; POPULATION COHORTS; SERUM CREATININE; RISK; HEALTH; PEOPLE; EPIDEMIOLOGY AB Background. As creatinine-based estimates of renal function are inaccurate in older adults, an alternative is an estimated glomerular filtration rate (eGFR(cys)) based on cystatin C. We examined the prospective association between chronic kidney disease (CKDcys) as determined by eGFR(cys) with the primary outcome of incident mobility disability and the secondary outcome of change in gait speed. Methods. Framingham Offspring Study participants older than 60 years and free of mobility disability at baseline (1998-2001) were eligible. Baseline CKDcys was defined as eGFR(cys) less than 60 mL/min/1.73 m(2). At follow-up (2005-2008), the outcomes of mobility disability, defined as self-reported inability to walk 1/2 mile and/or climb a flight of stairs, and gait speed were measured. Logistic and linear regression models were adjusted for age, sex, body mass index, smoking, diabetes, C reactive protein, and physical activity. Results. Of 1,226 participants, 230 (19%) had CKDcys at baseline. After a mean follow-up of 6.6 years, 185 (15%) developed mobility disability. Of those with CKDcys, 60 (26%) developed mobility disability. Those with CKDcys had greater odds of mobility disability in the age-and sex-adjusted (odds ratio [OR] 1.91, 95% CI 1.32, 2.75) and fully adjusted (OR 1.55, 95% CI 1.05, 2.31) models compared with those without CKDcys. In fully adjusted models, participants with CKDcys had greater gait speed declines than those without CKDcys (beta = 0.07 [SE 0.02], p = .0022). Conclusion. CKDcys was associated with higher odds of incident mobility disability and greater decline in gait speed, highlighting the loss of physical independence in elders with CKD. C1 [Liu, Christine K.] Boston Univ, Sch Med, Dept Med, Sect Geriatr, Boston, MA 02118 USA. [Liu, Christine K.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Lyass, Asya; Massaro, Joseph M.; D'Agostino, Ralph B., Sr.; Fox, Caroline S.; Murabito, Joanne M.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Lyass, Asya; D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Fox, Caroline S.] NHLBI, Bethesda, MD 20892 USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Endocrinol Metab & Diabet, Boston, MA 02115 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. RP Liu, CK (reprint author), Boston Med Ctr, 88 E Newton St,Robinson 2, Boston, MA 02118 USA. EM chliu@bu.edu FU National Heart, Lung, and Blood Institute; Boston University [N01-HC-25195]; National Institute on Aging [R01-AG029451]; American Federation for Aging Research; John A. Hartford Foundation (Center of Excellence in Geriatric Medicine); U.S. Department of Agriculture [1950-51000-068-01S] FX The Framingham Heart Study is supported by the National Heart, Lung, and Blood Institute in collaboration with Boston University (contract number N01-HC-25195). This work was supported by the National Institute on Aging (R01-AG029451) to J.M.Murabito. C. K. L. was supported by the American Federation for Aging Research, the John A. Hartford Foundation (Center of Excellence in Geriatric Medicine), and the U.S. Department of Agriculture, under Agreement no. 1950-51000-068-01S. NR 39 TC 11 Z9 12 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2014 VL 69 IS 3 BP 301 EP 307 DI 10.1093/gerona/glt096 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AD6QB UT WOS:000333384800009 PM 23913929 ER PT J AU Morgan, GJ Johnson, DC Weinhold, N Goldschmidt, H Landgren, O Lynch, HT Hemminki, K Houlston, RS AF Morgan, G. J. Johnson, D. C. Weinhold, N. Goldschmidt, H. Landgren, O. Lynch, H. T. Hemminki, K. Houlston, R. S. TI Inherited genetic susceptibility to multiple myeloma SO LEUKEMIA LA English DT Review DE myeloma; SNP; MGUS ID GENOME-WIDE ASSOCIATION; UNDETERMINED SIGNIFICANCE MGUS; CHROMOBOX PROTEIN CBX7; MONOCLONAL GAMMOPATHY; FAMILIAL MYELOMA; INCREASED RISK; COLORECTAL-CANCER; MONOZYGOTIC TWINS; TUMOR-SUPPRESSOR; AFRICAN-AMERICAN AB Although the familial clustering of multiple myeloma (MM) supports the role of inherited susceptibility, only recently has direct evidence for genetic predisposition been demonstrated. A meta-analysis of two genome-wide association (GWA) studies has identified single-nucleotide polymorphisms (SNPs) localising to a number of genomic regions that are robustly associated with MM risk. In this review, we provide an overview of the evidence supporting a genetic contribution to the predisposition to MM and MGUS (monoclonal gammopathy of unknown significance), and the insight this gives into the biological basis of disease aetiology. We also highlight the promise of future approaches to identify further specific risk factors and their potential clinical utility. C1 [Morgan, G. J.; Johnson, D. C.] Inst Canc Res, Div Mol Pathol, Haematooncol Res Unit, Sutton SM2 5NG, Surrey, England. [Weinhold, N.; Goldschmidt, H.] Heidelberg Univ, Dept Internal Med 5, Heidelberg, Germany. [Landgren, O.] NCI, Multiple Myeloma Sect, NIH, Bethesda, MD 20892 USA. [Lynch, H. T.] Creightons Hereditary Canc Ctr, Dept Prevent Med, Omaha, NE USA. [Hemminki, K.] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany. [Hemminki, K.] Lund Univ, Ctr Primary Hlth Care Res, Malmo, Sweden. [Houlston, R. S.] Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England. RP Morgan, GJ (reprint author), Inst Canc Res, Div Mol Pathol, Haematooncol Res Unit, 15 Cotswold Rd, Sutton SM2 5NG, Surrey, England. EM gareth.morgan@icr.ac.uk OI Houlston, Richard/0000-0002-5268-0242 FU Myeloma UK; Leukaemia Lymphoma Research and Myeloma UK; German Ministry of Education and Science [01ZX1309B]; German Cancer Aid, Deursche Krebshilfe; University Hospital Heidelberg FX Laboratory work of GJM is supported by funding from Myeloma UK. The work of RSH is supported by grants from Leukaemia Lymphoma Research and Myeloma UK. HG and KH are supported by funding was provided to Dietmar-Hopp-Stiftung in Walldorf, The German Ministry of Education and Science (Gliomics 01ZX1309B), the German Cancer Aid, Deursche Krebshilfe and the University Hospital Heidelberg. NR 107 TC 23 Z9 23 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD MAR PY 2014 VL 28 IS 3 BP 518 EP 524 DI 10.1038/leu.2013.344 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA AC9HR UT WOS:000332845700005 PM 24247655 ER PT J AU Cokic, BBB Cokic, VP Suresh, S Wirt, S Noguchi, CT AF Cokic, Bojana B. Beleslin Cokic, Vladan P. Suresh, Sukanya Wirt, Stacey Noguchi, Constance Tom TI Nitric oxide and hypoxia stimulate erythropoietin receptor via MAPK kinase in endothelial cells SO MICROVASCULAR RESEARCH LA English DT Article ID AKT PATHWAY; SYNTHASE; ACTIVATION; PROTEIN; EXPRESSION; APOPTOSIS; SURVIVAL; GROWTH; OXYGEN AB Erythropoietin receptor (EPOR) expression level determines the extent of erythropoietin (EPO) response. Previously we showed that EPOR expression in endothelial cells is increased at low oxygen tension and that EPO stimulation of endothelial cells during hypoxia can increase endothelial nitric oxide (NO) synthase (eNOS) expression and activation as well as NO production. We now observe that while EPO can stimulate NO production, NO in turn can regulate EPOR expression. Human umbilical vein endothelial cells (HUVEC) treated with 10-50 pM of NO donor diethylenetriamine NONOate (DETANO) for 24 h showed significant induction of EPOR gene expression at 5% and 2% of oxygen. Also human bone marrow microvascular endothelial cell line (TrHBMEC) cultured at 21 and 2% oxygen with 50 uM DETANO demonstrated a time and oxygen dependent induction of EPOR mRNA expression after 24 and 48 h, particularly at low oxygen tension. EPOR protein was also induced by DETANO at 2% oxygen in TrHBMEC and HUVEC. The activation of signaling pathways by NO donor stimulation appeared to be distinct from EPO stimulation. In reporter gene assays, DETANO treatment of HeLa cells at 2% oxygen increased EPOR promoter activity indicated by a 48% increase in luciferase activity with a 2 kb EPOR promoter fragment and a 71% increase in activity with a minimal EPOR promoter fragment containing 0.2 kb 5'. We found that DETANO activated MAPK kinase in TrHBMEC both in normoxia and hypoxia, while MAPK kinase inhibition showed significant reduction of EPOR mRNA gene expression at low oxygen tension, suggesting MAPK involvement in NO mediated induction of EPOR Furthermore, DETANO stimulated Ala anti-apoptotic activity after 30 min in normoxia, whereas it inhibited Akt phosphorylation in hypoxia. In contrast, EPO did not significantly increase MAPK activity while EPO stimulated Akt phosphorylation in TrHBMEC in normoxia and hypoxia. These observations provide a new effect of NO on EPOR expression to enhance EPO response in endothelial cells, particularly at low oxygen tensions. (C) 2014 Elsevier Inc. All rights reserved. C1 [Cokic, Bojana B. Beleslin] Clin Ctr Serbia, Clin Endocrinol Diabet & Metab Dis, Genet Lab, Belgrade 11000, Serbia. [Cokic, Vladan P.] Univ Belgrade, Inst Med Res, Lab Expt Hematol, Belgrade, Serbia. [Suresh, Sukanya; Wirt, Stacey; Noguchi, Constance Tom] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. RP Cokic, BBB (reprint author), Clin Ctr Serbia, Clin Endocrinol Diabet & Metab Dis, Genet Lab, Dr Subotica 13, Belgrade 11000, Serbia. EM miljuc@yahoo.com FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, USA; Serbian Ministry of Education and Science and Technological Development [175053] FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, USA and by a grant from the Serbian Ministry of Education and Science and Technological Development [175053]. NR 28 TC 7 Z9 9 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 0026-2862 EI 1095-9319 J9 MICROVASC RES JI Microvasc. Res. PD MAR PY 2014 VL 92 BP 34 EP 40 DI 10.1016/j.mvr.2014.01.009 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AD6NZ UT WOS:000333379000005 PM 24518819 ER PT J AU Sochacki, KA Shtengel, G van Engelenburg, SB Hess, HF Taraska, JW AF Sochacki, Kem A. Shtengel, Gleb van Engelenburg, Schuyler B. Hess, Harald F. Taraska, Justin W. TI Correlative super-resolution fluorescence and metal-replica transmission electron microscopy SO NATURE METHODS LA English DT Article ID CLATHRIN; PROTEIN; VISUALIZATION; ENDOCYTOSIS; CURVATURE; PROBES; IMAGE; EPSIN AB We combine super-resolution localization fluorescence microscopy with transmission electron microscopy of metal replicas to locate proteins on the landscape of the cellular plasma membrane at the nanoscale. We validate robust correlation on the scale of 20 nm by imaging endogenous clathrin (in two and three dimensions) and apply the method to find the previously unknown three-dimensional position of the endocytic protein epsin on clathrin-coated structures at the plasma membrane. C1 [Sochacki, Kem A.; Taraska, Justin W.] NHLBI, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Shtengel, Gleb; Hess, Harald F.] Howard Hughes Med Inst, Ashburn, VA USA. [van Engelenburg, Schuyler B.] NICHHD, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Taraska, JW (reprint author), NHLBI, US Natl Inst Hlth, Bldg 10, Bethesda, MD 20892 USA. EM hessh@janelia.hhmi.org; justin.taraska@nih.gov RI Taraska, Justin/H-8876-2016 OI Taraska, Justin/0000-0001-5355-9535 FU Intramural Research Program of the NHLBI, NIH; Howard Hughes Medical Institute FX We thank M. Daniels and the US National Heart, Lung, and Blood Institute (NHLBI) electron microscopy core for help with EM; H. Shroff, J. Shaw and K. Neuman for critical reading of the manuscript; W. Li and Y. Wang (Janelia Farm) for EM grid preparation; L. Greene (NHLBI) for antibodies; S. Yu (NHLBI) for plasmid preparation; A. Nagy for acquiring atomic force microscopy (AFM) images; and E. Tyler and A. Hoofring of NIH Medical Arts for design work on Figure 1. J. W. T. is supported by the Intramural Research Program of the NHLBI, NIH. G. S. and H. F. H. are supported by the Howard Hughes Medical Institute. NR 23 TC 29 Z9 30 U1 2 U2 37 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 EI 1548-7105 J9 NAT METHODS JI Nat. Methods PD MAR PY 2014 VL 11 IS 3 BP 305 EP U278 DI 10.1038/nmeth.2816 PG 6 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AB9CE UT WOS:000332086100025 PM 24464288 ER PT J AU Pfeffer, G Sambuughin, N Olive, M Tyndel, F Toro, C Goldfarb, LG Chinnery, PF AF Pfeffer, Gerald Sambuughin, Nyamkhishig Olive, Montse Tyndel, Felix Toro, Camilo Goldfarb, Lev G. Chinnery, Patrick F. TI A new disease allele for the p.C30071R mutation in titin causing hereditary myopathy with early respiratory failure SO NEUROMUSCULAR DISORDERS LA English DT Article DE Hereditary myopathy with early respiratory failure; Titin; Titinopathy; Myofibrillar myopathy; Haplotype AB Hereditary myopathy with early respiratory failure is an autosomal dominant myopathy caused by mutations in the 119th fibronectin-3 domain of titin. To date all reported patients with the most common mutation in this domain (p.C30071R) appear to share ancestral disease alleles. We undertook this study of two families with the p.C30071R mutation to determine whether they share the same haplotype as previously reported British families or whether the mutation arose as a de novo event. We sequenced the 119th fibronectin-3 domain in these two probands and flanking polymorphisms associated with the British haplotype in hereditary myopathy with early respiratory failure. A family of Indian descent had a haplotype that was not compatible with the British shared haplotype. Cloning of the 119th fibronectin-3 domain in this patient demonstrated polymorphisms rs191484894 and novel noncoding variant c.90225C>T on the same allele as the mutation, which is distinct from previously reported British families. This proves that the p.C30071R mutation itself (rather than the haplotype containing this mutation) causes hereditary myopathy with early respiratory failure and suggests its independent origin in different ethnic groups. (C) 2013 The Authors. Published by Elsevier B.V. All rights reserved. C1 [Pfeffer, Gerald; Chinnery, Patrick F.] Newcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England. [Pfeffer, Gerald; Chinnery, Patrick F.] Royal Victoria Infirm, Dept Neurol, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. [Sambuughin, Nyamkhishig] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Olive, Montse] IDIBELL Hosp Univ Bellvitge, Dept Pathol, Inst Neuropathol, Barcelona, Spain. [Olive, Montse] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain. [Olive, Montse] IDIBELL Hosp Univ Bellvitge, Inst Neuropathol, Dept Neurol, Barcelona, Spain. [Tyndel, Felix] Univ Toronto, Toronto Western Hosp, Toronto, ON M5T 2S8, Canada. [Toro, Camilo] NHGRI, NIH, Bethesda, MD 20892 USA. [Goldfarb, Lev G.] NINDS, NIH, Bethesda, MD 20892 USA. RP Chinnery, PF (reprint author), Newcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England. EM patrick.chinnery@ncl.ac.uk OI Olive, Montse/0000-0001-5727-0165 FU Canadian Institutes of Health Research FX GP is the recipient of a Bisby Fellowship from the Canadian Institutes of Health Research. PFC is an Honorary Consultant Neurologist at Newcastle upon Tyne Foundation Hospitals NHS Trust, is a Wellcome Trust Senior Fellow in Clinical Science (084980/Z/08/Z), and a UK NIHR Senior Investigator. PFC receives additional support from the Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z), the Medical Research Council (UK) Centre for Translational Research in Neuromuscular Diseases, and EU FP7 TIRCON, and the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The research was supported in part by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke. NR 10 TC 2 Z9 2 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD MAR PY 2014 VL 24 IS 3 BP 241 EP 244 DI 10.1016/j.nmd.2013.12.001 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AD8AH UT WOS:000333488400007 PM 24444549 ER PT J AU Ye, ZQ Chen, Z Lan, X Hara, S Sunkel, B Huang, THM Elnitski, L Wang, QB Jin, VX AF Ye, Zhenqing Chen, Zhong Lan, Xun Hara, Stephen Sunkel, Benjamin Huang, Tim H. -M. Elnitski, Laura Wang, Qianben Jin, Victor X. TI Computational analysis reveals a correlation of exon-skipping events with splicing, transcription and epigenetic factors SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TRACT-BINDING-PROTEIN; RNA-SEQ; INTRON STRUCTURE; FACTOR SC35; SPLICEOSOME; GENOME; QUANTIFICATION; MECHANISMS; REPRESSION; DISEASE AB Alternative splicing (AS), in higher eukaryotes, is one of the mechanisms of post-transcriptional regulation that generate multiple transcripts from the same gene. One particular mode of AS is the skipping event where an exon may be alternatively excluded or constitutively included in the resulting mature mRNA. Both transcript isoforms from this skipping event site, i.e. in which the exon is either included (inclusion isoform) or excluded (skipping isoform), are typically present in one cell, and maintain a subtle balance that is vital to cellular function and dynamics. However, how the prevailing conditions dictate which isoform is expressed and what biological factors might influence the regulation of this process remain areas requiring further exploration. In this study, we have developed a novel computational method, graph-based exon-skipping scanner (GESS), for de novo detection of skipping event sites from raw RNA-seq reads without prior knowledge of gene annotations, as well as for determining the dominant isoform generated from such sites. We have applied our method to publicly available RNA-seq data in GM12878 and K562 cells from the ENCODE consortium and experimentally validated several skipping site predictions by RT-PCR. Furthermore, we integrated other sequencing-based genomic data to investigate the impact of splicing activities, transcription factors (TFs) and epigenetic histone modifications on splicing outcomes. Our computational analysis found that splice sites within the skipping-isoform-dominated group (SIDG) tended to exhibit weaker MaxEntScan-calculated splice site strength around middle, 'skipping', exons compared to those in the inclusion-isoform-dominated group (IIDG). We further showed the positional preference pattern of splicing factors, characterized by enrichment in the intronic splice sites immediately bordering middle exons. Finally, our analysis suggested that different epigenetic factors may introduce a variable obstacle in the process of exon-intron boundary establishment leading to skipping events. C1 [Ye, Zhenqing; Huang, Tim H. -M.; Jin, Victor X.] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. [Chen, Zhong; Sunkel, Benjamin; Wang, Qianben] Ohio State Univ, Dept Mol & Cellular Biochem, Columbus, OH 43210 USA. [Chen, Zhong; Sunkel, Benjamin; Wang, Qianben] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Lan, Xun; Hara, Stephen] Ohio State Univ, Dept Biomed Informat, Columbus, OH 43210 USA. [Elnitski, Laura] NHGRI, Genome Technol Branch, NIH, Rockville, MD 20852 USA. [Jin, Victor X.] Univ Texas Hlth Sci Ctr San Antonio, Deparment Epidemiol & Biostat, San Antonio, TX 78229 USA. RP Jin, VX (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. EM qianben.wang@osumc.edu; jinv@uthscsa.edu FU Department of Molecular Medicine, University of Texas Health Science Center, San Antonio; National Institutes of Health (NIH) [R01CA151979, U54CA113001]; Department of Defense [W81XWH-12-1-0615]; University of Texas Health Science Center San Antonio, NIH FX Department of Molecular Medicine, University of Texas Health Science Center, San Antonio (to V.X.J.); National Institutes of Health (NIH) [R01CA151979 to Q.W., U54CA113001 to T.H.-M.H., Q.W., V.X.J.]; Department of Defense [W81XWH-12-1-0615 to Q.W.]. Funding for Open access charges: University of Texas Health Science Center San Antonio, NIH. NR 36 TC 7 Z9 7 U1 1 U2 18 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 MAR PY 2014 VL 42 IS 5 BP 2856 EP 2869 DI 10.1093/nar/gkt1338 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AD2VJ UT WOS:000333093600013 PM 24369421 ER PT J AU Singh, AP Archer, TK AF Singh, Ajeet Pratap Archer, Trevor K. TI Analysis of the SWI/SNF chromatin-remodeling complex during early heart development and BAF250a repression cardiac gene transcription during P19 cell differentiation SO NUCLEIC ACIDS RESEARCH LA English DT Article ID GLUCOCORTICOID-RECEPTOR; CARDIOVASCULAR DEVELOPMENT; PROTEASOMAL DEGRADATION; MOUSE EMBRYO; IN-VIVO; ACTIVATION; PLURIPOTENCY; RECRUITS; NUCLEOSOMES; EXPRESSION AB The regulatory networks of differentiation programs and the molecular mechanisms of lineage-specific gene regulation in mammalian embryos remain only partially defined. We document differential expression and temporal switching of BRG1-associated factor (BAF) subunits, core pluripotency factors and cardiac-specific genes during post-implantation development and subsequent early organogenesis. Using affinity purification of BRG1 ATPase coupled to mass spectrometry, we characterized the cardiac-enriched remodeling complexes present in E8.5 mouse embryos. The relative abundance and combinatorial assembly of the BAF subunits provides functional specificity to Switch/Sucrose NonFermentable (SWI/SNF) complexes resulting in a unique gene expression profile in the developing heart. Remarkably, the specific depletion of the BAF250a subunit demonstrated differential effects on cardiac-specific gene expression and resulted in arrhythmic contracting cardiomyocytes in vitro. Indeed, the BAF250a physically interacts and functionally cooperates with Nucleosome Remodeling and Histone Deacetylase (NURD) complex subunits to repressively regulate chromatin structure of the cardiac genes by switching open and poised chromatin marks associated with active and repressed gene expression. Finally, BAF250a expression modulates BRG1 occupancy at the loci of cardiac genes regulatory regions in P19 cell differentiation. These findings reveal specialized and novel cardiac-enriched SWI/SNF chromatin-remodeling complexes, which are required for heart formation and critical for cardiac gene expression regulation at the early stages of heart development. C1 [Singh, Ajeet Pratap; Archer, Trevor K.] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Archer, TK (reprint author), NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. EM archer1@niehs.nih.gov FU The Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES071006-13] FX Funding for open access charge: The Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Project no. Z01 ES071006-13). NR 57 TC 10 Z9 10 U1 0 U2 4 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 MAR PY 2014 VL 42 IS 5 BP 2958 EP 2975 DI 10.1093/nar/gkt1232 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AD2VJ UT WOS:000333093600021 PM 24335282 ER PT J AU Song, LH Carlson, JH Zhou, B Virtaneva, K Whitmire, WM Sturdevant, GL Porcella, SF McClarty, G Caldwell, HD AF Song, Lihua Carlson, John H. Zhou, Bing Virtaneva, Kimmo Whitmire, William M. Sturdevant, Gail L. Porcella, Stephen F. McClarty, Grant Caldwell, Harlan D. TI Plasmid-mediated transformation tropism of chlamydial biovars SO PATHOGENS AND DISEASE LA English DT Article ID TRACHOMATIS PLASMID; TRANSCRIPTIONAL REGULATOR; INFECTION; VARIANT; GENES; IDENTIFICATION; SEQUENCE; IMMUNITY; SWEDISH; VACCINE C1 [Song, Lihua; Carlson, John H.; Zhou, Bing; Whitmire, William M.; Sturdevant, Gail L.; Caldwell, Harlan D.] NIAID, Intracellular Parasites Lab, NIH, Hamilton, MT USA. [Song, Lihua] Inst Microbiol & Epidemiol, State Key Lab Pathogen & Biosecur, Beijing, Peoples R China. [Virtaneva, Kimmo; Porcella, Stephen F.] NIAID, Genom Unit Res Technol Sect, NIH, Hamilton, MT USA. [McClarty, Grant] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. RP Caldwell, HD (reprint author), Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM hcaldwell@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Kelly Matteson and Anita Mora for editorial and graphic assistance. Kayley Schulmeyer for assistance with the qRT-PCR analyses. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 26 TC 9 Z9 9 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2049-632X J9 PATHOG DIS JI Pathog. Dis. PD MAR PY 2014 VL 70 IS 2 BP 189 EP 193 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AC8GM UT WOS:000332771500011 PM 24214488 ER PT J AU Avila, I Lin, SC AF Avila, Irene Lin, Shih-Chieh TI Motivational Salience Signal in the Basal Forebrain Is Coupled with Faster and More Precise Decision Speed SO PLOS BIOLOGY LA English DT Article ID REACTION-TIME-TASK; PREFRONTAL CORTEX; NUCLEUS BASALIS; ALZHEIMERS-DISEASE; NEURONAL-ACTIVITY; SCHIZOPHRENIA; ATTENTION; PROJECTIONS; DEPRESSION; DEFICITS AB The survival of animals depends critically on prioritizing responses to motivationally salient stimuli. While it is generally believed that motivational salience increases decision speed, the quantitative relationship between motivational salience and decision speed, measured by reaction time (RT), remains unclear. Here we show that the neural correlate of motivational salience in the basal forebrain (BF), defined independently of RT, is coupled with faster and also more precise decision speed. In rats performing a reward-biased simple RT task, motivational salience was encoded by BF bursting response that occurred before RT. We found that faster RTs were tightly coupled with stronger BF motivational salience signals. Furthermore, the fraction of RT variability reflecting the contribution of intrinsic noise in the decision-making process was actively suppressed in faster RT distributions with stronger BF motivational salience signals. Artificially augmenting the BF motivational salience signal via electrical stimulation led to faster and more precise RTs and supports a causal relationship. Together, these results not only describe for the first time, to our knowledge, the quantitative relationship between motivational salience and faster decision speed, they also reveal the quantitative coupling relationship between motivational salience and more precise RT. Our results further establish the existence of an early and previously unrecognized step in the decision-making process that determines both the RT speed and variability of the entire decision-making process and suggest that this novel decision step is dictated largely by the BF motivational salience signal. Finally, our study raises the hypothesis that the dysregulation of decision speed in conditions such as depression, schizophrenia, and cognitive aging may result from the functional impairment of the motivational salience signal encoded by the poorly understood noncholinergic BF neurons. Author Summary Humans and animals face the constant challenge of identifying the subset of incoming sensory stimuli that are most behaviorally relevant and prioritizing behavioral responses accordingly. Critical to this decision is the ability to determine whether a stimulus is motivationally salientthat is, whether the stimulus predicts important behavioral outcomes such as reward or punishment. While it is generally assumed that motivational salience is related to faster decision speed and shorter reaction time, it remains unclear how motivational salience actually modulates the decision-making process. This study investigates how the motivational salience signal in the basal forebrain controls the fundamental properties of the decision-making processdecision speed and its variability. In rats performing a reward-biased simple reaction time task, we show that the basal forebrain motivational salience signal is associated with a faster and also precise decision speed. In support of a causal role for this association, artificially augmenting this basal forebrain motivational salience signal by electrical stimulation also leads to faster and more precise reaction times. These results suggest that decision speed and its variability are jointly determined by an early and previously unrecognized step in the decision-making process, dictated largely by the motivational salience signal encoded by poorly understood noncholinergic neurons in the basal forebrain. C1 [Avila, Irene; Lin, Shih-Chieh] NIA, Neural Circuits & Cognit Unit, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. RP Avila, I (reprint author), NIA, Neural Circuits & Cognit Unit, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. EM shih-chieh.lin@nih.gov OI Lin, Shih-Chieh/0000-0003-3693-5476 FU National Institute on Aging, NIH, United States of America FX This research is funded by the intramural research program of the National Institute on Aging, NIH, United States of America. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 15 Z9 15 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD MAR PY 2014 VL 12 IS 3 AR e1001811 DI 10.1371/journal.pbio.1001811 PG 13 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA AD6YF UT WOS:000333406800015 PM 24642480 ER PT J AU Presman, DM Ogara, MF Stortz, M Alvarez, LD Pooley, JR Schiltz, RL Grontved, L Johnson, TA Mittelstadt, PR Ashwell, JD Ganesan, S Burton, G Levi, V Hager, GL Pecci, A AF Presman, Diego M. Florencia Ogara, M. Stortz, Martin Alvarez, Lautaro D. Pooley, John R. Louis Schiltz, R. Grontved, Lars Johnson, Thomas A. Mittelstadt, Paul R. Ashwell, Jonathan D. Ganesan, Sundar Burton, Gerardo Levi, Valeria Hager, Gordon L. Pecci, Adali TI Live Cell Imaging Unveils Multiple Domain Requirements for In Vivo Dimerization of the Glucocorticoid Receptor SO PLOS BIOLOGY LA English DT Article ID TRANSCRIPTION FACTOR-BINDING; DNA-BINDING; LIVING CELLS; ANTIINFLAMMATORY FUNCTIONS; GENE-TRANSCRIPTION; RESPONSE ELEMENT; DIMER; REPRESSION; SEQUENCE; EXCHANGE AB Glucocorticoids are essential for life, but are also implicated in disease pathogenesis and may produce unwanted effects when given in high doses. Glucocorticoid receptor (GR) transcriptional activity and clinical outcome have been linked to its oligomerization state. Although a point mutation within the GR DNA-binding domain (GRdim mutant) has been reported as crucial for receptor dimerization and DNA binding, this assumption has recently been challenged. Here we have analyzed the GR oligomerization state in vivo using the number and brightness assay. Our results suggest a complete, reversible, and DNA-independent ligand-induced model for GR dimerization. We demonstrate that the GRdim forms dimers in vivo whereas adding another mutation in the ligand-binding domain (I634A) severely compromises homodimer formation. Contrary to dogma, no correlation between the GR monomeric/dimeric state and transcriptional activity was observed. Finally, the state of dimerization affected DNA binding only to a subset of GR binding sites. These results have major implications on future searches for therapeutic glucocorticoids with reduced side effects. Author Summary The powerful anti-inflammatory and immunosuppressive action of glucocorticoids have made them one of the most prescribed drugs worldwide. Unfortunately, acute or chronic treatment may have severe side-effects. Glucocorticoids bind to the glucocorticoid receptor (GR), a ligand-dependent transcription factor. GR regulates gene expression directly by binding to DNA or indirectly by modulating the activity of other transcription factors. It is currently accepted that the direct pathway is mostly responsible for glucocorticoids side-effects and that the oligomerization state of the GR (whether it is a dimer or a monomer) determines which pathway (direct or indirect) will prevail. Hence, scientists have tried to develop dissociated ligands able to specifically activate the GR indirect pathway. In the present work, we employed a novel microscopy method named the number and brightness assay, which measures GR oligomerization state inside the living cell. Our results suggest thatcontrary to the established viewthere is no clear correlation between the oligomerization state of GR and the mechanistic pathway the receptor will follow upon ligand binding. This discovery presents supporting evidence towards the increasing view of the inherent complexity of glucocorticoid action and might impact future approaches towards the design of safer synthetic glucocorticoids. C1 [Presman, Diego M.; Pooley, John R.; Louis Schiltz, R.; Grontved, Lars; Johnson, Thomas A.; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Presman, Diego M.; Florencia Ogara, M.; Stortz, Martin; Levi, Valeria; Pecci, Adali] Univ Buenos Aires, Sch Sci FCEN, Dept Biol Chem, Buenos Aires, DF, Argentina. [Presman, Diego M.; Florencia Ogara, M.; Pecci, Adali] Univ Buenos Aires, Sch Sci FCEN, IFIBYNE, CONICET, Buenos Aires, DF, Argentina. [Alvarez, Lautaro D.; Burton, Gerardo] Univ Buenos Aires, Sch Sci FCEN, Dept Organ Chem, UMYMFOR,CONICET, Buenos Aires, DF, Argentina. [Pooley, John R.] Univ Bristol, Henry Wellcome Labs Integrat Neurosci & Endocrino, Bristol, Avon, England. [Mittelstadt, Paul R.; Ashwell, Jonathan D.] NCI, Lab Immune Cell Biol, Ctr Canc Res, Bethesda, MD 20892 USA. [Ganesan, Sundar] NIAID, Biol Imaging Sect, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Presman, DM (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM hagerg@exchange.nih.gov; apecci@qb.fcen.uba.ar OI Alvarez, Lautaro Damian/0000-0001-8841-2330; Burton, Gerardo/0000-0002-8559-7306; Presman, Diego/0000-0003-4515-8058; Grontved, Lars/0000-0002-6735-8483 FU CONICET [PIP 112-200801-00859]; Agencia Nacional de Promociones Cientificas y Tecnicas [BID.PICT 2011-1321]; University of Buenos Aires (UBACyT); National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by grants from CONICET (PIP 112-200801-00859), Agencia Nacional de Promociones Cientificas y Tecnicas (BID.PICT 2011-1321), University of Buenos Aires (UBACyT), and 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 56 TC 26 Z9 26 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD MAR PY 2014 VL 12 IS 3 AR e1001813 DI 10.1371/journal.pbio.1001813 PG 14 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA AD6YF UT WOS:000333406800007 PM 24642507 ER PT J AU Alexopoulos, GS AF Alexopoulos, George S. TI This issue: Clinical and Neurobiological Findings, Treatment Developments in Late-Life Depression SO PSYCHIATRIC ANNALS LA English DT Editorial Material ID PROBLEM-SOLVING THERAPY; GERIATRIC DEPRESSION; EXECUTIVE DYSFUNCTION; FUNCTIONAL CONNECTIVITY; SUPPORTIVE THERAPY; MAJOR DEPRESSION; OLDER-ADULTS; REMISSION C1 [Alexopoulos, George S.] Weill Cornell Inst Geriatr Psychiat, New York, NY USA. [Alexopoulos, George S.] Natl Inst Mental Hlth, Adv Ctr Intervent & Serv Res Geriatr Mood Disorde, Bethesda, MD USA. [Alexopoulos, George S.] Amer Coll Psychiatrists, Chicago, IL USA. [Alexopoulos, George S.] Amer Psychiat Assoc, Washington, DC 20005 USA. RP Alexopoulos, GS (reprint author), Weill Cornell Inst Geriatr Psychiat, New York, NY USA. NR 16 TC 0 Z9 0 U1 0 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 EI 1938-2456 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD MAR PY 2014 VL 44 IS 3 BP 126 EP 129 DI 10.3928/00485713-20140306-03 PG 4 WC Psychiatry SC Psychiatry GA AE1OX UT WOS:000333739900003 ER PT J AU Burt, JR Zimmerman, SL Kamel, IR Halushka, M Bluemke, DA AF Burt, Jeremy R. Zimmerman, Stefan L. Kamel, Ihab R. Halushka, Marc Bluemke, David A. TI Myocardial T1 Mapping: Techniques and Potential Applications SO RADIOGRAPHICS LA English DT Article ID CARDIOVASCULAR MAGNETIC-RESONANCE; SYSTEMIC LUPUS-ERYTHEMATOSUS; INVERSION-RECOVERY MOLLI; GD-DTPA KINETICS; LOOK-LOCKER; HEART-FAILURE; EXTRACELLULAR-MATRIX; CARDIAC AMYLOIDOSIS; HYPERTROPHIC CARDIOMYOPATHY; DELAYED ENHANCEMENT AB Myocardial fibrosis is a common endpoint in a variety of cardiac diseases and a major independent predictor of adverse cardiac outcomes. Short of histopathologic analysis, which is limited by sampling bias, most diagnostic modalities are limited in their depiction of myocardial fibrosis. Cardiac magnetic resonance (MR) imaging has the advantage of providing detailed soft-tissue characterization, and a variety of novel quantification methods have further improved its usefulness. Contrast material-enhanced cardiac MR imaging depends on differences in signal intensity between regions of scarring and adjacent normal myocardium. Diffuse myocardial fibrosis lacks these differences in signal intensity. Measurement of myocardial T1 times (T1 mapping) with gadolinium-enhanced inversion recovery-prepared sequences may depict diffuse myocardial fibrosis and has good correlation with ex vivo fibrosis content. T1 mapping calculates myocardial T1 relaxation times with image-based signal intensities and may be performed with standard cardiac MR imagers and radiologic workstations. Myocardium with diffuse fibrosis has greater retention of contrast material, resulting in T1 times that are shorter than those in normal myocardium. Early studies have suggested that diffuse myocardial fibrosis may be distinguished from normal myocardium with T1 mapping. Large multicenter studies are needed to define the role of T1 mapping in developing prognoses and therapeutic assessments. However, given its strengths as a noninvasive method for direct quantification of myocardial fibrosis, T1 mapping may eventually play an important role in the management of cardiac disease. (C) RSNA, 2014 . radiographics.rsna.org C1 [Burt, Jeremy R.; Zimmerman, Stefan L.; Kamel, Ihab R.; Bluemke, David A.] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21218 USA. [Halushka, Marc] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Bluemke, David A.] Ctr Clin, Bethesda, MD 20892 USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21218 USA. EM bluemked@mail.nih.gov OI Halushka, Marc/0000-0002-7112-7389; Bluemke, David/0000-0002-8323-8086 FU RSNA Silver Anniversary Campaign Pacesetters Research Fellow Grant [RF1106] FX supported by an RSNA 2011 Silver Anniversary Campaign Pacesetters Research Fellow Grant (number RF1106). The other authors have no financial relationships to disclose. NR 82 TC 14 Z9 16 U1 0 U2 9 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD MAR-APR PY 2014 VL 34 IS 2 BP 377 EP + DI 10.1148/rg.342125121 PG 20 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AD0SS UT WOS:000332945000012 PM 24617686 ER PT J AU Hamilton, KJ Arao, Y Korach, KS AF Hamilton, Katherine J. Arao, Yukitomo Korach, Kenneth S. TI Estrogen hormone physiology: Reproductive findings from estrogen receptor mutant mice SO REPRODUCTIVE BIOLOGY LA English DT Review DE Estrogen receptor; Transactivation function; Genetically modified mouse; Uterus; Ovary; Fertility ID MUTATION PROVIDES EVIDENCE; ALPHA ER-ALPHA; IN-VIVO; TRANSACTIVATING FUNCTION; KNOCKOUT MOUSE; TRACT FUNCTION; GROWTH-FACTOR; HUMAN-DISEASE; SEX REVERSAL; FEMALE MICE AB Estrogen receptors (ERs) play a crucial role in reproduction and normal physiology. The two sub-types of ER (ER alpha and beta) are expressed in various levels in different tissues and selective cell types. Gene targeting technology allowed us to produce lines of mice with disrupted ER alpha (alpha ERKO) and ER beta genes (beta ERKO) as well as a compound alpha beta ERKO in the whole body. Male and female alpha ERKO mice are infertile. Estrogen, EGF and IGF-1 treatments failed to induce uterine growth and DNA synthesis in beta ERKO uteri. alpha ERKO females are infertile due to hypoplastic uteri and hyperemic ovaries with no corpora lutea due to persistent LH stimulation from loss of negative feedback. alpha ERKO males are infertile, with testicular atrophy and seminiferous tubule dysmorphogenesis producing decreased spermatogenesis and inactive sperm. beta ERKO females show arrested folliculogenesis and subfertility. Ovarian analyses indicate differential gene expression related to ovulatory stimulation deficits including lack of LH, PR, Cyp19 and Cox2 expression. A unique ovarian phenotype is found only in alpha beta ERKO females showing transdifferentiation of granulosa cells to Sertoli cells. We describe here several novel mouse models which possess ER alpha gene modification. To understand ERa function in uterine endometrial epithelial cells, we generated a tissue selective ER alpha gene disrupted mouse model, the uterine epithelial-specific ER alpha knockout (UtE-pi alpha ERKO). To understand the physiological role of ER alpha functional domains, we generated a mouse model with a mutation in the ligand dependent transcription activation domain of ER alpha (AF2ERKI). Findings from the ER alpha mutant mice suggest that the absence of functional ERa is not lethal and results in significant endocrine effects and altered physiological processes. Published by Elsevier Urban & Partner Sp. z o.o. on behalf of Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. C1 [Hamilton, Katherine J.; Arao, Yukitomo; Korach, Kenneth S.] NIEHS, Receptor Biol Sect, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Korach, KS (reprint author), NIEHS, Receptor Biol Sect, Lab Reprod & Dev Toxicol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM Korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU NIH, National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. Thanks to Dr. Yin Li and Ms. Brianna Pockette for critical reading of this manuscript. NR 47 TC 23 Z9 24 U1 2 U2 19 PU INST ANIMAL REPRODUCTION FOOD RESEARCH PI OLSZTYN PA POLISH ACAD SCIENCES OLSZTYN, UL BYDGOSKA 1-8, PO BOX 55, OLSZTYN, 10-243, POLAND SN 1642-431X J9 REPROD BIOL JI Reprod. Biol. PD MAR PY 2014 VL 14 IS 1 SI SI BP 3 EP 8 DI 10.1016/j.repbio.2013.12.002 PG 6 WC Reproductive Biology SC Reproductive Biology GA AD7KI UT WOS:000333442300003 PM 24607249 ER PT J AU Peay, HL Rosenstein, DL Biesecker, BB AF Peay, Holly Landrum Rosenstein, Donald L. Biesecker, Barbara Bowles TI Parenting with bipolar disorder: Coping with risk of mood disorders to children SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE Bipolar disorder; Coping; Parent; Risk; Genetic; Children; Mood disorder; United States ID SERIOUS MENTAL-ILLNESS; PSYCHOTIC DISORDERS; FAMILY ENVIRONMENT; HEALTH; MOTHERS; QUESTIONNAIRE; PERCEPTIONS; VALIDATION; ATTITUDES; SYMPTOMS AB Children of individuals with bipolar disorder (BPD) have increased risk for mood disorders and other adverse psychosocial outcomes due to genetic and environmental risk. Though parents with BPD are aware of increased risk to children, little is known about efforts undertaken in response or their perceived utility. Among parents who self-report with BPD, this study identifies key variables associated with parental coping with children's risk of mood disorders; and explores the relationship between monitoring children's moods and perceived coping efficacy. In this U.S. study, active parental coping with, and cognitive distancing from, child's risk were measured using novel scales. Parents (n = 266) who self-identified as having BPD completed a web-based survey. They had at least one unaffected child. Most participants endorsed monitoring their children's moods. Monitoring was associated with increased perceived control over the child's well-being (p < 0.005), but not feeling less worried. Active parental coping with risk to children was positively associated with active coping with own illness (beta = 0.25, p = 0.001), family history (beta = 0.24, p = 0.001), and self-report of current depression (beta = 0.16, p = 0.037), explaining 13.8% of the variance (F = 8.81, p < 0.001). Cognitive distancing from the child's risk was positively associated with confidence in diagnosis (beta = 0.25, p = 0.001), and negatively associated with self-report of current mania (beta = -0.19, p = 0.007), perceiving BPD as genetic (beta = -0.26, p < 0.001) and having more children (beta = -0.20, p = 0.004); explaining 16.2% of the variance (F = 8.63, p < 0.001). Parents' adaptation to their own BPD was modestly correlated with active coping with child's risk (r = 0.15, p < 0.05) but not with cognitive distancing. The findings support the importance of understanding causal attributions and the value of genetic education and counseling for parents with BPD. Further research is necessary to elucidate the psychological benefits of active coping versus cognitive distancing from child's risk, and explore additional variables that predict parental coping with children's risk of mood disorders. Published by Elsevier Ltd. C1 [Peay, Holly Landrum; Biesecker, Barbara Bowles] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Rosenstein, Donald L.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27514 USA. [Rosenstein, Donald L.] Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. RP Peay, HL (reprint author), NHGRI, Social & Behav Res Branch, NHGRI Bldg 31,Room B1B36 31 Ctr Dr,MSC 2073, Bethesda, MD 20892 USA. EM hpeay@mail.nih.gov; donald_rosenstein@med.unc.edu; barbarab@mail.nih.gov FU National Human Genome Research Institute, National Institutes of Health FX This work was funded by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. The authors have no conflicts to disclose. Cris Price (Abt Associates) provided valuable input into the statistical analysis. We thank the parents who were willing to share their perceptions and experiences in this survey. NR 35 TC 1 Z9 1 U1 3 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD MAR PY 2014 VL 104 BP 194 EP 200 DI 10.1016/j.socscimed.2013.10.022 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA AD8AM UT WOS:000333488900025 PM 24581078 ER PT J AU Lavi, O Greene, JM Levy, D Gottesman, MM AF Lavi, Orit Greene, James M. Levy, Doron Gottesman, Michael M. TI Simplifying the complexity of resistance heterogeneity in metastasis SO TRENDS IN MOLECULAR MEDICINE LA English DT Review DE mathematical model; clinical application; resistance level; tumor heterogeneity; cell density; metastasis ID RENAL-CELL CARCINOMA; BREAST-CANCER; TUMOR-GROWTH; INTRATUMORAL HETEROGENEITY; ADAPTIVE DYNAMICS; DRUG-RESISTANCE; EVOLUTION; CHEMOTHERAPY; SUNITINIB; KINETICS AB The main goal of treatment regimens for metastasis is to control growth rates, not eradicate all cancer cells. Mathematical models offer methodologies that incorporate high-throughput data with dynamic effects on net growth. The ideal approach would simplify, but not over-simplify, a complex problem into meaningful and manageable estimators that predict the response of a patient to specific treatments. We explore here three fundamental approaches with different assumptions concerning resistance mechanisms in which the cells are categorized into either discrete compartments or described by a continuous range of resistance levels. We argue in favor of modeling resistance as a continuum, and demonstrate how integrating cellular growth rates, density-dependent versus exponential growth, and intratumoral heterogeneity improves predictions concerning the resistance heterogeneity of metastases. C1 [Lavi, Orit; Gottesman, Michael M.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Greene, James M.; Levy, Doron] Univ Maryland, Dept Math, College Pk, MD 20742 USA. [Greene, James M.; Levy, Doron] Univ Maryland, Ctr Sci Computat & Math Modeling CSCAMM, College Pk, MD 20742 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM mgottesman@nih.gov FU Intramural NIH HHS [ZIA BC010830-07]; NCI NIH HHS [R01CA130817, R01 CA130817] NR 30 TC 5 Z9 5 U1 1 U2 15 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4914 EI 1471-499X J9 TRENDS MOL MED JI Trends Mol. Med PD MAR PY 2014 VL 20 IS 3 BP 129 EP 136 DI 10.1016/j.molmed.2013.12.005 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA AD8JJ UT WOS:000333512000001 PM 24491979 ER PT J AU Griffin, ML Dodd, DR Potter, JS Rice, LS Dickinson, W Sparenborg, S Weiss, RD AF Griffin, Margaret L. Dodd, Dorian R. Potter, Jennifer S. Rice, Lindsay S. Dickinson, William Sparenborg, Steven Weiss, Roger D. TI Baseline characteristics and treatment outcomes in prescription opioid dependent patients with and without co-occurring psychiatric disorder SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article DE Co-occurring psychiatric disorder; opioid analgesics; prescription drug abuse; prescription opioid dependence; treatment outcome ID METHADONE-MAINTENANCE TREATMENT; NATIONAL EPIDEMIOLOGIC SURVEY; MENTAL-DISORDERS; OPIATE ADDICTS; UNITED-STATES; SUBSTANCE USE; COMORBIDITY; BUPRENORPHINE; SEVERITY; ALCOHOL AB Background: Given the growing prevalence of prescription opioid dependence and the considerable rates of additional psychopathology in drug dependence, we examined the association between the presence of a co-occurring Axis I psychiatric disorder and sociodemographic and clinical characteristics in this secondary analysis of patients entering a treatment study for dependence on prescription opioids. Treatment outcomes were also compared. Methods: Patients dependent on prescription opioids participated in a multi-site, two-phase, randomized, controlled trial to assess different lengths of buprenorphine-naloxone pharmacotherapy and different intensities of counseling (Clinicaltrials.gov identifier: NCT00316277). Among the 653 participants entering the first phase of the trial, 360 entered the second phase, receiving 12 weeks of buprenorphine-naloxone treatment; they are reported here. Half of those participants (180/360) had a current co-occurring psychiatric disorder in addition to substance dependence. Results: Sociodemographic characteristics were similar overall between those with and without a co-occurring psychiatric disorder, but women were 1.6 times more likely than men to have a co-occurring disorder. On several clinical indicators at baseline, participants with a co-occurring disorder had greater impairment. However, they had better opioid use outcomes at the conclusion of 12 weeks of buprenorphine-naloxone stabilization than did participants without a co-occurring disorder. Conclusions: Prescription opioid-dependent patients with a co-occurring psychiatric disorder had a better response to buprenorphine-naloxone treatment despite demonstrating greater impairment at baseline. Additional research is needed to determine the mechanism of this finding and to adapt treatments to address this population. C1 [Griffin, Margaret L.; Dodd, Dorian R.; Potter, Jennifer S.; Rice, Lindsay S.; Weiss, Roger D.] McLean Hosp, Div Alcohol & Drug Abuse, Belmont, MA 02478 USA. [Griffin, Margaret L.; Potter, Jennifer S.; Weiss, Roger D.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Potter, Jennifer S.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Dickinson, William] Providence Reg Med Ctr, Everett, WA USA. [Sparenborg, Steven] NIDA, Ctr Clin Trials Network, NIH, Rockville, MD USA. RP Griffin, ML (reprint author), McLean Hosp, Div Alcohol & Drug Abuse, 115 Mill St, Belmont, MA 02478 USA. EM mgriffin@mclean.harvard.edu RI Potter, Jennifer/C-6720-2008 OI Potter, Jennifer/0000-0002-7250-4422 FU NIDA CTN [U10 DA015831, U10 DA020024, U10 DA013714]; NIDA [K24 DA022288, K23 DA02297] FX We thank the staff and participants at the community treatment programs and regional research and training centers of the National Institute on Drug Abuse Clinical Trials Network for their involvement in this project, including Chestnut Ridge Hospital, San Francisco General Hospital, St. Luke's Roosevelt Hospital, Long Island Jewish Medical Center-Addiction Recovery Services, Bellevue Hospital Center, McLean Hospital, East Indiana Treatment Center, Adapt Inc, UCLA Integrated Substance Programs, Behavioral Health Service of Pickens County, and Providence Behavioral Health Services. We also thank the staff of the Clinical Coordinating Center (The EMMES Corporation, Rockville, MD) and the Data and Statistics Center (The Duke Clinical Research Institute, Durham, NC), and the staff of the Center for the Clinical Trials Network at the National Institute on Drug Abuse (Rockville, MD) for their work on this project. This work was supported by NIDA CTN grants U10 DA015831, U10 DA020024, and U10 DA013714; and NIDA grants K24 DA022288 and K23 DA02297. NR 29 TC 7 Z9 7 U1 4 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0095-2990 EI 1097-9891 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PD MAR PY 2014 VL 40 IS 2 BP 157 EP 162 DI 10.3109/00952990.2013.842241 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA AD1VG UT WOS:000333021200012 PM 24219166 ER PT J AU Grange, LK Kouchouk, A Dalal, MD Vitale, S Nussenblatt, RB Chan, CC Sen, HN AF Grange, Landon K. Kouchouk, Amr Dalal, Monica D. Vitale, Susan Nussenblatt, Robert B. Chan, Chi-Chao Sen, H. Nida TI Neoplastic Masquerade Syndromes in Patients With Uveitis SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID PRIMARY INTRAOCULAR LYMPHOMA; 1ST TIME; DIAGNOSIS; EPIDEMIOLOGY; MANAGEMENT; DISEASE AB PURPOSE: To identify the demographic and clinical characteristics, along with the frequency, of neoplastic masquerade syndromes in a tertiary uveitis clinic. DESIGN: A retrospective observational cohort. METHODS: Demographic and clinical data on all patients presenting to the National Eye Institute (NET) with uveitis between 2004 and.2012 were used to compare neoplastic masquerade syndromes and uveitis. RESULTS: A total of 853 patients presenting with uveitis were identified. Of these, 21 (2.5%) were diagnosed with neoplastic masquerade syndromes. The average age at presentation of masquerade syndrome patients was 57 years (median, 55; range, 38-78); for uveitis, 42 years (median, 43; range, 3-98) (P = 0.0003). There were 48% females in the masquerade syndromes group, compared with 59% females in the uveitis group. African American patients represented 9% of the masquerade syndrome patients and 36% of uveitis patients (P = 0.01). Mean worse eye visual acuity was 0.89 (20/160) in neoplastic masquerade syndromes, and 0.66 (20/100) in the uveitis group (P = 0.21). Of masquerade syndrome patients, 90% had posterior inflammation, compared with 63% of uveitis patients (P = 0.006). Of those with masquerade syndromes, 48% of patients had unilateral disease, compared with 27% of the uveitis patients (P = 0.04). CONCLUSIONS: Patients with neoplastic masquerade syndromes were more likely to be older, male, or nonAfrican American and to have posterior segment inflammation and unilateral disease. Patients with masquerade syndromes also had worse visual acuity than did uveitis patients. These differences in clinical characteristics may help to raise the suspicion for neoplastic masquerade syndromes. C1 [Grange, Landon K.; Kouchouk, Amr; Dalal, Monica D.; Vitale, Susan; Nussenblatt, Robert B.; Chan, Chi-Chao; Sen, H. Nida] NEI, NIH, Bethesda, MD 20892 USA. RP Sen, HN (reprint author), NEI, NIH, 10 Ctr Dr,10-10N112, Bethesda, MD 20892 USA. EM senh@nei.nih.gov FU NEI Intramural Research Program, National Eye Institute, National Institutes of Health, Bethesda, MD; NIH FX ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and none were reported. This work was supported by the NEI Intramural Research Program, National Eye Institute, National Institutes of Health, Bethesda, MD. Additionally, this research was made possible through 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 Leona M. and Harry B. Helmsley Charitable Trust, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the foundation website at http://www.fnih.org/work/programs-development/medical-research-scholars- program. Contributions of authors: collection: (L.K.G., A.K.); analysis and interpretation of data (L.K.G., A.K., M.D., S.V., H.N.S.); preparation of article (L.K.G., A.K., M.D., H.N.S.); review of article (L.K.G., A.K., H.N.S., M.D., R.B.N., C.C.C., S.V.); approval of manuscript (L.K.G., A.K., H.N.S., S.V., M.D., R.B.N., C.C.C.). NR 25 TC 8 Z9 8 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD MAR PY 2014 VL 157 IS 3 BP 526 EP 531 DI 10.1016/j.ajo.2013.11.002 PG 6 WC Ophthalmology SC Ophthalmology GA AC2QX UT WOS:000332350100005 PM 24211361 ER PT J AU Nicholson, BP Nigam, D Miller, D Agron, E Dalal, M Jacobs-El, N Lima, BD Cunningham, D Nussenblatt, R Sen, HN AF Nicholson, Benjamin P. Nigam, Divya Miller, Darby Agron, Elvira Dalal, Monica Jacobs-El, Naima Lima, Breno da Rocha Cunningham, Denise Nussenblatt, Robert Sen, H. Nida TI Comparison of Wide-Field Fluorescein Angiography and 9-Field Montage Angiography in Uveitis SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID RETINOPATHY; MANAGEMENT AB PURPOSE: To compare qualitatively and quantitatively Optos fundus camera fluorescein angiographic images of retinal vascular leakage with 9-field montage Topcon fluorescein angiography (FA) images in patients with uveitis. We hypothesized that Optos images reveal more leakage in patients with uveitis. DESIGN: Retrospective, observational case series. METHODS: Images of all patients with uveitis imaged with same-sitting Optos FA and 9-field montage FA during a 9-month period at a single institution (52 eyes of 31 patients) were graded for the total area of retinal vascular leakage. The main outcome measure was area of fluorescein leakage. RESULTS: The area of apparent FA leakage was greater in Optos images than in 9-field montage images (median 22.5 mm(2) vs 4.8 mm(2), P < 0.0001). Of the 49 (45%) eyes with gradable photos, 22 had at least 25% more leakage in the Optos image than in the montage image; 2 (4.1%) had at least 25% less leakage in Optos; and 25 (51%) were similar in the 2 modalities. There were 2 eyes that had no apparent retinal vascular leakage in 9-field montage but were found to have apparent leakage in Optos images. Of the 49 eyes, 23 had posterior pole leakage, and of these, 17 (73.9%) showed more posterior pole leakage in the Optos image. A single 200-degree Optos FA image captured a mean 1.50 x the area captured by montage photography. CONCLUSIONS: More retinal vascular pathology, in both the periphery and the posterior pole, is seen with Optos FA in patients with uveitis when compared with 9-field montage. The clinical implications of Optos FA findings have yet to be determined. C1 [Nicholson, Benjamin P.; Nigam, Divya; Miller, Darby; Agron, Elvira; Dalal, Monica; Jacobs-El, Naima; Lima, Breno da Rocha; Cunningham, Denise; 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 FU Intramural Research Program of the National Institutes of Health, Bethesda, MD FX ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and the following were reported. This research was supported by the Intramural Research Program of the National Institutes of Health, Bethesda, MD; Design of study (H.N.S., D.M., D.N., B.N.); Conduct of study (B.N., D.M., D.N., N.J.E., B.L., M.D., R.N., D.C., H.N.S.); Data collection (B.N., D.M., D.N.); Data analysis (B.N., E.A., D.M., D.N., H.N.S.); Interpretation of data (B.N., D.M., D.N., E.A., R.N., H.N.S.); Preparation of manuscript (B.N., H.N.S.); Review of manuscript (B.N., D.N., D.M., E.A., M.D., N.J.E., B.L., D.C., R.N., H.N.S.); Approval of manuscript (B.N., D.N., D.M., E.A., M.D., N.J.E., B.L., D.C., R.N., H.N.S.). NR 10 TC 7 Z9 9 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD MAR PY 2014 VL 157 IS 3 BP 673 EP 677 DI 10.1016/j.ajo.2013.12.005 PG 5 WC Ophthalmology SC Ophthalmology GA AC2QX UT WOS:000332350100023 PM 24321475 ER PT J AU Tuo, JS Shen, DF Yang, HH Chan, CC AF Tuo, Jingsheng Shen, Defen Yang, Howard Hua Chan, Chi-Chao TI Distinct MicroRNA-155 Expression in the Vitreous of Patients With Primary Vitreoretinal Lymphoma and Uveitis SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID INTRAOCULAR LYMPHOMA; INTERLEUKIN-10; BIOMARKERS; DIAGNOSIS; CANCER; CELLS; INDUCTION; DISEASES; MIR-155; SERUM AB PURPOSE: To use micro-ribonucleic acid (microRNA) profiles in the vitreous for differential diagnosis of primary vitreoretinal lymphoma and uveitis. DESIGN: Prospective cross-sectional study. METHODS: This prospective cross-sectional study included 17 diffuse large B-cell primary vitreoretinal lymphoma and 12 uveitis patients. The supernatant of ocular fluid was subjected to total RNA extraction, followed by complementary deoxyribonucleic acid (cDNA) synthesis. Selected samples (primary vitreoretinal lymphoma, n = 3; uveitis, n = 3) were arrayed by a real-time polymerase chain reaction (RT-PCR)-based microRNA panel that detects 168 human mature microRNAs. The markers promising in distinct levels between uveitis and lymphoma were further tested for in all the other 23 samples by individual RT-PCR analysis. RESULTS: Of 168 microRNAs in the array, 66.5% were detectable with consistent higher microRNA-484, microRNA-197, and microRNA-132 in the primary vitreoretinal lymphoma vitreous and higher microRNA-155, microRNA-200c, and microRNA-22* in the uveitic ocular fluids. The results were normalized by different combinations of 7 control microRNAs (microRNA-103, microRNA-191, microRNA-42-5p, microRNA-16, microRNA-425, microRNA-93, and microRNA-451). After optimization, normalization against microRNA-16 was equally as reliable as the average of the 7 control microRNAs. Individual assays of all samples supported the pattern yielded from the array analysis. But only microRNA-155 was significantly higher in the uveitic vitreous compared to that with lymphoma. CONCLUSIONS: Mature microRNAs are detectable in ocular fluid samples. Primary vitreoretinal B-cell lymphoma and uveitis might be characterized by distinct microRNA signatures. Quantification of ocular microRNA-155 might be helpful in the differential diagnosis of these 2 diseases. Published by Elsevier Inc. C1 [Tuo, Jingsheng; Shen, Defen; Chan, Chi-Chao] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Yang, Howard Hua] NCI, Off Director, Ctr Canc Res, NIH, Rockville, MD USA. RP Chan, CC (reprint author), NEI, NIH, 10 Ctr Dr,Bldg 10,Rm 10N103, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov OI Chan, Chi-Chao/0000-0001-9460-8049 FU National Eye Institute Intramural Research Program, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA FX ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and none were reported. The study was supported by the National Eye Institute Intramural Research Program, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA. Contributions of authors: design of the study (J.T., C.C.C.); conduct of the study (J.T., D.S.); collection of the data (J.T., D.S.); management of the data (J.T.); analysis of the data (H.H.Y. for statistics, J.T., C.C.C.); interpretation of the data (J.T., C.C.C.); preparation of the manuscript (J.T.); review of the manuscript (D.S., H.H.Y., C.C.C.); and approval of the manuscript (J.T., D.S., H.H.Y., C.C.C.). NR 37 TC 13 Z9 15 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD MAR PY 2014 VL 157 IS 3 BP 728 EP 734 DI 10.1016/j.ajo.2013.12.014 PG 7 WC Ophthalmology SC Ophthalmology GA AC2QX UT WOS:000332350100029 PM 24345320 ER PT J AU Cullinane, AR Yeager, C Dorward, H Carmona-Rivera, C Wu, HP Moss, J O'Brien, KJ Nathan, SD Meyer, KC Rosas, IO Helip-Wooley, A Huizing, M Gahl, WA Gochuico, BR AF Cullinane, Andrew R. Yeager, Caroline Dorward, Heidi Carmona-Rivera, Carmelo Wu, Hai Ping Moss, Joel O'Brien, Kevin J. Nathan, Steven D. Meyer, Keith C. Rosas, Ivan O. Helip-Wooley, Amanda Huizing, Marjan Gahl, William A. Gochuico, Bernadette R. TI Dysregulation of Galectin-3 Implications for Hermansky-Pudlak Syndrome Pulmonary Fibrosis SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE biogenesis of lysosome-related organelles complex; fibroblast; Hermansky-Pudlak syndrome; type 2 cell ID SYNDROME TYPE-2; INTERSTITIAL PNEUMONIA; MURINE MODEL; MUTATIONS; EXPRESSION; SECRETION; APOPTOSIS; CELLS; MACROPHAGES; SUBUNIT AB The etiology of Hermansky-Pudlak syndrome (HPS) pulmonary fibrosis (HPSPF), a progressive interstitial lung disease with high mortality, is unknown. Galectin-3 is a beta-galactoside-binding lectin with profibrotic effects. The objective of this study was to investigate the involvement of galectin-3 in HPSPF. Galectin-3 was measured by ELISA, immunohistochemistry, and immunoblotting in human specimens from subjects with HPS and control subjects. Mechanisms of galectin-3 accumulation were studied by quantitative RT-PCR, Northern blot analysis, membrane biotinylation assays, and rescue of HPS1-deficient cells by transfection. Bronchoalveolar lavage galectin-3 concentrations were significantly higher in HPSPF compared with idiopathic pulmonary fibrosis or that from normal volunteers, and correlated with disease severity. Galectin-3 immunostaining was increased in HPSPF compared with idiopathic pulmonary fibrosis or normal lung tissue. Fibroblasts from subjects with HPS subtypes associated with pulmonary fibrosis had increased galectin-3 protein expression compared with cells from nonfibrotic HPS subtypes. Galectin-3 protein accumulation was associated with reduced Galectin-3 mRNA, normal Mucin 1 levels, and up-regulated microRNA-322 in HPSPF cells. Membrane biotinylation assays showed reduced galectin-3 and normal Mucin 1 expression at the plasma membrane in HPSPF cells compared with control cells, which suggests that galectin-3 is mistrafficked in these cells. Reconstitution of HPS1 cDNA into HPS1-deficient cells normalized galectin-3 protein and mRNA levels, as well as corrected galectin-3 trafficking to the membrane. Intracellular galectin-3 levels are regulated by HPS1 protein. Abnormal accumulation of galectin-3 may contribute to the pathogenesis of HPSPF. C1 [Cullinane, Andrew R.; Yeager, Caroline; Dorward, Heidi; Carmona-Rivera, Carmelo; Helip-Wooley, Amanda; Huizing, Marjan; Gahl, William A.; Gochuico, Bernadette R.] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. [Yeager, Caroline] Howard Hughes Med Inst, Chevy Chase, MD USA. [Wu, Hai Ping; Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. [O'Brien, Kevin J.; Gahl, William A.] NHGRI, Off Clin Director, Bethesda, MD 20892 USA. [O'Brien, Kevin J.; Gahl, William A.] NIH, Off Rare Dis Res, Bethesda, MD 20892 USA. [Nathan, Steven D.] Inova Fairfax Hosp, Adv Lung Dis & Transplant Program, Falls Church, VA USA. [Meyer, Keith C.] Univ Wisconsin, Sch Med & Publ Hlth, Sect Allergy Pulm & Crit Care Med, Madison, WI USA. [Rosas, Ivan O.] Brigham & Womens Hosp, Div Pulm & Crit Care, Boston, MA 02115 USA. RP Gochuico, BR (reprint author), 10 Ctr Dr,MSC 1851, Bethesda, MD 20892 USA. EM gochuicb@mail.nih.gov FU Intramural Research Programs of the National Human Genome Research Institute; National Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 40 TC 12 Z9 12 U1 1 U2 5 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1044-1549 EI 1535-4989 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD MAR PY 2014 VL 50 IS 3 BP 605 EP 613 DI 10.1165/rcmb.2013-0025OC PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA AC4TJ UT WOS:000332513500013 PM 24134621 ER PT J AU Murthy, S Rizzi, P Mewton, N Strauss, DG Liu, CY Volpe, GJ Marchlinski, FE Spooner, P Berger, RD Kellman, P Lima, JAC Tereshchenko, LG AF Murthy, Sindhoora Rizzi, Patricia Mewton, Nathan Strauss, David G. Liu, Chia Y. Volpe, Gustavo Jardim Marchlinski, Francis E. Spooner, Peter Berger, Ronald D. Kellman, Peter Lima, Joao A. C. Tereshchenko, Larisa G. TI Number of P- Wave Fragmentations on P- SAECG Correlates with Infiltrated Atrial Fat SO ANNALS OF NONINVASIVE ELECTROCARDIOLOGY LA English DT Article DE atrial fibrillation; P-SAECG; cardiac magnetic resonance; infiltrated atrial fat ID EPICARDIAL ADIPOSE-TISSUE; SIGNAL-AVERAGED ECG; PERICARDIAL FAT; SINUS RHYTHM; FIBRILLATION; RISK; DURATION; HEART; MYOCARDIUM; PREDICTION AB BackgroundAlthough atrial fibrillation (AF) triggers are known, the underlying AF substrate is less well understood. The goal of our study was to explore correlations between electrophysiological and structural characteristics of atria in patients with paroxysmal AF and individuals at AF risk. MethodsPatients in sinus rhythm (N = 90; age 57 10 year; 55 men [63.2%]) with structural heart disease and paroxysmal AF (n = 12 [13%]), or with AF risk factors and LVEF > 35% (n = 78), underwent SAECG and cardiac magnetic resonance study. Interatrial and epicardial fat was analyzed with a Dark-blood DIR-prepared Fat-Water-separated sequence in the horizontal longitudinal axis. All local P-wave extrema were identified on SAECG leads during sinus rhythm. A P-wave fragmentation (P-f) was defined as an absolute difference between adjacent extrema which was above three standard deviations of noise, and was normalized by the duration of the P wave in the corresponding lead. ResultsThe P-f was greater on the filtered than on the unfiltered P-SAECG signal (13.1 +/- 3.8 vs. 3.4 +/- 1.2; P < 0.0001). P-f was the greatest on the Y lead (13.0 +/- 3.5 on Y lead vs. 12.1 +/- 3.4 on Z lead; P = 0.003. P-f on Z lead correlated with interatrial fat index (r = 0.544; P = 0.001). Epicardial fat significantly correlated with body mass index (BMI; r = 0.302; P = 0.015). After adjustment for BMI, left atrium (LA) size, epicardial fat, and interatrial septum width, interatrial fat independently associated with the P-f on Z lead (-coefficient 0.009 [95%CI 0.0003-0.019]; P = 0.043). ConclusionsInfiltrated atrial fat correlates with discontinuous conduction on posterior LA wall and represents AF early substrate. C1 [Murthy, Sindhoora] Johns Hopkins Univ, Whiting Sch Engn, Baltimore, MD USA. [Rizzi, Patricia; Mewton, Nathan; Liu, Chia Y.; Volpe, Gustavo Jardim; Spooner, Peter; Berger, Ronald D.; Lima, Joao A. C.; Tereshchenko, Larisa G.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Strauss, David G.] US FDA, Silver Spring, MD USA. [Marchlinski, Francis E.] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Kellman, Peter] NHLBI, NIH, Bethesda, MD 20892 USA. RP Tereshchenko, LG (reprint author), Carnegie 568,600 N Wolfe St, Baltimore, MD 21287 USA. EM lteresh1@jhmi.edu OI Marchlinski, Francis/0000-0001-7962-9423; Tereshchenko, Larisa/0000-0002-6976-1313 FU Cardiac Translational Research Implementation Program (C-TRIP); NIH/National Heart, Lung and Blood Institute [P20HL101397]; Leducq Foundation FX Financial support & relationships with industry: Study was partially supported by Cardiac Translational Research Implementation Program (C-TRIP) grant from NIH/National Heart, Lung and Blood Institute #P20HL101397 and the Leducq Foundation. NR 39 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1082-720X EI 1542-474X J9 ANN NONINVAS ELECTRO JI Ann. Noninvasive Electrocardiol. PD MAR PY 2014 VL 19 IS 2 BP 114 EP 121 DI 10.1111/anec.12084 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AC6DH UT WOS:000332611100002 PM 24620844 ER PT J AU Falzarano, D Groseth, A Hoenen, T AF Falzarano, Darryl Groseth, Allison Hoenen, Thomas TI Development. and application of reporter-expressing mononegaviruses: Current challenges and perspectives SO ANTIVIRAL RESEARCH LA English DT Review DE Reverse genetics; Luciferase; Reporter; Green fluorescent protein; In vivo imaging; Mononegaviruses; In vitro screening ID GREEN FLUORESCENT PROTEIN; VESICULAR STOMATITIS-VIRUS; CANINE-DISTEMPER VIRUS; DEPENDENT RNA-POLYMERASE; NEWCASTLE-DISEASE VIRUS; REVERSE GENETICS SYSTEM; LABELED RABIES-VIRUS; OPEN READING FRAME; MEASLES-VIRUS; FOREIGN GENE AB Reverse genetics allows the generation of recombinant viruses entirely from cDNA. One application of this technology is the creation of reporter-expressing viruses, which greatly increase the detail and ease with which these viruses can be studied. However, there are a number of challenges when working with reporter-expressing viruses. Both the reporter protein itself as well as the genetic manipulations within the viral genome required for expression of this reporter can result in altered biological properties of the recombinant virus, and lead to attenuation in Vitro and/or in vivo. Further, instability of reporter expression and purging of the genetic information encoding for the reporter from the viral genome can be an issue. Finally, a practical challenge for in vivo studies lies in the attenuation of light signals when traversing tissues. Novel expression strategies and the continued development of brighter, red and far-red shifted reporters and the increased use of bioluminescent reporters for in vivo applications promise to overcome some of these limitations in future. However, a "one size fits all" approach to the design of reporter-expressing viruses has thus far not been possible. Rather, a reporter suited to the intended application must be selected and an appropriate expression strategy and location for the reporter in the viral genome chosen. Still, attenuating effects of the reporter on viral fitness are difficult to predict and have to be carefully assessed with respect to the intended application. Despite these limitations the generation of suitable reporter-expressing viruses will become more common as technology and our understanding of the intricacies of viral gene expression and regulation improves, allowing deeper insight into virus biology both in living cells and in animals. Published by Elsevier B.V. C1 [Falzarano, Darryl; Groseth, Allison; Hoenen, Thomas] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. RP Hoenen, T (reprint author), 903 S 4th St, Hamilton, MT 59840 USA. EM thomas.hoenen@nih.gov OI Hoenen, Thomas/0000-0002-5829-6305 FU Intramural Research Program of the NIH, NIAID FX This work was supported by the Intramural Research Program of the NIH, NIAID. The authors are very grateful to Martin Ludlow and Paul Duprex (Boston University) for providing image material. NR 82 TC 7 Z9 9 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD MAR PY 2014 VL 103 BP 78 EP 87 DI 10.1016/j.antiviral.2014.01.003 PG 10 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA AC8YM UT WOS:000332821000010 PM 24462694 ER PT J AU Rusner, C Streller, B Stegmaier, C Trocchi, P Kuss, O McGlynn, KA Trabert, B Stang, A AF Rusner, Carsten Streller, Brigitte Stegmaier, Christa Trocchi, Pietro Kuss, Oliver McGlynn, Katherine A. Trabert, Britton Stang, Andreas TI Risk of second primary cancers after testicular cancer in East and West Germany: a focus on contralateral testicular cancers SO ASIAN JOURNAL OF ANDROLOGY LA English DT Article DE cancer registry; incidence; neoplasms; second primary; testicular neoplasms ID CELL-CANCER; INTRAEPITHELIAL NEOPLASIA; POOLED ANALYSIS; LEUKEMIA; TUMORS; REGISTRIES; SURVIVORS; MEN AB Testicular cancer survival rates improved dramatically after cisplatin-based therapy was introduced in the 1970s. However, chemotherapy and radiation therapy are potentially carcinogenic. The purpose of this study was to estimate the risk of developing second primary cancers including the risk associated with primary histologic type (seminoma and non-seminoma) among testicular cancer survivors in Germany. We identified 16 990 and 1401 cases of testicular cancer in population-based cancer registries of East Germany (1961-1989 and 1996-2008) and Saarland (a federal state in West Germany; 1970-2008), respectively. We estimated the risk of a second primary cancer using standardized incidence ratios (SIRs) with 95% confidence intervals (95% CIs). To determine trends, we plotted model-based estimated annual SIRs. In East Germany, a total of 301 second primary cancers of any location were observed between 1961 and 1989 (SIR: 1.9; 95% CI: 1.7-2.1), and 159 cancers (any location) were observed between 1996 and 2008 (SIR: 1.7; 95% CI: 1.4-2.0). The SIRs for contralateral testicular cancer were increased in the registries with a range from 6.0 in Saarland to 13.9 in East Germany. The SIR for seminoma, in particular, was higher in East Germany compared to the other registries. We observed constant trends in the model-based SIRs for contralateral testicular cancers. The majority of reported SIRs of other cancer sites including histology-specific risks showed low precisions of estimated effects, likely due to small sample sizes. Testicular cancer patients are at increased risk especially for cancers of the contralateral testis and should receive intensive follow-ups. C1 [Rusner, Carsten; Trocchi, Pietro; Stang, Andreas] Univ Halle Wittenberg, Fac Med, Inst Clin Epidemiol, D-06108 Halle, Saale, Germany. [Streller, Brigitte] Common Canc Registry Berlin, Berlin, Germany. [Stegmaier, Christa] Saarland Canc Registry, Saarbrucken, Germany. [Kuss, Oliver] Univ Halle Wittenberg, Fac Med, Inst Med Epidemiol Biostat & Informat, D-06108 Halle, Saale, Germany. [McGlynn, Katherine A.; Trabert, Britton] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Stang, Andreas] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Rusner, C (reprint author), Univ Halle Wittenberg, Fac Med, Inst Clin Epidemiol, D-06108 Halle, Saale, Germany. EM carsten.rusner@medizin.uni-halle.de RI Trabert, Britton/F-8051-2015; OI Kuss, Oliver/0000-0003-3301-5869 FU Deutsche Forschungsgemeinschaft (DFG) [RU 1659/1-1]; National Cancer Institute, NIH, DHHS FX This work was supported by grants of the Deutsche Forschungsgemeinschaft (DFG) (grant no. RU 1659/1-1). BT was supported by the intramural research program of the National Cancer Institute, NIH, DHHS. NR 25 TC 7 Z9 7 U1 0 U2 3 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 1008-682X EI 1745-7262 J9 ASIAN J ANDROL JI Asian J. Androl. PD MAR PY 2014 VL 16 IS 2 BP 285 EP 289 DI 10.4103/1008-682X.122069 PG 5 WC Andrology; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA AC7RP UT WOS:000332729700020 PM 24407180 ER PT J AU Tae, H Kim, DY McCormick, J Settlage, RE Garner, HR AF Tae, Hongseok Kim, Dong-Yun McCormick, John Settlage, Robert E. Garner, Harold R. TI Discretized Gaussian mixture for genotyping of microsatellite loci containing homopolymer runs SO BIOINFORMATICS LA English DT Article ID SEQUENCING DATA; REPEATS; GENOMES AB Motivation: Inferring lengths of inherited microsatellite alleles with single base pair resolution from short sequence reads is challenging due to several sources of noise caused by the repetitive nature of microsatellites and the technologies used to generate raw sequence data. Results: We have developed a program, GenoTan, using a discretized Gaussian mixture model combined with a rules-based approach to identify inherited variation of microsatellite loci from short sequence reads without paired-end information. It effectively distinguishes length variants from noise including insertion/deletion errors in homopolymer runs by addressing the bidirectional aspect of insertion and deletion errors in sequence reads. Here we first introduce a homopolymer decomposition method which estimates error bias toward insertion or deletion in homopolymer sequence runs. Combining these approaches, GenoTan was able to genotype 94.9% of microsatellite loci accurately from simulated data with 40x sequence coverage quickly while the other programs showed <90% correct calls for the same data and required 5 similar to 30x more computational time than GenoTan. It also showed the highest true-positive rate for real data using mixed sequence data of two Drosophila inbred lines, which was a novel validation approach for genotyping. C1 [Tae, Hongseok; McCormick, John; Settlage, Robert E.; Garner, Harold R.] Virginia Tech, Virginia Bioinformat Inst, Blacksburg, VA 24061 USA. [Kim, Dong-Yun] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Garner, HR (reprint author), Virginia Tech, Virginia Bioinformat Inst, Blacksburg, VA 24061 USA. EM garner@vbi.vt.edu FU Medical Informatics and Systems Division director's funds; National Human Genome Research Institute; 1000 Genomes Project Dataset Analysis Grant [U01 HG005719-01, U01 HG005719-02] FX The Medical Informatics and Systems Division director's funds; the National Human Genome Research Institute (of the National Institute of Health) [The 1000 Genomes Project Dataset Analysis Grant; grant numbers U01 HG005719-01, U01 HG005719-02]. NR 15 TC 4 Z9 4 U1 1 U2 2 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 MAR 1 PY 2014 VL 30 IS 5 BP 652 EP 659 DI 10.1093/bioinformatics/btt595 PG 8 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 AC1ML UT WOS:000332259300009 PM 24135263 ER PT J AU Holzinger, ER Dudek, SM Frase, AT Pendergrass, SA Ritchie, MD AF Holzinger, Emily R. Dudek, Scott M. Frase, Alex T. Pendergrass, Sarah A. Ritchie, Marylyn D. TI ATHENA: the analysis tool for heritable and environmental network associations SO BIOINFORMATICS LA English DT Article ID GRAMMATICAL EVOLUTION; GENOME; CYTOTOXICITY; DISCOVERY; EPISTASIS; LOCI AB Motivation: Advancements in high-throughput technology have allowed researchers to examine the genetic etiology of complex human traits in a robust fashion. Although genome-wide association studies have identified many novel variants associated with hundreds of traits, a large proportion of the estimated trait heritability remains unexplained. One hypothesis is that the commonly used statistical techniques and study designs are not robust to the complex etiology that may underlie these human traits. This etiology could include nonlinear gene x gene or gene x environment interactions. Additionally, other levels of biological regulation may play a large role in trait variability. Results: To address the need for computational tools that can explore enormous datasets to detect complex susceptibility models, we have developed a software package called the Analysis Tool for Heritable and Environmental Network Associations (ATHENA). ATHENA combines various variable filtering methods with machine learning techniques to analyze high-throughput categorical (i.e. single nucleotide polymorphisms) and quantitative (i.e. gene expression levels) predictor variables to generate multivariable models that predict either a categorical (i.e. disease status) or quantitative (i.e. cholesterol levels) outcomes. The goal of this article is to demonstrate the utility of ATHENA using simulated and biological datasets that consist of both single nucleotide polymorphisms and gene expression variables to identify complex prediction models. Importantly, this method is flexible and can be expanded to include other types of high-throughput data (i.e. RNA-seq data and biomarker measurements). C1 [Holzinger, Emily R.] NHGRI, NIH, Inherited Dis Res Branch, Baltimore, MD USA. [Dudek, Scott M.; Frase, Alex T.; Pendergrass, Sarah A.; Ritchie, Marylyn D.] Penn State Univ, Ctr Syst Genom, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. RP Ritchie, MD (reprint author), Penn State Univ, Ctr Syst Genom, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. EM marylyn.ritchie@psu.edu FU NIH grants from the National Library of Medicine [LM010040]; National Heart, Lung, and Blood via the Pharmacogenomics Research Network [HL065962]; PGRN Statistical Analysis Resource (P-STAR); NIGMS [5T32GM080178] FX Funding for this work was provided by NIH grants from the National Library of Medicine: LM010040, National Heart, Lung, and Blood via the Pharmacogenomics Research Network, specifically HL065962 which funds the PGRN Statistical Analysis Resource (P-STAR), and E.R.H. was funded by an NIGMS training grant 5T32GM080178. NR 31 TC 7 Z9 7 U1 1 U2 7 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 MAR 1 PY 2014 VL 30 IS 5 BP 698 EP 705 DI 10.1093/bioinformatics/btt572 PG 8 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 AC1ML UT WOS:000332259300015 PM 24149050 ER PT J AU Palmer, J Williams, K Inamoto, Y Chai, XY Martin, PJ Tomas, LS Cutler, C Weisdorf, D Kurland, BF Carpenter, PA Pidala, J Pavletic, SZ Wood, W Jacobsohn, D Arai, S Arora, M Jagasia, M Vogelsang, GB Lee, SJ AF Palmer, Jeanne Williams, Kirsten Inamoto, Yoshihiro Chai, Xiaoyu Martin, Paul J. Tomas, Linus Santo Cutler, Corey Weisdorf, Daniel Kurland, Brenda F. Carpenter, Paul A. Pidala, Joseph Pavletic, Steven Z. Wood, William Jacobsohn, David Arai, Sally Arora, Mukta Jagasia, Madan Vogelsang, Georgia B. Lee, Stephanie J. TI Pulmonary Symptoms Measured by the National Institutes of Health Lung Score Predict Overall Survival, Nonrelapse Mortality, and Patient-Reported Outcomes In Chronic Graft-Versus-Host Disease SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic graft-versus-host disease; Bronchiolitis obliterans syndrome ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; BRONCHIOLITIS OBLITERANS SYNDROME; AIR-FLOW OBSTRUCTION; LONG-TERM SURVIVORS; CONCORDANCE CORRELATION-COEFFICIENT; TOTAL-BODY IRRADIATION; RISK-FACTORS; CHRONIC GVHD; COMPLICATIONS AB The 2005 National Institutes of Health (NIH) Consensus Conference recommended assessment of lung function in patients with chronic graft-versus-host disease (GVHD) by both pulmonary function tests (PFTs) and assessment of pulmonary symptoms. We tested whether pulmonary measures were associated with nonrelapse mortality (NRM), overall survival (OS), and patient-reported outcomes (PRO). Clinician and patient-reported data were collected serially in a prospective, multicenter, observational study. Available PFT data were abstracted. Cox regression models were fit for outcomes using a time-varying covariate model for lung function measures and adjusting for patient and transplantation characteristics and nonlung chronic GVHD severity. A total of 1591 visits (496 patients) were used in this analysis. The NIH symptom-based lung score was associated with NRM (P = .02), OS (P = .02), patient-reported symptoms (P < .001) and functional status (P < .001). Worsening of NIH symptom-based lung score over time was associated with higher NRM and lower survival. All other measures were not associated with OS or NRM; although, some were associated with patient-reported lung symptoms. In conclusion, the NIH symptom-based lung symptom score of 0 to 3 is associated with NRM, OS, and PRO measures in patients with chronic GVHD. Worsening of the NIH symptom-based lung score was associated with increased mortality. (C) 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved. C1 [Palmer, Jeanne] Med Coll Wisconsin, Div Hematol Oncol, Milwaukee, WI 53226 USA. [Williams, Kirsten; Jacobsohn, David] Ctr Canc & Blood Disorders, Childrens Natl Med Ctr, Div Blood & Marrow Transplantat, Washington, DC USA. [Inamoto, Yoshihiro; Chai, Xiaoyu; Martin, Paul J.; Carpenter, Paul A.; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Tomas, Linus Santo] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Cutler, Corey] Dana Farber Canc Inst, Boston, MA 02115 USA. [Weisdorf, Daniel; Arora, Mukta] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN USA. [Kurland, Brenda F.] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. [Pidala, Joseph] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Pavletic, Steven Z.] NCI, NIH, Bethesda, MD 20892 USA. [Wood, William] Univ N Carolina, Linenberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Arai, Sally] Stanford Univ Med Ctr, Div Blood & Marrow Transplantat, Stanford, CA USA. [Jagasia, Madan] Vanderbilt Univ Sch Med, Hematol & Stem Cell Transplant Program, Nashville, TN USA. [Vogelsang, Georgia B.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. RP Palmer, J (reprint author), Blood & Marrow Transplant Program, 5777 East Mayo Blvd, Phoenix, AZ 85054 USA. EM palmer.jeanne@mayo.edu OI Wood, William/0000-0001-7439-2543; Kurland, Brenda/0000-0002-5669-0595 FU National Institutes of Health (NIH) [CA118953, CA163438]; NIH Office of Rare Diseases Research at the National Center for Advancing Translational Science; National Cancer Institute; Fred Hutchinson Cancer Research Center FX This work was supported by grants CA118953 and CA163438 from the National Institutes of Health (NIH). The Chronic GVHD Consortium (U54 CA163438) is a part of the NIH Rare Diseases Clinical Research Network, supported through collaboration between the NIH Office of Rare Diseases Research at the National Center for Advancing Translational Science, the National Cancer Institute, and the Fred Hutchinson Cancer Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 35 TC 22 Z9 22 U1 0 U2 2 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 MAR PY 2014 VL 20 IS 3 BP 337 EP 344 DI 10.1016/j.bbmt.2013.11.025 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AC8WV UT WOS:000332816700008 PM 24315845 ER PT J AU Bevans, MF Mitchell, SA Barrett, JA Bishop, MR Childs, R Fowler, D Krumlauf, M Prince, P Shelburne, N Wehrlen, L Yang, L AF Bevans, Margaret F. Mitchell, Sandra A. Barrett, John A. Bishop, Michael R. Childs, Richard Fowler, Daniel Krumlauf, Michael Prince, Patricia Shelburne, Nonniekaye Wehrlen, Leslie Yang, Li TI Symptom Distress Predicts Long-Term Health and Well-Being in Allogeneic Stem Cell Transplantation Survivors SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Allogeneic hematopoietic stem cell transplantation; Health-related quality of life; Symptom experience; Fatigue; Functional status ID QUALITY-OF-LIFE; VERSUS-HOST-DISEASE; BENIGN PROSTATIC HYPERPLASIA; CUBAN-AMERICAN POPULATION; OLDER MEXICAN-AMERICANS; FUNCTIONAL ASSESSMENT; SPANISH VERSION; RESPONSE SHIFT; MARROW TRANSPLANTATION; CHRONIC LEUKEMIA AB The number of survivors after allogeneic hematopoietic stem cell transplantation (HSCT) continues to increase, yet their survivorship experience has not been fully characterized. This study examines the health status and health-related quality of life (HRQL) of HSCT survivors. The aims of the study were to: (1) explore the baseline and change over time in these health outcomes, and (2) characterize subgroups experiencing adverse outcomes. In this longitudinal study, adults who survived >3 years from date of allogeneic HSCT completed a series of patient-reported outcome measures annually, including measures of health status, HRQL, and symptoms. Data were analyzed using hierarchical linear modeling. Subjects (N = 171) were on average 44 (+/- 13.5) years of age and primarily male (62.6%); 40% were Hispanic. Mean scores for physical and mental health and HRQL were preserved relative to population norms. Hierarchical linear modeling revealed no significant change in the mean trajectories of these outcomes, although significant between-individual variability was observed. When controlling for demographic and clinical factors, physical symptom distress negatively affected all outcomes. The impact of symptom distress on physical health varied based on time since HSCT; impairment in physical health was greatest in survivors experiencing high symptom distress and who were within the first decade post transplantation. Extended treatment with systemic immunosuppressive therapy also predicted inferior physical health. These findings suggest that patient-centered outcomes are preserved relative to normative values and are generally stable after allogeneic HSCT, although survivors with persistent symptoms and those receiving systemic immunosuppression experience impairments in health status and HRQL. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation. C1 [Bevans, Margaret F.; Krumlauf, Michael; Prince, Patricia; Wehrlen, Leslie; Yang, Li] Natl Inst Hlth Clin Ctr, Dept Nursing, Bethesda, MD 20892 USA. [Mitchell, Sandra A.; Shelburne, Nonniekaye] NCI, Appl Res Program, Outcomes Res Branch, NIH, Rockville, MD USA. [Mitchell, Sandra A.; Fowler, Daniel] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Barrett, John A.; Childs, Richard] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Bishop, Michael R.] Univ Chicago, Sect Hematol Oncol, Chicago, IL 60637 USA. [Prince, Patricia] Natl Inst Hlth Clin Ctr, Dept Social Work, Bethesda, MD 20892 USA. [Shelburne, Nonniekaye] NCI, Div Canc Control & Populat Sci, NIH, Rockville, MD USA. RP Bevans, MF (reprint author), Natl Inst Hlth Clin Ctr, 10 Ctr Dr,Room 2B13,MSC 1151, Bethesda, MD 20892 USA. EM mbevans@cc.nih.gov FU NIH Clinical Center Intramural Research Program FX Funding for this study was provided by the NIH Clinical Center Intramural Research Program. NR 56 TC 7 Z9 7 U1 4 U2 8 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 MAR PY 2014 VL 20 IS 3 BP 387 EP 395 DI 10.1016/j.bbmt.2013.12.001 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AC8WV UT WOS:000332816700015 PM 24355521 ER PT J AU Jain, NA Chen, MY Shanbhag, S Lu, K Pophali, PA Ito, S Koklanaris, E Hourigan, CS Barrett, AJ Battiwalla, M AF Jain, N. A. Chen, M. Y. Shanbhag, S. Lu, K. Pophali, P. A. Ito, S. Koklanaris, E. Hourigan, C. S. Barrett, A. J. Battiwalla, M. TI Contrast enhanced cardiac CT reveals coronary artery disease in 45% of asymptomatic allo-SCT long-term survivors SO BONE MARROW TRANSPLANTATION LA English DT Letter ID HEMATOPOIETIC-CELL TRANSPLANTATION; EVENTS C1 [Jain, N. A.; Lu, K.; Pophali, P. A.; Ito, S.; Koklanaris, E.; Hourigan, C. S.; Barrett, A. J.; Battiwalla, M.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Chen, M. Y.; Shanbhag, S.] NHLBI, Cardiopulm Branch, NIH, Bethesda, MD 20892 USA. RP Jain, NA (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM minoo.battiwalla@nih.gov RI Pophali, Priyanka/P-8646-2016; Hourigan, Christopher/S-2476-2016 OI Hourigan, Christopher/0000-0002-6189-8067 FU Intramural NIH HHS [Z99 HL999999, ZIA HL006105-03] NR 10 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2014 VL 49 IS 3 BP 451 EP 452 DI 10.1038/bmt.2013.182 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA AC6MQ UT WOS:000332638100023 PM 24241580 ER PT J AU Greene, J Lavi, O Gottesman, MM Levy, D AF Greene, James Lavi, Orit Gottesman, Michael M. Levy, Doron TI The Impact of Cell Density and Mutations in a Model of Multidrug Resistance in Solid Tumors SO BULLETIN OF MATHEMATICAL BIOLOGY LA English DT Article DE Multidrug resistance; Chemotherapy; Mutation; Heterogeneity; Integro-differential equations ID DRUG-RESISTANCE; MATHEMATICAL-MODEL; CANCER-CHEMOTHERAPY; INTRATUMORAL HETEROGENEITY; GENE AMPLIFICATION; ADAPTIVE DYNAMICS; APOPTOSIS; GROWTH; TUMORIGENICITY; ARCHITECTURE AB In this paper we develop a mathematical framework for describing multidrug resistance in cancer. To reflect the complexity of the underlying interplay between cancer cells and the therapeutic agent, we assume that the resistance level is a continuous parameter. Our model is written as a system of integro-differential equations that are parameterized by the resistance level. This model incorporates the cell density and mutation dependence. Analysis and simulations of the model demonstrate how the dynamics evolves to a selection of one or more traits corresponding to different levels of resistance. The emerging limit distribution with nonzero variance is the desirable modeling outcome as it represents tumor heterogeneity. C1 [Greene, James; Levy, Doron] Univ Maryland, Dept Math, College Pk, MD 20742 USA. [Greene, James; Levy, Doron] Univ Maryland, Ctr Sci Computat & Math Modeling CSCAMM, College Pk, MD 20742 USA. [Lavi, Orit; Gottesman, Michael M.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Levy, D (reprint author), Univ Maryland, Dept Math, College Pk, MD 20742 USA. EM dlevy@math.umd.edu FU National Institutes of Health, Center for Cancer Research, National Cancer Institute; UMD-NCI Partnership for Cancer Technology; NSF/NIGMS [DMS-0758374]; National Cancer Institute [R01CA130817] FX We would like to thank George Leiman for editorial assistance. The work was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute and was supported in part by a seed grant from the UMD-NCI Partnership for Cancer Technology. The work of D.L. was supported in part by the joint NSF/NIGMS program under Grant Number DMS-0758374 and by Grant Number R01CA130817 from the National Cancer Institute. NR 54 TC 4 Z9 4 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0092-8240 EI 1522-9602 J9 B MATH BIOL JI Bull. Math. Biol. PD MAR PY 2014 VL 76 IS 3 BP 627 EP 653 DI 10.1007/s11538-014-9936-8 PG 27 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA AD3GD UT WOS:000333125400005 PM 24553772 ER PT J AU Grodzinski, P Farrell, D AF Grodzinski, Piotr Farrell, Dorothy TI Future Opportunities in Cancer Nanotechnology-NCI Strategic Workshop Report SO CANCER RESEARCH LA English DT Editorial Material ID NANOPARTICLES; DELIVERY AB There has been significant progress in utilizing nanotechnology in several areas of cancer care, including in vitro diagnostics, imaging, and therapy. The National Cancer Institute, which currently supports an array of research activities in cancer nanotechnology, convened a strategic workshop to explore the most promising directions and areas for future resource investment. The major discussion points as well as the opportunities identified are presented herein. (C) 2014 AACR. C1 [Grodzinski, Piotr; Farrell, Dorothy] NCI, Off Canc Nanotechnol Res, Bethesda, MD 20892 USA. RP Grodzinski, P (reprint author), NCI, 31 Ctr Dr,MSC 2580,Bldg 31,Room 10A52, Bethesda, MD 20892 USA. EM grodzinp@mail.nih.gov NR 10 TC 10 Z9 10 U1 0 U2 13 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 MAR 1 PY 2014 VL 74 IS 5 BP 1307 EP 1310 DI 10.1158/0008-5472.CAN-13-2787 PG 4 WC Oncology SC Oncology GA AC4FG UT WOS:000332475900004 PM 24413533 ER PT J AU Peng, HZ Talebzadeh-Farrooji, M Osborne, MJ Prokop, JW McDonald, PC Karar, J Hou, ZY He, M Kebebew, E Orntoft, T Herlyn, M Caton, AJ Fredericks, W Malkowicz, B Paterno, CS Carolin, AS Speicher, DW Skordalakes, E Huang, QH Dedhar, S Borden, KLB Rauscher, FJ AF Peng, Hongzhuang Talebzadeh-Farrooji, Mehdi Osborne, Michael J. Prokop, Jeremy W. McDonald, Paul C. Karar, Jayashree Hou, Zhaoyuan He, Mei Kebebew, Electron Orntoft, Torben Herlyn, Meenhard Caton, Andrew J. Fredericks, William Malkowicz, Bruce Paterno, Christopher S. Carolin, Alexandra S. Speicher, David W. Skordalakes, Emmanuel Huang, Qihong Dedhar, Shoukat Borden, Katherine L. B. Rauscher, Frank J., III TI LIMD2 Is a Small LIM-Only Protein Overexpressed in Metastatic Lesions That Regulates Cell Motility and Tumor Progression by Directly Binding to and Activating the Integrin-Linked Kinase SO CANCER RESEARCH LA English DT Article ID ANKYRIN REPEAT DOMAIN; TRANSCRIPTIONAL REPRESSION; STRUCTURAL BASIS; BACK AGAIN; PINCH; ILK; ADHESION; CANCER; DIFFERENTIATION; COMPLEX AB Proteins that communicate signals from the cytoskeleton to the nucleus are prime targets for effectors of metastasis as they often transduce signals regulating adhesion, motility, and invasiveness. LIM domain proteins shuttle between the cytoplasm and the nucleus, and bind to partners in both compartments, often coupling changes in gene expression to extracellular cues. In this work, we characterize LIMD2, a mechanistically undefined LIM-only protein originally found to be overexpressed in metastatic lesions but absent in the matched primary tumor. LIMD2 levels in fresh and archival tumors positively correlate with cell motility, metastatic potential, and grade, including bladder, melanoma, breast, and thyroid tumors. LIMD2 directly contributes to these cellular phenotypes as shown by overexpression, knockdown, and reconstitution experiments in cell culture models. The solution structure of LIMD2 that was determined using nuclear magnetic resonance revealed a classic LIM-domain structure that was highly related to LIM1 of PINCH1, a core component of the integrin-linked kinase-parvin-pinch complex. Structural and biochemical analyses revealed that LIMD2 bound directly to the kinase domain of integrin-linked kinase (ILK) near the active site and strongly activated ILK kinase activity. Cells that were null for ILK failed to respond to the induction of invasion by LIMD2. This strongly suggests that LIMD2 potentiates its biologic effects through direct interactions with ILK, a signal transduction pathway firmly linked to cell motility and invasion. In summary, LIMD2 is a new component of the signal transduction cascade that links integrin-mediated signaling to cell motility/metastatic behavior and may be a promising target for controlling tumor spread. (c) 2014 AACR. C1 [Peng, Hongzhuang; Karar, Jayashree; Hou, Zhaoyuan; Herlyn, Meenhard; Caton, Andrew J.; Paterno, Christopher S.; Carolin, Alexandra S.; Speicher, David W.; Skordalakes, Emmanuel; Huang, Qihong; Rauscher, Frank J., III] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. [Fredericks, William; Malkowicz, Bruce] Univ Penn, Dept Surg, Philadelphia, PA 19104 USA. [Fredericks, William; Malkowicz, Bruce] Vet Affairs Med Ctr, Philadelphia, PA USA. [He, Mei; Kebebew, Electron] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Prokop, Jeremy W.] Univ Akron, Akron, OH 44325 USA. [Orntoft, Torben] Aarhus Univ Hosp, Skejby, Denmark. [Talebzadeh-Farrooji, Mehdi; Osborne, Michael J.; Borden, Katherine L. B.] Univ Montreal, Inst Res Immunol & Canc, Dept Pathol & Cell Biol, Montreal, PQ H3C 3J7, Canada. [McDonald, Paul C.; Dedhar, Shoukat] British Columbia Canc Res Ctr, Dept Integrat Oncol, Vancouver, BC V5Z 1L3, Canada. RP Borden, KLB (reprint author), Univ Montreal, Inst Res Immunol & Canc, Dept Pathol & Cell Biol, Montreal, PQ H3C 3J7, Canada. EM katherine.borden@umontreal.ca; rauscher@wistar.org OI Skordalakes, Emmanuel/0000-0002-7600-2833 FU NIH [CA129833, CA010815, CA163761]; DOD-BCRP [W81XWH-11-1-0494] FX Work in the Rauscher laboratory is supported by NIH grants CA129833, CA010815, CA163761, and DOD-BCRP W81XWH-11-1-0494, The Samuel Waxman Cancer Research Foundation, Susan G. Komen for the Cure, and The Noreen O'Neill Foundation for Melanoma Research. K. L. B. Borden holds a Canada Research Chair and is supported by NIH grants NIH RO1-80728 and NIH 98571. NR 40 TC 7 Z9 10 U1 1 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 MAR 1 PY 2014 VL 74 IS 5 BP 1390 EP 1403 DI 10.1158/0008-5472.CAN-13-1275 PG 14 WC Oncology SC Oncology GA AC4FG UT WOS:000332475900013 PM 24590809 ER PT J AU Mitchell, SJ Martin-Montalvo, A Mercken, EM Palacios, HH Ward, TM Abulwerdi, G Minor, RK Vlasuk, GP Ellis, JL Sinclair, DA Dawson, J Allison, DB Zhang, YQ Becker, KG Bernier, M de Cabo, R AF Mitchell, Sarah J. Martin-Montalvo, Alejandro Mercken, Evi M. Palacios, Hector H. Ward, Theresa M. Abulwerdi, Gelareh Minor, Robin K. Vlasuk, George P. Ellis, James L. Sinclair, David A. Dawson, John Allison, David B. Zhang, Yongqing Becker, Kevin G. Bernier, Michel de Cabo, Rafael TI The SIRT1 Activator SRT1720 Extends Lifespan and Improves Health of Mice Fed a Standard Diet SO CELL REPORTS LA English DT Article ID GENETICALLY HETEROGENEOUS MICE; INSULIN-RESISTANCE; CIRCADIAN-RHYTHMS; RESVERATROL; LONGEVITY; PROTECTS; INHIBITION; EXPRESSION; MECHANISM; SURVIVAL AB The prevention or delay of the onset of age-related diseases prolongs survival and improves quality of life while reducing the burden on the health care system. Activation of sirtuin 1 (SIRT1), an NAD(+)-dependent deacetylase, improves metabolism and confers protection against physiological and cognitive disturbances in old age. SRT1720 is a specific SIRT1 activator that has health and lifespan benefits in adult mice fed a high-fat diet. We found extension in lifespan, delayed onset of age-related metabolic diseases, and improved general health in mice fed a standard diet after SRT1720 supplementation. Inhibition of proinflammatory gene expression in both liver and muscle of SRT1720-treated animals was noted. SRT1720 lowered the phosphorylation of NF-kappa B pathway regulators in vitro only when SIRT1 was functionally present. Combined with our previous work, the current study further supports the beneficial effects of SRT1720 on health across the lifespan in mice. C1 [Mitchell, Sarah J.; Martin-Montalvo, Alejandro; Mercken, Evi M.; Palacios, Hector H.; Ward, Theresa M.; Abulwerdi, Gelareh; Minor, Robin K.; Bernier, Michel; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Mitchell, Sarah J.] Royal N Shore Hosp, Kolling Inst Med Res, St Leonards, NSW 2065, Australia. [Mitchell, Sarah J.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Vlasuk, George P.; Ellis, James L.] Sirtris, Cambridge, MA 02139 USA. [Sinclair, David A.] Harvard Univ, Sch Med, Glenn Labs Biol Mechanisms Aging, Boston, MA 02115 USA. [Dawson, John; Allison, David B.] Univ Alabama Birmingham, Sch Publ Hlth, Birmingham, AL 35294 USA. [Zhang, Yongqing; Becker, Kevin G.] NIA, Gene Express & Genom Unit, NIH, Baltimore, MD 21224 USA. RP de Cabo, R (reprint author), NIA, Translat Gerontol Branch, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM decabora@grc.nia.nih.gov RI de Cabo, Rafael/J-5230-2016; Martin-Montalvo, Alejandro/C-2031-2017; OI de Cabo, Rafael/0000-0002-3354-2442; Martin-Montalvo, Alejandro/0000-0002-3886-5355; Bernier, Michel/0000-0002-5948-368X; Sinclair, David/0000-0002-9936-436X; Allison, David/0000-0003-3566-9399; , rafael/0000-0003-2830-5693 FU Intramural Research Program of the NIA/NIH; National Medical Health and Research Council of Australia [2010-01671]; University of Alabama at Birmingham Statistical Genetics Postdoctoral Training Program Grant [T32HL072757] FX This research was conducted under a Cooperative Research and Development Agreement (CRADA) between Sirtris, a GSK Company, and the National Institute on Aging, National Institutes of Health (NIA/NIH). Funding was provided by the Intramural Research Program of the NIA/NIH. We are grateful to Dawn Nines, Justine Lucas, and Dawn Phillips-Boyer for their excellent animal care. We thank Dr. Elin Lehrmann for microarray assistance. We thank Drs. Hua-Jun He (National Institute of Standards and Technology, Gaithersburg, MD), Yaping Zong (Full Moon Biosystems, Inc., Sunnyvale, CA), and Xiong Li (Department of Mathematics and Computer Science, Emory University, Atlanta, GA) for their contribution in carrying out the phosphoantibody array experiment and data analysis. We thank Dr. Norm Wolf for the assessment of cataracts in the mice and Olga Carlson for technical assistance with the multiplex assay. S.J.M. was supported by a National Medical Health and Research Council of Australia CJ Martin Early Career Fellowship (RGMS ID 2010-01671). J.D. is supported by a University of Alabama at Birmingham Statistical Genetics Postdoctoral Training Program Grant (T32HL072757). D. A. S. consults for and G. P. V. and J.L.E. are employed by Sirtris, a GSK Company that has a commercial interest in developing SIRT1 activators. NR 43 TC 83 Z9 85 U1 2 U2 29 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 MAR PY 2014 VL 6 IS 5 BP 836 EP 843 DI 10.1016/j.celrep.2014.01.031 PG 8 WC Cell Biology SC Cell Biology GA AD2BL UT WOS:000333037800008 PM 24582957 ER PT J AU Wang, IX Core, LJ Kwak, H Brady, L Bruzel, A McDaniel, L Richards, AL Wu, M Grunseich, C Lis, JT Cheung, VG AF Wang, Isabel X. Core, Leighton J. Kwak, Hojoong Brady, Lauren Bruzel, Alan McDaniel, Lee Richards, Allison L. Wu, Ming Grunseich, Christopher Lis, John T. Cheung, Vivian G. TI RNA-DNA Differences Are Generated in Human Cells within Seconds after RNA Exits Polymerase II SO CELL REPORTS LA English DT Article ID R-LOOP FORMATION; MESSENGER-RNA; ESCHERICHIA-COLI; ADENOSINE DEAMINASES; HUMAN TRANSCRIPTOME; TOPOISOMERASE-I; PARALLEL DNA; PROMOTERS; GENE; DROSOPHILA AB RNA sequences are expected to be identical to their corresponding DNA sequences. Here, we found all 12 types of RNA-DNA sequence differences (RDDs) in nascent RNA. Our results show that RDDs begin to occur in RNA chains similar to 55 nt from the RNA polymerase II (Pol II) active site. These RDDs occur so soon after transcription that they are incompatible with known deaminase-mediated RNA-editing mechanisms. Moreover, the 55 nt delay in appearance indicates that they do not arise during RNA synthesis by Pol II or as a direct consequence of modified base incorporation. Preliminary data suggest that RDD and R-loop formations may be coupled. These findings identify sequence substitution as an early step in cotranscriptional RNA processing. C1 [Wang, Isabel X.; Bruzel, Alan; Cheung, Vivian G.] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. [Core, Leighton J.; Kwak, Hojoong; Lis, John T.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. [Brady, Lauren] Univ Penn, Cell & Mol Biol Grad Program, Philadelphia, PA 19104 USA. [Kwak, Hojoong; Bruzel, Alan; Wu, Ming; Cheung, Vivian G.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [McDaniel, Lee] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Richards, Allison L.] Univ Michigan, Human Genet Grad Program, Ann Arbor, MI 48109 USA. [Grunseich, Christopher] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Cheung, Vivian G.] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Cheung, Vivian G.] Univ Michigan, Dept Genet, Ann Arbor, MI 48109 USA. RP Lis, JT (reprint author), Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. EM johnlis@cornell.edu; vgcheung@umich.edu RI Wu, Ming/K-4074-2014 FU National Institutes of Health [MH087384, ES015733, GM25232]; Howard Hughes Medical Institute FX We thank Dr. Nancy Zhang for discussions about estimating sequencing errors, Jonathan Toung for analysis of the sequencing data, and Zhengwei Zhu for data analysis. We thank Dr. Kenneth Fischbeck for discussion about juvenile ALS and patient samples. Part of this work was carried out at the University of Pennsylvania prior to the Cheung lab's move to the University of Michigan. This work was supported by grants from the National Institutes of Health (MH087384 and ES015733 to V. G. C., and GM25232 to J.T.L.) and funds from the Howard Hughes Medical Institute (to V.G.C.). NR 56 TC 18 Z9 18 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD MAR PY 2014 VL 6 IS 5 BP 906 EP 915 DI 10.1016/j.celrep.2014.01.037 PG 10 WC Cell Biology SC Cell Biology GA AD2BL UT WOS:000333037800014 PM 24561252 ER PT J AU Hendricks, C Lansford, JE Deater-Deckard, K Bornstein, MH AF Hendricks, Charlene Lansford, Jennifer E. Deater-Deckard, Kirby Bornstein, Marc H. TI Associations Between Child Disabilities and Caregiver Discipline and Violence in Low-and Middle-Income Countries SO CHILD DEVELOPMENT LA English DT Article ID PHYSICAL DISCIPLINE; CORPORAL PUNISHMENT; DISABLED-CHILDREN; MATERNAL STRESS; 10 QUESTIONS; ABUSE; PARENT; MALTREATMENT; ADJUSTMENT; ACCEPTANCE AB Using nationally representative samples of 45,964 two- to nine-year-old children and their primary caregivers in 17 developing countries, this study examined the relations between children's cognitive, language, sensory, and motor disabilities and caregivers' use of discipline and violence. Primary caregivers reported on their child's disabilities and whether they or anyone in their household had used nonviolent discipline, psychological aggression, and physical violence toward the target child and believed that using corporal punishment is necessary. Logistic regression analyses supported the hypothesis that children with disabilities are treated more harshly than children without disabilities. The findings suggest that policies and interventions are needed to work toward the United Nations' goals of ensuring that children with disabilities are protected from abuse and violence. C1 [Hendricks, Charlene; Bornstein, Marc H.] NIH, Bethesda, MD USA. [Lansford, Jennifer E.] Duke Univ, Durham, NC 27706 USA. [Deater-Deckard, Kirby] Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. RP Hendricks, C (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Suite 8030 6705,Rockledge Dr, Bethesda, MD 20892 USA. EM marc_h_bornstein@nih.gov FU Intramural NIH HHS [ZIA HD001119-26] NR 75 TC 7 Z9 7 U1 3 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-3920 EI 1467-8624 J9 CHILD DEV JI Child Dev. PD MAR PY 2014 VL 85 IS 2 BP 513 EP 531 DI 10.1111/cdev.12132 PG 19 WC Psychology, Educational; Psychology, Developmental SC Psychology GA AC9IM UT WOS:000332847900012 PM 23895329 ER PT J AU Wei, BR Simpson, RM AF Wei, Bih-Rong Simpson, R. Mark TI Digital pathology and image analysis augment biospecimen annotation and biobank quality assurance harmonization SO CLINICAL BIOCHEMISTRY LA English DT Article DE Biological specimen bank; Standards; Biomarkers; Isolation and purification; Morphometry; Quantitative pathology; Pattern recognition image analysis; Computer-assisted diagnosis ID MAST-CELL TUMORS; HUMAN TISSUES; CANCER; EXPERIENCE; SAMPLES; BLOOD; PERSPECTIVE; BIOMARKERS; INTEGRITY; BANKING AB Standardization of biorepository best practices will enhance the quality of translational biomedical research utilizing patient-derived biobank specimens. Harmonization of pathology quality assurance procedures for biobank accessions has lagged behind other avenues of biospecimen research and biobank development. Comprehension of the cellular content of biorepository specimens is important for discovery of tissue-specific clinically relevant biomarkers for diagnosis and treatment. While rapidly emerging technologies in molecular analyses and data mining create focus on appropriate measures for minimizing pre-analytic artifact-inducing variables, less attention gets paid to annotating the constituent makeup of biospecimens for more effective specimen selection by biobank clients. Both pre-analytic tissue processing and specimen composition influence acquisition of relevant macromolecules for downstream assays. Pathologist review of biorepository submissions, particularly tissues as part of quality assurance procedures, helps to ensure that the intended target cells are present and in sufficient quantity in accessioned specimens. This manual procedure can be tedious and subjective. Incorporating digital pathology into biobank quality assurance procedures, using automated pattern recognition morphometric image analysis to quantify tissue feature areas in digital whole slide images of tissue sections, can minimize variability and subjectivity associated with routine pathologic evaluations in biorepositories. Whole-slide images and pathologist-reviewed morphometric analyses can be provided to researchers to guide specimen selection. Harmonization of pathology quality assurance methods that minimize subjectivity and improve reproducibility among collections would facilitate research-relevant specimen selection by investigators and could facilitate information sharing in an integrated network approach to biobanking. Published by Elsevier Inc. on behalf of The Canadian Society of Clinical Chemists. C1 [Wei, Bih-Rong; Simpson, R. Mark] NCI, Ctr Canc Res, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Simpson, RM (reprint author), NCI, Ctr Canc Res, Lab Canc Biol & Genet, NIH Bldg 37,37 Convent Dr, Bethesda, MD 20892 USA. EM ms43b@nih.gov FU Intramural Research Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; Canine Comparative Oncology and Genomics Consortium, Inc. (CCOGC), Rockville, MD FX This research was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Additional support was provided by the Canine Comparative Oncology and Genomics Consortium, Inc. (CCOGC), Rockville, MD (www.ccogc.net). The authors appreciate the scholarly contributions of Jennifer Dwyer, Shelley Hoover and Josh Webster. NR 47 TC 5 Z9 5 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0009-9120 EI 1873-2933 J9 CLIN BIOCHEM JI Clin. Biochem. PD MAR PY 2014 VL 47 IS 4-5 BP 274 EP 279 DI 10.1016/j.clinbiochem.2013.12.008 PG 6 WC Medical Laboratory Technology SC Medical Laboratory Technology GA AD2IT UT WOS:000333058900007 PM 24362266 ER PT J AU Doumatey, AP Zhou, J Adeyemo, A Rotimi, C AF Doumatey, Ayo P. Zhou, Jie Adeyemo, Adebowale Rotimi, Charles TI High sensitivity C-reactive protein (Hs-CRP) remains highly stable in long-term archived human serum SO CLINICAL BIOCHEMISTRY LA English DT Article DE C-reactive protein; Archived samples; Long-term storage; Stability; Biomedical research ID PLASMA; COHORT; RISK AB Background: The stability of biomarkers in stored biomedical samples is crucial, especially when storage is for extended periods of time. High-sensitivity CRP (Hs-CRP) is a biomarker of low grade inflammation that is extensively used to identify and study cardiovascular and/or inflammatory processes in clinical care and large epidemiologic studies. Therefore, assessing Hs-CRP stability in archived samples at a given temperature is important to ensure precision of measurements over time and the validity of studies using archived samples. Methods: We evaluated the stability of Hs-CRP in 30 randomly selected human serum samples by measuring Hs-CRP concentrations in freshly collected sample [Hs-CRP (0)] and in the same set of samples after 7-11 years of storage at - 80 degrees C [Hs-CRP (LT)]. Results: Hs-CRP did not significantly change up to 11 years of storage at - 80 degrees C as shown by a negligible median difference between Hs-CRP (0) and Hs-CRP (LT), delta((Hs-CRP) ((0)-Hs-CRP) ((LT))) = -0.01, p = 0.45. There was a good concordance and agreement between Hs-CRP (0) and Hs-CRP (LT) as measured respectively by Lin's coefficient of correlation (rho(C) = 0.98) and Bland-Altman analysis (mean difference = -0.02, 95% CI [-0.04-0.0045] p = 0.107). In addition, the data also suggest that the time elapsed between collection and Hs-CRP measurement does not affect Hs-CRP stability over time when samples are kept under the appropriate conditions. Conclusions: Long-term storage at - 80 degrees C for up to 11 years did not significantly affect the stability of serum Hs-CRP. Given the cost and time for collecting fresh samples, this observation represents an important finding for biomedical research and clinical care. Published by Elsevier Inc. on behalf of The Canadian Society of Clinical Chemists. C1 [Doumatey, Ayo P.; Zhou, Jie; Adeyemo, Adebowale; Rotimi, Charles] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20852 USA. RP Doumatey, AP (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, 12 South Dr Bldg12A-4047, Bethesda, MD 20852 USA. EM doumateya@mail.nih.gov OI Adeyemo, Adebowale/0000-0002-3105-3231 FU Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH); Office of the Director, National Institute of Diabetes and Digestive and Kidney diseases (NIDDK); National Human Genome Research Institute (NHGRI) at National Institutes of Health [Z01HG200362]; National Institutes of Health [S06GM008016-320107, S06GM008016-380111] FX This work was supported in part by the Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by funds from the Office of the Director, National Institute of Diabetes and Digestive and Kidney diseases (NIDDK) and National Human Genome Research Institute (NHGRI) at National Institutes of Health [Z01HG200362]. The Howard University Family Study was supported by National Institutes of Health grants [S06GM008016-320107 to C.R., S06GM008016-380111 to A.A.]. NR 19 TC 10 Z9 10 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0009-9120 EI 1873-2933 J9 CLIN BIOCHEM JI Clin. Biochem. PD MAR PY 2014 VL 47 IS 4-5 BP 315 EP 318 DI 10.1016/j.clinbiochem.2013.12.014 PG 4 WC Medical Laboratory Technology SC Medical Laboratory Technology GA AD2IT UT WOS:000333058900013 PM 24373927 ER PT J AU Moss, HB Chen, CM Yi, HY AF Moss, Howard Barry Chen, Chiung M. Yi, Hsiao-ye TI Early adolescent patterns of alcohol, cigarettes, and marijuana polysubstance use and young adult substance use outcomes in a nationally representative sample SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Adolescent; Alcohol; Marijuana; Cigarettes; Polysubstance use; Substance use disorders ID CANNABIS USE DISORDER; NICOTINE DEPENDENCE; DRUG-USE; COMMON LIABILITY; PROBLEM DRINKING; ONSET; ABUSE; AGE; INITIATION; SMOKING AB Background: Alcohol, tobacco and marijuana are the most commonly used drugs by adolescents in the U.S. However, little is known about the patterning of early adolescent substance use, and its implications for problematic involvement with substances in young adulthood. We examined patterns of substance use prior to age 16, and their associations with young adult substance use behaviors and substance use disorders in a nationally representative sample of U.S. adolescents. Method: Using data from Wave 4 of the Add Health Survey (n = 4245), we estimated the prevalence of various patterns of early adolescent use of alcohol, cigarettes, and marijuana use individually and in combination. Then we examined the effects of patterns of early use of these substances on subsequent young adult substance use behaviors and DSM-IV substance use disorders. Results: While 34.4% of individuals reported no substance use prior to age 16,34.1% reported either early use of both alcohol and marijuana or alcohol, marijuana and cigarettes, indicating the relatively high prevalence of this type of polysubstance use behavior among U.S. adolescents. Early adolescent use of all three substances was most strongly associated with a spectrum of young adult substance use problems, as well as DSM-IV substance use disorder diagnoses. Conclusions: This research confirms the elevated prevalence and importance of polysubstance use behavior among adolescents prior to age 16, and puts early onset of alcohol, marijuana and cigarette use into the context of use patterns rather than single drug exposures. Published by Elsevier Ireland Ltd. C1 [Moss, Howard Barry] NIAAA, Bethesda, MD 20892 USA. RP Moss, HB (reprint author), NIAAA, OD, 5635 Fishers Lane, Bethesda, MD 20892 USA. EM psych.hmossmd@gmail.com FU National Institute on Alcohol Abuse and Alcoholism (NIAAA) FX This study was supported through internal funds provided by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). NIAAA had no involvement in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. The results presented and their interpretation are the author's, and not do not represent the views of NIAAA or the National Institutes of Health. NR 67 TC 48 Z9 49 U1 7 U2 32 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD MAR 1 PY 2014 VL 136 BP 51 EP 62 DI 10.1016/j.drugalcdep.2013.12.011 PG 12 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA AC8WW UT WOS:000332816800007 PM 24434016 ER PT J AU Weinberger, DM Harboe, ZB Viboud, C Krause, TG Miller, M Molbak, K Konradsen, HB AF Weinberger, Daniel M. Harboe, Zitta B. Viboud, Cecile Krause, Tyra G. Miller, Mark Molbak, Kare Konradsen, Helle B. TI Pneumococcal disease seasonality: incidence, severity and the role of influenza activity SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article ID STREPTOCOCCUS-PNEUMONIAE; VIRUS; CHILDREN; IMPACT AB We tested whether the effect of influenza activity on invasive pneumococcal disease incidence and severity varies between age and comorbidity groups. Weekly rates of invasive pneumococcal disease were obtained from the Danish National Laboratory Surveillance System (1977-2007). Influenza-like illness data were collected from a sentinel surveillance system at the Statens Serum Institut (Copenhagen, Denmark). We fitted Poisson regression models for invasive pneumococcal disease, with predictors of seasonality, trends and influenza activity, and allowed the influenza activity variable to vary by comorbidity level and clinical presentation. Influenza activity accounted for 8.4% (95% CI 4.8-11.9%) and 6.9% (95% CI 5.4-10.2%) of all invasive pneumococcal disease cases among those aged 15-39 and >= 40 years, respectively, but had no measurable impact among children aged <15 years. Influenza activity was associated with significant increases in the incidence of invasive pneumococcal pneumonia in both children and adults. The association was more pronounced among younger adults without comorbidities. Case fatality also varied seasonally among the elderly, and this variation might be associated with influenza activity. Pneumococcal incidence and the severity of disease varied seasonally and between age groups. The effect of influenza activity on pneumococcal disease varied between children and adults, and this difference was largely due to differences in disease presentation. C1 [Weinberger, Daniel M.; Viboud, Cecile; Miller, Mark] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Weinberger, Daniel M.] Yale Univ, Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT USA. [Harboe, Zitta B.; Konradsen, Helle B.] Statens Serum Inst, Neisseria & Streptococcus Reference Lab, Dept Microbiol & Infect Control, DK-2300 Copenhagen, Denmark. [Krause, Tyra G.; Molbak, Kare] Statens Serum Inst, Dept Infect Dis Epidemiol, DK-2300 Copenhagen, Denmark. RP Harboe, ZB (reprint author), Statens Serum Inst, Neisseria & Streptococcus Reference Lab, Dept Microbiol & Infect Control, Div Diagnost & Infect Control, Artillerivej 5, DK-2300 S Copenhagen, Denmark. EM zit@ssi.dk FU Office of Global Health Affairs' International Influenza Unit in the Office of the Secretary of the Department of Health and Human Services FX This work is conducted in the context of the Multinational Influenza Seasonal Mortality Study (MISMS), with funding from the Office of Global Health Affairs' International Influenza Unit in the Office of the Secretary of the Department of Health and Human Services. NR 28 TC 4 Z9 4 U1 0 U2 3 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD MAR PY 2014 VL 43 IS 3 BP 833 EP 841 DI 10.1183/09031936.00056813 PG 9 WC Respiratory System SC Respiratory System GA AC8WU UT WOS:000332816600027 PM 24036243 ER PT J AU Esworthy, RS Kim, BW Chow, J Shen, BH Doroshow, JH Chu, FF AF Esworthy, Robert S. Kim, Byung-Wook Chow, Joni Shen, Binghui Doroshow, James H. Chu, Fong-Fong TI Nox1 causes ileocolitis in mice deficient in glutathione peroxidase-1 and -2 SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Apoptosis; C57BL/6J; Glutathione peroxidase; Inflammatory bowel disease; NADPH oxidase; Mouse ileum; Mouse colon; TNF; Free radicals ID INFLAMMATORY-BOWEL-DISEASE; INDUCED LUNG INFLAMMATION; NADPH OXIDASES; CANCER-CELLS; RIBOFLAVIN KINASE; BREAST-CANCER; GPX2 GENES; EXPRESSION; INTESTINE; COLITIS AB We previously reported that mice deficient in two Se-dependent glutathione peroxidases, GPx1 and GPx2, have spontaneous ileocolitis. Disease severity depends on mouse genetic background. Whereas C57BL/6J (B6) GPx1/ 2-double-knockout (DKO) mice have moderate ileitis and mild colitis, 129S1SvIm/J (1 2 9) DKO mice have severe ileocolitis. Because GPx's are antioxidant enzymes, we hypothesized that elevated reactive oxygen species trigger inflammation in these DKO mice. To test whether NADPH oxidase 1 (Nox1) contributes to colitis, we generated B6 triple-KO (YKO) mice to study their phenotype. Because the Nox1 gene is X-linked, we analyzed the effects of Nox1 on male B6 TKO mice and female B6 DKO mice with the Nox1(+/-) (het-TKO) genotype. We found that the male TKO and female het-TKO mice are virtually disease-free when monitored from 8 through 50 days of age. Male TKO and female het-TKO mice have nearly no signs of disease (e.g., lethargy and perianal alopecia) that are often exhibited in the DKO mice; further, the slower growth rate of DKO mice is almost completely eliminated in male TKO and female het-11(0 mice. Male TKO and female het-TKO mice no longer have the shortened small intestine present in the DKO mice. Finally, the pathological characteristics of the DKO ileum, including the high level of crypt apoptosis (analyzed by apoptotic figures, TUNEL, and cleaved caspase-3 immunohistochemical staining), high numbers of Ki-67-positive crypt epithelium cells, and elevated levels of monocytes expressing myeloperoxidase, are all significantly decreased in male TKO mice. The attenuated heal and colonic pathology is also evident in female het-DKO mice. Furthermore, the male DKO ileum has eightfold higher TNF cytokine levels than TKO ileum. Nox1 mRNA is highly elevated in both B6 and 129 DKO ileum compared to wild-type mouse ileum. Taking these results together, we propose that ileocolitis in the DKO mice is caused by Nox1, which is induced by TNF. The milder disease in female het-TKO intestine is probably due to random or imprinted X-chromosome inactivation, which produces mosaic Nox1 expression. (C) 2013 Elsevier Inc All rights reserved. C1 [Esworthy, Robert S.; Chow, Joni; Shen, Binghui; Chu, Fong-Fong] City Hope Natl Med Ctr, Dept Radiat Biol, Duarte, CA 91010 USA. [Esworthy, Robert S.; Chow, Joni; Shen, Binghui; Chu, Fong-Fong] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. [Kim, Byung-Wook] City Hope Natl Med Ctr, Beckman Res Inst, Irell & Manella Grad Sch Biol Sci, Duarte, CA 91010 USA. [Doroshow, James H.] NCI, Bethesda, MD 20816 USA. RP Chu, FF (reprint author), City Hope Natl Med Ctr, Dept Radiat Biol, Duarte, CA 91010 USA. EM fchu@coh.org FU National Cancer Institute of the National Institutes of Health [P30CA033572, R01 CA114569] FX We thank Sofia Loera and Tina Montgomery at the Anatomic Pathology Core of the City of Hope for tissue processing and David Lu at the High-Throughput Core for operating the BMG PHERAstar plate reader. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Grant P30CA033572 and R01 CA114569 (FFC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 42 TC 9 Z9 9 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 MAR PY 2014 VL 68 BP 315 EP 325 DI 10.1016/j.freeradbiomed.2013.12.018 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA AC3OA UT WOS:000332429900032 PM 24374371 ER PT J AU Blein, S Berndt, S Joshi, AD Campa, D Ziegler, RG Riboli, E Cox, DG AF Blein, S. Berndt, S. Joshi, A. D. Campa, D. Ziegler, R. G. Riboli, E. Cox, D. G. CA NCI Breast Prostate Canc Cohort Co TI Factors associated with oxidative stress and cancer risk in the Breast and Prostate Cancer Cohort Consortium SO FREE RADICAL RESEARCH LA English DT Article DE MnSOD; GPX-1; mitochondria; alcohol; breast; prostate ID GPX ACTIVITY; ALCOHOL-CONSUMPTION; POLYMORPHISM; GENE; MNSOD; DNA; SUSCEPTIBILITY; VARIANTS; SMOKERS; REPAIR AB Both endogenous factors (genomic variations) and exogenous factors (environmental exposures, lifestyle) impact the balance of reactive oxygen species (ROS). Variants of the ND3 (rs2853826; G10398A) gene of the mitochondrial genome, manganese superoxide dismutase (MnSOD; rs4880 Val16Ala) and glutathione peroxidase (GPX-1; rs1050450 Pro198Leu), are purported to have functional effects on regulation of ROS balance. In this study, we examined associations of breast and prostate cancer risks and survival with these variants, and interactions between rs4880 -rs1050450, and alcohol consumption -rs2853826. Nested case-control studies were conducted in the Breast and Prostate Cancer Cohort Consortium (BPC3), consisting of nine cohorts. The analyses included over 10726 post-menopausal breast and 7532 prostate cancer cases with matched controls. Logistic regression models were used to evaluate associations with risk, and proportional hazard models were used for survival outcomes. We did not observe significant interactions between polymorphisms in MnSOD and GPX-1, or between mitochondrial polymorphisms and alcohol intake and risk of either breast (p-interaction of 0.34 and 0.98, respectively) or prostate cancer (p-interaction of 0.49 and 0.50, respectively). We observed a weak inverse association between prostate cancer risk and GPX-1 Leu198Leu carriers (OR 0.87, 95% CI 0.79- 0.97,p = 0.01). Overall survival among women with breast cancer was inversely associated with G10398 carriers who consumed alcohol (HR 0.66 95% CI 0.49 -0.88). Given the high power in our study, it is unlikely that interactions tested have more than moderate effects on breast or prostate cancer risk. Observed associations need both further epidemiological and biological confirmation. C1 [Blein, S.; Cox, D. G.] Univ Lyon, Lyon, France. [Blein, S.; Cox, D. G.] Univ Lyon 1, ISPB, F-69365 Lyon, France. [Blein, S.; Cox, D. G.] Ctr Rech Cancerol Lyon, INSERM U1052, Lyon, France. [Blein, S.; Cox, D. G.] Ctr Rech Cancerol Lyon, CNRS UMR5286, Lyon, France. [Blein, S.; Cox, D. G.] Ctr Leon Berard, F-69373 Lyon, France. [Berndt, S.; Ziegler, R. G.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Joshi, A. D.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Campa, D.] German Canc Res Ctr, Heidelberg, Germany. [Riboli, E.; Cox, D. G.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. RP Cox, DG (reprint author), Ctr Leon Berard, 28 Rue Laennec, F-69373 Lyon 8, France. EM david.cox@inserm.fr RI Cox, David/A-2023-2009; Albanes, Demetrius/B-9749-2015; Campa, Daniele/K-1617-2016 OI Cox, David/0000-0002-2152-9259; Campa, Daniele/0000-0003-3220-9944 FU National Cancer Institute Surveillance Epidemiology and End Results program; French Ligue Contre le Cancer, Comite de Savoie; French ANRT; LYRIC program FX The authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. The authors would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. David G. Cox is the recipient of a grant from the French Ligue Contre le Cancer, Comite de Savoie. Sophie Blein is the recipient of a CIFRE fellowship from the French ANRT and the LYRIC program. NR 33 TC 10 Z9 10 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1071-5762 EI 1029-2470 J9 FREE RADICAL RES JI Free Radic. Res. PD MAR PY 2014 VL 48 IS 3 BP 380 EP 386 DI 10.3109/10715762.2013.875168 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AC6YD UT WOS:000332671600013 PM 24437375 ER PT J AU Dey, BK Pfeifer, K Dutta, A AF Dey, Bijan K. Pfeifer, Karl Dutta, Anindya TI The H19 long noncoding RNA gives rise to microRNAs miR-675-3p and miR-675-5p to promote skeletal muscle differentiation and regeneration SO GENES & DEVELOPMENT LA English DT Article DE H19; miR-675; long noncoding RNA; skeletal muscle; differentiation; regeneration ID TUMOR-SUPPRESSOR; MYOBLAST DIFFERENTIATION; IGF2/H19 LOCUS; MOUSE; MICE; GENE; EXPRESSION; CELLS; MYOD; PROGRESSION AB Regulated expression of the H19 long noncoding RNA gene has been well characterized as a paradigm for genomic imprinting, but the H19 RNA's biological function remains largely unclear. H19 is abundantly expressed maternally in embryonic tissues but is strongly repressed after birth, and significant transcription persists only in skeletal muscle. Thus, we examined the role of the H19 RNA in skeletal muscle differentiation and regeneration. Knockdown of H19 RNA in myoblast cells and H19 knockout mouse satellite cells decreases differentiation. H19 exon1 encodes two conserved microRNAs, miR-675-3p and miR-675-5p, both of which are induced during skeletal muscle differentiation. The inhibition of myogenesis by H19 depletion during myoblast differentiation is rescued by exogenous expression of miR-675-3p and miR-675-5p. H19-deficient mice display abnormal skeletal muscle regeneration after injury, which is rectified by reintroduction of miR-675-3p and miR-675-5p. miR-675-3p and miR-675-5p function by directly targeting and down-regulating the anti-differentiation Smad transcription factors critical for the bone morphogenetic protein (BMP) pathway and the DNA replication initiation factor Cdc6. Therefore, the H19 long noncoding RNA has a critical trans-regulatory function in skeletal muscle differentiation and regeneration that is mediated by the microRNAs encoded within H19. C1 [Dey, Bijan K.; Dutta, Anindya] Univ Virginia, Sch Med, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. [Pfeifer, Karl] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Dutta, A (reprint author), Univ Virginia, Sch Med, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. EM ad8q@virginia.edu RI Dutta, Anindya/P-3203-2016; OI Pfeifer, Karl/0000-0002-0254-682X; Dutta, Anindya/0000-0002-4319-0073 FU Heart and Stroke Foundation of Canada (HSFC); [R01 AR053948]; [P01CA104106] FX We thank Megan Sampley and Claudia Gebert for primary myoblast culture and genotyping, and members of the Dutta laboratory for many helpful discussions. This work was supported by R01 AR053948 and P01CA104106 to A.D., and partially supported by a post-doctoral fellowship from Heart and Stroke Foundation of Canada (HSFC) to B.K.D. NR 53 TC 105 Z9 110 U1 4 U2 25 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 MAR 1 PY 2014 VL 28 IS 5 BP 491 EP 501 DI 10.1101/gad.234419.113 PG 11 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA AC4FE UT WOS:000332475600007 PM 24532688 ER PT J AU Dong, JS Munoz, A Kolitz, SE Saini, AK Chiu, WL Rahman, H Lorsch, JR Hinnebusch, AG AF Dong, Jinsheng Munoz, Antonio Kolitz, Sarah E. Saini, Adesh K. Chiu, Wen-ling Rahman, Hafsa Lorsch, Jon R. Hinnebusch, Alan G. TI Conserved residues in yeast initiator tRNA calibrate initiation accuracy by regulating preinitiation complex stability at the start codon SO GENES & DEVELOPMENT LA English DT Article DE accuracy; initiation; initiator; scanning; tRNA; translation; yeast ID EUKARYOTIC TRANSLATION INITIATION; 40S RIBOSOMAL-SUBUNIT; SACCHAROMYCES-CEREVISIAE; PROTEIN-SYNTHESIS; CRYSTAL-STRUCTURE; IN-VIVO; ESCHERICHIA-COLI; ANTICODON STEM; MESSENGER-RNA; FACTORS EIF1 AB Eukaryotic initiator tRNA (tRNAi) contains several highly conserved unique sequence features, but their importance in accurate start codon selection was unknown. Here we show that conserved bases throughout tRNAi, from the anticodon stem to acceptor stem, play key roles in ensuring the fidelity of start codon recognition in yeast cells. Substituting the conserved G31:C39 base pair in the anticodon stem with different pairs reduces accuracy (the Sui(-) [suppressor of initiation codon] phenotype), whereas eliminating base pairing increases accuracy (the Ssu(-) [suppressor of Sui(-)] phenotype). The latter defect is fully suppressed by a Su(i)(-) substitution of T-loop residue A54. These genetic data are paralleled by opposing effects of Sui(-) and Ssu(-) substitutions on the stability of methionylated tRNA(i) (Met-tRNA(i)) binding (in the ternary complex [TC] with eIF2-GTP) to reconstituted preinitiation complexes (PICs). Disrupting the C3:G70 base pair in the acceptor stem produces a Sui(-) phenotype and also reduces the rate of TC binding to 40S subunits in vitro and in vivo. Both defects are suppressed by an Ssu substitution in eIF1A that stabilizes the open/P-OUT conformation of the PIC that exists prior to start codon recognition. Our data indicate that these signature sequences of tRNA(i) regulate accuracy by distinct mechanisms, promoting the open/P-OUT conformation of the PIC (for C3:G70) or destabilizing the closed/P-IN state (for G31:C39 and A54) that is critical for start codon recognition. C1 [Dong, Jinsheng; Saini, Adesh K.; Chiu, Wen-ling; Rahman, Hafsa; Hinnebusch, Alan G.] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Munoz, Antonio; Kolitz, Sarah E.; Lorsch, Jon R.] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. RP Lorsch, JR (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Mech & Regulat Prot Synth, NIH, Bethesda, MD 20892 USA. EM jon.lorsch@nih.gov; ahinnebusch@nih.gov RI university, shoolini/K-9336-2015; OI Lorsch, Jon/0000-0002-4521-4999 FU National Institutes of Health (NIH) [GM62128] FX We are indebted to Sonia D'Silva and Eric Phizicky for analysis of t6A37 in tRNAi, Anders Bystrom and Katsura Asano for strains and plasmids, Ernest Hannig for Gcd11 antibodies, and Tom Dever for critical comments. This work was supported by the Intramural Research Program of the National Institutes of Health (NIH) and NIH grant GM62128 to J.R.L. NR 58 TC 12 Z9 12 U1 0 U2 4 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 MAR 1 PY 2014 VL 28 IS 5 BP 502 EP 520 DI 10.1101/gad.236547.113 PG 19 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA AC4FE UT WOS:000332475600008 PM 24589778 ER PT J AU Peterson, JC Link, AR Jobe, JB Winston, GJ Klimasiewfski, EM Allegrante, JP AF Peterson, Janey C. Link, Alissa R. Jobe, Jared B. Winston, Ginger J. Klimasiewfski, E. Marina Allegrante, John P. TI Developing self-management education in coronary artery disease SO HEART & LUNG LA English DT Article DE Angioplasty; Chronic disease; Coronary artery disease; Disease self-management; Health behavior; Patient education ID AMERICAN-HEART-ASSOCIATION; PHYSICAL-ACTIVITY QUESTIONNAIRE; SOCIAL COGNITIVE THEORY; CULTURAL APPROPRIATENESS; SCIENTIFIC STATEMENT; RANDOMIZED-TRIAL; COLLEGE ALUMNI; EXERCISE; HEALTH; RISK AB We describe a three-step approach to develop and evaluate. a novel coronary artery disease (CAD) self-management educational workbook. First, we conducted interviews using grounded theory methods with a diverse CAD cohort (n = 61) to identify needs and perceptions. Second, we developed the workbook, incorporating themes that emerged from the qualitative interviews. Finally, 225 people with CAD used the workbook in a longitudinal study and we evaluated their use of and experience with the workbook at 12 months. 12-month evaluation data revealed that the workbook: provided practical health information; enhanced behavior-specific self-efficacy; and reinforced that healthy behaviors decrease risk. Participants who read the workbook had greater within-patient increases in physical activity at 12-months compared with non-readers (p = 0.093) and among Black/Hispanic participants, workbook readers' increases were significant (592 vs. 645 kilocalories per week, p = 0.035). A self-management educational workbook developed using qualitative methods can provide relevant, disease-specific health information for patients with CAD. (C) 2014 Elsevier Inc. All rights reserved. C1 [Peterson, Janey C.] Weill Cornell Med Coll, Div Clin Epidemiol & Evaluat Sci Res, Ctr Integrat Med, New York, NY 10065 USA. [Peterson, Janey C.] Weill Cornell Med Coll, Dept Cardiothorac Surg, New York, NY 10065 USA. [Link, Alissa R.] NYU, Sch Med, Dept Populat Hlth, New York, NY 10003 USA. [Link, Alissa R.; Winston, Ginger J.; Klimasiewfski, E. Marina] Weill Cornell Med Coll, Ctr Integrat Med, Div Clin Epidemiol & Evaluat Sci Res, New York, NY 10065 USA. [Jobe, Jared B.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Jobe, Jared B.] NHLBI, Clin Applicat & Prevent Branch, Div Prevent & Populat Sci, NIH, Bethesda, MD USA. [Klimasiewfski, E. Marina] Columbia Univ, Med Ctr, Dept Nursing, New York, NY 10027 USA. [Allegrante, John P.] Columbia Univ, Teachers Coll, Dept Hlth & Behav Studies, New York, NY 10027 USA. [Allegrante, John P.] Columbia Univ, Mailman Sch Publ Hlth, Dept Sociomed Sci, New York, NY 10027 USA. RP Peterson, JC (reprint author), Weill Cornell Med Coll, Div Clin Epidemiol & Evaluat Sci Res, Ctr Integrat Med, 1300 York Ave,Box 46, New York, NY 10065 USA. EM jcpeters@med.cornell.edu FU National Institute on Aging; American Federation for Aging Research; National Heart, Lung, and Blood Institute of the National Institutes of Health [K23AG042869, N01-HC25196] FX Research reported in this publication was supported by a Paul B. Beeson Award from the National Institute on Aging, the American Federation for Aging Research, The John A. Hartford Foundation and The Atlantic Philanthropies & funding from the National Heart, Lung, and Blood Institute of the National Institutes of Health under awards K23AG042869 & contract N01-HC25196. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no financial conflicts to disclose. NR 62 TC 2 Z9 2 U1 3 U2 11 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0147-9563 EI 1527-3288 J9 HEART LUNG JI Heart Lung PD MAR-APR PY 2014 VL 43 IS 2 BP 133 EP 139 DI 10.1016/j.hrtIng.2013.11.006 PG 7 WC Cardiac & Cardiovascular Systems; Nursing; Respiratory System SC Cardiovascular System & Cardiology; Nursing; Respiratory System GA AC7BQ UT WOS:000332682400010 PM 24373484 ER PT J AU Otto, M AF Otto, Michael TI Phenol-soluble modulins SO INTERNATIONAL JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Review DE Phenol-soluble modulins; Staphylococcus aureus; Staphylococcus epidermidis; Cytolysis; Toxins; Leukotoxin; Neutrophils; Biofilm ID RESISTANT STAPHYLOCOCCUS-AUREUS; QUORUM-SENSING SYSTEM; IMMUNE EVASION; IN-VITRO; VIRULENCE DETERMINANTS; BIOFILM MATURATION; HUMAN NEUTROPHILS; AGR DYSFUNCTION; ALPHA-TOXIN; HUMAN SKIN AB PSMs are a recently discovered family of short, amphipathic, et-helical peptides in staphylococci. Several PSMs are key virulence determinants, particularly in highly virulent Staphylococcus aureus strains. PSMa peptides of S. aureus facilitate neutrophil lysis after phagocytosis, and are key contributors to several infection types, including skin infection and bacteremia. Furthermore, all PSMs contribute to biofilm structuring and the dissemination of biofilm-associated infection. Cytolytic PSMs as produced by S. aureus appear to have evolved from original functions in the non-infectious lifestyle of staphylococci. The surfactant properties of PSMs, which they all share, are believed to facilitate growth on epithelial surfaces. The basic role of PSMs in staphylococcal physiology is underscored, for example, by their exceptionally strict and direct control by quorum-sensing and the presence of a dedicated secretion system. Targeting PSMs for anti-staphylococcal drug development may be a promising approach to overcome the problems associated with widespread antibiotic resistance in staphylococci. Published by Elsevier GmbH. C1 [Otto, Michael] NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. RP Otto, M (reprint author), 9000 Rockville Pike,Bldg 33 1W10, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health. NR 67 TC 21 Z9 21 U1 3 U2 13 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 1438-4221 EI 1618-0607 J9 INT J MED MICROBIOL JI Int. J. Med. Microbiol. PD MAR PY 2014 VL 304 IS 2 BP 164 EP 169 DI 10.1016/j.ijmm.2013.11.019 PG 6 WC Microbiology; Virology SC Microbiology; Virology GA AC2RO UT WOS:000332351900009 PM 24447915 ER PT J AU Sublette, ME Galfalvy, HC Hibbeln, JR Keilp, JG Malone, KM Oquendo, MA Mann, JJ AF Sublette, M. Elizabeth Galfalvy, Hanga C. Hibbeln, Joseph R. Keilp, John G. Malone, Kevin M. Oquendo, Maria A. Mann, J. John TI Polyunsaturated fatty acid associations with dopaminergic indices in major depressive disorder SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Dopamine; polyunsaturated fatty acids; omega-3; major depressive disorder; prolactin ID RAT FRONTAL-CORTEX; BLOOD-CELL MEMBRANES; CEREBROSPINAL-FLUID; EXTRACELLULAR DOPAMINE; EICOSAPENTAENOIC ACID; OMEGA-3-FATTY-ACID LEVELS; SEROTONERGIC CHALLENGE; NORADRENALINE CARRIER; PROLACTIN RESPONSE; DIETARY DEFICIENCY AB Dopaminergic function is thought to be altered in major depression and, in animal studies, is reduced in omega-3 polyunsaturated fatty acid (PUFA) deficiency states. Therefore we studied PUFAs and resting prolactin, a marker for dopaminergic tone, and cerebrospinal fluid homovanillic acid (HVA), the chief dopamine metabolite. In medication-free adults (n=23) with DSM-IV major depressive disorder (MDD), we measured plasma phospholipid levels of omega-3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the omega-6 PUFA arachidonic acid (AA), and plasma prolactin levels before and after administration of dl-fenfluramine (FEN). In a subset of patients (n=14), cerebrospinal fluid levels of HVA and the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were obtained through lumbar puncture. Baseline prolactin was negatively correlated with omega-3 PUFAs (logDHA, F (1,21)=20.380, p<0.001; logEPA, F (1,21)=10.051, p=0.005) and positively correlated with logAA:DHA (F (1,21)=15.263, p=0.001), a measure of omega-6/omega-3 balance. LogDHA was negatively correlated with CSF HVA (Spearman's rho=-0.675, p=0.008) but not 5-HIAA (Spearman's rho=-0.143, p=0.626) after controlling for sex and HVA - 5-HIAA correlation. PUFAs did not predict the magnitude of the FEN-stimulated change in prolactin, considered to be a serotonin effect. The robust relationship of omega-3 PUFAs with dopaminergic but not serotonergic indices suggests that omega-6:omega-3 balance may impact depression pathophysiology through effects on the dopaminergic system. C1 [Sublette, M. Elizabeth; Galfalvy, Hanga C.; Keilp, John G.; Oquendo, Maria A.; Mann, J. John] Columbia Univ, Dept Psychiat, New York, NY USA. [Sublette, M. Elizabeth; Galfalvy, Hanga C.; Keilp, John G.; Oquendo, Maria A.; Mann, J. John] New York State Psychiat Inst & Hosp, Dept Mol Imaging & Neuropathol, New York, NY 10032 USA. [Hibbeln, Joseph R.] NIAAA, NIH, Bethesda, MD USA. [Malone, Kevin M.] Univ Coll Dublin, Sch Med & Med Sci, Dublin, Ireland. [Mann, J. John] Columbia Univ, Dept Radiol, New York, NY USA. RP Sublette, ME (reprint author), New York State Psychiat Inst & Hosp, 1051 Riverside Dr,Unit 42, New York, NY 10032 USA. EM es2316@columbia.edu RI Sublette, M/A-8391-2009; OI Sublette, M/0000-0001-7378-4262; Malone, Kevin M/0000-0001-5665-4706 FU [MH48514]; [MH062185]; [MH040695]; [MH079033] FX This work was funded in part by MH48514 (PI:Oquendo); MH062185 and MH040695 (PI:Mann); and MH079033 (PI:Sublette). NR 79 TC 10 Z9 10 U1 0 U2 17 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD MAR PY 2014 VL 17 IS 3 BP 383 EP 391 DI 10.1017/S1461145713001399 PG 9 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AD0XR UT WOS:000332958200002 PM 24300434 ER PT J AU Miller, R Tanofsky-Kraff, M Shomaker, LB Field, SE Hannallah, L Reina, SA Mooreville, M Sedaka, N Brady, SM Condarco, T Reynolds, JC Yanovski, SZ Yanovski, JA AF Miller, R. Tanofsky-Kraff, M. Shomaker, L. B. Field, S. E. Hannallah, L. Reina, S. A. Mooreville, M. Sedaka, N. Brady, S. M. Condarco, T. Reynolds, J. C. Yanovski, S. Z. Yanovski, J. A. TI Serum leptin and loss of control eating in children and adolescents SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE binge eating; leptin; loss of control eating; hormone resistance; adiposity ID BODY-FAT; CIRCULATING LEPTIN; DIETARY RESTRAINT; BULIMIA-NERVOSA; ADULT OBESITY; HIGH-RISK; FEMALE ADOLESCENTS; GENDER-DIFFERENCES; ANOREXIA-NERVOSA; PUBERTAL CHANGES AB BACKGROUND: Both insufficiency and resistance to the actions of the adipocyte-derived hormone leptin promote hunger, increased food intake and greater body weight. Some studies suggest that adults reporting binge eating have increased serum leptin compared with those without binge eating, even after adjusting for the greater adiposity that characterizes binge eaters. Pediatric binge or loss of control (LOC) eating are prospective risk factors for excessive weight gain and may predict development of metabolic abnormalities, but whether LOC eating is associated with higher leptin among children is unknown. We therefore examined leptin and LOC eating in a pediatric cohort. METHODS: A convenience sample of 506 lean and obese youth (7-18 years) was recruited from Washington, DC and its suburbs. Serum leptin was collected after an overnight fast. Adiposity was measured by dual-energy X-ray absorptiometry or air displacement plethysmography. LOC eating was assessed by interview methodology. RESULTS: Leptin was strongly associated with fat mass (r = 0.79, P<0.001). However, even after adjusting for adiposity and other relevant covariates, youth with LOC eating had higher serum leptin compared with those without LOC episodes (15.42 +/- 1.05 vs 12.36 +/- 1.04 ng ml(-1), P<0.001). Neither reported amount of food consumed during a recent LOC episode nor number of LOC episodes in the previous month accounted for differences in leptin (P>0.05). The relationship between LOC eating and leptin appeared to be significant for females only (P = 0.002). CONCLUSIONS: Reports of LOC eating were associated with higher fasting leptin in youth, beyond the contributions of body weight. Prospective studies are required to elucidate whether LOC eating promotes greater leptin or whether greater leptin resistance may promote LOC eating. C1 [Miller, R.; Tanofsky-Kraff, M.; Shomaker, L. B.; Field, S. E.; Hannallah, L.; Reina, S. A.; Mooreville, M.; Sedaka, N.; Brady, S. M.; Condarco, T.; Yanovski, S. Z.; Yanovski, J. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,DHHS,Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Miller, R.; Tanofsky-Kraff, M.; Shomaker, L. B.; Field, S. E.; Hannallah, L.] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Reynolds, J. C.] Hatfield Clin Ctr, Nucl Med Dept, Bethesda, MD USA. [Yanovski, S. Z.] Natl Inst Diabet & Digest & Kidney Dis, Div Digest Dis & Nutr, Bethesda, MD USA. RP Yanovski, JA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,DHHS,Hatfield Clin Res Ctr, 10 Ctr Dr,Room 1E-3330,MSC 1103, Bethesda, MD 20892 USA. EM jy15i@nih.gov OI Yanovski, Jack/0000-0001-8542-1637 FU National Research Service Award from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [1F32HD056762]; Uniformed Services University of the Health Sciences [R072IC]; National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) [5R01DK080906-04]; Intramural Research Program from the NICHD [1ZIAHD000641]; Division of Nutrition Research Coordination; National Institute of Minority Health and Health Disparities; Office of Behavioral and Social Sciences Research FX This research was supported by National Research Service Award 1F32HD056762 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (to LBS), Uniformed Services University of the Health Sciences grant R072IC (to MTK), National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) grant 5R01DK080906-04 (to MTK) and Intramural Research Program Grant 1ZIAHD000641 from the NICHD, with supplemental funding from the Division of Nutrition Research Coordination, the National Institute of Minority Health and Health Disparities and the Office of Behavioral and Social Sciences Research (to JAY). JAY is a Commissioned Officer in the US Public Health Service, Department of Health and Human Services. The funding organizations played no role in the design and conduct of the study; the collection, management, analysis and interpretation of data; or the preparation or review of the manuscript. Drs Yanovski and Tanofsky-Kraff take full responsibility for the work as a whole, including the study design, access to data and the decision to submit and publish the manuscript. NR 62 TC 7 Z9 7 U1 3 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 EI 1476-5497 J9 INT J OBESITY JI Int. J. Obes. PD MAR PY 2014 VL 38 IS 3 BP 397 EP 403 DI 10.1038/ijo.2013.126 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AC9DY UT WOS:000332835700010 PM 23835660 ER PT J AU Xiong, MY Korgavkar, K DiGiovanna, JJ Weinstock, MA AF Xiong, Michael Y. Korgavkar, Kaveri DiGiovanna, John J. Weinstock, Martin A. CA VATTC Trial Grp TI Fluorouracil and Other Predictors of Morpheaform Basal Cell Carcinoma Among High-Risk Patients: The Veterans Affairs Topical Tretinoin Chemoprevention Trial SO JAMA DERMATOLOGY LA English DT Letter C1 [Xiong, Michael Y.; Korgavkar, Kaveri; Weinstock, Martin A.] VA Med Ctr, Dermatoepidemiol Unit, Providence, RI 02908 USA. [Xiong, Michael Y.; Korgavkar, Kaveri; Weinstock, Martin A.] Brown Univ, Warren Alpert Med Sch, Dept Dermatol, Providence, RI 02912 USA. [DiGiovanna, John J.] NCI, DNA Repair Sect, Dermatol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Weinstock, Martin A.] Rhode Isl Hosp, Dept Dermatol, Providence, RI USA. [Weinstock, Martin A.] Rhode Isl Hosp, Dept Epidemiol, Providence, RI USA. RP Weinstock, MA (reprint author), VA Med Ctr, Dermatoepidemiol Unit, Mail Code 111D,830 Chalkstone Ave, Providence, RI 02908 USA. EM maw@brown.edu NR 7 TC 3 Z9 3 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD MAR PY 2014 VL 150 IS 3 BP 332 EP 334 DI 10.1001/jamadermatol.2013.5619 PG 3 WC Dermatology SC Dermatology GA AD2DQ UT WOS:000333043900027 PM 24258386 ER PT J AU Chew, EY Clemons, TE Agron, E Sperduto, RD SanGiovanni, JP Davis, MD Ferris, FL AF Chew, Emily Y. Clemons, Traci E. Agron, Elvira Sperduto, Robert D. SanGiovanni, John Paul Davis, Matthew D. Ferris, Frederick L., III CA Age-Related Eye Dis Study Res Grp TI Ten-Year Follow-up of Age-Related Macular Degeneration in the Age-Related Eye Disease Study AREDS Report No. 36 SO JAMA OPHTHALMOLOGY LA English DT Article ID BETA-CAROTENE; ZINC AB IMPORTANCE Providing long-term follow-up of the natural history of age-related macular degeneration (AMD) and associated risk factors will facilitate future epidemiologic studies and clinical trials. OBJECTIVE To describe 10-year progression rates to intermediate or advanced AMD. DESIGN, SETTING, AND PARTICIPANTS We observed the Age-Related Eye Disease Study (AREDS) participants for an additional 5 years after a randomized clinical trial of antioxidant vitamins and minerals was completed. Observation occurred at 11 clinical sites of medical retinal practices from academic institutions and community medical centers. Participants aged 55 to 80 years with no AMD or AMD of varying severity (n = 4757) were followed up in the AREDS trial for a median duration of 6.5 years. When the trial ended, 3549 of the 4203 surviving participants were followed for 5 additional years. EXPOSURE Treatment with antioxidant vitamins and minerals. MAIN OUTCOMES AND MEASURES Development of varying stages of AMD and changes in visual acuity. The rates of progression to large drusen and advanced AMD (neovascular AMD or central geographic atrophy) were evaluated using annual fundus photographs assessed centrally. Best-corrected visual acuity was measured at annual study visits. RESULTS The risk of progression to advanced AMD increased with increasing age (P = .01) and severity of drusen. Women (P =.005) and current smokers (P < .001) were at increased risk of neovascular AMD. In the oldest participants with the most severe AMD status at baseline, the risks of developing neovascular AMD and central geographic atrophy by 10 years were 48.1% and 26.0%, respectively. Similarly, rates of progression to large drusen increased with increasing severity of drusen at baseline, with 70.9% of participants with bilateral medium drusen progressing to large drusen and 13.8% to advanced AMD in 10 years. Median visual acuity at 10 years in eyes that had large drusen at baseline but never developed advanced AMD was 20/25; eyes that developed advanced AMD had a median visual acuity of 20/200. CONCLUSIONS AND RELEVANCE The natural history of AMD demonstrates relentless loss of vision in persons who developed advanced AMD. These progression data and the risk factor analyses may be helpful to investigators conducting research in clinic populations. C1 [Chew, Emily Y.; Agron, Elvira; SanGiovanni, John Paul; Ferris, Frederick L., III] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Clemons, Traci E.; Sperduto, Robert D.] EMMES Corp, Rockville, MD USA. [Davis, Matthew D.] Univ Wisconsin, Dept Ophthalmol, Madison, WI 53706 USA. RP Chew, EY (reprint author), NEI, Div Epidemiol & Clin Applicat, NIH, 10 Ctr Dr,MSC 1204,Bldg 10,CRC Room 3-2531, Bethesda, MD 20892 USA. EM echew@nei.nih.gov FU National Eye Institute, National Institutes of Health, Department of Health and Human Services [N0I-EY-0-2127] FX This study is supported by the intramural program funds and contract N0I-EY-0-2127 from the National Eye Institute, National Institutes of Health, Department of Health and Human Services. NR 9 TC 30 Z9 30 U1 3 U2 13 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD MAR PY 2014 VL 132 IS 3 BP 272 EP 277 DI 10.1001/jamaophthalmol.2013.6636 PG 6 WC Ophthalmology SC Ophthalmology GA AC8HL UT WOS:000332774000006 PM 24385141 ER PT J AU Kjellstrom, S Ghosh, F Vijayasarathy, C Andreasson, S AF Kjellstrom, Sten Ghosh, Fredrik Vijayasarathy, Camasamudram Andreasson, Sten TI Alteration of Vitreal Retinoschisin Level in Human Primary Retinal Detachment SO JAMA OPHTHALMOLOGY LA English DT Letter ID X-LINKED RETINOSCHISIS; JUVENILE RETINOSCHISIS; WAVE C1 [Kjellstrom, Sten; Ghosh, Fredrik; Andreasson, Sten] Lund Univ, Dept Ophthalmol, S-22185 Lund, Sweden. [Vijayasarathy, Camasamudram] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. RP Kjellstrom, S (reprint author), Lund Univ, Dept Ophthalmol, S-22185 Lund, Sweden. EM sten.kjellstrom@med.lu.se OI Ghosh, Fredrik/0000-0002-3302-1233 NR 11 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD MAR PY 2014 VL 132 IS 3 BP 353 EP 354 DI 10.1001/jamaophthalmol.2013.6306 PG 2 WC Ophthalmology SC Ophthalmology GA AC8HL UT WOS:000332774000019 PM 24370778 ER PT J AU Muraro, PA Robins, H Malhotra, S Howell, M Phippard, D Desmarais, C Sousa, ADA Griffith, LM Lim, N Nash, RA Turka, LA AF Muraro, Paolo A. Robins, Harlan Malhotra, Sachin Howell, Michael Phippard, Deborah Desmarais, Cindy Sousa, Alessandra de Paula Alves Griffith, Linda M. Lim, Noha Nash, Richard A. Turka, Laurence A. TI T cell repertoire following autologous stem cell transplantation for multiple sclerosis SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID TOLERANCE; NETWORK; DISEASE; NUMBER AB Autologous hematopoietic stem cell transplantation (HSCT) is commonly employed for hematologic and non-hematologic malignancies. In clinical trials, HSCT has been evaluated for severe autoimmunity as a method to "reset" the immune system and produce a new, non-autoimmune repertoire. While the feasibility of eliminating the vast majority of mature T cells is well established, accurate and quantitative determination of the relationship of regenerated T cells to the baseline repertoire has been difficult to assess. Here, in a phase II study of HSCT for poor-prognosis multiple sclerosis, we used high-throughput deep TCR beta chain sequencing to assess millions of individual TCRs per patient sample. We found that HSCT has distinctive effects on CD4(+) and CD8(+) T cell repertoires. In CD4(+) T cells, dominant TCR clones present before treatment were undetectable following reconstitution, and patients largely developed a new repertoire. In contrast, dominant CD8(+) clones were not effectively removed, and the reconstituted CD8(+) T cell repertoire was created by clonal expansion of cells present before treatment. Importantly, patients who failed to respond to treatment had less diversity in their T cell repertoire early during the reconstitution process. These results demonstrate that TCR characterization during immunomodulatory treatment is both feasible and informative, and may enable monitoring of pathogenic or protective T cell clones following HSCT and cellular therapies. C1 [Muraro, Paolo A.; Sousa, Alessandra de Paula Alves] Univ London Imperial Coll Sci Technol & Med, Dept Med, Div Brain Sci, London, England. [Robins, Harlan] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Malhotra, Sachin; Howell, Michael; Phippard, Deborah; Lim, Noha; Turka, Laurence A.] Immune Tolerance Network, Bethesda, MD USA. [Desmarais, Cindy] Adapt Biotechnol, Seattle, WA USA. [Griffith, Linda M.] NIAID, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. [Nash, Richard A.] Colorado Blood Canc Inst PSL, Denver, CO USA. [Turka, Laurence A.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Turka, Laurence A.] Harvard Univ, Sch Med, Boston, MA USA. RP Turka, LA (reprint author), Transplantat Biol Res Ctr MGH East, Bldg 149-9019,13th St, Boston, MA 02129 USA. EM lturka@partners.org OI Muraro, Paolo/0000-0002-3822-1218 FU NIAID; NIDDK; Juvenile Diabetes Research Foundation (JDRF); Autoimmune Disease Clinical Trials Statistical and Clinical Coordinating Center; UK MS society [938/10]; Multiple Sclerosis Trial Collaboration [WMCN P36769] FX This work was supported by the ITN, funded by the NIAID, with support from the NIDDK and the Juvenile Diabetes Research Foundation (JDRF). Additional support was received from the Autoimmune Disease Clinical Trials Statistical and Clinical Coordinating Center funded by the NIAID. P.A. Muraro was supported by the UK MS society (ref. 938/10). A.P.A. Sousa was supported by the Multiple Sclerosis Trial Collaboration (ref. WMCN P36769). We thank Alice Long (Benaroya Research Institute) for outstanding technical assistance. We also thank the patients who participated in this study. NR 15 TC 57 Z9 58 U1 3 U2 19 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD MAR PY 2014 VL 124 IS 3 BP 1168 EP 1172 DI 10.1172/JCI71691 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AC2PZ UT WOS:000332347700034 PM 24531550 ER PT J AU te Vruchte, D Speak, AO Wallom, KL Al Eisa, N Smith, DA Hendriksz, CJ Simmons, L Lachmann, RH Cousins, A Hartung, R Mengel, E Runz, H Beck, M Amraoui, Y Imrie, J Jacklin, E Riddick, K Yanjanin, NM Wassif, CA Rolfs, A Rimmele, F Wright, N Taylor, C Ramaswami, U Cox, TM Hastings, C Jiang, XT Sidhu, R Ory, DS Arias, B Jeyakumar, M Sillence, DJ Wraith, JE Porter, FD Cortina-Borja, M Platt, FM AF te Vruchte, Danielle Speak, Anneliese O. Wallom, Kerni L. Al Eisa, Nada Smith, David A. Hendriksz, Christian J. Simmons, Louise Lachmann, Robin H. Cousins, Alison Hartung, Ralf Mengel, Eugen Runz, Heiko Beck, Michael Amraoui, Yasmina Imrie, Jackie Jacklin, Elizabeth Riddick, Kate Yanjanin, Nicole M. Wassif, Christopher A. Rolfs, Arndt Rimmele, Florian Wright, Naomi Taylor, Clare Ramaswami, Uma Cox, Timothy M. Hastings, Caroline Jiang, Xuntian Sidhu, Rohini Ory, Daniel S. Arias, Begona Jeyakumar, Mylvaganam Sillence, Daniel J. Wraith, James E. Porter, Forbes D. Cortina-Borja, Mario Platt, Frances M. TI Relative acidic compartment volume as a lysosomal storage disorder-associated biomarker SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID NIEMANN-PICK-DISEASE; C DISEASE; MIGLUSTAT THERAPY; CHOLESTEROL; TRAFFICKING; PROGRESSION; DIAGNOSIS AB Lysosomal storage disorders (LSDs) occur at a frequency of 1 in every 5,000 live births and are a common cause ofpediatric neuroolegenerative disease. The relatively small number ofpatients with LSDs and lack of validated biomarkers are substantial challenges for clinical trial design. Here, we evaluated the use of a commercially available fluorescent probe, Lysotracker, that can be used to measure the relative acidic compartment volume of circulating B cells as a potentially universal biomarker for LSDs. We validated this metric in a mouse model of the LSD Niemann-Pick type Cl disease (NPC1) and in a prospective 5-year international study of NPC patients. Pediatric NPC subjects had elevated acidic compartment volume that correlated with age-adjusted clinical severity and was reduced in response to therapy with miglustat, a European Medicines Agency-approved drug that has been shown to reduce NPC1-associated neuropathology. Measurement of relative acidic compartment volume was also useful for monitoring therapeutic responses of an NPC2 patient after bone marrow transplantation. Furthermore, this metric identified a potential adverse event in NPC1 patients receiving i.v. cycloclextrin therapy. Our data indicate that relative acidic compartment volume may be a useful biomarker to aid diagnosis, clinical monitoring, and evaluation of therapeutic responses in patients with lysosomal disorders. C1 [te Vruchte, Danielle; Speak, Anneliese O.; Wallom, Kerni L.; Al Eisa, Nada; Smith, David A.; Wassif, Christopher A.; Jeyakumar, Mylvaganam; Platt, Frances M.] Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England. [Hendriksz, Christian J.; Simmons, Louise] Birmingham Childrens Hosp, Birmingham, W Midlands, England. [Lachmann, Robin H.; Cousins, Alison] Natl Hosp Neurol & Neurosurg, London, England. [Hartung, Ralf; Runz, Heiko; Beck, Michael; Amraoui, Yasmina] Univ Med Ctr Mainz, Ctr Paediat & Adolescent Med, Dept Lysosomal Storage Disorder Villa Meta, Mainz, Germany. [Mengel, Eugen] Johannes Gutenberg Univ Mainz, Childrens Hosp, Med Ctr, Mainz, Germany. [Imrie, Jackie; Jacklin, Elizabeth; Riddick, Kate; Wraith, James E.] St Marys Hosp, Manchester M13 0JH, Lancs, England. [Yanjanin, Nicole M.; Wassif, Christopher A.; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Rolfs, Arndt; Rimmele, Florian] Univ Rostock, Albrecht Kossel Inst Neuroregenerat, D-18055 Rostock, Germany. [Wright, Naomi; Taylor, Clare; Ramaswami, Uma] Addenbrookes Hosp, Paediat Metab Unit, Cambridge, England. [Cox, Timothy M.] Univ Cambridge, Biomed Res Ctr Metabol Theme, Natl Inst Hlth Res, Cambridge, England. [Hastings, Caroline] Childrens Hosp & Res Ctr, Oakland, CA USA. [Jiang, Xuntian; Sidhu, Rohini; Ory, Daniel S.] Washington Univ, Sch Med, St Louis, MO USA. [Arias, Begona] Hosp Sanitas Zarzuela, Madrid, Spain. [Sillence, Daniel J.] De Montfort Univ, Sch Pharm, Leicester LE1 9BH, Leics, England. [Cortina-Borja, Mario] UCL, MRC Ctr Epidemiol Child Hlth, Inst Child Hlth, London WC1E 6BT, England. RP Platt, FM (reprint author), Univ Oxford, Dept Pharmacol, S Parks Rd, Oxford OX1 3QT, England. EM frances.platt@pharm.ox.ac.uk RI Cortina Borja, Mario/A-3847-2009; Sidhu, Rohini/G-3547-2012; OI Speak, Anneliese/0000-0003-4890-4685; Wassif, Christopher/0000-0002-2524-1420 FU Wellcome Trust [084631]; Action Medical Research [SP4203, SP3775]; NiemannPick Disease Group UK; Actelion; UK Medical Research Council (MRC) [G0700851]; SOAR-NPC; Niemann-Pick Research Foundation (NPRF); King Saud bin Abdulaziz University for Health Sciences; Ministry of Higher Education, Kingdom of Saudi Arabia FX We thank the patients and their families for participating in this study, members of the University of Oxford Department of Pharmacology for control blood donations, and our control pediatric blood sample donors. We also thank the Hadley Hope Foundation for funding control blood draws from anonymous pediatric and adult donors through a commercial provider in the United States. The flow cytometer was funded by The Wellcome Trust (084631). D. te Vruchte was supported by Action Medical Research (SP4203 and SP3775), with interim and additional support from the NiemannPick Disease Group UK and unrestricted educational grants from Actelion. A.O. Speak was funded by the UK Medical Research Council (MRC; G0700851). D.A. Smith was supported by SOAR-NPC and the Niemann-Pick Research Foundation (NPRF). N. Al Eisa was supported by King Saud bin Abdulaziz University for Health Sciences and the Ministry of Higher Education, Kingdom of Saudi Arabia. This work was supported in part by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and a Bench to Bedside grant supported by the Office of Rare Diseases and NIH Clinical Center (to F.D. Porter). N.M. Yanjanin was supported by Ara Parseghian Medical Research Foundation (APMRF) and Dana's Angels Research Trust (DART). The University College London Institute of Child Health receives a portion of its funding from the Department of Health's NIH Research Biomedical Research Centres funding scheme. M. Cortina-Borja's work on this study was undertaken at the Centre for Paediatric Epidemiology and Biostatistics at University College London, which benefits from funding support from the MRC in its capacity as the MRC Centre of Epidemiology for Child Health (supported by MRC grant G0400546). F.M. Platt is a Royal Society Wolfson Research Merit Award holder. We dedicate this manuscript to the memory of our colleague and greatly missed friend, Ed Wraith. NR 27 TC 10 Z9 10 U1 1 U2 8 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD MAR PY 2014 VL 124 IS 3 BP 1320 EP 1328 DI 10.1172/JCI72835 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AC2PZ UT WOS:000332347700046 PM 24487591 ER PT J AU Roh, J Knight, S Chung, JY Eo, SH Goggins, M Kim, J Cho, H Yu, E Hong, SM AF Roh, Jin Knight, Spencer Chung, Joon-Yong Eo, Soo-Heang Goggins, Michael Kim, Jihoon Cho, HyungJun Yu, Eunsil Hong, Seung-Mo TI S100A4 expression is a prognostic indicator in small intestine adenocarcinoma SO JOURNAL OF CLINICAL PATHOLOGY LA English DT Article ID MTS1 GENE OVEREXPRESSION; HUMAN BREAST-CANCER; SMALL-BOWEL CANCER; PROTEIN S100A4; COLORECTAL-CANCER; E-CADHERIN; THYROID-CARCINOMA; UNITED-STATES; METASTASIS; CALCIUM AB Aims Due to the rarity of small intestine adenocarcinoma (SIAC), estimating the prognosis for patients with surgically resected SIAC is difficult. Overexpression of S100A4 has been linked to worse patient survival in several malignant neoplasms, but its significance in SIAC has not been determined. Methods S100A4 protein expression was assessed in 197 surgically resected SIAC cases and compared with clinicopathological factors, including patient survival. Results A progressive increase in S100A4 labelling was observed in normal intestinal epithelium, adenoma and adenocarcinoma (p<0.001), and 50 SIAC cases (26.2%) showed strong S100A4 expression. Patients with SIAC with strong S100A4 expression had a higher pT classification (p=0.05), as well as increased lymph node metastasis (p=0.009) and perineural invasion (p=0.002). Patients with SIAC with strong S100A4 expression had significantly worse survival (median survival, 21 months) than those with weak/ no S100A4 expression (42.5 months) by univariable (p=0.04) and multivariable (p=0.01) analyses. Conclusions S100A4 overexpression is observed in a subset of SIACs, is associated with advanced disease and can be used as a prognostic indicator of poor prognosis in patients with SIAC. C1 [Roh, Jin; Kim, Jihoon; Yu, Eunsil; Hong, Seung-Mo] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul 138736, South Korea. [Knight, Spencer; Goggins, Michael] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Chung, Joon-Yong] NCI, Appl Mol Pathol Lab, Bethesda, MD 20892 USA. [Eo, Soo-Heang; Cho, HyungJun] Korea Univ, Dept Stat, Seoul, South Korea. RP Hong, SM (reprint author), Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, 88,Olymp Ro 43 Gil, Seoul 138736, South Korea. EM smhong28@gmail.com OI Hong, Seung-Mo/0000-0002-8888-6007; Chung, Joon-Yong/0000-0001-5041-5982 FU Asan Institute for Life Sciences, Seoul, Korea [2013-554] FX This research was funded by a grant (2013-554) from the Asan Institute for Life Sciences, Seoul, Korea. NR 31 TC 5 Z9 6 U1 0 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0021-9746 EI 1472-4146 J9 J CLIN PATHOL JI J. Clin. Pathol. PD MAR PY 2014 VL 67 IS 3 DI 10.1136/jclinpath-2013-201883 PG 6 WC Pathology SC Pathology GA AA8ID UT WOS:000331338300005 PM 24062356 ER PT J AU Bloise, FF de Oliveira, FL Nobrega, AF Vasconcellos, R Cordeiro, A de Paiva, LS Taub, DD Borojevic, R Pazos-Moura, CC de Mello-Coelho, V AF Bloise, Flavia Fonseca de Oliveira, Felipe Leite Nobrega, Alberto Felix Vasconcellos, Rita Cordeiro, Aline de Paiva, Luciana Souza Taub, Dennis D. Borojevic, Radovan Pazos-Moura, Carmen Cabanelas de Mello-Coelho, Valeria TI High levels of circulating triiodothyronine induce plasma cell differentiation SO JOURNAL OF ENDOCRINOLOGY LA English DT Article DE hyperthyroidism; B lymphocyte; plasma cell; thyroid hormone; spleen; bone marrow ID THYROID-HORMONE; GRAVES-DISEASE; BONE-MARROW; MESSENGER-RNA; RECEPTOR GENE; B-CELLS; PRO-B; EXPRESSION; AUTOIMMUNITY; SPLEEN AB The effects of hyperthyroidism on B-cell physiology are still poorly known. In this study, we evaluated the influence of high-circulating levels of 3,5,3'-triiodothyronine (T-3) on bone marrow, blood, and spleen B-cell subsets, more specifically on B-cell differentiation into plasma cells, in C57BL/6 mice receiving daily injections of T-3 for 14 days. As analyzed by flow cytometry, T-3-treated mice exhibited increased frequencies of pre-B and immature B-cells and decreased percentages of mature B-cells in the bone marrow, accompanied by an increased frequency of blood B-cells, splenic newly formed B-cells, and total CD19(+) B-cells. T-3 administration also promoted an increase in the size and cellularity of the spleen as well as in the white pulp areas of the organ, as evidenced by histological analyses. In addition, a decreased frequency of splenic B220(+) cells correlating with an increased percentage of CD138(+) plasma cells was observed in the spleen and bone marrow of T-3-treated mice. Using enzyme-linked immunospot assay, an increased number of splenic immunoglobulin-secreting B-cells from T-3-treated mice was detected ex vivo. Similar results were observed in mice immunized with hen egg lysozyme and aluminum adjuvant alone or together with treatment with T-3. In conclusion, we provide evidence that high-circulating levels of T-3 stimulate plasmacytogenesis favoring an increase in plasma cells in the bone marrow, a long-lived plasma cell survival niche. These findings indicate that a stimulatory effect on plasma cell differentiation could occur in untreated patients with Graves' disease. C1 [Bloise, Flavia Fonseca; de Oliveira, Felipe Leite; Borojevic, Radovan; de Mello-Coelho, Valeria] Univ Fed Rio de Janeiro, Inst Biomed Sci, Immunophysiol Lab, BR-21941902 Rio De Janeiro, Brazil. [Bloise, Flavia Fonseca; Cordeiro, Aline; Pazos-Moura, Carmen Cabanelas] Univ Fed Rio de Janeiro, Inst Biophys Carlos Chagas Filho, Immunophysiol Lab, BR-21941902 Rio De Janeiro, Brazil. [Nobrega, Alberto Felix] Univ Fed Rio de Janeiro, Inst Microbiol Paulo Goes, BR-21941902 Rio De Janeiro, Brazil. [de Paiva, Luciana Souza] Univ Fed Rio de Janeiro, Inst Med Biochem, BR-21941902 Rio De Janeiro, Brazil. [Vasconcellos, Rita; de Paiva, Luciana Souza] Univ Fed Fluminense, Inst Biol, BR-24210150 Niteroi, RJ, Brazil. [Taub, Dennis D.] NIA, NIH, Baltimore, MD 21224 USA. RP de Mello-Coelho, V (reprint author), Univ Fed Rio de Janeiro, Inst Biomed Sci, Immunophysiol Lab, BR-21941902 Rio De Janeiro, Brazil. EM coelhova@histo.ufrj.br RI Pazos Moura, Carmen/M-9256-2014; Bloise, Flavia/R-3127-2016; OI Pazos Moura, Carmen/0000-0003-3944-6491; Bloise, Flavia/0000-0002-5207-2896; Borojevic, Radovan/0000-0002-2393-7280 FU National Council of Technological and Scientific Development/CNPq; Research Support Foundation of the State of Rio de Janeiro/FAPERJ, Brazil; National Institute on Aging/NIH, USA; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Ministry of Education, Brazil FX This work was partially supported by the National Council of Technological and Scientific Development/CNPq; the Research Support Foundation of the State of Rio de Janeiro/FAPERJ, Brazil; and the National Institute on Aging/NIH, USA. F F B received a PhD fellowship from the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Ministry of Education, Brazil. Current address of Dr Dennis Taub: VA Medical Center, 50 Irving St. NW, Washington, DC 20422, USA. NR 56 TC 2 Z9 2 U1 0 U2 2 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 EI 1479-6805 J9 J ENDOCRINOL JI J. Endocrinol. PD MAR PY 2014 VL 220 IS 3 BP 305 EP 317 DI 10.1530/JOE-13-0315 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AC7FN UT WOS:000332693200013 PM 24363450 ER PT J AU Kashanchi, F Iordanskiy, S Van Duyne, R Sampey, G Fry, K Romerio, F AF Kashanchi, F. Iordanskiy, S. Van Duyne, R. Sampey, G. Fry, K. Romerio, F. TI Irradiation-induced cellular stress activates virus replication and apoptosis of HIV-1 infected cells in vitro and in vivo SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Meeting Abstract C1 [Kashanchi, F.; Iordanskiy, S.; Sampey, G.; Fry, K.] George Mason Univ, Natl Ctr Biodef & Infect Dis, Manassas, VA 20110 USA. [Van Duyne, R.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. [Romerio, F.] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 EI 1557-1904 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD MAR PY 2014 VL 9 IS 1 BP 27 EP 27 PG 1 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA AD3ER UT WOS:000333121600064 ER PT J AU Parsons, C Siggins, R Martinez, R Poretta, C Zea, A Bagby, G Nelson, S Polhemus, D Lefer, D Whitby, D Doyle, L Molina, P Parsons, C AF Parsons, C. Siggins, R. Martinez, R. Poretta, C. Zea, A. Bagby, G. Nelson, S. Polhemus, D. Lefer, D. Whitby, D. Doyle, L. Molina, P. Parsons, C. TI Alcohol and an Oncogenic Herpesvirus-Potential Partners in Cancer Pathogenesis SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Meeting Abstract C1 [Parsons, C.; Siggins, R.; Martinez, R.; Poretta, C.; Zea, A.; Bagby, G.; Nelson, S.; Molina, P.] Louisiana State Univ, Hlth Sci Ctr, Comprehens Alcohol Res Ctr, New Orleans, LA 70112 USA. [Polhemus, D.; Lefer, D.] Louisiana State Univ, Hlth Sci Ctr, Cardiovasc Res Ctr, New Orleans, LA 70112 USA. [Whitby, D.] NCI, Epidemiol Branch, Frederick, MD 21702 USA. [Doyle, L.; Parsons, C.] Louisiana State Univ, Hlth Sci Ctr, HIV Malignancies Program, New Orleans, LA 70112 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 EI 1557-1904 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD MAR PY 2014 VL 9 IS 1 BP 43 EP 43 PG 1 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA AD3ER UT WOS:000333121600108 ER PT J AU Steiner, JP Nath, A AF Steiner, Joseph P. Nath, Avindra TI Neurotrophin Strategies for Neuroprotection: Are They Sufficient? SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Review DE Degeneration; Neurons; Neurotrophin; Neuroprotection ID FACTOR MESSENGER-RNA; INCREASES BDNF LEVELS; AMYOTROPHIC-LATERAL-SCLEROSIS; FOCAL CEREBRAL-ISCHEMIA; TRAUMATIC BRAIN-INJURY; FACTOR GENE-EXPRESSION; SPINAL-CORD-INJURY; UP-REGULATES BDNF; HUNTINGTONS-DISEASE; RAT HIPPOCAMPUS AB As people are living longer, the prevalance of neurodegenerative diseases continues to rise resulting in huge socio-economic consequences. Despite major advancements in studying the pathophysiology of these diseases and a large number of clinical trials currently there is no effective treatment for these illnesses. All neuroprotective strategies have either failed or have shown only a minimal effect. There has been a major shift in recent years exploring the potential of neuroregenerative approaches. While the concept of using neurotropins for therapeutic purposes has been in existence for many years, new modes of delivery and expression of this family of molecules makes this approach now feasilble. Further neurotropin mimetics and receptor agonists are also being developed. The use of small molecules to induce the expression of neurotropins including repurposing of FDA approved drugs for this approach is another strategy being pursued. In the review we examine these new developments and discuss the potential for such approaches in the context of the pathophysiology of neurodegenerative diseases. C1 [Steiner, Joseph P.; Nath, Avindra] NINDS, Translat Neurosci Ctr, NIH, Bethesda, MD 20892 USA. [Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. RP Steiner, JP (reprint author), NINDS, Translat Neurosci Ctr, NIH, Room 7C-105,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM steinerjp@mail.nih.gov NR 150 TC 7 Z9 9 U1 2 U2 19 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 EI 1557-1904 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD MAR PY 2014 VL 9 IS 2 BP 182 EP 194 DI 10.1007/s11481-014-9533-5 PG 13 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA AD3EV UT WOS:000333122000011 PM 24609976 ER PT J AU Zilbermint, M Ramnitz, MS Lodish, MB Kanaka-Gantenbein, C Kattamis, A Lyssikatos, C Patronas, NJ Quezado, MM Stratakis, CA AF Zilbermint, Mihail Ramnitz, Mary S. Lodish, Maya B. Kanaka-Gantenbein, Christina Kattamis, Antonis Lyssikatos, Charalampos Patronas, Nicholas J. Quezado, Martha M. Stratakis, Constantine A. TI Pituitary stalk lesion in a 13-year-old female SO JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM LA English DT Article DE germ-cell tumor; germinoma; pituitary stalk lesion ID GERM-CELL TUMORS; CENTRAL DIABETES-INSIPIDUS; RADIATION-THERAPY; CHILDREN AB Germinomas presenting with a pituitary stalk lesion and panhypopituitarism are rare in children, and their definite diagnosis is challenging. An invasive diagnostic approach, such as a transsphenoidal biopsy, is often required prior to establishing a treatment regimen. A 13-year-old female presented with 1 year of secondary amenorrhea, fatigue, and progressive thirst with polyuria. Laboratory work-up revealed panhypopituitarism (central hypothyroidism, hypogonadotropic hypogonadism, adrenal insufficiency and central diabetes insipidus). alpha-Fetoprotein and beta-human chorionic gonadotropin were not elevated in serum nor in cerebrospinal fluid. The magnetic resonance imaging (MRI) of the pituitary region showed an enhancing infundibular lesion, extending into the hypothalamus, and infiltrating the pituitary gland. A transsphenoidal biopsy of the infundibular lesion confirmed the diagnosis of germinoma (germ-cell tumor). After appropriate hormone replacement therapy, chemotherapy and low-dose radiation therapy, the patient achieved complete resolution of the pituitary stalk lesion on the MRI. C1 [Ramnitz, Mary S.; Lodish, Maya B.; Lyssikatos, Charalampos; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Zilbermint, Mihail] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Kanaka-Gantenbein, Christina; Kattamis, Antonis] Univ Athens, Sch Med, Dept Pediat 1, Aghia Sophia Childrens Hosp, GR-11527 Athens, Greece. [Patronas, Nicholas J.] NIH, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Quezado, Martha M.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bldg 10 CRC 1-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development [1997-CH-0076, NCT00001595] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development, protocol 1997-CH-0076 (ClinicalTrials.gov Identifier: NCT00001595). These organizations had no further role in the collection, analysis and interpretation of data; in the writing of the report, and in the decision to submit the paper for publication. The principal investigator had full access to all the data in the case and takes responsibility for the integrity of the data and the accuracy of the data interpretation. NR 10 TC 1 Z9 1 U1 0 U2 1 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0334-018X EI 2191-0251 J9 J PEDIATR ENDOCR MET JI J. Pediatr. Endocrinol. Metab. PD MAR PY 2014 VL 27 IS 3-4 BP 359 EP 362 DI 10.1515/jpem-2013-0274 PG 4 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA AC5AI UT WOS:000332532400024 PM 24129100 ER PT J AU Hernandez-Andrade, E Romero, R Korzeniewski, SJ Ahn, H Aurioles-Garibay, A Garcia, M Schwartz, AG Yeo, L Chaiworapongsa, T Hassan, SS AF Hernandez-Andrade, Edgar Romero, Roberto Korzeniewski, Steven J. Ahn, Hyunyoung Aurioles-Garibay, Alma Garcia, Maynor Schwartz, Alyse G. Yeo, Lami Chaiworapongsa, Tinnakorn Hassan, Sonia S. TI Cervical strain determined by ultrasound elastography and its association with spontaneous preterm delivery SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Cervical elasticity; cervical length; prematurity; short cervix; stiffness ID SONOGRAPHIC SHORT CERVIX; LIGHT-INDUCED FLUORESCENCE; CONNECTIVE-TISSUE CHANGES; PLACEBO-CONTROLLED TRIAL; HUMAN UTERINE CERVIX; VAGINAL PROGESTERONE; ELASTIC PROPERTIES; DOUBLE-BLIND; IN-VIVO; SINGLETON PREGNANCIES AB Objective: To determine if there is an association between cervical strain, evaluated using ultrasound elastography, and spontaneous preterm delivery (sPTD) <37 weeks of gestation. Methods: One hundred and eighty nine (189) women at 16-24 weeks of gestation were evaluated. Ultrasound elastography was used to estimate cervical strain in three anatomical planes: one mid-sagittal in the same plane used for cervical length measurement, and two cross sectional images: one at the level of the internal cervical os, and the other at the level of the external cervical os. In each plane, two regions of interest (endocervix and entire cervix) were examined; a total of six regions of interest were evaluated. Results: The prevalence of sPTD was 11% (21/189). Strain values from each of the six cervical regions correlated weakly with cervical length (from r=-0.24, P<0.001 to r=-0.03, P=0.69). Strain measurements obtained in a cross sectional view of the internal cervical os were significantly associated with sPTD. Women with strain values <= 25th centile in the endocervical canal (0.19) and in the entire cervix (0.14) were 80% less likely to have a sPTD than women with strain values >25th centile [endocervical: odds ratio (OR) 0.2; 95% confidence interval (CI), 0.03-0.96; entire cervix: OR 0.17; 95% CI, 0.03-0.9]. Additional adjustment for gestational age, race, smoking status, parity, maternal age, pre-pregnancy body mass index, and previous preterm delivery did not appreciably alter the magnitude or statistical significance of these associations. Strain values obtained from the external cervical os and from the sagittal view were not associated with sPTD. Conclusion: Low strain values in the internal cervical os were associated with a significantly lower risk of spontaneous preterm delivery <37 weeks of gestation. C1 [Hernandez-Andrade, Edgar; Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, Detroit, MI 48201 USA. [Hernandez-Andrade, Edgar; Korzeniewski, Steven J.; Ahn, Hyunyoung; Aurioles-Garibay, Alma; Garcia, Maynor; Schwartz, Alyse G.; Yeo, Lami; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Hernandez-Andrade, Edgar; Romero, Roberto; Korzeniewski, Steven J.; Ahn, Hyunyoung; Aurioles-Garibay, Alma; Garcia, Maynor; Schwartz, Alyse G.; Yeo, Lami; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Hernandez-Andrade, Edgar; Korzeniewski, Steven J.; Ahn, Hyunyoung; Aurioles-Garibay, Alma; Garcia, Maynor; Schwartz, Alyse G.; Yeo, Lami; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. RP Hernandez-Andrade, E (reprint author), Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM ehernand@med.wayne.edu; romeror@mail.nih.gov FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); Federal funds from NICHD, NIH [HHSN275201300006C] FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); and, in part, with Federal funds from NICHD, NIH under Contract No. HHSN275201300006C. The ultrasound experience and technical support of senior Registered Diagnostic Medical Sonographers (RDMS), Mrs. Catherine Ducharme and Mrs. Denise Haggerty are gratefully acknowledged. NR 132 TC 18 Z9 18 U1 1 U2 8 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 EI 1619-3997 J9 J PERINAT MED JI J. Perinat. Med. PD MAR PY 2014 VL 42 IS 2 BP 159 EP 169 DI 10.1515/jpm-2013-0277 PG 11 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA AC9GX UT WOS:000332843500003 PM 24356388 ER PT J AU Shang, F Wilmarth, PA Chang, ML Liu, K David, LL Caceres, MA Wawrousek, E Taylor, A AF Shang, Fu Wilmarth, Phillip A. Chang, Min-lee Liu, Ke David, Larry L. Caceres, Maria Andrea Wawrousek, Eric Taylor, Allen TI Newborn Mouse Lens Proteome and Its Alteration by Lysine 6 Mutant Ubiquitin SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE proteomics; mass spectrometry; mouse lens; nuclear cataract; ubiquitin; proteasome ID PIGMENT EPITHELIAL-CELLS; PROTEASOME PATHWAY; NUCLEAR CATARACTS; QUALITY CONTROL; B-CRYSTALLIN; EYE LENS; PROTEINS; MUTATION; DEGRADATION; EXPRESSION AB Ubiquitin is a tag that often initiates degradation of proteins by the proteasome in the ubiquitin proteasome system. Targeted expression of K6W mutant ubiquitin (K6W-Ub) in the lens results in defects in lens development and cataract formation, suggesting critical functions for ubiquitin in lens. To study the developmental processes that require intact ubiquitin, we executed the most extensive characterization of the lens proteome to date. We quantified lens protein expression changes in multiple replicate pools of PI wild-type and K6W-Ub-expressing mouse lenses. Lens proteins were digested with trypsin, peptides were separated using strong cation exchange and reversed-phase liquid chromatography, and tandem mass (MS/MS) spectra were collected with a linear ion trap. Transgenic mice that expressed low levels of K6W-Ub (low expressers) had normal, clear lenses at birth, whereas the lenses that expressed high levels of K6W-Ub (higher expressers) had abnormal lenses and cataracts at birth. A total of 2052 proteins were identified, of which 996 were reliably quantified and compared between wild-type and K6W-Ub transgenic mice. Consistent with a delayed developmental program, fiber-cell-specific proteins, such as gamma-crystallins (gamma A, gamma B, gamma C, and gamma E), were down-regulated in K6W-Ub higher expressers. Up-regulated proteins were involved in energy metabolism, signal transduction, and proteolysis. The K6W-Ub low expressers exhibited delayed onset and milder cataract consistent with smaller changes in protein expression. Because lens protein expression changes occurred prior to lens morphological abnormalities and cataract formation in K6W-Ub low expressers, it appears that expression of K6W-Ub sets in motion a process of altered protein expression that results in developmental defects and cataract. C1 [Shang, Fu; Chang, Min-lee; Liu, Ke; Caceres, Maria Andrea; Taylor, Allen] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Wilmarth, Phillip A.; David, Larry L.] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97239 USA. [Wawrousek, Eric] NEI, Genet Engn Core, NIH, Bethesda, MD 20892 USA. RP Shang, F (reprint author), Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, 711 Washington Steet, Boston, MA 02111 USA. EM fu.shang@tufts.edu; allen.taylor@tufts.edu FU NIH [EY 013250, EY 021212, EY 011717, EY 007755, EY 010572]; USDA [1950-510000-060-01A] FX This work is supported by NIH grants EY 013250, EY 021212, EY 011717, EY 007755, and EY 010572 and USDA contract 1950-510000-060-01A. NR 69 TC 1 Z9 1 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD MAR PY 2014 VL 13 IS 3 BP 1177 EP 1189 DI 10.1021/pr400801v PG 13 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AC8AV UT WOS:000332756300002 PM 24450463 ER PT J AU Uzasci, L Bianchet, MA Cotter, RJ Nath, A AF Uzasci, Lerna Bianchet, Mario A. Cotter, Robert J. Nath, Avindra TI Identification of Nitrated Immunoglobulin Variable Regions in the HIV-Infected Human Brain: Implications in HIV Infection and Immune Response SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE HIV; nitroproteome; HIV-associated neurocognitive disorders; nitration; mass spectrometry; antibody; immune response ID PROTEIN-TYROSINE NITRATION; NEUROCOGNITIVE DISORDERS; STRUCTURAL BASIS; PEROXYNITRITE; ANTIBODY; DEMENTIA; NEUTRALIZATION; THERAPEUTICS; TRYPTOPHAN; SULFATION AB HIV can infiltrate the brain and lead to HIV-associated neurocognitive disorders (HAND). The pathophysiology of HAND is poorly understood, and there are no diagnostic biomarkers for it. Previously, an increase in inducible nitric oxide synthase levels and protein tyrosine nitration in the brain were found to correlate with the severity of HAND.(1,2) In this study, we analyzed human brains from individuals who had HIV infection without encephalitis and with encephalitis/HAND and compared them to the brains of healthy individuals. We identified the nitrated proteins and determined the sites of modification using affinity enrichment followed by high-resolution and high-mass-accuracy nanoLC-MS/MS. We found that nitrated proteins were predominantly present in the HIV-infected individuals with encephalitis, and, interestingly, the modifications were predominantly located on immunoglobulin variable regions. Our molecular model indicated potential interactions with HIV envelope proteins and changes on the heavy and light chain interface upon the nitration and nitrohydroicylation of these residues.. Therefore, our findings suggest a role for these modifications in the immune response, which may have implications in disease pathogenesis. C1 [Uzasci, Lerna; Cotter, Robert J.] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Bianchet, Mario A.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. RP Uzasci, L (reprint author), Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. EM lerna.uzasci@nih.gov RI Bianchet, Mario/K-2131-2015 OI Bianchet, Mario/0000-0001-9032-7549 FU National Institute of Neurological Disorders and Stroke [R01NS039253]; intramural NIH funds FX R.J.C M.A.B., and L.U. were supported by grant R01NS039253 (to R.J.C.) from the National Institute of Neurological Disorders and Stroke. A.N. is supported by intramural NIH funds. We thank the Johns Hopkins School of Medicine Mass Spectrometry and Proteomics Facility for technical assistance and Drs. Stefani NR 49 TC 4 Z9 4 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD MAR PY 2014 VL 13 IS 3 BP 1614 EP 1623 DI 10.1021/pr401117m PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AC8AV UT WOS:000332756300040 PM 24479669 ER PT J AU Miglioretti, DL Zhang, Y Johnson, E Lee, C Morin, RL Vanneman, N Smith-Bindman, R AF Miglioretti, Diana L. Zhang, Yue Johnson, Eric Lee, Choonsik Morin, Richard L. Vanneman, Nicholas Smith-Bindman, Rebecca TI Personalized Technologist Dose Audit Feedback for Reducing Patient Radiation Exposure From CT SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE CT; radiation exposure; audit feedback; radiologic technologists ID COMPUTED-TOMOGRAPHY; QUANTILE REGRESSION; CAMPAIGN AB Purpose: The aim of this study was to determine whether providing radiologic technologists with audit feedback on doses from CT examinations they conduct and education on dose-reduction strategies reduces patients' radiation exposure. Methods: This prospective, controlled pilot study was conducted within an integrated health care system from November 2010 to October 2011. Ten technologists at 2 facilities received personalized dose audit reports and education on dose-reduction strategies; 9 technologists at a control facility received no intervention. Radiation exposure was measured by the dose-length product (DLP) from CT scans performed before (n = 1,630) and after (n = 1,499) the intervention and compared using quantile regression. Technologists were surveyed before and after the intervention. Results: For abdominal CT, DLPs decreased by 3% to 12% at intervention facilities but not at the control facility. For brain CT, DLPs significantly decreased by 7% to 12% at one intervention facility; did not change at the second intervention facility, which had the lowest preintervention DLPs; and increased at the control facility. Technologists were more likely to report always thinking about radiation exposure and associated cancer risk and optimizing settings to reduce exposure after the intervention. Conclusions: Personalized audit feedback and education can change technologists' attitudes about, and awareness of, radiation and can lower patient radiation exposure from CT imaging. C1 [Miglioretti, Diana L.] Univ Calif Davis, Div Biostat, Dept Publ Hlth Sci, Davis, CA 95616 USA. [Miglioretti, Diana L.; Johnson, Eric; Vanneman, Nicholas] Grp Hlth Res Inst, Seattle, WA USA. [Zhang, Yue] Univ Utah, Dept Internal Med, Div Epidemiol, Salt Lake City, UT 84112 USA. [Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Morin, Richard L.] Mayo Clin, Dept Radiol, Jacksonville, FL 32224 USA. [Smith-Bindman, Rebecca] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Smith-Bindman, Rebecca] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Smith-Bindman, Rebecca] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA USA. RP Miglioretti, DL (reprint author), Univ Calif Davis, Sch Med, Dept Publ Hlth Sci, One Shields Ave,Med Sci 1C,Room 144, Davis, CA 95616 USA. EM dmiglioretti@ucdavis.edu RI Lee, Choonsik/C-9023-2015 OI Lee, Choonsik/0000-0003-4289-9870 FU Group Health Foundation FX The Group Health Foundation supported this study as part of its Partnership for Innovations program. Mark Steffen, Carl Mayberry, Ron Becker, and David Hillier, MD, from the Group Health Radiology Service Line provided valuable information on the performance of CT at the participating facilities and supported the intervention planning and conduct. The authors thank Julianne Endres and Deborah Seger of Group Health Research Institute for their valuable assistance in gathering radiologic data for this study. Chris Tachibana, PhD, from Group Health Research Institute provided scientific editing. Yue Zhang, PhD, and Nicholas Vanneman, MA, were with the Group Health Research Institute when this research was conducted. NR 21 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD MAR PY 2014 VL 11 IS 3 BP 300 EP 308 DI 10.1016/j.jacr.2013.10.017 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AC2SR UT WOS:000332354800022 PM 24589406 ER PT J AU Dayan, E Averbeck, BB Richmond, BJ Cohen, LG AF Dayan, Eran Averbeck, Bruno B. Richmond, Barry J. Cohen, Leonardo G. TI Stochastic reinforcement benefits skill acquisition SO LEARNING & MEMORY LA English DT Article ID UNCERTAINTY; REWARD; ATTENTION; MODEL; STIMULATION; KNOWLEDGE; MEMORY AB Learning complex skills is driven by reinforcement, which facilitates both online within-session gains and retention of the acquired skills. Yet, in ecologically relevant situations, skills are often acquired when mapping between actions and rewarding outcomes is unknown to the learning agent, resulting in reinforcement schedules of a stochastic nature. Here we trained subjects on a visuomotor learning task, comparing reinforcement schedules with higher, lower, or no stochasticity. Training under higher levels of stochastic reinforcement benefited skill acquisition, enhancing both online gains and long-term retention. These findings indicate that the enhancing effects of reinforcement on skill acquisition depend on reinforcement schedules. C1 [Dayan, Eran; Cohen, Leonardo G.] NINDS, Human Cort Physiol & Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. [Averbeck, Bruno B.; Richmond, Barry J.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Dayan, E (reprint author), NINDS, Human Cort Physiol & Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. EM dayane@ninds.nih.gov OI Dayan, Eran/0000-0001-9710-9210 FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health FX We thank G. Dold, G. Melvin, A. Harris, J. Hamann, and K. Zherdeva for technical help and N. Censor, B. Almog, H. Schambra, J. Reis, and Y. Niv for helpful suggestions. This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 32 TC 7 Z9 7 U1 0 U2 7 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1072-0502 EI 1549-5485 J9 LEARN MEMORY JI Learn. Mem. PD MAR PY 2014 VL 21 IS 3 BP 140 EP 142 DI 10.1101/lm.032417.113 PG 3 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA AD3ZD UT WOS:000333184100003 PM 24532838 ER PT J AU Bryan, FW Xu, ZB Asman, AJ Allen, WM Reich, DS Landman, BA AF Bryan, Frederick W. Xu, Zhoubing Asman, Andrew J. Allen, Wade M. Reich, Daniel S. Landman, Bennett A. TI Self-assessed performance improves statistical fusion of image labels SO MEDICAL PHYSICS LA English DT Article DE STAPLE; self-assessment; confidence; WebMill; rater model ID BRAIN-TUMOR SEGMENTATION; SPATIALLY VARYING PERFORMANCE; CLASSIFIER COMBINATION; EM ALGORITHM; ATLAS; MODEL; VALIDATION; SIMILARITY; FRAMEWORK; STAPLE AB Purpose: Expert manual labeling is the gold standard for image segmentation, but this process is difficult, time-consuming, and prone to inter-individual differences. While fully automated methods have successfully targeted many anatomies, automated methods have not yet been developed for numerous essential structures (e. g., the internal structure of the spinal cord as seen on magnetic resonance imaging). Collaborative labeling is a new paradigm that offers a robust alternative that may realize both the throughput of automation and the guidance of experts. Yet, distributing manual labeling expertise across individuals and sites introduces potential human factors concerns (e. g., training, software usability) and statistical considerations (e. g., fusion of information, assessment of confidence, bias) that must be further explored. During the labeling process, it is simple to ask raters to self-assess the confidence of their labels, but this is rarely done and has not been previously quantitatively studied. Herein, the authors explore the utility of self-assessment in relation to automated assessment of rater performance in the context of statistical fusion. Methods: The authors conducted a study of 66 volumes manually labeled by 75 minimally trained human raters recruited from the university undergraduate population. Raters were given 15 min of training during which they were shown examples of correct segmentation, and the online segmentation tool was demonstrated. The volumes were labeled 2D slice-wise, and the slices were unordered. A self-assessed quality metric was produced by raters for each slice by marking a confidence bar superimposed on the slice. Volumes produced by both voting and statistical fusion algorithms were compared against a set of expert segmentations of the same volumes. Results: Labels for 8825 distinct slices were obtained. Simple majority voting resulted in statistically poorer performance than voting weighted by self-assessed performance. Statistical fusion resulted in statistically indistinguishable performance from self-assessed weighted voting. The authors developed a new theoretical basis for using self-assessed performance in the framework of statistical fusion and demonstrated that the combined sources of information (both statistical assessment and self-assessment) yielded statistically significant improvement over the methods considered separately. Conclusions: The authors present the first systematic characterization of self-assessed performance in manual labeling. The authors demonstrate that self-assessment and statistical fusion yield similar, but complementary, benefits for label fusion. Finally, the authors present a new theoretical basis for combining self-assessments with statistical label fusion. c 2014 American Association of Physicists in Medicine. C1 [Bryan, Frederick W.; Xu, Zhoubing; Asman, Andrew J.; Allen, Wade M.; Landman, Bennett A.] Vanderbilt Univ, Nashville, TN 37235 USA. [Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, NIH, Bethesda, MD 20892 USA. RP Bryan, FW (reprint author), Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. EM frederick.w.bryan@vanderbilt.edu RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 FU NIH [1R21NS064534, 1R03EB012461, 1T32EB014841]; NIH/NINDS Intramural Research Program; National Multiple Sclerosis Society FX The authors are grateful for the imaging sequences developed by Dr. Seth Smith and acquired by Peter Calebresi. The authors would also like to thank the WebMill and secondary study volunteers for their time and effort. This research was supported by in part by NIH 1R21NS064534, NIH 1R03EB012461, NIH 1T32EB014841, the NIH/NINDS Intramural Research Program, and the National Multiple Sclerosis Society (Peter Calabresi). The authors appreciate the insightful comments and assistance of the editors in improving this paper. NR 36 TC 1 Z9 1 U1 0 U2 9 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD MAR PY 2014 VL 41 IS 3 AR 031903 DI 10.1118/1.4864236 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AC4IW UT WOS:000332485600019 PM 24593721 ER PT J AU Shufelt, CL Merz, CNB Prentice, RL Pettinger, MB Rossouw, JE Aroda, VR Kaunitz, AM Lakshminarayan, K Martin, LW Phillips, LS Manson, JE AF Shufelt, Chrisandra L. Merz, C. Noel Bairey Prentice, Ross L. Pettinger, Mary B. Rossouw, Jacques E. Aroda, Vanita R. Kaunitz, Andrew M. Lakshminarayan, Kamakshi Martin, Lisa W. Phillips, Lawrence S. Manson, JoAnn E. TI Hormone therapy dose, formulation, route of delivery, and risk of cardiovascular events in women: findings from the Women's Health Initiative Observational Study SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE Menopause hormone therapy; Cardiovascular disease; Stroke ID RANDOMIZED CONTROLLED-TRIAL; ESTROGEN PLUS PROGESTIN; CORONARY-HEART-DISEASE; POSTMENOPAUSAL WOMEN; CLINICAL-TRIAL; REPLACEMENT; MENOPAUSE; STATEMENT; SOCIETY; STROKE AB Objective Research comparing hormone therapy (HT) doses, regimens, and routes of delivery in relation to cardiovascular disease (CVD) outcomes has been limited. This study directly compared different estrogen doses, routes of delivery, and HT formulations in postmenopausal women in relation to the risk of coronary heart disease (CHD), stroke, CVD mortality, total CVD, and all-cause mortality. Methods The Women's Health Initiative Observational Study is a multicenter prospective cohort study that was conducted at 40 US sites. Analyses included 93,676 postmenopausal women aged 50 to 79 years at study entry who were recruited from September 1994 to December 1998, with annual follow-up through August 14, 2009. Results The mean follow-up was 10.4 years. In direct comparisons, oral estradiol was associated with lower hazard ratios (HRs) for stroke than oral conjugated equine estrogens (CEE; HR, 0.64; 95% CI, 0.40-1.02), but statistical power was limited. Similarly, transdermal estradiol was associated with a moderate but nonsignificantly lower risk of CHD compared with oral CEE (HR, 0.63; 95% CI, 0.37-1.06). For other outcomes, comparisons revealed no appreciable differences by estrogen doses, formulations, or routes of delivery. Absolute risks of CVD events and all-cause mortality were markedly lower in younger women compared with older women. Conclusions In direct comparisons, various HT doses and regimens are associated with similar rates of cardiovascular events and all-cause mortality. However, oral estradiol may be associated with a lower risk of stroke, and transdermal estradiol may be associated with a lower risk of CHD, compared with conventional-dose oral CEE. Additional research is needed to confirm these hypotheses. C1 [Shufelt, Chrisandra L.; Merz, C. Noel Bairey] Cedars Sinai Heart Inst, Barbra Streisand Womens Heart Ctr, Los Angeles, CA USA. [Prentice, Ross L.; Pettinger, Mary B.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Rossouw, Jacques E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Aroda, Vanita R.] MedStar Hlth Res Inst, Hyattsville, MD USA. [Kaunitz, Andrew M.] Univ Florida, Coll Med Jacksonville, Jacksonville, FL USA. [Lakshminarayan, Kamakshi] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Martin, Lisa W.] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. [Phillips, Lawrence S.] Atlanta VA Med Ctr, Decatur, GA USA. [Phillips, Lawrence S.] Emory Univ, Sch Med, Dept Med, Div Endocrinol & Metab, Atlanta, GA USA. [Manson, JoAnn E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, Boston, MA 02115 USA. RP Shufelt, CL (reprint author), Suite 740 East,8631 West Third St, Los Angeles, CA 90048 USA. EM Chrisandra.Shufelt@cshs.org OI Martin, Lisa Warsinger/0000-0003-4352-0914 FU National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; General Clinical Research Center from the National Center for Research Resources [MO1-RR00425]; Clinical and Translational Sciences Institute [UL1TR000124]; Edythe L. Broad Women's Heart Research Fellowship (Cedars-Sinai Medical Center); Barbra Streisand Women's Cardiovascular Research and Education Program (Cedars-Sinai Medical Center); Bayer; Noven; Teva; Gilead; Eli Lilly; Novo Nordisk; PhaseBio; Amylin; Roche; Takeda; Sanofi-Aventis; GI Dynamics; GSK; Boehringer Ingelheim; N-Gene; Bristol-Myers Squibb FX The Women's Health Initiative program was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. This work was supported by General Clinical Research Center grant MO1-RR00425 from the National Center for Research Resources, Clinical and Translational Sciences Institute grant UL1TR000124, the Edythe L. Broad Women's Heart Research Fellowship (Cedars-Sinai Medical Center), and the Barbra Streisand Women's Cardiovascular Research and Education Program (Cedars-Sinai Medical Center).; A.M.K. has received research funding (to the institution) from Bayer, Noven, and Teva, and has served on the advisory boards of Bayer and Noven. C. N. B. M. has received research funding (to the institution) from Gilead and consulting money from Bristol-Myers Squibb for Data Safety Monitoring Board service, and has served on the advisory board of Abbott Vascular. L. S. P. has received research funding from Eli Lilly, Novo Nordisk, PhaseBio, Amylin, and Roche, and has served on the advisory board of Boehringer Mannheim. V. R. A. has served as consultant to Novo Nordisk and Sanofi-Aventis, and has received grants from Takeda, Novo Nordisk, Sanofi-Aventis, GI Dynamics, Amylin, GSK, Boehringer Ingelheim, and N-Gene. NR 20 TC 22 Z9 22 U1 1 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 MAR PY 2014 VL 21 IS 3 BP 260 EP 266 DI 10.1097/GME.0b013e31829a64f9 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AC5YS UT WOS:000332597500012 PM 24045672 ER PT J AU Tinelli, A Mettler, L Malvasi, A Hurst, B Catherino, W Mynbaev, OA Guido, M Alkatout, I Schollmeyer, T AF Tinelli, Andrea Mettler, Liselotte Malvasi, Antonio Hurst, Brad Catherino, William Mynbaev, Ospan A. Guido, Marcello Alkatout, Ibrahim Schollmeyer, Thoralf TI Impact of surgical approach on blood loss during intracapsular myomectomy SO MINIMALLY INVASIVE THERAPY & ALLIED TECHNOLOGIES LA English DT Review DE Uterine myomas; fibroids; myomectomy; laparoscopy; fertility; complications; carbon dioxide pneumoperitoneum; peritoneal trauma ID CARBON-DIOXIDE PNEUMOPERITONEUM; UTERINE FIBROID PSEUDOCAPSULE; LAPAROSCOPIC MYOMECTOMY; ABDOMINAL MYOMECTOMY; INTRAABDOMINAL PRESSURE; CO2 PNEUMOPERITONEUM; MYOMAS; INSUFFLATION; MULTICENTER; MODEL AB Background: Myomectomy is one of the most common surgical procedures in gynecology and has implications on fertility and subsequent pregnancies. We compared the impact of surgical approach on blood loss during laparoscopic and abdominal intracapsular myomectomy. Material and methods: The evaluation comprised 124 fertile women with subserous or intramural myomas: 66 patients treated by laparoscopy and 58 patients treated by laparotomy. The intracapsular myoma enucleation technique was similar for both approaches. All procedures were analyzed for the evaluation of intra- and postsurgical blood loss and intra-and short-term post-operative surgical outcomes. Results: The operating time for laparoscopic intracapsular myomectomy was longer (95 +/- 7.2 min vs. 63 +/- 5.6, p < 0.0001), but was associated with reduced intra- (65 +/- ml vs. 105 +/- 5, p < 0.0001) and post-surgical blood loss (30 +/- 5 vs. 60 +/- 5 ml, p < 0.0001), as well as diminished application of pain relief medication (8 patients vs. 17, p < 0.05), compared to open intracapsular myomectomy. Conclusions: The surgical approach did not substantially affect the technique of intracapsular myomectomy; however, laparoscopy significantly reduced intra-and postoperative blood loss and resulted in better short-term outcomes than after open surgery. Our results underscore the advantages of trying to reduce the rate of laparotomic myomectomy, one of the leading surgical interventions associated with infertility and sterility. C1 [Tinelli, Andrea] Vito Fazzi Hosp, Dept Obstet & Gynecol, Lecce, Italy. [Mettler, Liselotte; Alkatout, Ibrahim; Schollmeyer, Thoralf] Univ Hosp Schleswig Holstein, Kiel Sch Gynaecol Endoscopy, Dept Obstet & Gynaecol, D-24105 Kiel, Germany. [Malvasi, Antonio] Hosp Santa Maria, Dept Obstet & Gynecol, Bari, Italy. [Hurst, Brad] Carolinas Med Ctr, Assisted Reprod Ctr, Charlotte, NC 28203 USA. [Catherino, William] USUHS, Dept Obstet & Gynecol, Bethesda, MD USA. [Catherino, William] NICHD, Div REI, PRAE, NIH, Bethesda, MD USA. [Mynbaev, Ospan A.] Moscow State Univ Med & Dent, Expt Res & Modelling Div, Moscow, Russia. [Guido, Marcello] Univ Salento, Fac Sci, Dept Biol & Environm Sci & Technol, Hyg Lab, Lecce, Italy. RP Mettler, L (reprint author), Univ Hosp Schleswig Holstein, Kiel Sch Gynaecol Endoscopy, Dept Obstet & Gynaecol, Campus Kiel,Arnold Heller Str 3,House 24, D-24105 Kiel, Germany. EM kiel.school@uksh.de RI Mynbaev, Ospan/K-5326-2013; OI Mynbaev, Ospan/0000-0002-9309-1938; Malvasi, Antonio/0000-0001-6940-7608; Tinelli, Andrea/0000-0001-8426-8490 NR 33 TC 8 Z9 8 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1364-5706 EI 1365-2931 J9 MINIM INVASIV THER JI Minim. Invasive Ther. Allied Technol. PD MAR PY 2014 VL 23 IS 2 BP 87 EP 95 DI 10.3109/13645706.2013.839951 PG 9 WC Surgery SC Surgery GA AD2WL UT WOS:000333096800004 PM 24044380 ER PT J AU Kuzu, G Keskin, O Nussinov, R Gursoy, A AF Kuzu, Guray Keskin, Ozlem Nussinov, Ruth Gursoy, Attila TI Modeling Protein Assemblies in the Proteome SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID MOLECULAR-SURFACE RECOGNITION; DOCKING ALGORITHM; MACROMOLECULAR ASSEMBLIES; STRUCTURE PREDICTION; MASS-SPECTROMETRY; HOT-SPOTS; DATA-BANK; C-N; INTERFACES; COMPLEXES AB Most (if not all) proteins function when associated in multimolecular assemblies. Attaining the structures of protein assemblies at the atomic scale is an important aim of structural biology. Experimentally, structures are increasingly available, and computations can help bridge the resolution gap between high- and low-resolution scales. Existing computational methods have made substantial progress toward this aim; however, current approaches are still limited. Some involve manual adjustment of experimental data; some are automated docking methods, which are computationally expensive and not applicable to large-scale proteome studies; and still others exploit the symmetry of the complexes and thus are not applicable to nonsymmetrical complexes. Our study aims to take steps toward overcoming these limitations. We have developed a strategy for the construction of protein assemblies computationally based on binary interactions predicted by a motif-based protein interaction prediction tool, PRISM (Protein Interactions by Structural Matching). Previously, we have shown its power in predicting pairwise interactions. Here we take a step toward multimolecular assemblies, reflecting the more prevalent cellular scenarios. With this method we are able to construct homo-/hetero-complexes and symmetric/asymmetric complexes without a limitation on the number of components. The method considers conformational changes and is applicable to large-scale studies. We also exploit electron microscopy density maps to select a solution from among the predictions. Here we present the method, illustrate its results, and highlight its current limitations. C1 [Kuzu, Guray; Keskin, Ozlem; Gursoy, Attila] Koc Univ Rumelifeneri Yolu, Ctr Computat Biol & Bioinformat, TR-34450 Sariyer, Turkey. [Kuzu, Guray; Keskin, Ozlem; Gursoy, Attila] Koc Univ Rumelifeneri Yolu, Coll Engn, TR-34450 Sariyer, Turkey. [Nussinov, Ruth] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Gursoy, A (reprint author), Koc Univ Rumelifeneri Yolu, Ctr Computat Biol & Bioinformat, TR-34450 Sariyer, Turkey. EM agursoy@ku.edu.tr RI Gursoy, Attila/E-9565-2015 OI Gursoy, Attila/0000-0002-2297-2113 FU NIGMS [P41-GM103311]; Scientific and Technological Research Council of Turkey (TUBITAK); TUBITAK [109T343]; NCI, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX Molecular graphics and analyses were performed with the UCSF Chimera package. Chimera is developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIGMS P41-GM103311).; Guray Kuzu is supported by a Scientific and Technological Research Council of Turkey (TUBITAK) fellowship. This work has been supported by TUBITAK Research Grant No. 109T343. It has also been funded in whole or in part with federal funds from the NCI, National Institutes of Health, under Contract No. HHSN261200800001E. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 76 TC 7 Z9 7 U1 0 U2 12 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 MAR PY 2014 VL 13 IS 3 BP 887 EP 896 DI 10.1074/mcp.M113.031294 PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AC3BX UT WOS:000332391100015 PM 24445405 ER PT J AU Carr, SA Abbatiello, SE Ackermann, BL Borchers, C Domon, B Deutsch, EW Grant, RP Hoofnagle, AN Huttenhain, R Koomen, JM Liebler, DC Liu, T MacLean, B Mani, D Mansfield, E Neubert, H Paulovich, AG Reiter, L Vitek, O Aebersold, R Anderson, L Bethem, R Blonder, J Boja, E Botelho, J Boyne, M Bradshaw, RA Burlingame, AL Chan, D Keshishian, H Kuhn, E Kinsinger, C Lee, JSH Lee, SW Moritz, R Oses-Prieto, J Rifai, N Ritchie, J Rodriguez, H Srinivas, PR Townsend, RR Van Eyk, J Whiteley, G Wiita, A Weintraub, S AF Carr, Steven A. Abbatiello, Susan E. Ackermann, Bradley L. Borchers, Christoph Domon, Bruno Deutsch, Eric W. Grant, Russell P. Hoofnagle, Andrew N. Huettenhain, Ruth Koomen, John M. Liebler, Daniel C. Liu, Tao MacLean, Brendan Mani, D. R. Mansfield, Elizabeth Neubert, Hendrik Paulovich, Amanda G. Reiter, Lukas Vitek, Olga Aebersold, Ruedi Anderson, Leigh Bethem, Robert Blonder, Josip Boja, Emily Botelho, Julianne Boyne, Michael Bradshaw, Ralph A. Burlingame, Alma L. Chan, Daniel Keshishian, Hasmik Kuhn, Eric Kinsinger, Christopher Lee, Jerry S. H. Lee, Sang-Won Moritz, Robert Oses-Prieto, Juan Rifai, Nader Ritchie, James Rodriguez, Henry Srinivas, Pothur R. Townsend, R. Reid Van Eyk, Jennifer Whiteley, Gordon Wiita, Arun Weintraub, Susan TI Targeted Peptide Measurements in Biology and Medicine: Best Practices for Mass Spectrometry- based Assay Development Using a Fit- for- Purpose Approach SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID DATA-INDEPENDENT ACQUISITION; PROTEIN IDENTIFICATION DATA; EUROPEAN BIOANALYSIS FORUM; LC-MS/MS ASSAY; ISOTOPE-DILUTION; INBORN-ERRORS; ABSOLUTE QUANTIFICATION; QUANTITATIVE PROTEOMICS; CARDIOVASCULAR-DISEASE; BIOMARKER DISCOVERY AB Adoption of targeted mass spectrometry (MS) approaches such as multiple reaction monitoring (MRM) to study biological and biomedical questions is well underway in the proteomics community. Successful application depends on the ability to generate reliable assays that uniquely and confidently identify target peptides in a sample. Unfortunately, there is a wide range of criteria being applied to say that an assay has been successfully developed. There is no consensus on what criteria are acceptable and little understanding of the impact of variable criteria on the quality of the results generated. Publications describing targeted MS assays for peptides frequently do not contain sufficient information for readers to establish confidence that the tests work as intended or to be able to apply the tests described in their own labs. Guidance must be developed so that targeted MS assays with established performance can be made widely distributed and applied by many labs worldwide. To begin to address the problems and their solutions, a workshop was held at the National Institutes of Health with representatives from the multiple communities developing and employing targeted MS assays. Participants discussed the analytical goals of their experiments and the experimental evidence needed to establish that the assays they develop work as intended and are achieving the required levels of performance. Using this fit-for-purpose approach, the group defined three tiers of assays distinguished by their performance and extent of analytical characterization. Computational and statistical tools useful for the analysis of targeted MS results were described. Participants also detailed the information that authors need to provide in their manuscripts to enable reviewers and readers to clearly understand what procedures were performed and to evaluate the reliability of the peptide or protein quantification measurements reported. This paper presents a summary of the meeting and recommendations. C1 [Carr, Steven A.; Abbatiello, Susan E.; Mani, D. R.; Keshishian, Hasmik; Kuhn, Eric] Broad Inst MIT & Harvard, Cambridge, MA USA. [Ackermann, Bradley L.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Borchers, Christoph] Univ Victoria, Victoria, BC, Canada. [Domon, Bruno] Luxembourg Clin Prote Ctr, Luxembourg, Luxembourg. [Deutsch, Eric W.; Moritz, Robert] Inst Syst Biol, Seattle, WA USA. [Grant, Russell P.] Lab Corp Amer, Burlington, NC USA. [Hoofnagle, Andrew N.; MacLean, Brendan] Univ Washington, Seattle, WA 98195 USA. [Huettenhain, Ruth; Aebersold, Ruedi] Swiss Fed Inst Technol, Inst Mol Syst Biol, Zurich, Switzerland. [Huettenhain, Ruth; Bradshaw, Ralph A.; Burlingame, Alma L.; Oses-Prieto, Juan; Wiita, Arun] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Koomen, John M.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Liebler, Daniel C.] Vanderbilt Univ, Nashville, TN 37235 USA. [Liu, Tao] Pacific NW Natl Lab, Richland, WA 99352 USA. [Mansfield, Elizabeth; Boyne, Michael] US FDA, Silver Spring, MD USA. [Neubert, Hendrik] Pfizer, Andover, MA USA. [Paulovich, Amanda G.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Reiter, Lukas] Biognosys Schlieren, Zurich, Switzerland. [Vitek, Olga] Purdue Univ, Purdue, IN USA. [Anderson, Leigh] SISCAPA Assay Technol Inc, Washington, DC USA. [Bethem, Robert] RAB Consulting, Novato, CA USA. [Blonder, Josip; Boja, Emily; Kinsinger, Christopher; Lee, Jerry S. H.; Rodriguez, Henry] NCI, NIH Bethesda, Bethesda, MD 20892 USA. [Botelho, Julianne] Ctr Dis Control & Prevent, Atlanta, GA USA. [Chan, Daniel; Lee, Jerry S. H.; Van Eyk, Jennifer] Johns Hopkins Univ, Baltimore, MD USA. [Lee, Sang-Won] Korea Univ, Seoul, South Korea. [Rifai, Nader] Childrens Hosp, Boston, MA 02115 USA. [Ritchie, James] Emory Univ, Atlanta, GA 30322 USA. [Srinivas, Pothur R.] NHLBI, NIH Bethesda, Bethesda, MD USA. [Townsend, R. Reid] Washington Univ, St Louis, MO USA. [Whiteley, Gordon] Liedos Biomed Res Inc, Frederick Natl Lab Canc Res, Washington, DC USA. [Weintraub, Susan] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. RP Carr, SA (reprint author), Broad Inst MIT & Harvard, Dept Prote, 7 Cambridge Ctr, Cambridge, MA 02142 USA. EM scarr@broad.mit.edu RI Lee, Sang-Won/H-6760-2013; Lee, Jerry/K-4553-2014; OI Lee, Sang-Won/0000-0002-5042-0084; Oses-Prieto, Juan/0000-0003-4759-2341; Lee, Jerry/0000-0003-1515-0952; Liebler, Daniel/0000-0002-7873-3031 FU Broad Institute of MIT and Harvard; US National Institutes of Health from the National Cancer Institute Clinical Proteomics Tumor Analysis Consortium Initiative [U24CA160034]; US National Institutes of Health from the National Heart, Lung, and Blood Institute [HHSN268201000033C, R01HL096738] FX This work was supported in part by the Broad Institute of MIT and Harvard and by the following grants from the US National Institutes of Health: grant U24CA160034 from the National Cancer Institute Clinical Proteomics Tumor Analysis Consortium Initiative (to S.A.C.) and grants HHSN268201000033C and R01HL096738 from the National Heart, Lung, and Blood Institute (to S.A.C.). NR 98 TC 142 Z9 143 U1 11 U2 61 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 MAR PY 2014 VL 13 IS 3 BP 907 EP 917 DI 10.1074/mcp.M113.036095 PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AC3BX UT WOS:000332391100017 PM 24443746 ER PT J AU Rajagopala, SV Sikorski, P Kumar, A Mosca, R Vlasblom, J Arnold, R Franca-Koh, J Pakala, SB Phanse, S Ceol, A Hauser, R Siszler, G Wuchty, S Emili, A Babu, M Aloy, P Pieper, R Uetz, P AF Rajagopala, Seesandra V. Sikorski, Patricia Kumar, Ashwani Mosca, Roberto Vlasblom, James Arnold, Roland Franca-Koh, Jonathan Pakala, Suman B. Phanse, Sadhna Ceol, Arnaud Haeuser, Roman Siszler, Gabriella Wuchty, Stefan Emili, Andrew Babu, Mohan Aloy, Patrick Pieper, Rembert Uetz, Peter TI The binary protein-protein interaction landscape of Escherichia coli SO NATURE BIOTECHNOLOGY LA English DT Article ID YEAST 2-HYBRID SYSTEM; INTERACTION NETWORKS; INTERACTION MAP; COLI K-12; COMPLEXES; IDENTIFICATION AB Efforts to map the Escherichia coli interactome have identified several hundred macromolecular complexes, but direct binary protein-protein interactions (PPIs) have not been surveyed on a large scale. Here we performed yeast two-hybrid screens of 3,305 baits against 3,606 preys (similar to 70% of the E. coli proteome) in duplicate to generate a map of 2,234 interactions, which approximately doubles the number of known binary PPIs in E. coli. Integration of binary PPI and genetic-interaction data revealed functional dependencies among components involved in cellular processes, including envelope integrity, flagellum assembly and protein quality control. Many of the binary interactions that we could map in multiprotein complexes were informative regarding internal topology of complexes and indicated that interactions in complexes are substantially more conserved than those interactions connecting different complexes. This resource will be useful for inferring bacterial gene function and provides a draft reference of the basic physical wiring network of this evolutionarily important model microbe. C1 [Rajagopala, Seesandra V.; Sikorski, Patricia; Franca-Koh, Jonathan; Pakala, Suman B.; Pieper, Rembert] J Craig Venter Inst, Rockville, MD USA. [Kumar, Ashwani; Vlasblom, James; Phanse, Sadhna; Babu, Mohan] Univ Regina, Res & Innovat Ctr, Dept Biochem, Regina, SK S4S 0A2, Canada. [Mosca, Roberto; Ceol, Arnaud; Aloy, Patrick] Inst Res Biomed IRB Barcelona, Joint IRB BSC Program Computat Biol, Barcelona, Spain. [Arnold, Roland; Emili, Andrew] Univ Toronto, Banting & Best Dept Med Res, Donnelly Ctr, Toronto, ON, Canada. [Haeuser, Roman; Siszler, Gabriella] German Canc Res Ctr, Heidelberg, Germany. [Wuchty, Stefan] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Aloy, Patrick] Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain. [Uetz, Peter] Virginia Commonwealth Univ, Ctr Study Biol Complex, Richmond, VA USA. RP Rajagopala, SV (reprint author), J Craig Venter Inst, Rockville, MD USA. EM raja@jcvi.org; mohan.babu@uregina.ca RI Ceol, Arnaud/H-3386-2012; Uetz, Peter/A-7119-2012; OI Ceol, Arnaud/0000-0001-9533-4246; Uetz, Peter/0000-0001-6194-4927; Mosca, Roberto/0000-0002-3244-1885; Aloy, Patrick/0000-0002-3557-0236; Rajagopala, Seesandra/0000-0001-7176-5770 FU US National Institutes of Health [GM079710]; Seventh Research Framework Programme of the European Union (AntiPathoGN; EU) [HEALTH-F3-2009-223101]; Natural Sciences and Engineering Research Council [DG-20234] FX S.V.R. and P.U. were supported by US National Institutes of Health grant GM079710. P.U., R.H. and P.A. were supported by the Seventh Research Framework Programme of the European Union (AntiPathoGN; EU grant HEALTH-F3-2009-223101). M.B. was supported by the Discovery Grant from the Natural Sciences and Engineering Research Council (DG-20234). We thank X. De Bolle (University of Namur, Belgium) for providing pRH016 and pRH018 vectors. NR 40 TC 48 Z9 49 U1 2 U2 39 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD MAR PY 2014 VL 32 IS 3 BP 285 EP 290 DI 10.1038/nbt.2831 PG 6 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA AC8YA UT WOS:000332819800028 PM 24561554 ER PT J AU Moon, AF Pryor, JM Ramsden, DA Kunkel, TA Bebenek, K Pedersen, LC AF Moon, Andrea F. Pryor, John M. Ramsden, Dale A. Kunkel, Thomas A. Bebenek, Katarzyna Pedersen, Lars C. TI Sustained active site rigidity during synthesis by human DNA polymerase mu SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID STRAND BREAK REPAIR; HUMAN POL-MU; TERMINAL DEOXYNUCLEOTIDYLTRANSFERASE; CATALYTIC CYCLE; V(D)J RECOMBINATION; BRCT DOMAIN; LAMBDA; FIDELITY; MECHANISM; INSIGHTS AB DNA polymerase mu (Pol mu) is the only template-dependent human DNA polymerase capable of repairing double-strand DNA breaks (DSBs) with unpaired 3' ends in nonhomologous end joining (NHEJ). To probe this function, we structurally characterized Pol mu's catalytic cycle for single-nucleotide incorporation. These structures indicate that, unlike other template-dependent DNA polymerases, Pol mu shows no large-scale conformational changes in protein subdomains, amino acid side chains or DNA upon dNTP binding or catalysis. Instead, the only major conformational change is seen earlier in the catalytic cycle, when the flexible loop 1 region repositions upon DNA binding. Pol mu variants with changes in loop 1 have altered catalytic properties and are partially defective in NHEJ. The results indicate that specific loop 1 residues contribute to Pol mu's unique ability to catalyze template-dependent NHEJ of DSBs with unpaired 3' ends. C1 [Moon, Andrea F.; Kunkel, Thomas A.; Bebenek, Katarzyna; Pedersen, Lars C.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Pryor, John M.; Ramsden, Dale A.] Univ N Carolina, Curriculum Genet & Mol Biol, Chapel Hill, NC USA. [Kunkel, Thomas A.; Bebenek, Katarzyna] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Bebenek, K (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM bebenek@niehs.nih.gov OI Pryor, John/0000-0001-7000-9383 FU Division of Intramural Research of the US National Institute of Environmental Health Sciences, National Institutes of Health (NIH) [ES 102645, ES065070]; NIH [CA097096]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX We thank G. Mueller and B. Beard for critical reading of the manuscript. This research was supported by the Division of Intramural Research of the US National Institute of Environmental Health Sciences, National Institutes of Health (NIH) grants ES 102645 (L.C.P.), and ES065070 (T.A.K.) and by NIH grant CA097096 (D.A.R.). Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences contract W-31-109-Eng-38. NR 47 TC 12 Z9 12 U1 0 U2 4 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 MAR PY 2014 VL 21 IS 3 BP 253 EP 260 DI 10.1038/nsmb.2766 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AC5XS UT WOS:000332594900007 PM 24487959 ER PT J AU McLaughlin, T Lamendola, C Coghlan, N Liu, TC Lerner, K Sherman, A Cushman, SW AF McLaughlin, T. Lamendola, C. Coghlan, N. Liu, T. C. Lerner, K. Sherman, A. Cushman, S. W. TI Subcutaneous Adipose Cell Size and Distribution: Relationship to Insulin Resistance and Body Fat SO OBESITY LA English DT Article ID CARDIOVASCULAR-DISEASE; IMPAIRED ADIPOGENESIS; OBESE INDIVIDUALS; SUPPRESSION TEST; NORMAL-WEIGHT; TISSUE; METABOLISM; NUMBER; WOMEN; MEN AB Objective: Metabolic heterogeneity among obese individuals may be attributable to differences in adipose cell size. We sought to clarify this by quantifying adipose cell size distribution, body fat, and insulin-mediated glucose uptake in overweight to moderately-obese individuals. Methods: A total of 148 healthy nondiabetic subjects with BMI 25-38 kg/m(2) underwent subcutaneous adipose tissue biopsies and quantification of insulin-mediated glucose uptake with steady-state plasma glucose (SSPG) concentrations during the modified insulin suppression test. Cell size distributions were obtained with Beckman Coulter Multisizer. Primary endpoints included % small adipose cells and diameter of large adipose cells. Cell-size and metabolic parameters were compared by regression for the whole group, according to insulin-resistant (IR) and insulin-sensitive (IS) subgroups, and by body fat quintile. Results: Both large and small adipose cells were present in nearly equal proportions. Percent small cells was associated with SSPG (r = 0.26, P = 0.003). Compared to BMI-matched IS individuals, IR counterparts demonstrated fewer, but larger large adipose cells, and a greater proportion of small-to-large adipose cells. Diameter of the large adipose cells was associated with % body fat (r 0.26, P = 0.014), female sex (r = 0.21, P = 0.036), and SSPG (r = 0.20, P = 0.012). In the highest versus lowest % body fat quintile, adipose cell size increased by only 7%, whereas adipose cell number increased by 74%. Conclusions: Recruitment of adipose cells is required for expansion of body fat mass beyond BMI of 25 kg/m(2). Insulin resistance is associated with accumulation of small adipose cells and enlargement of large adipose cells. These data support the notion that impaired adipogenesis may underlie insulin resistance. C1 [McLaughlin, T.; Lamendola, C.; Coghlan, N.; Liu, T. C.; Lerner, K.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Sherman, A.; Cushman, S. W.] NIDDK, NIH, Bethesda, MD 20892 USA. RP McLaughlin, T (reprint author), Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. EM tmclaugh@stanford.edu FU National Institutes of Health/National Institute of Digestive Diseases and Diabetes [R01 DK080436, R01DK071309] FX Funding agencies: Grant support for this study was provided by National Institutes of Health/National Institute of Digestive Diseases and Diabetes, R01 DK080436, R01DK071309. NR 39 TC 23 Z9 23 U1 0 U2 11 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 MAR PY 2014 VL 22 IS 3 BP 673 EP 680 DI 10.1002/oby.20209 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AC0ZU UT WOS:000332224800011 PM 23666871 ER PT J AU Liu, JK Coady, S Carr, JJ Hoffmann, U Taylor, HA Fox, CS AF Liu, Jiankang Coady, Sean Carr, J. Jeffery Hoffmann, Udo Taylor, Herman A. Fox, Caroline S. TI Differential Associations of Abdominal Visceral, Subcutaneous Adipose Tissue with Cardiometabolic Risk Factors between African and European Americans SO OBESITY LA English DT Article ID ETHNIC-DIFFERENCES; HERITAGE FAMILY; INSULIN ACTION; FAT; HEART; RACE; DISEASE; OBESITY; HEALTH; ADULTS AB Objective: To examine the relative association of abdominal visceral adipose tissue (VAT) with cardiometabolic risk factors between African and European Americans. Methods: A cross-sectional study of 2,035 African Americans from the Jackson Heart Study (JHS) and 3,170 European Americans from the Framingham Heart Study (FHS) who underwent computed tomography assessment of VAT and subcutaneous adipose tissue (SAT) was conducted. The FHS participants were weighted to match the age distribution of the JHS participants, and the metabolic risk factors were examined by study groups in relation to VAT. Results: JHS participants had higher rates of obesity, hypertension, diabetes, and metabolic syndrome than FHS participants (all P = 0.001). The associations were weaker in JHS women for VAT with blood pressure, triglycerides, HDL-C, and total cholesterol (P-interaction = 0.03-0.001) than FHS women. In contrast, JHS men had stronger associations for VAT with high triglycerides, low HDL, and metabolic syndrome (all P-interaction = 0.001) compared to FHS men. Similar associations and gender patterns existed for SAT with most metabolic risk factors. Conclusions: The relative association between VAT and cardiometabolic risk factors is weaker in JHS women compared to FHS women, whereas stronger associations with triglycerides and HDL were observed in JHS men. C1 [Liu, Jiankang; Taylor, Herman A.] Jackson State Univ, Univ Mississippi, Med Ctr, Jackson Heart Study, Jackson, MS USA. [Coady, Sean; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Coady, Sean; Fox, Caroline S.] NHLBI, Ctr Populat Studies, Framingham, MA USA. [Carr, J. Jeffery] Wake Forest Univ, Sch Med, Dept Radiol, Winston Salem, NC 27109 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. EM jliu@umc.edu; foxca@nhlbi.nih.gov RI Carr, John/A-1938-2012 OI Carr, John/0000-0002-4398-8237 FU National Heart, Lung, and Blood Institute; National Center on Minority Health and Health Disparities [N01-HC-95170, N01-HC-95171, N01-C-95172, N01-HC-25195] FX The Jackson Heart Study and the Framingham Heart Study are supported by the National Heart, Lung, and Blood Institute, and the National Center on Minority Health and Health Disparities (N01-HC-95170, N01-HC-95171, N01-C-95172 and N01-HC-25195). NR 22 TC 9 Z9 9 U1 1 U2 5 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 MAR PY 2014 VL 22 IS 3 BP 811 EP 818 DI 10.1002/oby.20307 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AC0ZU UT WOS:000332224800028 PM 23408700 ER PT J AU Fox, CS Pencina, MJ Heard-Costa, NL Shrader, P Jaquish, C O'Donnell, CJ Vasan, RS Cupples, LA D'Agostino, RB AF Fox, Caroline S. Pencina, Michael J. Heard-Costa, Nancy L. Shrader, Peter Jaquish, Cashell O'Donnell, Christopher J. Vasan, Ramachandran S. Cupples, L. Adrienne D'Agostino, Ralph B. TI Trends in the Association of Parental History of Obesity over 60 Years SO OBESITY LA English DT Article ID BODY-MASS INDEX; CARDIOVASCULAR EVENTS; RISK-FACTOR; US ADULTS; OVERWEIGHT; COHORT; PREDICTORS; CHILDHOOD; MORTALITY; CHILDREN AB Objective: The association of familial as compared to genetic factors in the current obesogenic environment, compared with earlier, leaner time periods, is uncertain. Methods: Participants from the Framingham Heart Study were classified according to parental obesity status in the Original, Offspring, and Third Generation cohorts; mean BMI levels were estimated and we compared the association of parental history across generations. Finally, a genetic risk score comprised of 32 well-replicated single nucleotide polymorphisms for BMI was examined in association with BMI levels in 1948, 1971, and 2002. Results: BMI was 1.49 kg/m(2) higher per each affected parent among the Offspring, and increased to 2.09 kg/m(2) higher among the Third Generation participants (P-value for the cohort comparison = 0.007). Parental history of obesity was associated with increased weight gain (P< 0.0001) and incident obesity (P = 0.009). Despite a stronger association of parental obesity with offspring BMI in more contemporary time periods, we observed no change in the effect size of a BMI genetic risk score from 1948 to 2002 (P = 0.11 for test of trend across the time periods). Conclusions: The association of parental obesity has become stronger in more contemporary time period, whereas the association of a BMI genetic risk score has not changed. C1 [Fox, Caroline S.; Pencina, Michael J.; Jaquish, Cashell; O'Donnell, Christopher J.; Vasan, Ramachandran S.; D'Agostino, Ralph B.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Fox, Caroline S.; Jaquish, Cashell; O'Donnell, Christopher J.] NHLBI, Framingham, MA USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Endocrinol Hypertens & Diabet, Boston, MA 02115 USA. [Pencina, Michael J.; Shrader, Peter; D'Agostino, Ralph B.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Heard-Costa, Nancy L.] Boston Univ, Sch Med, Div Cardiol Sect, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Div Prevent Med, Cardiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195, 2K24 HL04334] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (N01-HC-25195) and 2K24 HL04334 (RSV). NR 25 TC 3 Z9 4 U1 0 U2 0 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 MAR PY 2014 VL 22 IS 3 BP 919 EP 924 DI 10.1002/oby.20564 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AC0ZU UT WOS:000332224800042 PM 23836774 ER EF